SECTION 21
Cardiology 195.
Back to Bedside Basics - Pulse, Blood Pressure and Jugular Venous Pulse Ruchit A Shah, BR Bansode
889
196.
Coagulation Cascade - What’s New BL Bhardwaj, Harnoor S Bhardwaj, Pallav Jain, Kanchan Saini
900
197.
Anti-Platelet Therapy Nihar Mehta, Nikesh Jain
903
198.
Combined Oral Anticoagulation and Antiplatelet Therapy - Management of a Difficult Situation Jamshed J Dalal
910
199.
How to Prevent and Control the Epidemic of Coronary Artery Disease in Indians Julian Johny Thottian, Binjo Vazhappilly, Mohanan Padinharepurayil
912
200.
Noninvasive Testing for Diagnosis of Stable Coronary Artery Disease Srinivasan Narayanan, Ajit Mullasari
915
201.
Management Strategies in Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) in India Satyavan Sharma, Nikhil Raut
919
202.
Management of Stable Ischemic Heart Disease – Current Perspective Dev Pahlajani
923
203.
STEMI Care in India and the Real World: Role of Thrombolysis HK Chopra
925
204.
Risk Stratification and Management Algorithm of NSTEMI Lekha Pathak, Ankur Jhavar
934
205.
Cardiac Intervention Pawan K Suri
943
206.
Recent Developments in Intensive Cardiac Care for Acute Cardiac Disorders Suraj Kumar Arora, Abhishek Goyal, Gurpreet S Wander
946
207.
Five Recent Land Mark Trials in Cardiology: How have They Changed Our Practice VK Bahl, Anunay Gupta
951
208.
To Assess Predictive Value of Carotid Artery Intima Media Thickness as a Non-Invasive Marker for Coronary and Cerebral Artery Disease Gurmukh S Sainani, Mitul A Shah
954
209.
Two-and Three-Dimensional Echocardiographic Assessment of the Aortic Valve Efstathia Andrikopoulou, Garima Arora, Navin C Nanda
958
210.
Management of Atrial Fibrillation in Indian Scenario Saumitra Ray, Amitava Mazumdar
963
211.
Heart Failure in Young and Elderly – Management Strategies Brian Pinto, Chetan Rathi, Ankeet Dedhia
966
212.
Cardiac Pacemakers: Indications, Choices and Follow Up Sandeep Bansal, Praloy Chakraborty
976
213.
Sudden Cardiac Death in Young People: Can it be Prevented Harendra Kumar
980
214. Update in Preoperative Cardiovascular Evaluation and Perioperative Cardiovascular Medical Management Michael A Mikhail, Arya B Mohabbat, Amit K Ghosh
983
215.
992
Transcatheter Aortic Valve Implantation (TAVI) Vivek Gupta, Alain Criber
C H A P T E R
195
Back to Bedside Basics - Pulse, Blood Pressure and Jugular Venous Pulse
INTRODUCTION
In the era of electrocardiogram and echocardiography, clinical bedside examination is a forgotten art. However accurate these investigations may be, evaluation of the patient is incomplete without a detailed physical examination. In this chapter we shall discuss the basic bedside art and clinical relevance of examination of the arterial pulse, blood pressure and jugular venous pulse.
THE ARTERIAL PULSE
Physiology - The arterial pulse begins with aortic valve opening and ejection of blood from the left ventricle into the aorta. The nature of arterial pulse depends on left ventricular stroke volume, ejection velocity, compliance, distensiblity and capacity of arterial system. The pulse contour is a result of frequency waves produced by antegrade blood flow and reflection of the waves returning from the peripheral circulation. The central aortic pulse wave is described as early systolic, late systolic and diastolic component (Figure 1). The early systolic component (percussion wave) has a rapid upstroke. It is due to early systolic ejection of blood which is stored in central aorta. The normal pulse has a brief crest which is slightly sustained and somewhat rounded. The mid and late systolic component (anacrotic notch and shoulder) has a rounded summit or peak. It is due to propagation of blood from central aorta to periphery and reflection of the waves from the upper limbs. Diastole is initiated by a negative wave (dicrotic notch). The nadir of dicrotic notch coincides with aortic leaflet closure (A2 component of S2) and the positive wave is due to reflection of waves from the lower limbs. Normally only the systolic
Ruchit A Shah, BR Bansode
peak is palpable. Percussion wave is more prominent than the tidal wave. Anacrotic notch, tidal wave, dicrotic notch and dicrotic wave are not palpable. As the pulse wave travels from aortic valve to the peripheral arteries; i) the upstroke becomes steeper, ii) systolic peak becomes high, iii) systolic upstroke time becomes shorter, iv) ejection time increases, v) systolic pressure increases, vi) pulse pressure increases, vii) diastolic pressure decreases, viii) mean pressure decreases, ix) anacrotic shoulder disappears, x) sharp incisura is replaced by a smoother and latter dicrotic notch, followed by a dicrotic wave. The carotid artery is a large artery close to the aortic valve and its contour resembles that of central aortic pulse. Hence the carotid pulse and not the peripheral pulse is used to assess the volume and contour (Table 1). With aging, arteriosclerosis and hypertension, there is decreased compliance, increased vascular resistance and vasoconstriction of the arterial tree. The noncompliant arterial tree contributes to increased pulse wave velocity and the tidal wave becomes more sustained. Examination - Varying degrees of pressure is applied with the finger pads of the thumb or first two fingers to assess upstroke, systolic peak and diastolic slope of the pulse (trisection method). Attempt should be made to assess the rate, rhythm, volume, amplitude, contour and stiffness of the arterial wall. Focus on the speed and quality of early rise, peak and drop off of the arterial pulse. A.
Rate and Rhythm - This information is derived from the radial artery. Count the arterial pulse for 15 s and multiply by 4 to get the pulse rate. The heart rate should be compared with the pulse rate. A pulse deficit of >6 beats/min is suggestive
Table 1: Comparison of the pulse in central aorta and peripheral artery
Fig. 1: Normal arterial pulse. Note the rapid upstroke of percussion wave, rounded peak of tidal wave and fall off in late systole. The dicrotic notch coincides with S2
Central artery (Aorta)
Peripheral artery (Brachial)
i. Upstroke has a rounded dome
i. Steep upstroke
ii. Anacrotic notch on ascending limb
ii. Disappearance of anacrotic notch on ascending limb
iii. Descending limb has incisura followed by replaced dicrotic wave by dicrotic wave
iii. Incisura in descending limb is by dicrotic notch followed
CARDIOLOGY
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Table 2: Causes of tachycardia and bradycardia Tachycardia (>100 beats per minute)
Bradycardia (<60 beats per minute)
a. Sinus tachycardia
a. Sinus Bradycardia
i. Physiological Infancy, Early childhood, exercise, anxiety, excitement
i. Physiological Athletes, during sleep
ii Pharmacological - Amyl nitrate, amiodarone, epinephrine, isoproterenol, ephedrine, atropine, alcohol, nicotine, caffeine
ii. Pharmacological - Beta blockers, propafenone, Lithium
iii. Pathological - Cardiac - Heart failure, acute myocardial infarction, pulmonary embolism, myocarditis, shock Non cardiac - Fever, thyrotoxicosis, anemia, hemorrhage, hypotension, hypoxia
iii. Pathological - Cardiac - Inferior wall myocardial infarction, vasovagal syncope, sinoatrial block, post cardiac transplant Non cardiac myxedema, raised intracranial pressure, hypothermia, obstructive jaundice, enteric fever, sepsis, Chagas disease
b. Tachyarrhythmia Atrial fibrillation, atrial tachycardia, supraventricular tachycardia, ventricular tachycardia
b. Bradyarrhythmia complete heart block, second degree AV block.
Fig. 2: Carotid pulse waveforms and heart sounds. A - Normal, B - Severe Aortic stenosis - anacrotic pulse with slow upstroke, C Severe aortic regurgitation - bifid pulse with two systolic peaks, D - Hypertrophic obstructive cardiomyopathy - bifid pulse with spike and dome pattern, E - Dicrotic pulse - one peak in systole, another in diastole of atrial fibrillation and <6 beats/min is suggestive of premature ventricular contraction. The normal pulse occurs at regular intervals. When the cycle length shortens with inspiration and lengthens with expiration by >120 ms during quiet breathing, it is called sinus arrhythmia. It is associated with autonomic dysfunction and is a risk factor for sudden cardiac death. Normal sinus rhythm varies between 60-100 beats per minute (Tables 2, 3).
Table 3: Irregular pulses Regularly irregular
Irregularly irregular
i. Sinus arrhythmia
i. Atrial fibrillation
ii. Pulsus bigeminy
ii. Multifocal atrial tachycardia
iii. Pulsus alternans
iii. Frequent premature ventricular contractions
iv. 1st and 2nd degree heart block Differentiating between irregular pulses Ventricular premature complex - There is a large pause following the premature beat. Atrial premature complex - There is a short pause following two beats Atrial fibrillation - Irregular in rate and rhythm with apex pulse deficit of >6 beats/min.
B.
Character and volume of the pulse (Figure 2)
a.
Hyperkinetic (Bounding) Pulse - It has larger pulse wave amplitude. It is due to increase in left ventricular ejection, stroke volume, arterial pressure, sympathetic activity or decreased arterial compliance. It is seen in i) elderly subjects with arteriosclerosis and systolic hypertension, ii) anxiety, iii) anemia, iv) thyrotoxicosis, v) exercise, vi) hot and humid environment, vii) alcohol intake and viii) high output states with increased distal arterial runoff like aortic regurgitation, patent ductus arteriosus, large A-V fistula, Pagetâ&#x20AC;&#x2122;s disease and severe cirrhosis.
b.
Hypokinetic Pulse - A small or diminished pulse is due to low cardiac output with reduced left ventricular stroke volume, shorter left ventricular ejection time or intense vasoconstriction. An unsustained pulse suggests decreased stroke volume without left ventricular outflow obstruction, whereas a slow rising sustained pulse of small volume suggests aortic stenosis. It is seen in i) severe left ventricular dysfunction, ii) congestive cardiac failure, iii) hypotension and iv) left ventricular outflow tract obstruction. Pulsus parvus et tardus - It is a slow rising pulse with delayed systolic peak and upstroke. It is best appreciated with simultaneous auscultation and carotid palpation. In aortic stenosis, it is associated with a carotid thrill (carotid shudder).
d.
Water Hammer (Collapsing pulse) or Corrigan pulse or Pulsus Celer - This term was coined by Thomas Watson after a Victorian toy which comprised of a glass vessel partly filled with water and vacuum. It produces a slapping impact on being turned over. In aortic regurgitation, there is an early, brief peak and a swift descent without dicrotic notch which gives a collapsing sensation. To elicit this, the patient’s arm is suddenly raised above the head and the wrist grasped with the examiner’s hand so that the palm faces the anterior aspect of wrist. The collapsing nature can be felt after each systole. The brief peak is due to rapid ejection of increased stroke volume. The swift descent is due to diastolic run off (back flow into left ventricle), rapid run off to the periphery due to decreased systemic vascular resistance and reflex vasodilatation mediated by carotid baroreceptors. It may also be seen in hyperkinetic circulatory states like patent ductus arteriosus, aortopulmonary window, arteriovenous fistula, rupture of sinus of valsalva into right heart and tetrology of Fallot with bronchopulmonary collaterals.
e.
Double beating pulse - Simultaneous auscultation and palpation are necessary to delineate the timing of the twice beating pulse.
i.
Bisferiens pulse - The double peaked pulse occurs in systole and is best detected by light but firm compression of the brachial artery with a single finger. It is seen in pure aortic regurgitation, combined aortic stenosis with predominant aortic regurgitation and high output states with normal heart. It is likely to disappear after onset of congestive cardiac failure.
ii.
Bifid pulse - A bifid or spike and dome pattern in systole is recorded, but rarely palpable in significant hypertrophic obstructive cardiomyopathy.
iii
Dicrotic pulse - The first wave occurs in systole and the second accentuated component is a diastolic reflection wave occurring in diastole. On simultaneous auscultation, S2 separates the
e.
Pulsus alternans - It is present during sinus rhythm when patient’s peak systolic arterial pressure and pulse volume are alternately strong and weak. It occurs due to beat to beat alteration in left ventricular ejection pressure and signifies severe left ventricular dysfunction. (It is not related to electrical alternans which has a beat to beat variation in the amplitude of QRS complex as seen in massive pericardial effusions). It is best appreciated clinically in the radial or brachial arteries. It may be associated with signs of heart failure like S3 gallop. It can also be detected by slow decompression of the sphygmomanometer cuff while listening to the alteration of Korotkoff sounds. When systolic pressure alternates by >20 mm Hg it can be detected by palpation of the peripheral pulse with patient’s breath held in deep expiration. It is accentuated after a PVC, Valsalva maneuver, abrupt upright posture or deep inspiration.
f.
Pulsus paradoxus - This term was coined by Kussmaul. There is marked and exaggerated inspiratory fall in systolic blood pressure in which palpable peripheral arterial pulse and audible Korotkoff sounds disappear in inspiration. The blood pressure cuff is inflated beyond the peak systolic pressure and slowly deflated. The degree of paradoxus is the difference between the systolic pressure at which the Korotkoff sounds are first heard during expiration and the point at which all beats are well heard during both phases of respiration. The word paradoxus is a misnomer because systolic pressure normally falls during inspiration by 4-6 mm Hg. In pulsus paradoxus the difference is >10 mm Hg. The patient must be breathing quietly and not deep breathing or performing Valsalva maneuver. It is seen in pericardial tamponade, constrictive pericarditis, emphysema, asthma, severe congestive cardiac failure and marked obesity.
Mechanism - Cardiac tamponade is a continuum from effusion to full blown circulatory collapse. The hemodynamic effects depend on the amount of effusion and the pericardial pressure volume relationship. As fluid accumulates in pericardial sac, there is increased left and right sided atrial and ventricular pressures which equalize at a pressure similar to intrapericardial pressure. Inspiration increases the venous return to the right side of the heart at a period when the total heart volume is
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c.
two pulse waves. It is better appreciated during inspiration. It is seen in young patients having cardiomyopathy with severe left ventricular dysfunction, low cardiac output, low blood pressure, high systemic vascular resistance, tachycardia, during inspiration in pericardial tamponade, post valve replacement for aortic or mitral regurgitation with left ventricular dysfunction and occasionally with fever in young.
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Table 4: Grading of pulses
Table 5: Sites of palpation of various pulses
Grading of pulses
i. Superficial temporal artery - It is palpable over the zygomatic process anterior to the tragus.
Grade 0 - Absent pulse Grade 1 - Feeble Grade 2 - Palpable but diminished Grade 3 - Normal Grade 4 - High volume/bounding
CARDIOLOGY
fixed. This increases the right ventricular diastolic dimensions pushing the interventricular septum to the left. This reduces left ventricular dimensions, compliance and filling. Also inspiratory pooling of blood into the pulmonary circulation causes under filling of the left atrium and left ventricle. The under filled left ventricle in tamponade operates on the steep ascending limb of Starling curve, so inspiratory reduction of left ventricle filling causes a marked depression of stroke volume and systolic pressure.
Reverse pulsus paradoxus may be seen in cardiac tamponade with positive pressure ventilation and isorrhythmic AV dissociation.
Pulsus paradoxus may be absent in cases of cardiac tamponade with atrial septal defect/ ventricular septal defect/ aortic regurgitation/ pericardial adhesions.
C.
Condition of the arterial wall - The examiner must roll the vessel wall between the index and second finger. In young age, it seems to merge with surrounding tissue, in middle age it is palpable and in old age it feels like a cord. Also try to note the irregularity of surface seen in arteriosclerosis and tortuosity.
D.
All pulses should be palpated and compared bilaterally (Tables 4 and 5).
Unequal/ diminished/ absent pulse i.
Takayusu arteritis
ii.
Thoracic outlet syndrome - cervical rib, scalenus anticus syndrome
iii.
Subclavian steal syndrome
iv.
Atherosclerosis of innominate, left subclavian artery
v.
Acute micro embolism
vi.
Coarctation of aorta
vii.
Dissection of aorta
Radiofemoral Delay - The central aortic pulse reaches the carotids at 40 ms, brachials at 60 ms, femorals at 75 ms and radials at 80 ms. Radiofemoral delay is seen in coarctation of aorta and obstructive diseases of aortic bifurcation, common iliac or external iliac artery. Coarctation should be suspected in patients with hypertension or infants with heart failure. The brachial and carotid pulses are
ii. Common carotid artery - It terminates at C4 level at the upper border of thyroid cartilage. There it bifurcates into the external and internal carotid artery. It is best felt in the lower half of the patient’s neck. Rotating the neck slightly towards the examiner relaxes the sternocleidomastoid. The left thumb is used to palpate the right artery and vice versa. iii. Subclavian artery - It is effectively compressed against the first rib with shoulder depressed with pressure exerted down back and medially in the angle between the sternocleidomastoid and clavicle. iv. Axillary - It is felt against the middle of humerus v. Brachial - It is felt against the humerus just above the antecubital fossa medial to biceps tendon. vi. Radial - It is felt with the tip of index, middle and ring fingers compressing against the head of the radius with the forearm slightly pronated and wrist slightly flexed. vii. Femoral - It is felt midway between the iliac crest and pubic ramus below the inguinal ligament against the head of the femur. viii. Popliteal - The patient lies supine with the knees flexed at 120 degrees. The fingertips of both hands are placed in the popliteal fossa with thumbs resting on the patella. ix. Posterior Tibial - The patient’s foot should be relaxed between plantar and dorsiflexion. It is felt 1 cm behind the medial malleolus of the tibia. x. Dorsalis Pedis - It is best felt between the tendons of extensor hallucis longus and extensor digitorum (between first and second toe) against the first metatarsal. It may be impalpable in 2% of normal individuals. bounding, whereas lower extremity pulses have a slow rate of rise, late peak and a low pulse pressure. This can be demonstrated by placing the patient’s wrist over the femoral artery so that the examiner’s fingers at the radial pulse are above the fingers at the femoral pulse. Vary the compression pressure till both pulses are felt equally with both hands. The radiofemoral delay may be absent when coarctation is associated with bicuspid aortic valve + aortic stenosis/ aortic regurgitation, supravalvular aortic stenosis and mitral regurgitation.
BLOOD PRESSURE
Physiology - The blood pressure is the measure of potential energy or lateral force per unit area of the vessel wall. Systolic blood pressure is the maximum pressure exerted by the heart during systole. It is the amount of
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Table 6: Sphygmomanometer cuff size Sphygmomanometer cuff size (cm): Cuff type
Mid arm circumference
Bladder width
Bladder length
Child
13-20
8
13
Small adult
17-26
11
17
Standard adult
24-33
12-13
22-24
Large adult
33-42
15-17
32-33
Thigh
42-50
18-20
35-42
Measurement of blood pressure - The blood pressure is measured with an aneroid or mercury manometer. The bladder length/width should be 80%/40% of the arm circumference. The ratio of cuff width to length should be 1:2 (Table 6). The center of the rubber bladder should be on the brachial artery. The blood pressure cuff is wrapped tightly around the arm. The diaphragm or bell of the stethoscope is firmly placed at the brachial artery, so that the upper edge of the stethoscope is in contact with the distal edge of the cuff. The patient should be seated comfortably, back supported, bared upper arm, legs uncrossed with the arm at level of heart. The cuff is inflated 20 mm Hg above the point when the radial pulse is no longer palpable. This palpatory method prevents underestimation of blood pressure due to auscultatory gap. The systolic and diastolic pressures are then estimated by auscultatory method. Cuff should be deflated at <3 mm Hg/sec. The column should be read to the nearest 2 mm Hg. The level of peak systolic pressure is the point at which two consecutive Korotkoff sounds are heard. The disappearance of the Korotkoff sounds is the true diastolic pressure. After every cuff inflation, deflate the cuff completely and allow sufficient time for venous return. There should be no talking between the subject and observer. In severe aortic regurgitation and hyperkinetic circulatory states, the diastolic pressure should be recorded in both phase IV and V. In atrial fibrillation, there is beat to beat variation in blood pressure; hence an average of three readings is taken as a blood pressure. For measurement of lower limb pressure, the patient lies prone; the thigh cuff is wrapped around and auscultate the popliteal fossa. If a thigh cuff is not available, an arm cuff can be wrapped around the lower leg and auscultate
the posterior tibial artery or dorsalis pedis artery with a pediatric bell chest piece. Korotkoff sounds arise as a result of oscillation from distension of arterial walls with every cardiac impulse due to partial occlusion of the artery by the blood pressure cuff. Shock, low stroke volume and peripheral vasoconstriction cause weak Korotkoff sounds. This can be enhanced by hand elevation or isometric handgrip exercises for 5-10 times.
Phases of Korotkoff sounds I
Onset of auscultatory sound
Represents peak systole Initially low intensity
II
Swishing sound or murmur
Occurs 10-15 mm Hg below peak systolic pressure Auscultatory gap occurs when phase 2 sounds are soft, absent or missed by examiner
III Crisp, easily heard
15-20 mm Hg below phase II
IV Abrupt damping or muffling of tapping sounds
It occurs 5-8 mm Hg above the diastolic sounds
V
Disappearance of sound Used as true diastolic pressure
Orthostatic hypotension - In a normal individual, systolic blood pressure falls by 10-12 mm Hg and diastolic blood pressure remains same or may increase on standing. Orthostatic hypotension is fall in systolic blood pressure by >20 mm Hg and/or diastolic blood pressure by >10 mm Hg on moving from supine to standing position within 3 minutes. It may or may not be associated with compensatory tachycardia. It manifests as postural giddiness or syncope. It is seen in hypovolemia, baroreflex dysfunction, autonomic insufficiency, diabetics, elderly and with vasodilators (alpha blockers, beta blockers, nitrates, diuretics). Ambulatory BP monitoring - It gives a record of 24 hours of blood pressure. Blood pressure is higher when awake, alert, mentally or physically active and early morning. It is lower during rest and sleep. Patients in whom the blood pressure does not fall by 10-20% at night or an average greater than 135/85 mm Hg are at a higher risk of cardiovascular events. It is indicated in
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work done by the heart. Systolic arterial pressure depends on the stroke volume, velocity of left ventricular ejection, distensiblity of vessels and volume of blood at end diastole. Diastolic blood pressure is the minimum pressure exerted during diastole. It is the load against which the heart has to work. The diastolic arterial pressure depends on peripheral arteriolar resistance, cardiac cycle length and compliance of the arterial tree. Cardiac output is the product of heart rate and stroke volume (CO=HRxSV). Arterial blood pressure is the product of cardiac output and peripheral resistance (BP=COxPR). The pulse pressure is the difference between systolic and diastolic blood pressure (approximately 40 mm Hg). Mean blood pressure is the sum of diastolic blood pressure and 1/3rd pulse pressure (approximately 95-100 mm Hg).
CARDIOLOGY
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Table 7: Differential blood pressure
Table 8: Causes of narrow and wide pulse pressure
Differential BP in upper limbs (>10 mm Hg) mm
Differential BP in arm and leg (>20 Hg)
Wide pulse pressure
Narrow pulse pressure
i. Arterial occlusion - embolism, atherosclerosis, Takayusu’s arteritis, post cardiac catheterization
i. Coarctation of aorta
i. Hyperkinetic circulation pregnancy, exercise, anemia, hyperthyroidism, arteriovenous fistula, hot weather
i. Heart failure
ii. Dissecting aortic aneurysm
v. Severe aortic regurgitation (Hill’s sign)
ii. Aortic dissection iii. Aortic arch syndrome iv. Subclavian steal syndrome
iii. Supravalvular aortic stenosis
iii. Patent ductus arteriosus iv. Truncus arteriosus v. Complete heart block
v. Subclavian steal syndrome
vii. Arm above heart level
vi. Error in technique, Physiologic variations
Jugular venous pulse
i.
Drug resistant hypertension
ii.
Drug induced hypotension
iii.
White coat hypertension
iv.
Autonomic dysfunction
v.
Episodic hypertension
Ankle brachial index - It is the ratio of systolic blood pressure in ankle divided by the higher of the two arm systolic pressures (normal >0.9). Values <0.9 is suggestive of peripheral vascular disease, and <0.3 indicates rest pain and critical ischemia. Blood pressure should be measured in both arms. Normally the difference in both arms is less than 10 mm Hg. Systolic leg pressures exceed arm pressures by <20 mm Hg (Table 7). A wide pulse pressure arises due to increase in stroke volume and decreased peripheral resistance. A narrow pulse pressure arises due to increased peripheral resistance and decreased intravascular volume (Table 8).
Sources of error in blood pressure measurement i. Failure to detect peak Insufficient inflation, too systolic pressure rapid initial inflation, failure to recognize auscultatory gap Falsely elevated readings
iii. Fat arm with small cuff Pseudohypertension iv. Thin arm with large cuff Pseudohypotension v. Excessive venous Decreased intensity congestion in arm Korotkoff sounds
of
Widened auscultatory gap vi. Arm below heart level
iii. Diabetic ketoacidosis
ii. Aortic regurgitation
iv. Thoracic outlet syndrome
ii. Cuff applied too loose
ii. Severe aortic stenosis
Overestimation of blood pressure
Underestimation of blood pressure
Physiology - Careful examination of the venous pulse can provide useful information about the right sided cardiac physiology (Figure 3). When the right atrium contracts, its pressure rises pushing the blood from right atrium to the right ventricle at end of ventricular diastole. It also causes blood to flow retrogradely into the superior vena cava and jugular veins. This produces a positive wave called the A wave. The A wave begins at the peak of the P wave of ECG, immediately prior to S1 and the carotid upstroke. As the right atrium starts relaxing, pressure falls causing the early portion of X descent. Simultaneously, the right ventricular systole commences causing the intraventricular pressure to rise above the atrial pressure. This leads to closure of the tricuspid valve. The upward bulging motion of closed tricuspid valve during isovolumic systole produces a positive wave called C wave. The onset of C wave corresponds to the tricuspid component of S1. It can be confused with transmitted carotid pulsations. It is usually not visible as a separate wave. As the right atrial relaxation continues, right atrial pressure falls during early right ventricular systole. During this phase the tricuspid valve ring is also pulled downwards. The latter part of X descent, X’ reaches its lowest point. The X descent begins during systole and ends before S2. The great veins empty into the right atrium during ventricular systole with a closed tricuspid valve. This leads to a rise in the right atrial pressure causing a second positive wave called the V wave. It begins in late systole and ends in early diastole. It is synchronous with the carotid pulse and peaks after S2. At this point of early ventricular diastole, the ventricular pressure falls below the intra atrial pressure causing the tricuspid valve to open and blood flows from right atrium to right ventricle. This causes a negative wave called the Y descent. The H (H from Hirschfelder) wave arises due to passive right heart filling during diastole. In normal individuals, the A wave is larger than the V wave and X descent is more prominent than the Y descent. During inspiration, negative intrathoracic pressure causes increased venous
Table 9: Differences between Jugular venous pulse and Carotid arterial pulse Carotid arterial pulse
Location
Low in neck, lateral Better seen than felt
Deep in neck, Medial Better felt than seen
Contour
Two crests and two troughs Descent more obvious than crest
Single brief visible upstroke
Inspiration
A and V waves more prominent
No change
Upright position
Decrease in mean pressure
No change
Compressibility
Can be obliterated with gentle pressure
Not easily compressible
Abdominal compression
Transient increase in pressure
No change
cm is the upper limit of normal for venous pulsations. By adding 5 cm, we can obtain the actual venous pressure. If it is not visible, deep inspiration can bring out the waves. The normal level is 4 cm above the angle of Louis which is equal to 9 cm of water or 6 mm Hg.
Fig. 3: Normal jugular venous pulse. The large A wave almost coincides with S1 and the V wave coincides with S2. The X descent occurs in systole and Y descent in diastole pooling of blood which leads to prominent X and Y descent. During expiration, A wave diminishes and V wave becomes the dominant positive reflection. Examination - The patient should be reclining comfortably without any tension on neck tissues. The chin is elevated and head rotated to the left. It is preferable to have tangential lighting. Lean over to the left side of the patient while examining the right side of the neck. The sternal angle of Louis is 5 cm above the mid right atrium whether supine, 45 degree or 90 degree position is given. The venous pressure is measured from the angle of Louis. The thorax should be positioned at an angle where the peak of the venous column is well identified. If the venous pressure is too low, place the patient supine with leg elevation and ask him to take deep breaths. If the pressure is too high, the pulsations may be behind the angle of the mandible, so keep the patient at 90 degree and examine. The height of the A and V wave during inspiration is taken as the venous pressure. Two scale method is used. A horizontal scale at the peak of the venous column cuts the vertical scale kept at the angle of Louis. For supine 2 cm is the upper limit of normal and for 45 degree 4.5
It is recommended to use the X and Y descent to time the venous pulse. The negative X descent is between S1 and S2 and Xâ&#x20AC;&#x2122; is simultaneous with radial pulse. The A wave is visible as a flickering pulsation just before the carotid pulse is felt. During auscultation, the A wave coincides with S4 and is almost simultaneous with S1. The V wave peaks just after S2 and Y descent begins after the V wave. Internal jugular pulsations are visible but not palpable. The indirect pulsations of the jugular bulb and internal jugular veins are transmitted to the overlying skin and soft tissue. The internal jugular veins are preferred to the external jugular veins - i) the internal jugular veins have no valves. ii) The external jugulars communicate with superior vena cava with two bends each of nearly 90 degrees whereas internal jugulars communicate directly. iii) External jugular vein passes through many fascial planes and is easily affected by extrinsic compression. iv) Increased sympathetic stimulation in heart failure causes vasoconstriction of external jugular veins. Right internal jugular vein is preferred because it runs a straight line course to the superior vena cava. Left internal jugular vein runs into the left innominate vein which is not a straight line. Abdominojugular (Hepatojugular) reflux - The patient is positioned such that the upper level of venous column is at mid neck level. Gentle but firm compression is applied with the hand in the right upper quadrant for at least 10
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Jugular venous pulse
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seconds. The patient is instructed not to strain and breathe comfortably with an open mouth. In a normal person, prolonged pressure will not cause a sustained elevation of venous pressure. Elevation of the venous pressure more than 3 cm for at least 15 seconds is a positive response. It will be positive in latent right ventricular failure, silent tricuspid regurgitation, hypervolemia and systemic vasoconstriction. It predicts heart failure and PA wedge pressure greater than 15mm Hg. Patients with chronic obstructive lung disease may have a false positive test.
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CARDIOLOGY
Elevated venous pressure can also be estimated by looking at the veins of the dorsum of the hand and under surface of tongue (Mayâ&#x20AC;&#x2122;s sign) Differences between Jugular venous pulse and Carotid arterial pulse (Table 9)
ABNORMALITIES OF JUGULAR VENOUS PULSE (FIGURE 4)
Increased jugular venous pressure i.
Reduced right ventricular compliance - pulmonary stenosis, pulmonary artery hypertension, right ventricular failure following left ventricular failure. In right ventricular infarction myocardial necrosis may cause the right ventricle to stiffen leading to elevation of right ventricular filling pressure
ii.
Right ventricular inflow impedance - Tricuspid stenosis, right atrial myxoma, constrictive pericarditis
iii.
Fluid overload, renal failure
Decreased jugular venous pressure i.
Hypovolemia, dehydration
ii.
Hypotension, shock
INCREASED A WAVE AMPLITUDE
Large A waves
Fig. 4: Abnormal jugular venous waveforms. A - Large A wave associated with reduced RV compliance and elevated RV end diastolic pressure. It corresponds to right sided S4. B - Compared to the normal waveform, in mild TR, there is a prominent V wave. In severe TR, there is ventriculization with a rapid Y descent. C - Constrictive pericarditis with a prominent Y descent which corresponds to the pericardial knock (K)
i.
Increased resistance to right atrial emptying causes increased right atrial contraction - Tricuspid stenosis, right atrial myxoma, tricuspid atresia
ii.
Reduced right ventricular compliance is seen in right ventricular hypertrophy. It leads to increased right ventricular end diastolic pressure - severe pulmonary arterial hypertension, pulmonic stenosis, pulmonary vascular disease, acute pulmonary embolism, right ventricular infarction, right ventricular cardiomyopathy
iii.
In left ventricular hypertrophy, the hypertrophied interventricular septum alters the pressure volume relationship of right ventricle causing the Bernheim effect - seen in hypertrophic cardiomyopathy (symmetric and asymmetric) and valvular aortic stenosis,
Giant or Cannon A waves - Intermittent giant A waves called cannon A waves occur when the right atrium contracts against a closed tricuspid valve. Paul Wood described giant A waves as venous Corrigan. i.
Regular cannon waves - Junctional rhythm,
ii.
Ventricular tachycardia with 1:1 retrograde conduction, isorrhythmic AV dissociation
ii.
Severe tricuspid regurgitation has a prominent Y descent following the large regurgitant wave
Irregular cannon waves - complete heart block, A-V dissociation, ventricular pacing, ventricular extrasystoles and ventricular tachycardia.
iii.
Severe right ventricular failure
iv.
Atrial septal defect with mitral regurgitation
Decreased A wave amplitude - Right atrial injury during surgical cannulation in open heart surgery can cause reduction in A wave amplitude. Absent A waves - In atrial fibrillation, the atrial kick is lost.
i.
As severity of tricuspid regurgitation increases, the x descent gets blunt and is replaced by a large regurgitant wave.
ii.
In atrial fibrillation, the X trough is reduced in size, but preserved.
Prominent X descent i.
The x descent becomes deeper when vigorous right ventricular contraction occurs - cardiac tamponade, constrictive pericarditis.
ii.
In right ventricular overload states the x descent may be prominent - atrial septal defect.
V WAVE
Prominent V wave - In severe cases it may cause head bobbing, systolic pulsations of earlobe, pulsatile exophthalmos and pistol shot sound over the internal jugular veins i.
In tricuspid regurgitation, increased right atrial blood during ventricular systole causes blunting or obliteration of x descent with a prominent v wave called systolic or regurgitant wave (Lanci’s sign)
ii.
In atrial fibrillation, loss of A waves causes the V waves to become more prominent
iii.
Other - large atrial septal defect, ventricular septal defect with left ventricle to right atrial shunt (Gerbode’s defect), severe heart failure, cor pulmonale.
Diminished V waves - It is seen in hypovolemic states and hypotension following use of nitrates Equal A and V waves may be seen in non restrictive atrial septal defect, constrictive pericarditis with increased venous pressure, right ventricular failure in sinus rhythm with increased venous pressure
Y DESCENT
Rapid Y descent (Diastolic collapse) - The Y descent trough is exaggerated due to elevated venous pressure. i.
In constrictive pericarditis, a prominent Y descent is associated with a diastolic filling sound (pericardial knock). This is called Fredrich’s sign.
The Y descent is diminutive when right atrial emptying or right ventricular filling is hampered - pericardial tamponade, tricuspid stenosis and right atrial myxoma Kussmaul’s sign - Normally during inspiration, due to negative intrathoracic pressure, there is fall in the jugular venous pressure by at least 3 mm Hg. A rise in venous pressure or failure to decrease with inspiration is called Kussmaul’s sign. In states of right sided volume overload and reduced right ventricular compliance, the right ventricle cannot accommodate the increased volume and the pressure rises. It is seen in constrictive pericarditis, restrictive cardiomyopathy, pulmonary embolism, right ventricular infarction, and advanced systolic heart failure. Cervical venous hum - The hum is a continuous murmur, loudest in diastole produced by turbulence in neck veins when head is turned to the left. It occurs due to mild compression of the internal jugular veins by the transverse process of the atlas. It is detected by auscultating the right supraclavicular area and base of the neck in sitting position. It is common in children, young adults, high output states and patients undergoing hemodialysis. It can be confused with murmurs of aortic regurgitation, patent ductus arteriosus, A-V fistula and carotid arterial bruits.
CARDIAC DISORDERS
Aortic stenosis - Pulse - In aortic stenosis, there is obstruction to left ventricular ejection and is best detected in the carotid artery. The classic pulse is called pulsus parvus et tardus or anacrotic pulse. The hallmark of carotid pulse in valvular aortic stenosis is slow rising with delayed upstroke (pulsus parvus), delayed peak which is a smooth prolonged peak with a gradual drop off (pulsus tardus or plateau pulse), small volume due to hemodynamic obstruction at the valve, palpable thrill due to turbulence caused by ejection of blood across a narrow orifice and a prominent anacrotic notch due to jet effect produced by ejection of blood across a narrow valve or decreased velocity of blood flow during early ejection (anacrotic pulse). Palpation cannot detect the anacrotic notch. The severity of valvular obstruction is proportional to the degree of abnormality of the carotid pulse. A lag between onset of apical impulse and carotid impulse predicts a valve area of <1 sq cm (100% specific). The severity of aortic stenosis may be masked with high cardiac output states in children, increased vessel stiffness in elderly, associated aortic regurgitation, hypertension, low stroke volume and congestive heart failure. The severity of aortic stenosis is exaggerated by impaired left ventricular function, hypovolemia and mitral stenosis. A bisferiens pulse may be seen when aortic stenosis is associated with moderate to severe aortic regurgitation and preserved left ventricular function. Bisferiens pulse disappears with onset of congestive heart failure. Pulsus
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X DESCENT
Absent X descent
897
898
alternans may be seen in severe aortic stenosis with left ventricular dysfunction.
CARDIOLOGY
Blood pressure - As the severity of aortic stenosis increases, the systolic arterial pressure decreases and pulse pressure narrows. Patients with hypertension can have high blood pressure associated with aortic stenosis. If there is associated aortic regurgitation, depending on severity there would be lower diastolic pressure and widening pulse pressure.
40 mm Hg - angiographic 2+ AR, 40-60 mm Hg angiographic 3+ AR, >60 mm Hg - angiographic 4+ AR iv.
Eyes
Palmar click - A palpable, abrupt flushing of the palms in systole
v.
Landolfi’s sign - Contraction and dilatation of pupil in systole and diastole respectively
Jugular venous pulse - In most of the cases it will be normal. In presence of left ventricular hypertrophy and hypertrophied septum, there would be decreased left ventricular compliance leading to prominent A wave (Bernheim effect). It may be elevated when aortic stenosis is associated with mitral stenosis and pulmonary artery hypertension or tricuspid stenosis.
vi.
Becker’s sign - Prominent retinal artery pulsations
Supravalvular aortic stenosis - Patients have selective jet streaming of blood in the right innominate vessels which causes greater pulse amplitude in right carotid, subclavian and brachial arteries with left carotid pulse having features of aortic valve obstruction. The blood pressure in the right arm may be 10-20 mm Hg higher than the left arm.
ix.
Muller’s sign - Visible pulsations of the uvula
x.
Minervi’s sign - Strong lingual pulsations demonstrated by up and down movement of the tongue depressor
xi.
Logue’s sign - Pulsatile sternoclavicular joint when aortic regurgitation is associated with aortic dissection
Aortic regurgitation - Pulse - The pulse of aortic regurgitation has a collapsing quality. The large stroke volume increases the force and amplitude of ejection followed by an abrupt fall or collapsing pulse caused by low systemic vascular resistance and early diastolic reflux of blood into the left ventricle. Arterial pulses all along the arterial tree have a bounding quality giving rise to the nonauscultatory signs of aortic regurgitation. The presence of these signs indicates moderate or severe chronic aortic regurgitation. These signs may be attenuated with low cardiac output, heart failure, arterial vasoconstriction and tachycardia in congestive heart failure.
Head and Neck vii.
De Musset’s sign - Visible oscillation or bobbing of the head with each heart beat
viii. Corrigan’s sign - Visible pulsations of carotid artery (dancing carotids)
Upper limb xii.
Locomotor brachialis - Pulsations of the brachial artery
xiii. Quincke’s pulse - Exaggerated sequential reddening and blanching of the fingernail when light pressure is applied to the tip of fingernail. A similar phenomenon can be observed by pressing a glass slide against the lips. xiv. Palfrey’s sign - Pistol shot sounds over the radial artery
Blood pressure - As the severity of aortic regurgitation increases, the diastolic pressure decreases and pulse pressure widens. The degree of decrease of diastolic pressure is a better indicator to assess the severity of aortic regurgitation, than the increase in systolic blood pressure. Though the sphygmomanometer measured pressure approaches zero, true diastolic pressure is never lower than the maximal left ventricular end diastolic pressure. Hence diastolic pressure is measured at muffling of Korotkoff sounds and disappearance of sound. Tachycardia shortens the time for diastolic reflux and increases the diastolic pressure, whereas bradycardia increases duration of diastolic reflux and decreases the diastolic pressure.
Lower limb
PERIPHERAL SIGNS OF AORTIC REGURGITATION
xix.
i.
Bisferiens pulse - A double peaked systolic impulse, best appreciated in brachial artery
ii.
Water hammer pulse
iii.
Hill’s sign - A difference in systolic blood pressure between the brachial and popliteal arteries is used to assess the severity of aortic regurgitation - 20-
Acute aortic regurgitation - In acute aortic regurgitation, there will be sinus tachycardia, slightly low systolic blood pressure with a near normal diastolic blood pressure with pulsus alternanas. Peripheral signs may be absent. The mean jugular venous pressure may be elevated.
xv.
Pistol shot of Traube - A large systolic sound with the stethoscope lightly placed on the femoral artery
xvi. Durozeiz’s sign - Light pressure applied to the femoral artery distal to the edge of the stethoscope produces a to and fro bruit caused by exaggerated reversal of flow in diastole.
A systolic murmur is perceived by pressing the femoral artery proximal to the stethoscope.
Abdomen
xvii. Rosenbach’s sign - Pulsatile liver xviii. Gerhardts’s sign - Pulsatile spleen Dennison’s sign - Pulsatile cervix
Hypertrophic cardiomyopathy - Pulse - The carotid pulse
Jugular venous pulse - The A wave is prominent and appears as a flicking motion prior to carotid upstroke. It is due to stiff RV myocardium and strong right atrial contraction. A more prominent A wave indicates right ventricular outflow tract obstruction. Mitral stenosis - Pulse - The carotid arterial pulse is normal or has decreased pulse volume and normal contour. If associated with atrial fibrillation, the pulse will be irregular with variable pulse volume. If associated with mitral or aortic regurgitation, there is an increase in the carotid pulse amplitude and rate of rise. Jugular venous pulse - It may be normal in uncomplicated mitral stenosis. There will be a prominent A wave in patients with pulmonary artery hypertension in sinus rhythm as a result of right ventricular hypertrophy and decreased right ventricular compliance. In presence of right ventricular failure, mean pressure will be elevated. In atrial fibrillation, A wave disappears, X descent is attenuated with irregular V waves. Mitral regurgitation - Pulse - In moderate or severe mitral regurgitation, the carotid pulse is brisk or jerky with decreased pulse volume or quick rising, poorly sustained and low amplitude. It is due to decreased forward stroke volume because of regurgitation. Jugular venous pulse - It is normal in uncomplicated cases. As right heart failure sets in, pulmonary artery hypertension causes rise in mean venous pressure. This causes a prominent A wave suggestive of an elevated right ventricular end diastolic pressure. Patients with functional tricuspid regurgitation have a prominent V wave which increases on inspiration. Mitral valve prolapse - Majority of patients have no abnormality of the arterial or venous pulse. When
associated with severe mitral regurgitation, the arterial pulse is brisk and collapsing. A retraction notch coincident with midsystolic click has been recorded but is not palpable.
899
Tricuspid regurgitation - Pulse - Hemodynamically significant tricuspid regurgitation may result in low amplitude arterial pulse. Many patients may have associated atrial fibrillation. Jugular venous pressure - It has more diagnostic importance than auscultation. Sometimes, in severe tricuspid regurgitation, the mean venous pressure is elevated. In such a situation, it may be necessary to examine the patient in a sitting or standing position. Do not conclude that the jugular venous pulse is normal unless the upper level of the wave form is identified in supine, 45 degree or sitting position. As the severity increases, X descent is attenuated and ultimately disappears. The V wave is augmented and Y descent is more prominent. In severe tricuspid regurgitation, there is a rounded or plateau like severe regurgitant C-V wave, V wave or S wave. This V wave is a systolic wave which is followed by a sharp, steep trough called the Y descent. In severe cases, prominent eyeballs and pulsatile earlobes have been observed. With inspiration, due to increase in right ventricular inflow, the V wave has a higher peak and a prominent Y descent. In atrial fibrillation, there is disappearance of A wave with presence of a dominant V wave which may simulate the V wave of tricuspid regurgitation.
REFERENCES
1. Mark E Silverman. Essentials of cardiac physical diagnosis by Jonathan Abrams, Philadelphia, Lea and Febiger, 1987:13-54. 2. Narasimhan R, Vahe S, Franklin S. The art and science of cardiac physical examination with heart sounds, jugular and precordial pulsations, 2nd ed. New Delhi: Jaypee, 2015:20-140. 3. Jules Constant. Essentials of bedside cardiology, 2nd ed. Humana press inc, 2003:29-88. 4. Mann, Zipes, Libby, Bonow. Braunwald’s heart disease a textbook of cardiovascular medicine, 10th ed. Philadelphia: Elsevier Saunders, 2015:98-102. 5. Kasper, Fauci, Hauser et al. Harrison’s principles of internal medicine, 19th ed. 2015 6. Michael G, William D. Hutchison’s clinical methods, 23rd ed. Saunders, 2012. 7. Andrew H, David G. Chamberlain’s symptoms and signs in clinical medicine, 13th ed. 2010.
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has a rapid, jerky, sharp upstroke which taps against the fingers, followed by a midsystolic dip or collapse which is followed by a second late diastolic wave (spike and dome or pointed finger pulse). The rapid upstroke is due to early, exaggerated emptying of the left ventricle and the second peak is probably a reflected wave or rebound phenomenon. The magnitude of midsystolic dip correlates with the left ventricular - aortic pressure gradient. In a normal individual, the postextrasystolic pulse after a long pause is larger than normal. In obstructive variety of hypertrophic cardiomyopathy, after an extrasystolic pulse, there is Starling effect which causes increase contractility and increase obstruction. So, the pulse stays the same or reduces. This is called Brokenborough phenomenon.
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Coagulation Cascade - Whatâ&#x20AC;&#x2122;s New BL Bhardwaj, Harnoor S Bhardwaj, Pallav Jain, Kanchan Saini
Deficiencies of coagulation factors have been recognized for centuries. Patients with genetic deficiencies of plasma coagulation factors exhibit life-long recurrent bleeding episodes into joints, muscles, and closed spaces, either spontaneously or following an injury. The most common inherited factor deficiencies are haemophilia, X-linked diseases caused by deficiency of factor (F) VIII (haemophilia A) or factor IX (F IX, haemophilia B). Acquired deficiencies of plasma coagulation factors are more frequent than congenital disorders; the most common disorders include haemorrhagic diathesis of liver disease, disseminated intravascular coagulation (DIC), vitamin K deficiency and lupus anticoagulant associated thromboembolism. Haemostasis is a tightly regulated homeostatic mechanism that maintains blood flow under physiologic conditions and permits rapid, localized coagulation in the event of tissue damage. A delicate balance exists between four components the vascular endothelium, platelets, the coagulation pathway and fibrinolysis & the major events are: 1.
Primary haemostasis( vasoconstriction and platelet plug formation)
2.
Secondary haemostasis (activation of coagulation factors and generation of thrombin)
3.
Fibrin clot formation and stabilization
4.
Inhibition of coagulation (inhibition of thrombin generation and fibrin clot breakdown)
There are 2 pathways: Intrinsic pathway and extrinsic pathway. The extrinsic pathway, involving tissue factor and factor VII, and the intrinsic pathway, in which factors XII, XI, IX, VIII, and V participate. Both pathways converge to activate factor X and lead to transformation of prothrombin into thrombin and, through the action of thrombin, of fibrinogen into fibrin. The role of platelets in coagulation was considered independent. There is new perspective built on the classic coagulation cascade (Figure 1) in the following ways: The complex formed by tissue factor and factor VII participates in the activation of factor IX, indicating that the intrinsic and extrinsic coagulation pathways are linked almost from the beginning of the process; The complete process does not occur continuously but rather requires 3 consecutive phases: an initial phase, an amplification phase, and a propagation phase. Platelets and thrombin are actively involved in the last 2 phases. Initial Phase: The tissue factorâ&#x20AC;&#x201C;factor VII complex activates factor X, either directly
or indirectly via factor IX, and transforms prothrombin into thrombin in small amounts that are insufficient to complete the process of fibrin formation. Amplification Phase: The thrombin that has been formed, along with calcium from the blood and acidic phospholipids derived from platelets, actively participates in a positive feedback process for the activation of factors XI, IX, VIII, and V, and, especially, to accelerate platelet activation. Simultaneously, the factors mentioned are attracted through chemotactic mechanisms to the surface of the platelets, where very rapid and extensive activation and amplification occurs. Propagation Phase: The amplification of the process through feedback mechanisms involving thrombin and platelets and the activation of all these factors allow large quantities of factor X to be activated and form the prothrombinase complex to convert prothrombin into thrombin and, through the action of thrombin, fibrinogen into fibrin. The final process, always occurring on the surface of the platelets, accelerates and leads to the explosive generation of large quantities of thrombin and fibrin. Activation of platelets alters the permeability of the membrane and allows entry of calcium and release of chemotactic substances that attract coagulation factors to the surface. At the same time, factor V and acidic phospholipids are released, providing the necessary complement for the coagulation process. The new coagulation cascade presents fibrin formation as the result of 2 complementary processes: coagulation (represented by thrombin) and platelet activation. The prothrombin time (PT) measures the integrity of extrinsic and common pathways of coagulation (factors VII, X and V; prothrombin and fibrinogen). The activated partial thromboplastin time (aPTT) measures the integrity of the intrinsic and common pathways of coagulation (high molecular weight kininogen; prekallikrein; factors XII, XI, IX, VIII, X and V; prothrombin and fibrinogen). The sensitivity of the PT and aPTT in detecting coagulation factors deficiencies may vary with the reagent used to perform these tests, and each laboratory must determine its own reference standards. The thrombin time (TT) is a screen for quantitative deficiencies and qualitative defects of plasma fibrinogen. Heparin increases PTT, it also activates Antithrombin III and affects the intrinsic pathway. Fibrinogen levels are decreased by heparin. Antidote to heparin is protamine sulfate. Warfarin increases PT, inhibits vitamin K. Thus warfarin affects the extrinsic pathway and factors II, VII, IX & X. It also affects the protein C & S. Warfarin is
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Fig. 1: Coagulation Cascade teratogenic as its small size allows it to cross the placenta. Its antidote is vitamin K. The goal INR should be kept between 2.0 & 3.0 and in cases of mechanical valves it should be kept between 2.5 to 3.5. Low Molecular Weight Heparin (LMWH) (enoxaparin) inhibits factor Xa. Mostly it needs no monitoring. It should be given once or twice daily. Heparin to warfarin conversion is necessary as warfarin inhibits proteins C & S before other vitamin K dependent factors (like factor II, VII, IX & X) leading to a brief period of paradoxical hypercoagulability before anticoagulation. The unexplained prolongation of PT and aPTT is investigated by simple correction tests by making 50:50 mixtures of patientâ&#x20AC;&#x2122;s plasma and normal plasma. Correction indicates a possible coagulation factor deficiency whereas; failure indicates presence of circulatory anticoagulant. The commonest anticoagulant
is lupus anticoagulant (LAC). LAC prolongs phospholipid dependent test such as PT & aPTT. Though these show recurrent venous thromboembolism, cerebrovascular accidents and in women in recurrent abortions and fetal loss. It needs demonstration of LAC in patients with these features. The paradigm shift in our understanding about classical coagulation cascade occurred due to introduction of a cell based model which emphasizes the importance of tissue factor as the initiator of the coagulation cascade and the pivotal role of platelets for intact haemostasis. This new understanding explains the poor correlation between traditional tests of coagulation and clinical bleeding and has generated renewed interest in viscoelastic tests for
CARDIOLOGY
902
diagnosing derangement in haemostasis and to guide transfusion therapy. Thromboelastography (TEG) assesses the viscoelastic properties of blood samples under low shear conditions. It measures the clot’s physical property by using a stationary cylindrical cup that hold the blood sample and oscillates through an angle of 4o45 with each rotation cycle lasting 10 sec. Besides standard TEG, Platelet Mapping which is an extension of TEG technology, in addition to providing information on clot formation and lyses of whole blood sample, it quantifies the contribution of fibrin, adenosine diphosphate (ADP) receptor and thromboxane A2 (Tx A2) receptor in clot strength. The TEG Platelet Mapping assay enables relating the percent platelet inhibition to the individual’s maximum uninhibited platelet function. This information allows monitoring of effectiveness of antiplatelet agents, aspirin and clopidogrel, via inhibition of TxA2 and ADP receptors. Various studies suggest that TEG could be a complimentary test to current standard coagulation assays and in some cases, a superior method altogether. Thromboelastographic results need to be carefully interpreted in presence of severe anaemia, thrombocytopenia and hemodilution as these conditions can variably affect the test results.
REFERENCES
1.
Arruda V R, High K A. Coagulation disorders. In: Harrison’s Principles of Internal Medicine- 18th ed. Eds. Longo DL, Fauci AS, Kasper DC, Hauser SL, Jameson JL, Loscalzot. McGraw-Hill New York, 2012; Vol 1:973-982.
2.
Black L, Selby R. The Basics of Coagulation and clot breakdown. In: Bloody Easy. Eds Lin Y, Selby R. ORBCON 2013 March; 4-7.
3.
Coagulation cascade pathway. Available at www. sigmaaldrich.com/content/dam/sigma-aldrich/docs/ sigma../coagpathway.pdf
4.
Gomez FP and Bover R .The New Coagulation Cascade and Its Possible Influence on the delicate balance between thrombosis and haemorrhage. Rev Esp Cardiol 2007; 60:12179.
5.
Schafer AI. Approach to the patients with bleeding and thrombosis. In: Goldman-Cecil Medicine (25th) ed. Eds: Schafer AI, Goldman L. Reed Elsevier India Pvt. Ltd. 2016; 1:1154-1159.
6.
Bolliger D, Seeberger MD, Tanaka KA. Principles and practice of thromboelastography in clinical coagulation management and transfusion practice. Transfusion Medicine Reviews 2012; 26:1-13.
7.
Agarwal S, Coakley M, Reddy K, Riddell A, Mallett S. Quantifying the effect of antiplatelet therapy: A comparison of the platelet function analyzer (PFA-100) and modified thromboelastography (mTEG) with light transmission platelet aggregometry. Anesthesiology 2006; 105:676-83.
8.
Verma A. Thromboelastography. In: Transfusion Update. Ed. Bhardwaj K, Bhardwaj BL, Thakur KK, Bassi R, Bhardwaj HS. 2016. Jay Pee Brothers Medical Publishers (P) Ltd. New Delhi. 42-3.
Anti-Platelet Therapy
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Nihar Mehta, Nikesh Jain
The pathophysiology of acute myocardial infarction (MI), ischemic stroke, and limb gangrene is centered around arterial thrombosis. Arterial thrombosis is the complex interplay between platelet activation, aggregation and adhesion and the coagulation system with fibrin formation. Due to the central role of platelets in arterial thrombogenesis, the treatment focuses on drugs that block platelet function.
of salicylic acid that works by inhibiting the enzyme prostaglandin H-synthase also known as cyclooxygenase (COX).
Mechanism of Action: Prostaglandin H-synthase 1 and 2 (also known as COX 1 and 2) catalyze the conversion of arachidonic acid to prostaglandin H2 (PGH2). Human platelets and vascular endothelial cells convert COX2 primarily to thromboxane A2 (TXA2) and prostaglandin I2 (PGI2).2 TXA2 induces platelet aggregation and vasoconstriction, whereas PGI2 inhibits platelet aggregation and induces vasodilatation. Platelet TXA2 synthesis is reduced by about 98% following ASA administration.
Clinical Uses: ASA is used in primary as well as secondary prevention of CAD, Ischemic stroke and Peripheral Vascular disease. Also ASA has been studied in a wide range of diseases ranging from preeclampsia, polycthemia vera to bowel cancer, usually at doses of 50 to 100 mg/day. The mechanisms of action for the observed benefits in these conditions remain to be elucidated.
Use of the lowest effective dose (50-100 mg/day for long-term treatment) is currently the most appropriate strategy to maximize efficacy and minimize toxicity.3
ROLE OF PLATELETS IN HEMOSTASIS
The initial response of the hemostatic system to tissue or endothelial injury is to produce a platelet plug (primary hemostasis). Platelets have multiple surface receptors, which when stimulated, produce a shape change involving the energy-dependent actin-myosin system. Principal among these receptors are the glycoprotein Ib (GpIb) receptor, which binds to von Willebrand factor (vWF) in response to endothelial injury. Additionally, there are receptors for adenosine diphosphate (ADP), thrombin, and thromboxane A2. With the shape change, the surface of the platelet also changes, leading to expression of a second binding site, the glycoprotein IIb/IIIa (GpIIb/ IIIa) receptor. GpIIb/IIIa receptors bind fibrinogen to provide bridging between adjacent platelets. The surface of the platelet also expresses binding sites for factor V, an essential cofactor in the generation of thrombin (Figure 1).1
Side Effects of Aspirin
ANTIPLATELET AGENTS
Platelets can be activated in a number of ways. The targets and agents in clinical use or development are shown in figure below.
a.
Bleeding: Bleeding is dose-dependent in patients treated for stroke and with acute coronary syndrome.4 A retrospective subgroup analysis of the relationship between the aspirin dose and risk of major bleeding found that a dose of 100 mg/day to have the lowest rate of major or life-threatening bleeding complications.(5) Bleeding risks increased with increasing ASA dose with or without clopidogrel.
b.
Hypersenitivity: The mechanism of Aspirin Hypersensitivity is upregulation of the 5-Lipooxygenase pathway leading to increased leukotrienes. The effects include bronchospasm, urticaria, rhinitis, angioedema or anaphylaxis. Aspirin Sensitive Ashtma includes a triad of Bronchial Asthma, Aspirin Sensitivity and Nasal Polyps.
c.
Gasterointestinal: Dyspepsia (epigastric distress, heartburn, nausea, ulcers), Gastric mucosal lesions, Peptic ulcers, Hemorrhage and Perforation are some of the gastrointestinal side effects of aspirin.
ORAL ANTIPLATELET AGENTS
I.
Aspirn: Acetylsalicylic acid (ASA) is a derivative Collagen
ADP ATP
Ticlopidine clopidogrel prasugrel
TxΑ2 TRA
TPα
TPβ
GPV1
P2X1
CYP450 metabolism
P2Y1
PAR1
Ca2+
PAR4
Adenyl cyclase
cAMP
P2Y12
Ticagrelor Cangrelor
ACTIVATION
Thrombin
ASA
-1
TxA2
COX
GP IIb/IIIa* ATP, ADP, Ca2+
Amplification
Dense granule secretion
Coagulation factors Pro-inflammatory mediators
Fibrinogen
α-granule secretion
GP IIb/IIIa Shape change
GP IIb/IIIa*
Transient aggregation
Fig. 1: Platelet Activation Pathways1
GP IIb/IIIa inhibitor
Stable aggregation
904
COOCH3 N S
CYP1A2 CYP2B6 CYP2C19
CI
Clopidogrel
O CH3 CO
S
CI
2-Oxo-clopidogrel
O
O N
Prasugrel
CARDIOLOGY
N
O
N S
F
COOCH3
COOCH3
Esterases
O
S
CYP3A4/5 CYP2C9 CYP2B6 CYP2C19
HOOC HS
N CI
Active metabolite O
F
Intermediate metabolite
CYP3A4/5 CYP2B6 CYP2C9 CYP2C19 CYP2D6
HOOC HS
N
F
Active metabolite
Fig. 2: Major pathways leading to activation of Thienopyridines. Clopidogrel requires two CYP-Dependanct steps to get converted to its active metabolite. Prasugrel requires one CYPâ&#x20AC;&#x201C;Dependant step for conversion to its active metabolite.1 II.
III.
A.
Dipyridamole: Mechanism of Action: Dipyridamole is a pyrimidopyrimidine derivative with vasodilator and antiplatelet properties. The mechanism of action of dipyridamole as an antiplatelet agent involves increased intracellular cyclic adenosine monophosphate (cAMP), which inhibits the platelet shape change. Increased cAMP concentration is due to two mechanisms: (1) inhibition of phosphodiesterase and (2) blockade of uptake of adenosine (which acts at adenosine A2 receptors to stimulate platelet adenylyl cyclase and thus increase cAMP). Clinical Uses: Though early clinical trials questioned the efficacy of dipyridamole, recent studies have suggested significant benefit with new formulation. In a study addition of modifiedrelease dipyridamole 200 mg twice daily to ASA 25 mg twice daily was associated with a 22% relative risk reduction of major vascular events compared with ASA alone.(6) In another study of ASA (30325 mg/day) with or without dipyridamole (200 mg twice daily) in patients within 6 months of a transient ischemic attack (TIA) or minor stroke showed 20% reduction of a composite of major vascular events by the combined treatment.(7) Platelet Receptor Inhibitors: Purigenic Receptors: There are three known subtypes of ADP receptors on platelets: P2X1, P2Y1, and P2Y12. Sustained ADP-induced platelet aggregation requires coactivation of P2Y1 and P2Y12 receptors. The P2Y12 receptor acts by inhibiting adenylyl cyclase via a Gi protein and potentiates dense granule secretion, procoagulant activity, and platelet aggregation. Without continued P2Y12 activation, aggregated platelets disaggregate. Inhibition of the P2Y12 receptor is a major target for anti-platelet drug development. Thienopyridines: Thienopyridines which are CLOPIDOGREL and PRASUGREL (Ticlopidine not in use now), selectively inhibit ADP-induced platelet aggregation with no direct effects on arachidonic acid metabolism. The thienopyridines
do not act directly, but are administered as prodrugs requiring hepatic transformation. The active metabolites of both clopidogrel and prasugrel couple through a covalent disulfide bond to P2Y12 receptors rendering the receptor unresponsive to ADP, and as the bond is covalent it causes irreversible inhibition (Figure 2). B.
Adenosine Diphosphate Analogues
i.
Ticagrelor: Ticagrelor is a cyclopentyltriazolopyrimidines, and is an oral P2Y12 receptor antagonist that exerts antiplatelet effects by blocking ADP. Ticagrelor is not a prodrug, and the block is reversible. The parent drug is metabolized, principally by CYP 3A to about 10 metabolites. The major metabolite, AR-C124910XX, formed by O-deethylation, is as active as ticagrelor in inhibiting ADP-induced platelet aggregation.
ii.
Cangrelor: Cangrelor is an intravenous P2Y12 purinoreceptor antagonist.17 Cangrelor is not a prodrug and produces concentration-dependent inhibition of thrombin receptor-activating, peptideinduced aggregation in human platelets.
Cangrelor was studied in two large-scale phase 3 studies that were both ended early as it did not show any clinical efficacy needed for regulatory approval
Clinical Use in CAD
Clopidogrel, Prasugrel and Ticagrelor are indicated in patients with acute coronary syndromes, which includes patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI) and patients with STelevation myocardial infarction (STEMI) when managed with primary or delayed percutaneous coronary intervention (PCI) (Table 1).
Specific Regimens in CAD Patients A.
Antiplatelets in Stable Ischemic Heart Disease: Aspirin at dose of 75 to 162 mg daily, is preferred for secondary prevention in the absence of recent intracoronary stenting.
Clopidogrel may be substituted for aspirin, in patients intolerant or resistant to aspirin.
Table 1: Basic Pharmacology and Safety aspects of P2Y12 Receptors Antagonists
905
Prasugrel
Ticagrelor
Thienopyridine
Thienopyridine
Cyclopentyltirazolopyridine
Prodrug
Yes
Yes
No
Administration
Oral
Oral
Oral
Time to peak effect
Dose dependent
2 hr
2 hr
% Platelet Inhibition 2 hrs after loading dose
40-50%
70-90%
80-90%
Half Life
6 hr
8 hr
6-12 hr
Time to recovery of platelet inhibition
4-5 days
2-4 days
2-3 days
Reversible
5 days
7 days
24-48 hr
Indications
ACS and Stable CAD undergoing PCI
ACS undergoing PCI
ACS (full spectrum)
Safety with prior CVA
Yes
No
Yes
Increased risk
Increased risk
Increased risk
Reduced risk
Bleeding. Caution in
Bleeding
1. Weight <60 kg,
Dyspnoea
2. Age >75 years,
Sinus pauses
Non-CABG bleeding CABG bleeding Side Effects
Bleeding
3. Prior CVA
There is no significant benefit in adding clopidogrel to aspirin.
B.
C.
Antiplatelets in ACS - NSTEMI: All patients should be given 162 to 325 mg of uncoated aspirin, which should be taken as chewed or crushed, as soon as possible after the diagnosis has been made.
Anti-Platelet use In STEMI: Aspirin should be given to all patients at a loading dose of 162-325mg in uncoated form and to be chewed or crushed. Aspirin at maintainence dose should be continued thereafter.
All patients should receive P2Y12 receptor inhibitor in addition to aspirin.
P2Y12 receptor blocker should be added but its choice depends on choice of reperfusion strategy.
For most patients going for an early invasive strategy, ticagrelor 180 mg as loading dose is preferred choice.
In patients undergoing fibrinolytic therapy, only clopidogrel is to be used.
In patients undergoing primary PCI, prasugrel or ticagrelor should be used rather than clopidogrel.
For patients in whom there is a concern about a need for urgent coronary artery bypass graft surgery, the P2Y12Â receptor blocker may be given after diagnostic coronary angiography.
In patients undergoing Fibrinolysis - Loading dose of clopidogrel 300mg can be given, followed by 75mg once a day. In patients>75 years of age, 75mg once a day without loading dose can be given.
If the P2Y12 receptor blocker is given after angiography, ticagrelor (180 mg as loading dose followed by 90mg twice a day as maintainence) or prasugrel (60 mg as loading dose followed by 10 mg once a day as maintainence dose) should be given.
Duration of Anti-Platelet Therapy in Patients with CAD
If ischemia guided (conservative) strategy is used, ticagrelor is preferred. Clopidogrel (600mg loading dose followed by 75mg once a day) can also be used.
Aspirin at dose of 75-100 mg should be continued indefinitely for secondary prevention.
For patients on ticagrelor, aspirin dose should be <100 mg.
The addition of a P2Y12Â inhibitor to aspirin and prolongation of DAPT requires an assessment of the risk benefit ratio of ischemic risk versus the bleeding risk.
Clinical Use in TIA or Stroke 1.
In TIA or Acute Ischemic Stroke, Aspirin and Clopidogrel are given as 300mg loading dose each (to be given within 24-48 hours, not to be loaded if thrombolysed), followed by 75mg each as once a day for 3 weeks. Aspirin is continued thereafter.
2.
Clopidogrel has not been proved to be superior to Aspirin for secondary prevention, no dual antiplatelet therapy.
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Clopidogrel
Chemical Structure
906
Table 2: Major Clinical studies on use of P2Y12 Receptor Inihibitors Trial
Pateints enrolled
Treatment arms
Primary endpoint
Result
Cure
Patients with ACS without STEMI
Aspirin plus
CV deaths, nonfatal MI, or Stroke
9.3% vs 11.4%, RR 0.80, p<0.001
CV death, nonfatal MI, or nonfatal
9.9% vs 12.1%
Clopidogrel vs Aspirin plus Placebo
Triton-TIMI 38
ACS undergoing PCI
Aspirin plus Prasugrel vs
HR 0.81, 95% CI Stroke at 14.5 months 0.73-0.90,
CARDIOLOGY
Aspirin plus Clopidogrel Triology â&#x20AC;&#x201C; ACS
Medically managed NSTE-ACS
P<0.001
Aspirin plus Prasugrel vs Aspirin plus Clopidogrel
CV death, MI, or Stroke at 17 months in patients age <75 years
13.9% vs 16% HR 0.91. 95% CI 0.79.1.05, p-0.21
ACCOAST
Patients with NSTEMI scheduled for CAG
Pretreatment with Prasugrel 30 mg vs placebo
CV death, MI, Stroke, 10% vs 9.8%, HR GP IIb/IIIa inhibitor 1.02, 95% ci 0.84.1.25, bailout, or urgent p-0.81 revascularization at 7 days
Plato
Patients with ACS
Aspirin plus
Death from vascular causes, MI, or Stroke at 12 months
9.8% vs 11.7%, HR 0.84, 95% CI 0.770.92, p<0.001
Ticagrelor vs Aspirin plus Clopidogrel Pegasus TIMI 54
Patients with a MI 1-3 Ticagrelor 90 mg years ago BD plus Aspirin, Ticagrelor 60 mg BD plus Aspirin, Placebo plus Aspirin
Cardiovascular Death, MI or Stroke at 3 years
Ticagrelor 90 mg vs Placebo â&#x20AC;&#x201C; HR 0.85, 95% CI 0.75-0.96 (p=0.008); Ticagrelor 60 mg vs Placebo HR 0.84, 95% CI 0.74-0.95 (p=0.004)
Champion-Phoenix
Patients undergoing PCI
Death from any cause, MI, Ischemia-driven revascularisation, and Stent thrombosis at 48 hours
4.7% vs 5.9%, OR 0.78, 95% CI 0.660.93, p=0.005
Aspirin plus Clopidogrel plus cangrelor vs Aspirin plus Clopidogrel
3.
Aspirin and Dipyridamole combination has been proved to be superior to Aspirin alone in secondary prevention.
4.
Other anti-platelets have not been studied in stroke patients.
Clopidogrel: Also among clopidogrel-treated subjects in TRITON-TIMI 38, carriers of the CYP 2C19 variant had a relative increase of 53% in the risk of death from cardiovascular causes, MI, or stroke compared with noncarriers (12.1% vs. 8.0%); and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 8%).12 A parallel study of prasugrel found no effect of this polymorphism on pharmacodynamic or clinical outcomes.13
Prasugrel: is contraindicated in (1) patients with a history of prior TIA or stroke, (2) for patients 75 years of age or older due to an increased incidence of fatal and intracranial bleeding. and (3) in patients weighing less than 60 kg (although not absolutely contraindicated, a higher rate of bleeding is noted because the active metabolite of prasugrel is 30-
Side Effects of P2Y12 Receptor Blockers a.
Bleeding: The principal adverse outcome related to the use of thienopyridines is bleeding.9 The CURE study showed similar rates for nonfatal and major hemorrhage but highlighted dose-dependent effects of ASA on rates for bleeding, and also an effect of age in clopidogrel-treated patients.10 In the TRITON TIMI38 study, bleeding rates with prasugrel were markedly higher than with clopidogrel (Tables 2 and 3).11
907
Table 3: Duration of Antiplatelet Therapy in Subsets of CAD8 Subset of CAD
Recommendation
In all CAD patients
Aspirin therapy 75 – 100 mg daily. Continued Indefinitely; unless there are contraindications like bleeding or hypersensitivity
Stable ischemic hert disease after PTCA: DAPT with Aspirin and Clopidogrel should be given for at least 6 months (Class I)
After Bare-Metasl Stent (BMS)
DAPT with Aspirin and Clopidogrel should be given for at least 1 month (Class I)
After DES / BMS who have tolerated DAPT without a bleeding complication and who are not at high bleeding risk
DAPT may be continued for longer if tolerated well. (Class IIb)•
Acute Coronary Syndrome (ACS) after PCI After BMS or DES implantation
DAPT with P2Y12 inhibitors (Clopidogrel, Prasugrel or Ticagrelor) should be given for at least 12 months (Class I).
After DES / BMS who have tolerated DAPT without a bleeding complication and who are not at high bleeding risk
Continuation of DAPT with P2Y12 inhibitors (Clopidogrel, Prasugrel or Ticagrelor) for longer than 12 months, for 18-24 months may be reasonable (Class IIb).
ACS# after PCI with DES / BMS
Reasonable to use Ticagrelor in preference to Clopidogrel for maintenance P2Y12 inhibitor therapy (Class IIa)
or UA / NSTEMI on Medical management (without PCI)
Reasonable to choose Prasugrel over Clopidogrel for maintenance P2Y12 inhibitor therapy (Class IIa), if not at high risk of bleeding and no prior stroke
ACS# - Post coronary Artery Bypass Grafting (CABG)
P2Y12 inhibitor therapy should be resumed after CABG to complete 12 months of DAPT therapy after ACS (Class I).
Elective Noncardiac Surgery
Delayed 30 days after BMS implantation Delayed 6 months after DES implantation
#ACS include unstable angina (UA), Non-ST elevation myocardial infarction (NSTEMI) or ST elevation myocardial infarction (STEMI); •A new risk score (the “DAPT score”), derived from the Dual Antiplatelet Therapy study, may be useful to decide about prolonged DAPT in patients treated post PCI
40% higher in these patients. Prasugrel can be used in a dose of 5 mg daily).14
Ticagrelor - In the PLATO study15, the two treatment groups did not differ significantly in the rates of CABG-related major bleeding (11.6% and 11.2%). However, there was a higher rate of non–CABGrelated major bleeding.
b.
Adenosine Related Side Effects of Ticagrelor - Ticagrelor is metabolized to adenosine and administration is associated with related effects like of
•
Dyspnea (10%-20%), but led to its withdrawal in only 1% of cases, and
•
Sinus Pauses lasting more than 3 seconds (6%) were noted on holter but were asymptomatic and did not require pacemaker implantation.
ANTI-PLATELET RESISTANCE
Aspirin Resistance: Patients developing recurrent ischemic inspite being on adequate doses of aspirin can be attributed to aspirin resistance, that encompasses a wide variety of factors that contribute to this phenomenon (Figure 3).16 One systematic review of 15 studies revealed a wide range in estimates of the prevalence of laboratory aspirin resistance (5% to 65%). Studies have shown increasing urinary thromboxane levels in aspirin resistance patients and was associated with combined endpoint of MI, stroke and death.
Clopidogrel Resistance
Clopidogrel is a prodrug and requires its conversion to active metabolite through CYP2C19 isoenzyme. Among healthy volunteers, Mega and colleagues129 demonstrated a 30% prevalence of the CYP2C19 allele, a genetic polymorphism that confers loss of function and
CHAPTER 197
After Drug –eluting stent (DES)
908
hence a reduction of the active metabolite of clopidogrel. In retrospective analysis of TRITON-TIMI 38 trial, there was a 54% increase in the risk of the composite endpoint of myocardial infarction, cardiovascular death, or stroke among carriers of at least one CYP2C19 allele over that of noncarriers. Presence of the CYP2C19 allele was also associated with a threefold increase in the risk of stent thrombosis.
CARDIOLOGY
Optimal management of patients with clopidogrel resistance is not known. Ongoing GRAVITAS study may add important information in such patients.
INTRAVENOUS ANTI-PLATELET AGENTS:
Glycoprotein IIB/IIIA antagonists (Table 4)
GpIIb/IIIa is a member of a family of adhesive receptors CELLULAR FACTORS ● Insufficient suppression of COX-1 ● Overexpression of COX-2 mRNA ● Increased norepinephrine ● Generation of i-iso-PGF2α CLINICAL FACTORS ● Failure to prescribe ● Noncompliance ● Nonabsorption ● Interaction with ibuprofen or naproxen
(integrins) composed of α and β transmembrane proteins and an estimated 50,000 to 80,000 GpIIb/IIIa receptors on the surface of each platelet. Platelet activation results in a change in the shape of the receptor, which greatly increases its normal low affinity for fibrinogen and vWF. Two types of GpIIb/IIIa receptor antagonists are available17,18: noncompetitive (monoclonal antibodies) and competitive (a peptide and a peptidomimetic).
Clinical Use
Platelet GpIIb/IIIa antagonist should be used in patients with moderate-to high-risk ACS in whom catheterization and PCI are planned (ACC/AHA guideline - class I, level A).19 Abxicimab has been found to superior to tirofiban and eptifibatide as shown in TARGET, IMACT II and RESTORE trials and it has also been found to superior in diabetic patients and safer in renal failure pateients.20-22
Side Effects
GENETIC POLYMORPHISMS ● COX-1 ● GP IIIa receptor ● Collagen receptor ● vWF receptor Aspirin Resistance
a.
Bleeding – most common site is vascular access site.
b.
Thrombocytopenia – Incidence is 1.1-5.6% and is immune mediated.
EMERGING DEVELOPMENT IN ANTI-PLATELET THERAPY
Protease Activated Receptor 1 (Thrombin receptor) – Compounds have been developed that inhibit the ligandbinding site on PAR-1, which is a G protein–coupled receptor known as protease activated receptor-1 (PAR1) receptor for thrombin. Two compounds which are in development are Atopaxar and Voropaxar which achieve 90% and 80% platelet inhibition respectively.23,24
Fig. 3: Factors contributing to Aspirin Resistance Table 4: Basic Pharmacokinetics of GPIIb/IIIa antagonists Drug
Dosage
Chemistry
Plasma Half Life
Biologic Half Life
Clearance Mechanism
% Inhibition of platelet aggregation
Abxicimab
Bolus: 0.25 mg/kg IV Maintenance: 0.125 mcg/mkg/ min (max 10 mcg/min for 12 hours
Monoclonal antibody
10 min
12-24 hr
Reticuloendothelial system
>80%
Tirofiban
Bolus: 0.25 mcg / kg IV in 5 min Maintenance: 0.15 mcg/kg/min infusion for 18 hours
Peptidomimetic 2 hr
4-8 hr
Renal
>90%
Eptifibatide
Bolus: 180 mcg/ kg IV Maintenance: 2 mcg/kg/min infusion for 72 hours
Polypeptide
4-6 hr
Renal
85% after bolus, >90% during steady state infusion
2.5 hr
REFERENCES
Lars Wallentin: P2Y12 inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. European Heart Journal 2009; 30:1964–1977.
2.
Majerus PW. Arachidonate metabolism in vascular disorders. J Clin Invest 1983; 72:1521-1525
3.
Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353:2373-2383.
4.
Slattery J, Warlow CP, Shorrock CJ, Langman MJ. Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial. Gut 1995; 37:509-511.
5.
6.
Peters RJ, Mehta SR, Fox KA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003; 108:1682-1687. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143:1-13.
7.
Dengler R, Diener HC, Schwartz A, et al; EARLY Investigators. Early treatment with aspirin plus extendedrelease dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010; 9:159-166. Epub 2010 Jan 7.
8.
Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery DiseaseA Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68:1082-1115.
9.
Quinlan DJ, Eikelboom JW, Goodman SG, et al. Implications of variability in definition and reporting of major bleeding in randomized trials of oral P2Y12 inhibitors for acute coronary syndromes. Eur Heart J 2011; 32:2256-2265.
10. The CURE trial investigators. Effects of Clopidogrel in addition to Aspirin in patients with Acute Coronary Syndromes without ST-Segment Elevation. NEJM MED 2001; 345:495-502. August 16, 2001. 11. Stephen D. Wiviott et al. TRITON-TIMI 38 investigators. Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. NEJM 2007; 357:2001-2015. November 15, 2007.
909
13. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119:2553-2560. 14. Alexopoulos D, Xanthopoulou I, Mylona P, et al. Prevalence of contraindications and conditions for precaution for prasugrel administration in a real world acute coronary syndrome population. J Thromb Thrombolysis 2011; 32:328333. 15. Held C, Asenblad N, Bassand JP. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 2011; 57:672-684. 16. Bhatt DL: Aspirin Resistance: More Than Just a Laboratory Curiosity. J Am Coll Cardiol 2004; 43:1127-29. 17. Schneider DJ. Anti-platelet therapy: glycoprotein IIb-IIIa antagonists. Br J Clin Pharmacol 2011; 72:672-682. 18. Amsterdem et al. 2014 AHA/ACC NSTE-ACS guideline. JACC 2014; 64:2645-87. 19. Topol EJ. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. NEJM 2001; 344:1888-94. 20. The IMPACT II investigators. Randomised placebocontrolled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. The Lancet 1997; 349:1422-1428. 21. The RESTORE Investigators. Effects of Platelet Glycoprotein IIb/IIIa Blockade With Tirofiban on Adverse Cardiac Events in Patients With Unstable Angina or Acute Myocardial Infarction Undergoing Coronary Angioplasty. Circulation 1997; 96;1445-53. 22. Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL; J-LANCELOT (Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin) Investigators. Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. 23. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing nonurgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 2009; 373:919-928.
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1.
12. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360:354-362.
C H A P T E R
198
Combined Oral Anticoagulation and Antiplatelet Therapy - Management of a Difficult Situation Jamshed J Dalal
The combination of atrial fibrillation (AF) and coronary artery disease (CAD), is not only an uncommon clinical setting, but also a complex setting associated with significantly higher mortality rates1 that requires doctors to deal with using a combination of anticoagulation (OAC) and antiplatelet therapy. The benefit of the combination has to be balanced with the increased bleeding risk. A common clinical dilemma regarding treatment of patients with AF is the need to use concomitant antiplatelet agents for a variety of reasons including, primary prevention of CAD, or for secondary prevention after a diagnosis of coronary disease, or for maintenance therapy after percutaneous coronary intervention (PCI). In some of these situations, dual antiplatelet therapy may be utilized, for example after an acute myocardial infarction or after PCI. While the combination of OAC and antiplatelet therapy carry the potential of additive benefits, they also carry the danger of increased risk of bleeding.2 Fortunately, we have subgroup data available from the various novel oral anticoagulant (NOAC) trials looking at concomitant antiplatelet use with NOACs. In ARISTOTLE trial, concomitant aspirin was used in around 20–25% of patients with AF treated with an anticoagulant and was associated with a higher risk of bleeding. Similar effects of apixaban, compared with warfarin, on stroke or systemic embolism, major bleeding, or mortality were observed irrespective of concomitant aspirin use. Clopidogrel use was an exclusion criterion at randomization and only started in a small proportion of patients included in the ARISTOTLE trial thus limiting ability to assess the outcomes associated with concomitant apixaban or warfarin and either clopidogrel or dual antiplatelet therapy.3 In RE-LY trial, concomitant antiplatelet use led to a significant rise in the overall risk of major bleeding when dabigatran was combined with any OAC. The risk appeared to increase by 50% with a single antiplatelet, and doubled when dual antiplatelet was used at any time. The relative increase in risk was similar with dabigatran 110mg, 150mg or warfarin.2 In ENGAGE AF‐TIMI 48 trial, the addition of a single antiplatelet drug to an anticoagulant (warfarin or edoxaban) was associated with a significantly greater risk of bleeding. However, the addition of a single drug did not modify the relative efficacy and safety of edoxaban
as compared to warfarin. Notably, when compared to warfarin, both edoxaban regimens resulted in a significant reduction in all forms of bleeding, including intracranial hemorrhage and life‐threatening bleeding, both in patients who were as well as those who were not, receiving a single antiplatelet therapy.4 There is no randomized study comparing vitamin K antagonist (VKA) and NOACs in patients with AF undergoing PCI for acute coronary syndromes (ACS) or for stable CAD, i.e. patients who have an indication to receive single or DAPT.1 There are no large-scale randomized studies published evaluating the newer antiplatelet agents in patients with AF receiving either VKAs or NOACs, adding to the uncertainty on how to use these antithrombotic agents in combination when both CAD (ACS or stable disease) and AF converge in a given patient.1 There are currently three ongoing large-scale outcome studies evaluating combinations of NOAC or VKA and antiplatelets in patients with AF that undergo a PCI with stenting (elective or due to an ACS), providing hope that within the next few years there will be more evidence in this field. 1.
The PIONEER AF PCI study (NCT01830543) evaluates the safety of two different rivaroxaban treatment strategies vs. VKA: (i) 15 mg rivaroxaban OD plus clopidogrel; (ii) 2.5 mg BID plus low-dose aspirin 75–100 mg plus clopidogrel, prasugrel or ticagrelor, followed by rivaroxaban 15 mg OD (or 10 mg for subjects with moderate renal impairment) plus aspirin for 12 months; or (iii) VKA treatment strategy utilizing similar combinations of antiplatelet therapy.
2.
The RE-DUAL PCI study (NCT02164864) evaluates dual antithrombotic therapy regimens of (i) 110 mg dabigatran BID plus clopidogrel or ticagrelor, or (ii) 150 mg dabigatran BID plus clopidogrel or ticagrelor, with (iii) a triple antithrombotic therapy combination of warfarin plus clopidogrel or ticagrelor plus low-dose aspirin for 1–3 months.
3.
The AUGUSTUS trial (NCT02415400), apixaban will be evaluated vs. VKA in AF patients with a recent ACS. All patients will be receiving a P2Y12 inhibitor and will be randomized in a 2 × 2 factorial design to 6 months of apixaban 5 mg BID vs. VKA, and aspirin vs. placebo.
911
CHAPTER 198
Fig. 1: Management of acute coronary syndrome in atrial fibrillation (Dalal et al IHJ; 67, 2015, s13-34) The optimal combination, or duration of combination antithrombotic therapy for AF patients undergoing percutaneous coronary intervention is not known, but the increased bleeding risk suggests all efforts must be made to keep the duration short. Expert consensus, reviewed and reconsidered by the ESC 2016 Guidelines Task Force, suggests the following principles:5 AF patients at risk for stroke, patients with mechanical valves, and patients with recent or recurrent deep vein thrombosis or pulmonary embolism should continue OAC during and after stenting. In general, a short period of triple therapy (OAC, aspirin and clopidogrel) for six weeks to three months only is recommended, especially for those with less thrombotic and high bleeding risk, followed by a period of dual therapy (OAC plus a single antiplatelet) upto one year. For those with less bleeding and high thrombotic profile, triple therapy may be continued for six months and changed to single antiplatelet pus OAC for one year. At the end of one year, antiplatelet therapy may be stopped and only OAC continued. A review of the combination therapy of AF and ACS is shown in Figure 1.7 There is data to show that VKA plus clopidogrel is preferred to VKA plus aspirin to reduce bleeding complications,6 however no data is available whether aspirin or clopidogrel combination is better with NOACs. Newer antiplatelet agents such as prasugrel and ticagrelor are presently not recommended with NOACS or VKAs. When a NOAC is used, the consensus recommendation is that the lowest dose effective for stroke prevention in AF should be considered. Dose reduction beyond the approved dosing tested in phase III trials is not currently recommended,
and awaits assessment in ongoing controlled trials.
ACKNOWLEDGEMENT
Acknowledge thanks to Dr. Arun Kataria, Medical Advisor, Pfizer India, for his assistance in the preparation of this manuscript.
REFERENCES
1.
2. 3. 4.
5.
6.
7.
Heidbuchel H, Verhamme P, Alings M et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with nonvalvular atrial fibrillation. Europace 2015; 17:1467–1507. Dans et al. Concomitant antiplatelet therapy in RE-LY. Circulation 2013; 127:634-640. Alexander JH et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. European Heart Journal 2014; 35:224–232. Xu Haiyan et al. Concomitant Use of Single Antiplatelet Therapy With Edoxaban or Warfarin in Patients With Atrial Fibrillation: Analysis From the ENGAGE AF‐TIMI48 Trial. J Am Heart Assoc 2016; 5:e002587. Kirchof P, Benussi S, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016. doi: 10.1093/eurheartj/ ehw210. Dewilde WJ, Oirbans T, Verheught FW et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381:1107-15. Jamshed Dalal, Abhay Bhave, Abraham Oomman et al. The Indian consensus guidance on stroke prevention in atrial fibrillation: An emphasis on practical use of nonvitamin K oral anticoagulants. Indian Heart Journal 2015; 67:s13–s34.
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How to Prevent and Control the Epidemic of Coronary Artery Disease in Indians Julian Johny Thottian, Binjo Vazhappilly, Mohanan Padinharepurayil
Coronary artery disease (CAD) prevalence in India is ever increasing. There is a 300% increase in the number of cases since 1970-2000. In the next 15 years, India is projected to have more than half of the cases of CAD in the world.1 Demographic profile of CAD in Indians points out that it affects the younger population than other CAD subsets across the world.2 Hence it therefore affects India`s economic growth as the younger section of the society is involved and mainly number of working days are lost.
BURDEN OF CAD
It is the first among top five causes of deaths in Indian population (rural vs. urban, economically backward vs. developed states, men vs. women and at all stages vs. middle age). In 2000, there were nearly 29.8 million people with CAD in India. In 2011, World Health Organisation (WHO) reported the age standardized CAD mortality rates among males and females in India (per 100,000) at 363â&#x20AC;&#x201C;443 and 181â&#x20AC;&#x201C;281, respectively.3
REASONS FOR INCREASED CAD IN INDIA
The potential explanations for the ongoing epidemic of CAD in India include:
such high blood pressure, dyslipidemia, and diabetes. 13.
Genetic predisposition due to Lp (a) excess
Current estimates from epidemiologic studies from various parts of the country indicate a prevalence of CAD to be between 7% and 13% in urban and 2% and 7% in rural populations.4,5 The Global Burden of Diseases Study reported that the disability adjusted life years lost by CAD in India during 1990 was 5.6 million in men and 4.5 million in women; the projected figures for 2020 were 14.4 million and 7.7 million in men and women respectively.
INTERPLAY OF FACTORS
Apolipoproteins: According to INTERHEART study, acute myocardial infarction (AMI) in south Asians occurred at 5 to 10 years earlier than western population; South Asian men encountering AMI were 5.6 year younger than women. This may be due to abnormal ApoB/ApoA1 ratio.6 Asian Indian dyslipidemia is characterised by increased apo-B, triglycerides, Lp(a) and non HDL cholesterol and low levels of HDL and Apo A-1. Among patients with Lp (a) excess, the CAD risk is increased by 3-fold even in the absence of any other risk factors, and by 8-fold in the presence of low HDL cholesterol levels.7
1.
Urbanization of rural areas
2.
Large-scale migration of rural population to urban areas
3.
Dyslipidemia, particularly high non-HDL cholesterol, apo B/apo A ratio and total cholesterol / HDL ratio.
4.
Low HDL cholesterol and small dense dysfunctional HDL
5.
Increase in sedentary lifestyle
6.
Increase in obesity, particularly abdominal obesity.
7.
Increase in metabolic syndrome and diabetes.
8.
Inadequate consumption of fruits and vegetables.
9.
Increased use of atherogenic diet including fried foods, processed foods, fast foods, that are high in calories, saturated fat, and trans fat.
Diabetes: India has one of the largest populations of diabetics (over 32 million) with a projected escalation to 57.2 million in 2025.10 The prevalence of type2 diabetes in urban Indian adults has been reported to have increased from less than 3.0% in 1970 to about 12.0% in 2000. On the basis of recent surveys, the Indian Council of Medical Research (ICMR) estimates the prevalence of diabetes in adults to be 3.8% in rural areas and 11.8% in urban areas.11
10.
Increased consumption of foods -high in glycemic index (high glycemic load).
Hypertension: The count of hypertensives is expected to rise from 118 million in 2000 to 214 million in 2025.12
11.
Tobacco abuse
Smoking: India is the third largest country in the world
12.
Poor awareness and control of CAD risk factors
Asian Indians not only have low levels of protective HDL cholesterol, but they also have a preponderance of small dense dysfunctional HDL-cholesterol particles. The latter are associated with less efficient reverse cholesterol transport and less protection against CAD.8 The level of HDL-2b, the most protective component of HDL cholesterol, is low in over 90% of Asian Indians.9
in both tobacco production and consumption. Of the 1.1 billion smokers worldwide, 182 million live in India.13 Fruits and vegetables: Replacement of a traditional diet rich in fruit and vegetables by a diet rich in calories provided by animal fats and low in complex carbohydrates, is happening in all but the poorest countries. Obesity: Particularly abdominal obesity. Increased waist hip ratio is common in both urban and rural Indians.
Globalization: Increasing openness to ideas, trade, finances and interconnectedness of countries has had both beneficial and detrimental effects to the burden of non-communicable diseases
FUTURE TRENDS
There will be younger age of escalation of CAD. In fact, the prevalence rate among women is likely to keep pace with that of men in all age groups. In case of rural men and women across age groups, it shows an increase in percentage prevalence in both males and females.
ECONOMIC IMPACT
In Western countries where CAD is considered to be a disease of the aged, 23% of CAD deaths occur below 70 years of age while in India 52% of CAD deaths occur below 70 years of age.15 The economic impact was estimated to be 9 billion dollars in national income from premature deaths due to heart disease, stroke, and diabetes in 2005 alone, with projected estimates of 237 billion dollars by 2015.2 The total years of life lost due to cardiovascular disease among the Indian men and women aged 35â&#x20AC;&#x201C;64 has been estimated to be higher than comparable countries such as Brazil and China. These estimates are predicted to increase by 2030, when differences may be even more marked. Thus, India suffers a tremendous loss of productivity due to increased prevalence of CHD. Age standardized CVD death rates in people 30â&#x20AC;&#x201C;69 years old are 180 per 100,000 in Britain, 280 per 100,000 in China, and 405 per 100,000 in India. Also, 50% of CVD related deaths in India occur in people <70 years of age, whereas only 22% of CVD related deaths in Western countries occurs in this age group.16 According to the INTERHEART STUDY, the median age for the first presentation of acute myocardial infarction in South Asian (Bangladesh, India, Nepal, Pakistan, Sri Lanka) is 53 years, whereas that in Western Europe, China
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HOW CAN THIS MATTER BE CURBED!!!
Prevention measures should be initiated at root level. Diabetes , smoking, hypertension should controlled. CAD is seen in much younger Indian population hence strict guidelines and new cut off levels for risk factors should be made. Better support systems and insurance schemes for the young should be initiated. Lifestyle modifications should be explained.
PROPOSALS TO CURB THE RISING INCIDENCE OF CAD
Primordial prevention- Aims at preventing risk factors from developing. Population or public based strategy should be applied. Lifestyle modifications, maintaining ideal body weight, exercises , eating fruits and vegetables, public education and health awareness. Involvement of government and non governmental organisations should be made for this.17 Primary prevention- Primary prevention, also called high-risk prevention, aims at identifying individuals with markedly elevated risk factors (high blood pressure, high cholesterol, or smoking) who have not yet suffered a coronary event, and targeting them for interventions. Encouraging exercises for 3-45 minutes daily for 5-7 days a week is an example.18 Secondary prevention- Most rapid impact on CAD outcome. Those with CAD has a mortality of 5% throughout their lives. Drugs like antiplatelets, statins, beta blockers and ACE inhibitors should be made available freely ensuring uninterrupted supply in both government and private sector. Various support groups organizing classes for public to create awareness and importance of the need for taking medicines should be emphasized.18
CONCLUSION
Herculean task of containing and reversing this epidemic that is affecting the very young working population that India desperately needs at a time of current unprecedented economic boom has to be done. Effective treatments are available, preventive interventions have been identified and their benefits are well-documented in the literature. This has to be instituted at large. Obesity, metabolic syndrome and diabetes are emerging as major risk factors. These risk factors are increasing in prevalence in India. They are highly amenable to clinical intervention through primordial prevention (prevention of risk factors) and primary prevention (treatment of existing risk factors). Barriers to implementation of preventive cardiology are many and include economic constraints, lack of interest by the patient, and lack of skill and/or motivation of the provider. These need to be tackled as well. The first Indo US summit had been organised to tackle these issues.
REFERENCES
1. Enas EA, Yusuf S, Mehta J. Meeting of International
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Socioeconomic status: Studies in India over the past half century have revealed a similar trend towards a progressive reversal of the social gradient for CHD. Although studies conducted from the 1960s to the early 1990 suggested a direct relationship between income and CAD risk, studies conducted in the last decade have reported an inverse relationship between education and/ or income with prevalent or incident CAD.14
and Hong Kong is 63 years with more men than women affected.6
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Working Group on coronary artery disease in South Asians. Indian Heart J 1996; 48:727−732.
individuals of Asian Indian descent: The National Asian Indian Heart Disease Project. Prev Cardiol 2005; 8:81−86.
2. World Health Organization. Preventing Chronic Disease: A Vital Investment World Heath Organization, Geneva 2005
10. Enas EA. Indian diet and cardiovascular disease: an update. In: Chatterjee SS .Update in Cardiology Hyderabad. Cardiology Society of India 2007
3. WHO- Global Atlas on Cardiovascular Disease Prevention and Control 2011.
11. Ramachandran A. Epidemiology of diabetes in India-three decades of research. J Assoc Physicians India 2005; 53:34-38.
4. Gupta AK, Bharadwaj A, Ashotra S, et al. Feasibility and training of multipurpose workers in detection, prevention and control of coronary artery disease in apple-belt of Shimla hills. South Asian J Prev Cardiol 2002; 6:17-22.
12. Reddy KS, Shah B, Varghese C, Ramadoss A. Responding to the challenge of chronic diseases in India. Lancet 2005; 366:1744-1749.
5. Kumar R, Singh MC, Ahlawat SK, et al. Urbanization and coronary heart disease: a study of urban and rural differences in northern India. Indian Heart J 2006; 58:126130. 6. Yusuf S, Hawken S, Ounpuu S, et al. The INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART Study): case control study. Lancet 2004; 364:937-952. 7. Enas EA, Chacko V, Senthilkumar A, Puthumana N, Mohan V. Elevated Lipoprotein(a)—A genetic risk factor for premature vascular disease in people with and without standard risk factors: A Review. Dis Mon 2006; 52:5−50. 8. Joshi P, Islam S, Pais P, et al. Risk factors for early myocardial infarction in South Asians compared with individuals in other countries. JAMA 2007; 297:286−294. 9. Superko HR, Enas EA, Kotha P, Bhat NK, Garrett B. Highdensity lipoprotein subclass distribution in
13. Beaglehole R, Yach D. Globalization and the prevention and control of non-communicable diseases: the neglected chronic diseases of adults. Lancet 2003; 362:903e908. 14. Chadha SL, Radhakrishnan S, Ramachandran K, Kaul U, Gopinath N. Indian J Med Res 1990; 92:423e430. 15. Ghaffar A, Reddy KS, Singhi M. Burden of noncommunicable diseases in South Asia. BMJ 2004; 328:807– 10. 16. Gaziano T, Reddy KS, Paccaud F, Horton S, Chaturvedi V. Cardiovascular Disease-Disease control priorities in developing world, Oxford: Oxford University Press, 2006, p. 645–62. 17. Enas A Enas, Vibhuti Singh, YP Munjal, Suman Bhandari, Ram Dev Yadave, SC Manchanda. Reducing the Burden of Coronary Artery Disease in India: Challenges and Opportunities. Indian Heart J 2008; 60:161–175. 18. Krishnan MN. Coronary heart disease and risk factors in India. On the brink of an epidemic? Indian Heart J 2012; 64:364 -367.
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Noninvasive Testing for Diagnosis of Stable Coronary Artery Disease Srinivasan Narayanan, Ajit Mullasari
INTRODUCTION
Coronary artery disease (CAD) is narrowing of small blood vessels supplying the heart due to plaque build up and can result in angina, damage to cardiac muscle and death. CAD is a leading cause of death in adults over the age of 35 years. Because of its high prevalence timely diagnosis and treatment is crucial. Earlier detection and treatment of patients with known or suspected CAD results in better outcomes and decreased mortality. Apart from clinical history and risk factors noninvasive imaging tests can help in determining the presence, extent and location of coronary atherosclerosis and myocardial ischemia. A wide array of functional as well as as anatomic noninvasive tests including exercise treadmill (TMT), stress echo, Myocardial perfusion imaging modalities like single photon computed tomography (SPECT) & PET, multislice CT angio (MSCT) and stress cardiac MRI(CMR) have shown utility in the diagnosis of CAD. Available tests have advantages and limitations and none can be considered suitable for all the patients. Noninvasive test selection is challenging for many clinicians and a controversial topic for practice guidelines. Current guidelines for imaging stable chest pain of suspected cardiac etiology do not yet incorporate recent randomised trials comparing functional versus anatomical testing strategies. In this review we attempt to discuss the advantages, costs, diagnostic accuracy and appropriateness of each available modality in a stable symptomatic patient with suspected ischemic heart disease and provide a concise approach to non-invasive
Table 1: Diamonds Clinical Classification for Chest Pain Typic angina (definite)
Meets all three of the following characteristics: 1. Substernal chest discomfort of characteristic quality and duration 2. Provoked by exertion or emotional stress 3. Relieved by rest and / or nitrates within minutes
Atypical angina (probable) Meets two of these characteristics Non-anginal chest pain
Lacks or meets only one or none of the characteristics
test selection based on recent guidelines and emerging evidence.
PATIENT SELECTION FOR NON-INVASIVE TESTING
Clinical classification of chest pain
According to symptoms chest pain can be classified as per Diamonds criteria shown below in table 1 as typical, atypical angina and non angina chest pain.
Quantification of “intermediate” pretest probability of Ischemic Heart Disease (IHD) and role in test selection
The history along with age should be used to quantify the pretest probability (PTP) of underlying coronary artery disease and will determine the eligibility for specific noninvasive testing. While there is no strict definition of intermediate pretest probability the ACC/AHA uses the value of 10-90% while the ESC stratifies patients into four groups: <15%,15%–65%, 66%–85% and >85%. Sensitivity - the true positive rate - of most modalities is around or below 85% and specificity - the true negative rate - is approximately or below 85%, thus a key message is that specific non-invasive testing to establish diagnosis of SCAD is only recommended for patients with intermediate clinical likelihood of SCAD (15-85%), but not for individuals with higher PTP >85% or lower PTP <15%. Strong clinical evidence of SCAD with comorbidities and quality of life making revascularization an unlikely option should be put on medical management without need to confirm the diagnosis. Typical angina and depressed left ventricular ejection fraction (LVEF) <50% should prompt direct referral for invasive coronary angiogram (ICA) as part of a more aggressive approach.
FUNCTIONAL TESTING VERSUS ANATOMIC TESTING
Functional Testing
Detection of CAD by assessing the hemodynamic significance of an epicardial coronary artery lesion. Ischemia is based on the principle of imbalance between oxygen demand and supply. Functional tests include exercise treadmill testing (TMT), stress echo, SPECT, PET and CMR. Exercise Tread mill testing (TMT): Is a time honored simple and generally safe and least costly of all the non invasive tests available. It has a higher specificity of 85-90% suggesting a higher efficacy for exclusion rather than confirmation of diagnosis of SCAD. It is a useful test in intermediate PTP between 15-65% in patients
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Table 2: Sensitivities and Specificities of non invasive tests for detection of CAD (Data from ACC/AHA 2012 & ESC 2013 guidelines) ACC/AHA 2012 Specificity
Sensitivity
Specificity
Exercise Treadmill
0.66
0.77
0.45-0.50
0.80-0.90
Exercise or Pharm Echo
0.76
0.88
Exercise Echo
0.80-0.85
0.80-0.88
Pharmacological Echo
0.79-0.83
0.82-0.86
Exercise SPECT
0.73-0.92
0.63-0.87
Pharm SPECT
0.90-0.91
0.75-0.84
Pharm PET
0.81-0.97
0.74-0.91
Dobutamine CMR
0.79-0.88
0.82-0.86
Pharma CMR
0.67-0.94
0.61-0.85
CT Angio
0.95-0.99
0.64-0.93
Exercise or Pharm SPECT
CARDIOLOGY
ESC 2013
Sensitivity
EXER or Pharm Pet
0.88
0.91
with interpretable normal resting ECG without baseline ST-T abnormalities. TMT is absolutely contraindicated in patients with acute myocardial infarction within 2 days, unstable angina, severe symptomatic aortic stenosis, uncontrolled arrhythmias with hemodynamic instability, decompensated heart failure, acute pulmonary embolism/infarction, myocarditis or pericarditis or active endocarditis, acute aortic dissection, acute non-cardiac disorder that may affect exercise performance like infection, renal failure and thyrotoxicosis and inability to get consent. Stress imaging: The addition of imaging to exercise TMT provides incremental benefit for the accurate diagnosis of CAD with an acceptable increase in cost. The diagnostic endpoint of stress imaging is either of LV wall motion abnormalities and endocardial systolic thickening (stress echo, stress CMR) or myocardial perfusion (SPECT, PET, CMR). Pharmacological stress testing using dobutamine or with vasodilator stress agents like adenosine, dipyridamole or selective A2A receptor agonists like regadenoson, binodenoson and apadenoson is preferable over TMT in case of (1) inability to exercise to an adequate level of workload (2) Baseline ECG features like LBBB, ventricular paced rhythm, pre-excitation syndromes, repolarization abnormalities due to LVH and digoxin. Advantages of stress echo include wide availability, relatively low cost and lack of ionizing radiation. Myocardial perfusion scintigraphy using SPECT: Can be done with either Technetium 99m or thallium 201. Reduced regional tracer uptake during stress compared with preserved perfusion at rest is the hallmark of reversible myocardial ischemia on SPECT. Additional markers of significant CAD include transient ischemic dilatation of LV during stress and extensive RWMA. SPECT has better sensitivity whereas stress echo has higher specificity (Table 2). Advantages of SPECT include
0.77
0.82
good quality imaging despite presence of lung disease. In patients with resting ECG abnormalities it is preferable to do vasodilator stress SPECT. Limitations of SPECT include exposure to radiation, long imaging protocol, high costs, artifacts related to respiratory motion, breast tissue and sub-diaphragmatic attenuation. Myocardial perfusion scintigraphy using PET: PET can uniquely quantify blood flow thus allowing diagnosis of microvascular angina. Advantage of PET over SPECT is lower radiation, higher resolution and fewer attenuation artefacts with better image quality even in obese patients. Cardiac Magnetic resonance stress imaging: CMR may detect either ischemia inducedRWMA (dobutamine stress CMR) or myocardial perfusion (vasodilator stress CMR). Advantages of perfusion CMR include lack or radiation, high spatial resolution, ability to perform absolute quantification of perfusion with limited operator dependence and additional information on cardiac structure. However CMR is costly with limited availability and expertise.
ANATOMICAL IMAGING
Invasive angiographic assessment of the lumen is the gold standard for the detection of obstructive disease but is associated with a small risk of complications because of its invasive nature. In properly selected group of patients noninvasive anatomic evaluation of the coronary tree may be a more accurate screening technique than functional imaging. It is also of value when functional testing is non-diagnostic or in certain populations like LBBB where functional imaging may have suboptimal diagnostic performance. Available noninvasive techniques include MSCT angio (CTA) and MR angiography (MRA). Coronary CTA: Has a sensitivity of 95-99% and specificity of 64-83% with the diagnostic performance being higher in patients with lower range of intermediate PTP (15-50%) and is therefore most useful for ruling out(high negative predictive value) rather than conforming the diagnosis.
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Table 3: Advantages and Disadvantages of Cardiac Imaging Modalities Availability Feasibility
Portable Versatility
Stress Echo
Very High
High (limited in obese and COPD) Operator skill dependent
Yes
High (Anatomy & Lv Function)
Medium
1
30-45 Mins
2,500
SPECT
High
High (Limited In Young Women)
No
Medium (LV Function)
High
6-8
2.5-3 Hrs
8,000
PET
Low
High (Limited In Young Women) Flow Quantification
No
Medium (LV Function)
High
2-4
30-45 Mins
10,000
CMR
Low
High (Limited In Claustrophobic Patient) No Ionising Radiation
No
High(Anatomy, LV Function & Valves) Precise Scar Imaging
High
0.5-1
45-60 Mins
10,000
CTA
Medium
High (Limited In Patients with CKD & Arrythmia) Radiation Risk
No
Medium (Anatomy LV Function Valves) Limited Assesment with Extensive Calcium
Medium Low NPV In Higher PTP
0.4-0.7
30 Mins
7,000
Proper patient selection includes non-obese patient with adequate breath holding capacity with heart rate less than 65 in sinus rhythm with Agatson calcium score less than 400 with normal or near normal renal function. Contraindications include renal dysfunction, prior contrast allergy, pregnancy and inability to cooperate The sensitivities and specificities of various available noninvasive tests for the detection of CAD as reported in the ACC/AHA 2012 guidelines and ESC 2013 guidelines is shown in Table 2 below.
GENERAL APPROACH FOR TEST SELECTION
In patients with clinically suspected SCAD following key questions need to be answered to determine patient suitability for non-invasive testing, type of stress (exercise or pharmacological) and functional vs anatomic testing: 1.
What is the clinical pretest probability for SCAD?
2.
Would the patient benefit from revascualrisation? It is more reasonable to optimes medical management
Reproducible
Axial Testing Approx resolution time cost RS in mm mins
in the presence of significant comorbidities or poor QOL. 3.
Can the patient exercise adequately?Does the patient have any contraindiacation to TMT? This would help to decide on pharmacological stress.
4.
Is resting ECG interpretable?
5.
Does the patient have any contraindication to pharmacological stress testing? If the patient is not a candidate for exercise or pharmacological stress testing an anatomical strategy with coronary computed tomography (CTA) should be considered.
The strength and weakness of various imaging modalities is shown in Table 3 below:
CHOOSING THE TEST: WHAT DO THE GUIDELINES SAY?
ACC/AHA 2012 GUIDELINES: ETT for patients with intermediate PTP of IHD and exercise stress with nuclear MPI or echocardiogram for those with intermediate to high PTP of IHD who have uninterpretable ECG (class I). For patients unable to exercise pharmacological
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Test
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stress with nuclear MPI or echocardiography is class I recommendation. The guidelines discourage the use of pharmacological stress with nuclear MPI, echo or CMR for patients who can exercise with an interpretable ECG and low PTP(class III) There are currently no strong class I recommendations for CTA as the initial test.
CARDIOLOGY
CTA can be considered for patients who cannot exercise or for those with prior normal functional test but ongoing symptoms, an inconclusive functional test or unable to undergo stress MPI or echo (class IIa). While no recommendations are made for PTP more than 90% it is reasonable to send such patients for invasive coronary angiogram.
ESC 2013 GUIDELINES
Exercise TMT is class I recommendation as the initial test for patients with suspected CAD and symptoms of angina and intermediate PTP of CAD of 15-65%. Stress imaging (echo, CMR, SPECT or PET) is strongly recommended as initial option if local expertise and availability permit (class I). In patients without typical angina and high PTP 65-80% imaging stress test is recommended as initial test for diagnosing CAD (class I). While there are no recommendations for pharmacological stress test exercise TMT is recommended over pharmacological testing whenever possible (class I ) Similar to ACC guidelines there are no strong recommendations for CTA as initial test. In patients with non-conclusive TMT or stress imaging test or those with contraindications to stress testing with low-intermediate PTP 15-65%. CTA can be considered (class IIa) Class III recommendations include using CTA for patients with prior revascularization and not using as a screening test in asymptomatic individuals.
CONCLUSION
Optimal test selection for the diagnosis of CAD in stable patients with chest pain begins with the history
and physical examination and assessment of pretest probability of CAD using validated tools. Patients who are both and intermediate pretest probability of CAD and who are revascularization candidates should be sent for noninvasive testing. Either a functional or anatomical strategy is reasonable for many patients and the choice of test may be driven by the presence of important patient factors.
REFERENCES
1. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012; 60:e44–164. 2. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34:2949–3003. 3.
Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med 2015; 372:1291–300.
4. Wolk MJ, Bailey SR, Doherty JU, et al ACCF/AHA/ ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2013 multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014; 63:380–406. 5. Fordyce CB, Douglas PS Optimal non invasive imaging test selection for the diagnosis of ischaemic heart disease. Heart 2016; 0:1-10.
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Management Strategies in Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) in India Satyavan Sharma, Nikhil Raut
INTRODUCTION
The clinical spectrum of non-ST elevation acute coronary syndrome (NSTE-ACS) may range from unstable angina to non-ST segment myocardial infarction (NSTEMI). The clinical presentation depends on the severity of coronary stenosis and the degree of thrombus. Unstable angina is defined as myocardial ischemia at rest or on minimal exertion in the absence of cardiomocyte necrosis. These patients have substantially lower risk of death and derive less benefit from intensified antiplatelet therapy as well as early coronary angiography. Those patients who have an acute chest pain and cardiomyocyte necrosis as evidenced by troponin elevation are labelled as NSTEMI. These individuals may present with ongoing ischemia, electrical or hemodynamic instability and require angiography and appropriate revascularization at the earliest.
CHALLENGES IN ACS MANAGEMENT IN INDIA
The management strategies often depend on risk assessment, available facilities and financial constraints. An analysis of data from Indian ACS registries highlight the problems related to accessibility of health care, literacy and economic status on management outcomes. NSTEMI patients are older, have more risk factors and present late. The utilization of evidence based medication is less. The mortality rate was high in regions that faced inadequate access to health care and was 5% and 6% in Himachal Pradesh and North East registry. Inadequate access to health care, difficulty in transportation and poor socioeconomic background are impediments to the care of patients in rural areas. In urban centres, out of pocket expenses remain challenging for patients. All patients presenting to a health care provider with
Table 1: Type of hospitals/ centres treating ACS patients in India Category
Facilities
A
Advanced care with ICCU, catheterization laboratory, IABP, PCI and CABG surgery
B
ICCU with trained staff for thrombolysis, CPR, defibrillation, pacing, etc.
C
ICU with no special cardiac care
D
No ICCU or ICU
Abbreviations: ICCU- Intensive coronary care unit, IABP- Intraaortic balloon pump, ICU- Intensive care unit, CPR- Cardiopulmonary resuscitation. Others as in text.
symptoms suggestive of ACS should be considered as high priority. An arbitrary division is made to categorize the health care facilities available in India for care of ACS patients (Table 1). In big cities, centres with varying degree of sophistication are usually available. On the other hand, in parts of India (especially rural) even the basic facilities are not available. Telemedicine is advancing rapidly in India and networking between the centres can be helpful. The risk stratification at presentation is useful, however it is important to understand that patients who are stable initially, may become a high risk subsequently or vice versa. TIMI risk score is easy to use in day to day clinical practise and can be accessed at www.timi.org. A low TIMI score <3 usually indicates a low risk and a TIMI score >3 indicates intermediate or high risk. Data from western countries suggest that patients with acute chest pain might be better served by transportation to an advanced centre (category A) than by sending them to a less equipped facility (category B, C or D). It is well documented that early invasive therapy (early coronary angiography followed by appropriate revascularization) is preferable in majority of patients. These patients should preferably be admitted to category A hospitals or promptly transferred to such a facility.
MANAGEMENT STRATEGIES
Patients who are awaiting hospitalization should receive non enteric coated aspirin (162-325 mg), 300mg of clopidogrel and 40mg atorvastatin. Nitrates should be used for pain relief. Table 2 summarise recommendations and duration for rhythm monitoring. Fibrinolytic (thrombolytic) therapy and upstream use of
Table 2: Recommended hospital category and duration of cardiac rhythm monitoring in patients after NSTE-ACS diagnosis Clinical presentation
Hospital category
Rhythm monitoring
NSTEMI at low risk for cardiac arrhythmias
A, B
â&#x2030;¤ 24hours
NSTEMI at intermediate or high risk for cardiac arrhythmias
A
> 24 hours
A, B, C
Variable
Unstable angina Abbreviations as in text.
glycoprotein IIb/IIIa agents should not be used as these agents can prove harmful. The management will be discussed as follows: 1.
Anti-ischemic and analgesic therapy: The goal of the anti-ischemic therapy is to decrease myocardial oxygen demand. Oxygen should be administered when oxygen saturation is < 90% or if the patient is in respiratory distress. Opiate administration is reasonable if symptoms persist.
Nitrates: Nitrates are recommended for pain relief. Intravenous nitroglycerin (NTG) is particularly helpful in patients who are unresponsive to sublingual NTG. Nitrates should be used with caution if systolic blood pressure is below 100mm of Hg.
Beta-blockers: Beta blockers are useful for pain relief and reduce myocardial oxygen consumption by multiple mechanisms. Early administration of beta blockers particularly intravenous can precipitate shock and their use should be avoided in unstable patients.
2.
Platelet inhibition: Platelet activation plays a key role in NSTE-ACS and antiplatelet therapy should be administered once the diagnosis is entertained. Aspirin should be administered to all patients unless contraindicated.
P2Y12 inhibitors: The dual antiplatelet regimen includes one of the P2Y12 inhibitors along with aspirin and is used for 1 year following NSTE-ACS.
Clopidogrel (300-600 mg loading and 75 mg maintenance dose) along with aspirin has been shown to reduce recurrent ischemic events as compared to aspirin alone. In patients considered for percutaneous coronary intervention (PCI), a loading dose of 600 mg is advised. In India, clopidogrel remains the most popular P2Y12 inhibitor for use in NSTE ACS treated by conservative or invasive treatment. The drug is cost effective, safe, efficacious and widely available in our country.
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920
Prasugrel (60 mg loading and 10 mg/ day maintenance dose) is a prodrug that irreversibly blocks platelet P2Y12 receptors with a faster onset and a more profound inhibition effect than clopidogrel. The drug is recommended in patients who are proceeding to PCI and loading dose is administered after the coronary anatomy is known.
Ticagrelor (180 mg loading followed by 90 mg twice a day) is an oral, reversibly binding P2Y12 inhibitor with a plasma half life of 6-12 hours. It has a rapid and consistent onset of action as well as faster offset of action with rapid recovery of platelet function.
It is recommended for conservative or interventional treatment. The drug is expensive, needs to be taken twice a day and has side effects including dyspnea.
Cangrelor is an intravenous agent and is currently not available in India.
Glycoprotein IIb/IIIa inhibitors: Intravenous GP IIb/IIIa inhibitors block platelet aggregation and the indications for their use have undergone a major change. In patients treated with newer antiplatelets, GP IIb/IIIa inhibitors should be limited to bail out situations or thrombotic complications during PCI.
3.
Anticoagulation: Anticoagulants are used to inhibit thrombin generation and activity, thereby reducing thrombus related events. There is evidence that anticoagulation is effective in reducing ischemic events in NSTE ACS and that the combination with platelet inhibitors is more effective than either treatment alone.
Unfractionated Heparin (UFH) remains a widely used anticoagulant. In the PCI setting, UFH is given as an intravenous bolus, either under activated clotting time (ACT) guidance or in a weight adjusted manner.
Low molecular weight heparin: Enoxaparin (1mg/ kg twice daily) is a preferred anticoagulant and is a good option in patients treated conservatively or by invasive strategy. It should be administered up to hospital discharge in conservative strategy.
Fondaparinux is a selective factor X a inhibitor that binds reversibly and prevents thrombin formation. It has favourable efficacy-safety profile and is recommended regardless of the management strategy, unless the patient is scheduled for immediate coronary angiography.
Bivalirudin is recomended as an alternative anticoagulant for urgent and elective PCI in moderate or high risk NSTE ACS. It reduces the risk of bleeding as compared with UFH/ LMWH plus GP IIb/IIIa inhibitor.
4.
Other medications: Lipid lowering treatment
It is recommended to initiate high intensity statin therapy as early as possible after admission in all patients.
ACE inhibition: ACE inhibitors are recommended in patients with systolic left ventricular (LV) dysfunction or heart failure. ARBs are indicated in patients who are intolerant of ACE inhibitors.
5.
Invasive coronary angiography and revascularization: Invasive coronary angiography, followed by coronary revascularization is performed in the majority of patients hospitalised with NSTE-ACS. Angiography identifies the culprit lesion and assesses suitability for PCI and coronary artery bypass graft (CABG) surgery.
Routine invasive versus selective invasive approach
A large number of studies and several metaanalysis have shown that a routine invasive
on non-invasive testing. Even if hospital transfer is required, the 72 hour window for coronary angiography should be compiled with.
Table 3: Risk criteria mandating invasive strategy in NSTE-ACS Very-high-risk criteria • Haemodynamic instability or cardiogenic shock • Recurrent or ongoing chest pain refractory to medical treatment
Selective invasive strategy: Patients with no recurrence of symptoms and none of the criteria listed in table 3 are considered at low risk of ischemic events. In these patients, a non-invasive stress test (preferably with imaging) for inducible ischemia is recommended before deciding on an invasive strategy.
Percutaneous coronary revascularization or CABG.
The main difference between management of patients with stable ischemic heart disease and NSTE-ACS is a stronger impetus for early revascularization in those with NSTE-ACS. The PCI of culprit vessel is performed immediately. The non-culprit vessels are treated in same sitting or in a staged fashion. New generation drug eluting stents (DES) are recommended over bare metal stent.
In patients with left main coronary artery (LMCA), complex coronary artery disease (CAD), a heart team approach to revascularization decisions is recommended.
Conservative treatment: Conservative management is continued in low risk patients who have stabilized on medical management and have negative stress test. It is also recommended in patients with non-obstructive CAD or CAD not amenable to revascularization due to severe or diffuse disease.
6.
Long tem therapy: The goals for continued medical therapy after discharge relate to potential prognostic benefits (primarily shown for antiplatelet agents, betablockers, statins and ACEI/ ARB ). Lifestyle changes such as diet, exercise and smoking cessation, are of paramount importance.
• Life-threatening arrhythmias or cardiac arrest • Mechanical complications of MI • Acute heart failure • Recurrent dynamic ST-T wave changes, particularly with intermittent ST-elevation High-Risk criteria • Rise or fall in cardiac troponin compatible with MI • Dynamic ST-or T-wave changes (symptomatic or silent) • GRACE score >140 Intermediate-risk criteria • Diabetes mellitus • Renal insufficiency (eGFR <60 mL/min/1.73 m2) • LVEF <40% or congestive heart failure • Early post-infarction angina • Prior PCI • Prior CABG • GRACE risk score >109 and <140 Low-risk criteria • Any characteristics not mentioned above Abbreviations: eGFR- estimated glomerular filteration rate, GRACE- Global Registry of Acute Coronary Events, LVEF- left ventricular ejection fraction. Other abbreviations as in text. Adapted from Reference 4.
strategy is better to a selective invasive strategy and improves clinical outcomes and reduces recurrent ACS episodes, subsequent rehospitalisation and revascularization.
Table 3 shows the risk criteria for determining the timing of invasive strategy
A.
Immediate invasive strategy (<2 hours): Very high NSTE-ACS patients (i.e with at least one criteria according to Table 3) carry a poor prognosis. As mentioned earlier, these patients should be immediately transferred to centres with PCI capabilities.
B.
Early invasive strategy (<24 hours): Early invasive strategy is defined as coronary angiography performed within 24 hours of hospital admission (table 3). This implies timely transfer for patients admitted to hospital without onsite catheterization facilities.
C.
Invasive strategy (<72 hours): This is the recommended maximal delay for angiography in patients with at least one intermediate risk criterion, recurrent symptoms or known ischemia
CONCLUSION
NSTE-ACS is a leading cause of cardiovascular mortality and morbidity. Management of NSTE-ACS has evolved considerably during the recent years. Pharmacotherapy includes potent antiplatelet agents, a variety of anticoagulants, statins, and other drugs. The major shift is a general acceptance of an early invasive strategy for those patients who display very high, high or intermediate risk criteria. These patients benefit from an early revascularization.
REFERENCES
1.
Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation 2000; 101:2557-67.
2.
Xavier D, Pais P, Devereaux PJ, et al. CREATE registry investigators. Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data. Lancet 2008; 371:1435-42.
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D.
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3.
Negi PC, Merwaha R, Panday D et al. Multicenter HP ACS registry. Indian Heart J 2016; 68:118-27.
4.
Roffi M, Patrono C, Collet JP, et al. Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37:267-315.
5.
Amsterdam EA, Wenger NK, Brindis RG, et al. American College of Cardiology; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association for Clinical Chemistry. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 64:e139 228.
6.
Chatterjee S, Chaudhuri D, Vedanthan R, et al. Early intravenous beta-blockers in patients with acute coronary syndrome- a meta-analysis of randomized trials. Int J Cardiol 2013; 168:915-21.
7.
Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITONTIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376:1312–1319.
8.
Wallentin L, Becker RC, Budaj A, et al, for the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045–1057.
9.
O’Donoghue M, Boden WE, Braunwald E, et al. Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: a meta-analysis. JAMA 2008; 300:71– 80.
10. Amsterdam EA, Kirk JD, Bluemke DA, et al. Testing of lowrisk patients presenting to the emergency department with chest pain: a scientific statement from the American Heart Association. Circulation 2010; 122:1756–1776.
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Management of Stable Ischemic Heart Disease â&#x20AC;&#x201C; Current Perspective
INTRODUCTION
Stable ischemic heart disease (SIHD), stable coronary artery disease and stable angina are loosely and interchangeably terms used in the common day to day clinical practice. While stable angina is the symptomatic form of SIHD, stable coronary artery disease could be present in the asymptomatic form as well symptomatic form. To look from the patho physiological angle SIHD is said to be present when atheromatous plaques could be documented either by the known imaging modalities like coronary angiography, IVUS or CT coronary angiography or physiologic testing viz. stress test or myocardial perfusion scanning. The disease becomes symptomatic when more than 50% luminal diameter is compromised by the plaque. With the progression of disease a phenomenon of remodeling described by Glagov could maintain the luminal diameter that is adequate to maintain the blood flow. That would explain to a large extent asymptomatic form of the disease. There are other factors like recruitment of the collaterals and ischemic preconditioning that could keep the patient asymptomatic despite severe degree of block.. As long as the disease process remains stable, the patient could be minimally symptomatic or experience stable or predictable form of angina on effort. The progression or conversion of the disease to unstable form that could lead to acute coronary syndrome (ACS) or myocardial infarction (MI) is determined by the volume of the lipid score, thickness of the fibrous cap over the plaque and the infiltration of the fibrous cap with microphages and release of matrix metalloproteinases. Such an inflammatory process leads to plaque rupture and acute occlusion of the vessel. Once the inflammation is controlled by appropriate treatment or natural healing over period of weeks or months, the disease can reassume stable form. Thus atherosclerotic disease is dynamic in nature that swings from asymptomatic to stable angina to ACS, MI, and if the patient survives, the disease process can get back into the stable form through the healing process.
Diagnostic testing
While the diagnosis of stable angina is basically arrived at by careful history and presence of the risk factors as per the Framingham risk score charts, the definite diagnosis could be established by either stress testing,
Dev Pahlajani
myocardial perfusion scanning with thallium, sestamibi or dobutamine stress echo. Invasive testing with coronary angiography is not recommended for all individuals with suspected SIHD. However, AHA/ACC guidelines recommend coronary angiography for patients with presumed SIHD who have unacceptable ischemic symptoms despite being on guidelines recommended optimum treatment. It also gives Class IIa indication for those in whom non-invasive testing indicates high probability of severe coronary artery disease or those who cannot undergo diagnostic stress testing.1 In the STAR registry from India, Pahlajani et al2 studied the practice pattern in the private clinics in the management of patients with stable angina. Study enrolled 2079 patients with class I and II (NYHA) angina. They found that diagnostic testing rates were low. Only 12% were underwent stress testing, while 8% had CT or conventional coronary angiography. Practitioners relied heavily on their clinical skills.
MEDICAL TREATMENT
While medical treatment with aspirin, statins, beta blockers and ivabradine has been useful in controlling symptoms and preventing the conversion to ACS, several treatments like chelation therapy has been touted as non-invasive means to treat atherosclerotic vessels. The treatment consists of infusion of disodium ethylenediaminetetraacetic acid (EDTA) along with some other substances. A randomized control trial (RCT) examined the value of chelation therapy in 84 patients with stable angina and positive stress test. Patients on therapy received chelation therapy for 3 hours twice weekly for 15 weeks. There was no difference in the ischemia reduction or improvement in exercise tolerance and quality of life score between the patients allocated to treatment versus those on placebo. National Centre of complimentary and alternate medicine and the National Heart Lung and Blood institution conducted RCT which compared chelation with placebo. The primary composite end point consisted of total mortality, recurrent MI, stroke, coronary revascularization or history of angina. There was no individual end points difference between the groups. The investigators did not recommend routine use of chelation therapy despite some over all modest benefit in diabetic patients. The EDTA therapy is not without side effects and when infused rapidly can cause hypocalcemia, death or stroke.3,4
CARDIOLOGY
924
CORONARY ARTERY REVASCULARIZATION
Recently results of MASS II, BARI 2D and COURAGE5-7 have been published. These randomized control trials were performed to assess the choice of revascularization strategy and value of medical treatment in patients with SIHD. MASS II trial, enrolled and randomized 611 patients to medical treatment, CABG or PCI. At 10 year follow up investigators found no difference in mortality between 3 modalities of treatment. However, there was a trend towards the reduction in the Q wave MI and revascularization in the CABG patients. Trial also showed higher rate of MI in medically treated patients as compared to PCI and CABG. In BARI 2D trial 2368 patients were enrolled. These patients had SIHD with Type 2 diabetes mellitus and concluded that medical treatment is as effective as the revascularization by PCI as well as by CABG. However, the freedom from revascularization was higher in patients who underwent PCI or CABG. In STAR registry most of the patients despite not having undergone additional invasive testing received guideline recommended treatment like statins, beta blockers, nitrates and antiplatelets. In the COURAGE trial optimal medical treatment (OMT) was compared to PCI with OMT. The investigators randomized 1149 patients to PCI followed by OMT and 1138 patients received OMT. The cardiac death rate was 3.8% in the PCI with OMT arm and 3.9% in OMT arm. Cardiac death, MI and stroke was also similar in both the groups. Thus COURAGE trial concluded that PCI with OMT did not provide additional benefit to patients with SIHD as compared to those treated only with OMT. Following the publication of COURAGE trial there was a significant drop in the number of patients who underwent PCI for SIHD.8 Thus most of the patients with SIHD can be managed with optimum medical treatment. PCI or CABG should be reserve for patients who a) have uncontrolled symptoms despite being on medical treatment b) severe angina of class III or lV c) large area of myocardium at jeopardy d) left main coronary artery obstruction or proximal LAD lesion e) patients with MVD and LV dysfunction.
REFERENCES
1.
2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease. J Am Coll Cardiol 2014; 64:1929-1949.
2.
Pahlajani Dev,Kaul Upendra,Mishra Anil,et al :Medical Management and Diagnostic Testing among Stable Angina Patients in India: The Stable Angina observational (STAR) Registry. Journal of Association of Physicians of India 2015; 63:20-26.
3.
Knudtson ML, Wyse DG, Galbraith PD, et al. Chelation therapy for ischemic heart disease: a randomized controlled trial. JAMA 2002; 287:481–6.
4.
Lamas GA, Goertz C, Boineau R, et al Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA 2013; 309:1241–50.
5.
Whady Hueb, Neuza Lopes, Bernard J. Gersh, Paulo R. Soares, Expedito E. Ribeiro, Alexandre C. Pereira, Desiderio Favarato, Antonio Sérgio C. Rocha, Alexandre C. Hueb, Jose A.F. Ramire Ten-Year Follow-Up Survival of the Medicine, Angioplasty, or Surgery Study (MASS II) A Randomized Controlled Clinical Trial of 3 Therapeutic Strategies for Multivessel Coronary Artery Disease. Circulation 2010; 122:949-957.
6.
William E. Boden, M.D., Robert A. O’Rourke, M.D., Koon K. Teo, M.B., B.Ch., Ph.D., Pamela M. Hartigan, Ph.D., David J. Maron, M.D., William J. Kostuk, M.D., Merril Knudtson, M.D., Marcin Dada, M.D., Paul Casperson, Ph.D., Crystal L. Harris, Pharm.D., Bernard R. Chaitman, M.D., Leslee Shaw, Ph.D., Gilbert Gosselin, M.D., Shah Nawaz, M.D., Lawrence M. Title, M.D., Gerald Gau, M.D., Alvin S. Blaustein, M.D., David C. Booth, M.D., Eric R. Bates, M.D., John A. Spertus, M.D., M.P.H., Daniel S. Berman, M.D., G.B. John Mancini, M.D., and William S. Weintraub, M.D., for COURAGE Trial Research Group* Optimal Medical Therapy with or without PCI for Stable Coronary Disease. N Engl J Med 2007; 356:1503-16.
7.
A Randomized Trial of Therapies for Type 2 Diabetes and Coronary Artery Disease : The BARI 2D Study Group. N Engl J Med 2009; 360:2503-2515.
8. Arun V Mohan, Reza Fazel, Pei –Hsiu Huang, Yu Chu Shen, David Howard: Changes in Geographic Variation in the Use of PCI for Stable Ischemic HeaRT Disease after publication of clinical outcomes utilizing Revascularization and aggressive drug evaluation (COURAGE). Circ Cardiovascular Outcomes 2014; 7;125-130.
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STEMI Care in India and the Real World: Role of Thrombolysis HK Chopra
INTRODUCTION
The principal clinical syndromes that result are acute ST elevation myocardial infarction (STEMI), deep vein thrombosis, pulmonary embolism, acute ischemic stroke, acute peripheral arterial occlusion, and occlusion of indwelling catheters. Of these, AMI accounts for maximum number of morbidity and mortality. Over the last century, thrombolytic therapy has gained prominence in the management of STEMI and has helped hundreds of physicians in reanalyzing coronary vessel occlusions. This chapter reviews major milestones in the history of thrombolysis in STEMI.
DEVELOPMENT OF THROMBOLYTIC THERAPY
The discovery of streptokinase
The first thrombolytic, streptokinase was discovered by Dr. William Smith Tillett in 1933 by sheer serendipity. He was Associate Professor of Medicine and Director of the Biological Division at Johns Hopkins University, at that time. He observed that streptococci agglutinated in test tubes that contained human plasma but not in those that contained human serum. He hypothesized that the agglutination of streptococci is caused by fibrinogen in plasma that is deficient in serum. The fibrinogen probably is adsorbed onto the surface of streptococci, rendering the plasma devoid of free fibrinogen. In order to prove his hypothesis, Tillett devised a simple experiment. He took oxalated human plasma containing fibrinogen, which would not clot due to calcium depletion. He added calcium to the control test tubes, and hemolytic streptococci and calcium to the rest of the test tubes,
hoping that the hemolytic streptococci would adsorb the fibrinogen and prevent the formation of a clot. However, the results of this experiment were uniformly negative: there was clot formation in all the tubes, regardless of the presence of streptococci. Dejected with the results of this experiment, he left the tubes in the tray without cleaning. After some time, to his surprise, he found that there was clot lysis in the tubes containing streptococcal cultures. This led him to conclude that the streptococci had synthesized a fibrinolytic agent that was responsible for dissolving the clots (Table 1). This was the probable mechanism for clot lysis, rather than adsorption of fibrinogen as he had earlier presumed. He confirmed these findings on larger scale and on 27 June 1933, Tillett and Garner submitted their findings as ‘Fibrinolytic activity of hemolytic streptococci’. The agent was termed as streptococcal fibrinolysin which was crude and impure, thus could not be used clinically.1,2
Mechanism of action of streptokinase
In 1941, Milstone reported the existence of a substance, normally present in plasma that was required for dissolution of clot. He termed it the “lytic factor.” Christensen and Kaplan independently determined that the lytic factor was a proteolytic enzyme normally present in plasma as an inactive precursor. The streptococcal substance (fibrinolysin) activates the proteinase precursor, converting it to an active enzyme in a manner analogous to the conversion of trypsinogen to trypsin by enterokinase. The active serum proteinase then lyses the fibrin clot. Christensen and MacLeod proposed the term
Table 1: Milestones of Fibrinolysis Research Year
Investigator
Observation
1933
Tillett & Garner
Fibrinolytic principal in hemolytic Streptococcal broth.
1941-1945
Milstone,Tagnon, Christensen
Precursor of plasmin converted by streptococcal agent to active enzyme.
1948-54
Mullertz, Williams, Sobel et al., Lack, Ratnoff et al
Fibrinolytic inhibitors and activators (t-PA, UK, Staphylokinase).
1949
Sol Sherry
Successfully used fibrinous, purulent, and sanguinous pleural exudations, hemothorax, and tuberculous meningitis
1953
Kline , Mullertz
Purification of plasminogen.
1961
Guest & Celander
Urokinase.
1981
Rijken & Collen
Activator purified from melanoma line.
1983
Pennica et al.
Cloning and expression of rt-PA.
1990s
Meta Analysis
Recombinant mutant derivatives of rt-PA.
926
“streptokinase” in 1945 to replace the term fibrinolysin originally applied to the streptococcal component of the system. They further suggested the name “plasminogen” for the inactive form of the serum proteinase and “plasmin” for the active enzyme.2
CARDIOLOGY
The source for streptokinase
Evans reported the discovery of fibrinolytic properties in certain strains of Streptococcus equisimilis.3 Christensen reported that the strain S. equisimilis H46A can act as a commercial source for streptokinase as it does not produce erythrogenic toxins, is less fastidious in its growth requirements than are most other group A strains and could be grown on semi-synthetic media. This was a discovery of immense importance as till date, the commercial streptokinase used for thrombolytic therapy is derived from S. equisimilis (Lancefield Group C).
Human studies on Streptokinase
In late 1949, Tillett and Sherry successfully used streptokinase to treat fibrinous, purulent, and sanguineous pleural exudations, hemothorax, and tuberculous meningitis.4,5 In these studies, streptokinase was associated with few side effects such as a pyrogenic reaction with associated malaise, headache, arthralgia, and occasionally nausea and febrile responses.6 This was probably due to impurities in the existing formulation. Later on, further purification of streptokinase was taken up by Lederle Laboratories. The first report on intravascular thrombolysis in humans came up in 1956 by E. E. Cliffton at the Cornell University Medical College, New York, who used streptokinase in 40 patients with intravascular thrombosis of diverse etiology. His study was associated with non-uniform canalization results and frequent bleeding complications. Despite this fact, he must be credited with the first use of thrombolytic agents for the treatment of pathological thrombi, as well as with the first catheter-directed administration of a thrombolytic agent. In late 1958, Fletcher and associates performed new studies regarding an intravenous approach to the treatment of STEMI patients. Their patients were infused with streptokinase in massive doses and for prolonged periods after MI. Except for the development of a hemorrhagic diathesis in a few patients, there were no significant complications, and the mortality rate was significantly lower in patients who had received streptokinase, in comparison with other treatments. This proved that streptokinase infusion via the intravenous route was a promising therapeutic approach to STEMI.7, 8 After the success of intravascular thrombolysis with streptokinase, Ruegsegger and colleagues successfully dissolved intracoronary clots for the 1st time in various animal models. With serial angiography, they clearly showed dissolution of clots in high proportion of animals. An important finding of this study was that the heart muscle could not be saved from death if more than a few hours passed between clotting and lysis which has now emerged as the concept of golden hour in the management of STEMI. The earlier thrombolysis resulted in smaller area of infarction as compared to controls in this study.9
In spite of the success spurts, the production of streptokinase in US was stopped due to the inefficiency in production of less pyrogenic preparations. It still remained the drug of choice in Europe and Australia for several decades. However, in US the focus was shifted to another thrombolytic molecule, urokinase. Several small scale trials conducted on streptokinase during 1960s and 1970s failed to establish the therapeutic superiority of streptokinase till 1979 when European Cooperative Study Group for Streptokinase Treatment in Acute Myocardial Infarction published its findings from a large scale trial. The trial conducted in 2,388 patients found that the overall mortality rates within 6 months of streptokinase therapy after AMI were significantly lower (P <0.01) in the streptokinase group (15.6%) than in the control group (30.6%).10 In 1980s, several trials demonstrated that use of streptokinase within 1.5 to 3 hours of infarction was associated with high reperfusion rates. Still, these results were not sufficient to establish practice guidelines. Intracoronary use of Streptokinase: Post 1979 intracoronary streptokinase use in few STEMI patients, which are associated with cardiac complication like reperfusion arrhythmis in 80% patients. Despite the more effective clot lysis, intracoronary administration fell to an equal footing with intravenous administration due to the associated side effects. There was no clear protocol design for use of streptokinase in STEMI, but the observation made was that when streptokinase was administered within 1.5 to 3 hours of symtom onset, reperfusion rate as high as 90% were achieved,and with delay in treatment the prognosis worsened. Intravenous streptokinase in evolving STEMI was published for the first time from India in a Pilot Observational Study11. Finally, in 1986, a landmark trial, GISSI (Gruppo Italiano per la Sperimentazione della Streptochinasi nell’Infarto Miocardico) in 11,806 patients in 176 coronary care units dissipitated the confusion. There was a significant difference in mortality rates between the streptokinase group and the non-streptokinase group (controls) at 12 months (17.2% in the streptokinase group vs 19.0% in controls, P=0.008; relative risk, 0.90), especially in the 0–3 and 3–6-hr groups (relative risks, 0.89 and 0.87, respectively). Thus, GISSI succeeded in firmly establishing the efficacy of intravenously administered streptokinase.12 Intravenous Streptokinase in STEMI 6-36 months follow up published in India13. This was followed by many clinical trials to reinforce the benefit of streptokinase. Large multicenter trials like GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), GISSI-2 (Gruppo Italiano per so Studio della Sopravvienza nell’Infarto Miocardico), and ISIS-3 (Third International Study of Infarct Survival Collaborative Group) compared the efficacy of tissue plasminogen activator (t-PA) with that of streptokinase. GUSTO shows no difference in mortality at end of 30 days. 14 GISSI-2 reported similar mortality rates at 6 months, while ISIS-3 found no significant difference in mortality
rates in patients treated with t-PA or streptokinase. The development of antibodies against streptokinase is the major concern for reuse of streptokinase. Although, t-PA has become a popular thrombolytic agent today, Streptokinase continues to be choice of thrombolytic agent in millions suffering from AMI due to the cost benefit.
Urokinase
Tissue-type plasminogen activator: In early 1947 it was reported that Fibrinokinase present in animal tissue can activate plasminogen, many authors tried purification and characterization of plasminogen activators from sources like pig heart, ovaries and human post mortem vascular perfusates. The first highly purified form of t-PA was obtained from uterine tissue (about 1 mg of t-PA from 5 kg tissue). t-PA has been purified from the culture fluid of a stable human melanoma cell line (Bowes, RPMI-7272). D. Pennica (1982) from the Department of Molecular Biology of Genentech Inc. initiated the cloning and expression of the t-PA gene (Sixth Congress on Fibrinolysis in Lausanne, Switzerland). The recombinant t-PA (rt-PA) was shown to be indistinguishable from the natural activator isolated from human melanoma cell culture, with respect to biochemical properties.
Alteplase (tPA and rtPA)
Tissue plasminogen activator (tPA), originally developed in the mid 1980s after molecular cloning techniques were used to express human (tPA) DNA. Alteplase is a naturally occurring fibrinolytic agent produced by endothelial cells and is intimately involved in the balance between intravascular thrombogenesis and thrombolysis. Natural tPA is a single chain (527 amino acid) serine protease, and in contrast to most serine proteases (e.g., urokinase), the single-chain form has significant activity. tPA exhibits significant fibrin specificity. In plasma, the
A predominantly single-chain form of rtPA was eventually approved for the indications of acute MI and massive pulmonary embolism. rtPA has been studied extensively in the setting of coronary occlusion.16 In the GUSTO-I study of 41,000 patients with acute MI; rtPA was more effective than streptokinase in achieving vascular patency. Alteplase demonstrate statistically significant reduction in 30 days mortality compared with streptokinase. Despite a slightly greater risk of intracranial hemorrhage with rtPA, overall mortality was significantly reduced (GUSTO Investigators, 1993). COBALT trial was carried out to test the hypothesis that double dose Alteplase is equivalent to accelerated dose of Alteplase (n=7169). The 30 days mortality was higher in double bolus group than in accelerated group, therefore accelerated Alteplase over period of 90 min remains the preferred choice.Alteplase is approved by FDA in treatment of STEMI (2002), Pulmonary Embolism (2002), and Ischemic Stroke (1996).
Reteplase (rPA)
Reteplase was developed as a third-generation recombinant tissue type plasminogen activator. It consists of only the kringle-2 and protease domain of the t-PA molecule. Reteplase is similar to Alteplase but the modification provides a longer half life (13-16 min). The fibrin affinity of Reteplase is low compared to Alteplase which improves its penetration into the clot. Due to higher penetration inside the thrombi additional fibrinolytic activity is achieved which helps in rapid reperfusion leading to less bleeding episodes. Reteplase was developed with the goal of avoiding the necessity of a continuous intravenous infusion, thereby simplifying ease of administration. Reteplase produced in Escherichia coli cells, is nonglycosylated, demonstrating a lower fibrin-binding activity and a diminished affinity to hepatocytes. This latter property accounts for a longer half-life than rtPA, potentially enabling bolus injection versus prolonged infusion. Reteplase has been studied in several small trials, and its safety and efficacy appear to be similar to alteplase.17 Reteplase was approved by FDA in year 1996 for treatment of STEMI. Several trials have been conducted to prove the efficacy of the Reteplase in management of AMI. GUSTO-III trial compared the double bolus Reteplase against accelerated infusion of Alteplase. The observation proves Reteplase efficacy as equal to accelerated Alteplase. In RAPID- 1, 2 trials the angiography patency was assessed post AMI. The angiography findings shows higher rate of patency and greater TIMI 3 flow with Reteplase than Alteplase. INJECT trial (The International Joint Efficacy Comparison of Thrombolytics) compared the mortality rate following
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CHAPTER 203
The fibrinolytic potential of human urine was first described by Macfarlane and Pilling in 1947. The active molecule was extracted, isolated, and named ‘‘urokinase’’ in 1952. Unlike streptokinase, urokinase directly activates plasminogen to form plasmin; prior binding to plasminogen or plasmin is not necessary for activity. The advantage of urokinase over streptokinase is that it is non-antigenic, preformed antibodies are not observed and the untoward reactions of fever or hypotension are rare. The high molecular weight form of urokinase is isolated from urine while the low molecular weight form is derived from tissue culture of kidney cells. The most commonly employed urokinase has been of tissue-culture origin, manufactured from human neonatal kidney cells. A recombinant form of urokinase (rUK) was tested in a single trial of patients with acute myocardial infarction (MI) and in two multicenter trials of patients with peripheral arterial occlusion. It had a higher molecular weight and a shorter half-life than its low molecularweight counterpart. Despite these differences, however, the clinical effects of the two agents have been quite similar. McNamara and Fischer were the first to describe the use of urokinase for local thrombolytic treatment, using a high-dose protocol featuring graded, stepwise reductions in dose as the infusion progressed.15
agent is associated with little plasminogen activation. At the site of the thrombus, however, the binding of tPA and plasminogen to the fibrin surface induces a conformational change in both molecules, greatly facilitating the conversion of plasminogen to plasmin and dissolution of the clot. tPA also manifests the property of fibrin affinity, that is, it binds strongly to fibrin. Other fibrinolytic agents, such as prourokinase, do not demonstrate fibrin affinity.
928
randomization with Reteplase vs Streptokinase. The mortality rate was lower with Reteplase compared with Streptokinase. Reteplase has longer half life, higher and faster thrombolytic patency than alteplase, lower hemorrhagic risk than alteplase. It is given as a bolus without weight adjustment.
CARDIOLOGY
Tenecteplase (TNK-tPA)
This molecule was bioengineered in an effort to lengthen the duration of bioavailability of tPA. Three regions in kringle-1 and the protease portion of tPA which mediated hepatic clearance, fibrin specificity, and resistance to plasminogen activator inhibitor were identified. These three sites were modified to create TNK-tPA, a novel molecule with a greater half-life and fibrin specificity. The longer half-life of TNK-tPA allowed successful administration as a single bolus, in contrast to the infusion required for rtPA. In addition, TNK-tPA manifests greater fibrin specificity than rtPA, resulting in less fibrinogen depletion. In studies of acute coronary occlusion, TNKtPA performed at least as well as rtPA, concurrent with greater ease of administration.17 It received US FDA approval for the management of acute MI in the year 2000. The first biosimilar tenecteplase (Elaxim) was indigenously developed in India by Gennova Biopharmaceuticals at Pune. Several clinical trials have been conducted to establish efficacy of Tenecteplase. Efficacy for clot lysis of single bolus Tenecteplase was studied in Thrombolysis in Myocardial Infarction (TIMI) 10 A and 10 B trials while safety was assessed in ASSENT 1(Assessment of the Safety of a New Thrombolytic). The results of these studies suggest that body weight adjusted single bolus dose of Tenecteplase is equivalent to 90 min regime of Alteplase. Indigenous tenecteplase has convincing evidence supporting its utility in Indian STEMI patients. In STEPPAMI study, the primary end point occurred in 11.1% in pharmacoinvasive (PI) group and in 3.9% in primary PCI (PPCI) group, p=0.07 (RR=2.87; 95% CI 0.92 to 8.97). The infarct-related artery patency at angiogram was 82.2% in PI group and 22.6% in PPCI group (p<0.001).15 The Indian registry on use of indigenous tenecteplase in 15222 STEMI patients revealed that overall rate for achieving clinically successful thrombolysis (CST) by TNK was 95.43%.18 Pre-hospital Thrombolysis (PHT): PHT plays important role in early and effective management of STEMI. The American Heart Association (AHA) and the American College of Cardiology (ACC) favours the use of prehospital thrombolysis over percutaneous coronary intervention (PCI).20 CAPTIM trial reports that prehospital thrombolysis within 2 hours of symptom onset is superior to PCI.21
Advantages of newer agents over the older agents
Alteplase was found to have a more favorable mortality results than streptokinase in GUSTO study. It had better thrombolytic/fibrinolytic action than urokinase. The disadvantages were higher bleeding risk and lack of resistance to plasminogen activator inhibitor (PAI-1). Reteplase although was more potent than alteplase was associated with higher bleeding risk. The advantage
associated with reteplase was that it could be given in form of bolus injection rather than continuous infusion. With the introduction of tenecteplase, we now have a thrombolytic that can be given as a bolus injection, is more fibrin specific and resistant to plasminogen activator inhibitor.
TRENDS IN THROMBOLYSIS FOR STEMI
Although the first thrombolytic was discovered in 1933. The clinical use of thrombolytics in the management of acute MI was delayed till 1980s. This was due to the controversies in the pathogenesis of MI. It was earlier thought that coronary thrombosis is a consequence rather than cause of myocardial infarction. This confusion was resolved in 1980, when DeWood and his colleagues showed that 87% of patients presenting within 4 hours of acute MI had total coronary occlusion. He showed the angiographic evidence for coronary thrombosis in STEMI patients for the first time and was able to retrieve the thrombus using Fogarty catheter in 88% of these patients. DeWood’s paper led to credence to the concept of endogenous fibrinolysis and ushered the era of fibrinolytics.22 By the end of 1980s, large randomized trials had been conducted in this area. The meta-analysis of these trials suggested that the sooner the thrombolytic given after the onset of chest pain, the greater the survival benefit. This led to the concept of ‘golden hour’ in myocardial thrombolysis which was later lengthened to a period of three hours. The findings of GREAR trial suggested that modest delays in the treatment may be detrimental as myocardial cell death starts within minutes of symptom onset and pre-hospital thrombolysis is effective in saving lives.23 Pre-hospital thrombolysis: Although, primary PCI within first 6 hours of chest pain is suggested as the most preferred therapy for STEMI, it is not feasible in routine clinical settings due to delays in transfer, unavailability of catheterization facility and scarcity of skilled personnel (Kushner et al, 2009). Five year follow-up of a multicentric trial CAPTIM shows that pre-hospital fibrinolysis with immediate transfer for rescue angioplasty if needed is associated with similar mortality as compared to P-PCI if managed within 6 hours of onset of chest pain and prehospital thrombosis improved long term mortality when administered within first 2 hours.20 Major breakthroughs in treatment of STEMI have been summarized in Table 2.
Thrombolytic therapy followed by PCI
Thrombolytic therapy despite its convenience has certain limitations owing to the risk of reocclusion, failure of thrombolysis which can increase the mortality in STEMI patients. Thrombolysis at the site of a ruptured atherosclerotic plaque provides a further nidus for rethrombosis and occlusion. Immediate thrombolysis followed by angioplasty is likely to reduce the chances of reocclusion due to rethrombosis or residual thrombus. This hypothesis led to emergence of pharmacoinvasive therapy that combined the benefits of both thrombolysis and PCI.
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Table 2: Major Breakthroughs in the Treatment of STEMI Author
Treatment
1912
James Herrick
Importance of Rest in MI management
1923
Wearn
Rest, hydric restriction, digitalis use for pulmonary congestion
1928
Parkinson and Bedford
Morphine use to relieve pain, rest for long time
1946 1949 1957 1958 1959
Wright IS Tillett & Sherry Cliffton Fletcher et al. Ruegsegger and colleague
Use of warfarin in treatment of coronary thrombosis with MI Streptokinase use in humans (fibrinous pleural adhesions) Plasmin (fibrinolysin) in human thrombotic disease Streptokinase in patients with acute MI Lysis of artificial clots in man by streptokinase
1959
McLean J.
The discovery of Heparin
1960
Bernard Lown
Intense fluid replacement, use of O2, early mobility
1961
Desmond Julian
Coronary Care Unit
1963,1967
Shumway NE, et al
Heart Transplant
1965 1966
James Black Schmutzler et al
Described Beta blocker Propranolol IV Streptokinase in AMI
1971 1979 1981 1981 1984 1984 1984 1985 1986-88
John Vane Rentrop et al. Schroder et al. Weimar et al. Chazov E, et al Willam Ganz et al Chopra HK et al van de Werf et al. William Ganz et al GISSI, ISIS-2, ASSET, AIMS
Discovery of antiplatelet activity of aspirin Intracoronary and intravenous streptokinase for acute MI t-PA for human thrombosis (deep vein thrombosis) Administration of fibrinolysin in AMI Intravenous streptokinase in evolving acute myocardial infarction Intravenous Streptokinase in AMI Recombinant t-PA in acute MI The Effect of rate of IV STK in AMI Survival benefit with IV streptokinase, rt-PA vs. placebo in acute MI
1988
ISIS-2
Aspirin became mainstay treatment
1988
Pfeffer MA, et al
Development of ACE inhibitors
1988
TIMI trial
Early open artery theory
1988 1990 1993
Sabatine MS, et al, ISIS-2 Chopra HK et al Braunwald E, et al, GUSTO
Anticoagulants to fibrinolytics IV Streptokinase in AMI 6-36 month follow up Thrombolytic trials
1994
Grines CL, et al
Primary PCI
2002 2008
Zhao Z-Q et al NINDS [80], Hacke et al. [83]
Postconditioning Recombinant t-PA in ischemic stroke
2011
Shah VK, et al
Stem cell therapy
2011
Ishikawa K, et al
Gene Therapy
2012
Brodie BR, et al
Aspiration thrombectomy prior to coronary stenting
2012 2013 2014
Soler-Botija C et al Iyengar SS et al Dalal JJ et al
Tissue engineering Pharmacologic reperfusion therapy with TNK in STEMI Consensus Statement of Pharmaco invasive approach in STEMI
2015
Thomas Alexander et al
CSI Forum: Consensus Statement Framework for a National STEMI Program: Consensus document developed by STEMI INDIA, Cardiological Society of India and Association Physicians of India
Facilitated PCI: The initial trials of facilitated PCI (i.e. preceded by thrombolytics) (ASSENT-4 and FINESSE) evaluated the benefits of thrombolysis immediately followed by PCI. However, these were not associated with consistent mortality benefits in all patient groups. Full dose tenecteplase followed by immediate PCI in ASSENT-4 was associated with increased risk of thrombosis. This was probably due to restricted use of
clopidogrel and GpIIb/IIa inhibitors in ASSENT-4 trial. On the other hand, FINESSE trial was associated with increase in the bleeding events as compared to PPCI despite using similar dose of heparin.23 Pharmacoinvasive approach: Multiple trials evaluated the effect of immediate thrombolysis followed by PCI after a gap of 2- 24 hours. This enabled PCI at a later stage with full dose GpIIb/IIIa inhibitors, heparin and antiplatelet
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without increased risk of bleeding. These trials include GRACIA-2, FAST-MI, TRANSFER-AMI and WEST. The largest randomized clinical trial so far, TRANSFER-AMI (n=1059) showed that thrombolysis using tenecteplase, aspirin and LMW heparin followed by PCI within 6 hours was associated with lower ischemic complications as compared to standard thrombolysis followed by rescue PCI if necessary. The other three trials have shown efficacy of pharmacoinvasive strategy as comparable to PPCI. 22 The 1-year results from STREAM confirm that mortality rates were low, and that a PI strategy resulted in a similar mortality as PPCI. The composite end point of death, shock, congestive heart failure, and reinfarction was numerically lower in the PI arm at 30 days. 25 The 5 year survival data from FAST-MI study shows that crude five-year survival rate was 65% in patients without reperfusion therapy, 88% for patients with fibrinolysis and 84% for those with PPCI. Direct comparison of the two reperfusion techniques showed a nonsignificant trend favouring fibrinolytic treatment (HR 0.73, 0.50-1.06; P=0.10).26 Reasons for superiority of Pharmacoinvasive approach: •
Most feasible and effective reperfusion strategy in clinical settings with lack of immediate availability of PCI
•
Immediate thrombolysis in this strategy can be more conveniently achieved now with the availability of newer thrombolytics like Tenecteplase
•
Widens the window between thrombolysis and PCI that allows greater time for transfer of patients to PCI-capable hospitals
•
The time gap between thrombolysis and PCI allows liberal use of GP IIb/IIIa inhibitor, clopidogrel and heparin without inadvertent increased risk of bleeding
Hence, pharmacoinvasive strategy has been recommended more strongly for high risk STEMI patient than non-high risk AMI patient in STEMI guidelines. A scenario not infrequently encountered in our practice is given below. A 45-year-old normotensive and non-diabetic male shopkeeper had chest and upper abdominal pain beginning early in the morning. The pain initially was intermittent and temporarily subsided. Our patient attributed the discomfort to upper gastrointestinal discomfort and he had some home available remedies for gastric discomfort. Four hours later, after reaching his workplace, the pain returned in a severe form and associated with vomiting. He reached out to the local general practitioner, who evaluated him and administered injectable ranitidine and antiemetics. There was temporary improvement and he went back to his office. He applied for leave and reached home. On the way home, he had an episode of fainting and was rushed to the hospital in the nearby town which was 40 km away. He was admitted and evaluated to have extensive ST Elevation anterior wall myocardial infarction (STEMI) with qRBBB. He was thrombolysed with streptokinase
with a window period of 14 hours. He seemed to be stable. Later in the night, the patient developed acute pulmonary edema and required intravenous diuretics, nitroglycerine and morphine. Next day morning the patient was referred to a PCI capable centre, which was 50 km away. He underwent an angiogram that showed an occluded proximal left anterior descending artery and an ejection fraction of 20-25%. He underwent rescue PCI and stenting to proximal LAD with non medicated stent. The procedure was complicated by no flow and hypotension, for which adjunctive pharmacotherapy along with intraaortic balloon pump were used. He remained in CCU for 7 days and was later discharged with an ejection fraction of 20-25%. The patient was discharged on multiple medications. One month after his acute MI, the patient continued to have class III dyspnea with exertion and was unable to return to work. A follow-up echocardiogram demonstrated impaired left ventricular systolic function (EF 25%) with severe apical hypokinesis. He was advised an implantable cardiac defibrillator, which he could not afford. The above scenario is fairly frequently seen by Indian cardiologists even in 2016. The case brings out glaring deficiencies at various levels in STEMI care in India. Individually, we have excellent hospitals, physicians, clinical cardiologists, and cardiac interventionists. Of late we are having good ambulance services, at least in some states. However, we do not have ANY system in place for STEMI care across the country. The world-over dedicated STEMI programs are successfully implemented in many Western countries for nearly three decades. This commentary focuses on the possible systems that may be put in place to improve the acute care of STEMI across India. Most of the improvement in outcomes in Indian patients could be achieved by timely implementation of the proven therapies focusing the time window.
Problems in STEMI care in India Indian ACS patients, for reasons not exactly clear, seem to present with higher percentage of STEMI. They are less likely to receive timely reperfusion therapy, invasive therapy and evidence based medicines 27. The above patient scenario brings forth a few major lacunae in STEMI care that include lack of dedicated STEMI care systems, lack of instantaneously available ECG facility at first point of medical contact, lack of patient awareness, lack of physician readiness, lack of equipped ambulance systems network for patient transport (Emergency Cardiac Services : ECS) and pay from pocket for even Emergency Medical Services (EMS). These are the major reasons for the excess mortality and poorer outcomes seen in Indian patients with STEMI27. In a registry involving 50 cities, only 58·5% of patients with STEMI were thrombolysed mostly with streptokinase and a minority received percutaneous coronary intervention (PCI). The average delay in presentation was > 6 hours. The real situation in most parts of India is likely to lower as these registries have sampled data from tertiary care centres and some of the better developed states. The reported 30-day outcomes for patients with STEMI in the
Create registry were death (8·6%), reinfarction (2·3%), and stroke (0·7%). Mortality benefits of PPCI lost if it is delayed more than 60 minutes as depicted in the Global Registry of Acute Coronary Event 28. Importantly, the poor are marginalized in STEMI care and are less likely to receive thrombolytics, percutaneous coronary intervention and even lipid-lowering drugs. Consequently, the mortality was also higher for poor patients29
In the recently published Indian registry on STEMI consisting of 15,222 patients 722 centres treated with indigenous tenecteplase (TNK) has shown clinically successful thrombolysis in 96.5% of patients in less than three hours, 96% in three to six hours and 85.3% in more than six hours of STEMI37. Pharmaco invasive therapy including early administration of thrombolysis (TNK) followed by PCI within 3-24 hours after initiation of thrombolytic therapy regardless of success of thrombolysis. However in case of thrombolytic failure, a rescue PCI should be instantaneously performed. Timely guided protocol for early thrombolysis with tenecteplase (Grade IA) at the level of physician, non-PCI capable centres/nursing homes with intensive care facility and subsequent access to PCI capable centres improves STEMI outcome38. Such a strategy may be the preferred strategy in India as PPCI possible only in 10% of STEMI patients39.
STEMI care in India: Problems and Solutions
There are significant barriers to effective STEMI care. They are at public awareness level, patient level, hospital/ physician level and at Government and societal levels. Patients often ignore symptoms, self medicate and even when they decide to seek medical attention, they consult non-physicians in India. To overcome these barriers, organized patient education and awareness programs are urgently needed. Cardiological society of India (CSI), Association of physicians of India (API) and the Indian medical association (IMA) should join hands in these awareness programs. Such programs should not only use the traditional methods like public lectures, print materials, but should also focus on television, internet
Another most important barrier is at the level of hospital systems. For a country like India, wherein only less than 10% of STEMI patients receive PCI, primary PCI cannot and will not be the answer for every patient of STEMI. We should rely on thrombolysis, especially bolus agents like Tenecteplase (TNK), and promptly shifting the patients to a PCI capable centre. Considering the efficacy, a strategy of prehospital thrombolysis should be ideally suited for Indian conditions. Considering the diverse Indian conditions, a combination of strategies could be more appropriate. For instance, primary PCI should be the preferred strategy in most of the hospitals, who are already offering 24 x 7 emergency PCI services and the patient can reach the available STEMI Care PPCI capable centres less than 90 min40. In case there is a delay in access to PPCI capable centre due to lack of transfer facility, densely populated cities, traffic congestions etc. Other cities and small district towns would have certified STEMI care physicians and hospitals. These hospitals should do the initial care, thrombolysis with TNK, management of complications and then should have an organized way of early transfer to nearby cities wherein early angiogram and PCI are possible. For rest of rural India, pre-hospital thrombolysis with TNK could be the ideal strategy. For these to become practical, we need to have “Integrated STEMI Care Systems”. We need to have emergency (108) ambulances, equipped with a facility to do an ECG and transmit to a central station, wherein a cardiologist can ascertain STEMI. Upon confirmation of STEMI, the patient should receive aspirin and statin. These ambulances should also have medical and paramedical personnel who can assess sickness, administer a questionnaire to assess the suitability for thrombolysis with TNK. The patient should be taken in the ambulance that has facility to monitor rhythm and defibrillator. Automated algorithms can decide, based on the place, distance to a STEMI hospital or a PCI capable centre, whether to shift for primary PCI or to a hospital for thrombolysis or pre-hospital thrombolysis in the ambulance itself. Accordingly the hospital should be activated and no time should be wasted at the hospital emergency. If prehospital thrombolysis is decided, the patient or relative may talk to a centrally stationed cardiologist and the medical personnel get a consent and administer the agent under cardiac monitoring inside the ambulance, while the patient is being shifted to a nearby hospital. The above ambitious plan could only work if there is governmental participation and the STEMI care is integrated to the existing emergency care systems in India. The government should make emergency STEMI treatment at subsidized cost to all Indians, may be through medical insurance schemes. The Government should identify STEMI care centres in each city, district and rural areas and certify them. The information on the list of PCI
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In the Italian Registry of TNK in STEMI of 27,000 patients30. It has been shown the thrombolysis with TNK is easily n, accessible, and available everywhere. Door to balloon time in PPCI exceeds 90 minutes practically. Then, PPCI does not reduce mortality consistently. Rapid diagnosis and early reperfusion are pillars of success in STEMI Care. TNK is Class 1A recommendation for STEMI ACCP Guideline31 and is recommended in Pre- Hospital Thrombolysis Protocol (Vienna STEMI Registry32 The Mayo Clinic STEMI Protocol33 and The French FAST-MI registry34). The potential of TNK cannot be overemphasized. It is given a bolus dose with no hypertension, no allergic reactions, longer half life, high fibrin specificity and simplified weight adjusted dose, with mostly very minor manageable bleeding. It is an agent of first choice for pre-hospital thrombolysis in STEMI. It has been shown in one of the study that only 4% of transferred patients received PPCI within 90 Min.35 Pre-hospital thrombolysis is the strongest independent predictor of in-hospital survivor in UK36.
and social media. The public should be educated that for anyone beyond their teens, an ECG is a must for acute pain or discomfort from jaw to umbilicus including upper limbs. Public should be educated about the significance of time, seeking immediate medical attention and timely reaching the ‘right’ hospital or physician for STEMI care.
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capable and other STEMI care centres should be widely and easily available. Government should also ensure the availability of thrombolytic, especially bolus agents like TNK at subsidized cost to the poor. Recently published STREAM Trial 2014 with 1 year mortality follow up data has shown that PPCI less than 60 minutes is not practical in most of the STEMI patients, thus, TNK followed by PCI in 24 Hours is strongly recommended protocol40 Therefore, Golden time window intervention of < 2 hours is most powerful predictor of salvaging jeopardized myocardium in STEMI and significantly reduce STEMI inflicted morbidity and mortality. If TNK is given in <60 minutes, it may reduce infarct size from larger to smaller, transmural to subendocardial or may even abort MI, thus help improving subsequent PCI outcome by reducing thrombus burden and better TIMI flow. Time delay > 90 minutes reduce the benefit of PPCI. Thus the objective of Integrated TIMI Care is to minimize time from chest discomfort to ECG < 30 minutes ((FMC), ECG to drug intervention <60 minutes, drug intervention to PCI < 90-120 minutes will definitely have STEMI inflicted morbidity and mortality benefit in our country to create global impact. We must act locally to impact globally.
Future Directions for STEMI Programme in India
CSI Forum: Consensus Statement: Framework for a National STEMI Program: Consensus document developed by STEMI INDIA, Cardiological Society of India and Association Physicians of India41: Addressing some of these issues, STEMI India, a not-for-profit organization, Cardiological Society of India (CSI) and Association Physicians of India (API) have developed a protocol of “systems of care” for efficient management of STEMI, with integrated networks of facilities. Leveraging newly-developed ambulance and emergency medical services, incorporating recent state insurance schemes for vulnerable populations to broaden access, and combining innovative, “state-of-the-art” information technology platforms with existing hospital infrastructure, are the crucial aspects of this system. A pilot program was successfully employed in the state of Tamilnadu. The purpose of this statement is to describe the framework and methods associated with this programme with an aim to improve delivery of reperfusion therapy for STEMI in India. This programme can serve as model STEMI systems of care for other low-and-middle income countries.
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10. Streptokinase in acute myocardial infarction. European Cooperative Study Group for Streptokinase Treatment in Acute Myocardial Infarction. N Engl J Med 1979; 301:797802. 11. K L Chopra, H K Chopra, K K Aggarwal, S K Parashar et al. Intravenous streptokinase and oral nifedipine in evolving myocardial infarction--a pilot study. Indian Heart J 1984; 36:347-51 12. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Lancet 1986;1:397-402. 13. Chopra KL, Chopra HK, Aggarwal KK. Et al. IV stk in AMI. 6-36 months follow up HK Chopra, Indian Heart Journal, Indian Heart J 1990; 42:13-25. 14. The GUSTO Investigators. An international randomized trial comparing four thrombolytic therapies for acute myocardial infarction. N Engl J Med 1993; 329:673-682. 15. Ouriel K. A history of thrombolytic therapy. J Endocvascular Ther 2004; 11:128-133. 16. Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A dose-ranging trial. Circulation 1997; 95:351-356. 17. Victor SM, Subban V, Alexander T, G BC, Srinivas A, S S. A prospective, observational, multicentre study comparing tenecteplase facilitated PCI versus primary PCI in Indian patients with STEMI (STEPP-AMI). Open Heart 2014; 1:e000133. 18. Iyengar SS, Nair T, Hiremath JS, Jadhav U, Katyal VK, Kumbla D, et al. Pharmacologic Reperfusion Therapy with Indigenous Tenecteplase in 15,222 patients with ST Elevation Myocardial Infarction - The Indian Registry. Indian Heart J 2013; 65:436-41. 19. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al; CF/AHA Task Force. 2013 ACCF/ AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127:529-55. 20. Bonnefoy E, Steg PG, Boutitie F, Dubien PY, Lapostolle F, Roncalli J, Et al. Comparison of primary angioplasty and pre-hospital fibrinolysis in acute myocardial infarction (CAPTIM) trial: a 5-year follow-up. European Heart Journal 2009; 30:1598-1606.
21. Maroo A, Topol EJ. The early history and development of thrombolysis in acute myocardial infarction. J Thromb Haemost 2004; 2:1867–70. 22. Gray D. Thrombolysis: Past, present and future. Postgraduate Med J 2006; 82:372-375. 23. Hanna EB, et al. The evolving role of glycoprotein IIb/ IIIa inhibitors in the setting of percutaneous coronary intervention strategies to minimize bleeding risk and optimize outcomes. JACC Cardiovasc Interv 2010; 3:1209-19. 24. Cantor WJ. Routine early angioplasty after fibrinolysis for acute myocardial infarction. N Engl J Med 2009 25; 360:270518.
26. Danchin N, Coste R, Ferrières J, Steg P, Cottin Y, Blanchard D, et al. Comparison of Thrombolysis Followed by Broad Use of Percutaneous Intervention With Primary Percutaneous Coronary Intervention for Myocardial Infarction (FASTMI) ST-Segment Elevation Acute Myocardial Infarction: Data From the French Coronary Registry on Acute STElevation (FAST-MI). Circulation 2008; 118;268-276. 27. Xavier D, Pais P, Devereaux PJ, Xie C, Prabhakaran D, Reddy KS, Gupta R, Joshi P, Kerkar P, Thanikachalam S, Haridas KK, Jaison TM, Naik S, Maity AK, Yusuf S; CREATE registry investigators. Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data, Lancet 2008; 371:143542. 28. Nallamothu B, Fox KA, Kennelly BM, Van de Werf F, Gore JM, StegPG, Granger CB, Dabbous OH, Kline-Rogers E, Eagle KA; GRACE Investigators. Relationship of treatment delays and mortality in patients undergoing fibrinolysis and primary percutaneous coronary intervention.The Global Registry of Acute Coronary Events. Heart 2007; 93:1552-1555. 29. Mehta Sameer. et al STEMI Interventions - Future Perspectives, Excerpt from: Chapter 19, Cath Lab Digest Volume 16 - Issue 2- February, 2008. 30. G. Melandri et al Italy Review of tenecteplase (TNKase) in the treatment of acute myocardial infarction Vascular Health and Risk Management 2009; 5:249-256. 31. Jack Hirsh, MD, FCCP, Chair; Gordon Guyatt, MD, FCCP; Gregory W. Albers, MD; Robert Harrington, MD, FCCP; Holger J. Schünemann, MD, PhD, FCCP Antithrombotic and Thrombolytic Therapy*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition), Chest 2008; 133:110S-112. 32. Kalla K1, Christ G, Karnik R, Malzer R, Norman G, Prachar H, Schreiber W, Unger G, Glogar HD, Kaff A, Laggner AN, Maurer G, Mlczoch J, Slany J, Weber HS, Huber K; Vienna STEMI Registry Group.Implementation of guidelines improves the standard of care: the Viennese registry on reperfusion strategies in ST-elevation myocardial infarction (Vienna STEMI registry). Circulation 2006; 113:2398-405. Epub 2006 May 15.
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34. Cambou JP1, Simon T, Mulak G, Bataille V, Danchin N.The French registry of Acute ST elevation or non-ST-elevation Myocardial Infarction (FAST-MI): study design and baseline characteristics. Arch Mal Coeur Vaiss 2007; 100:52434. 35. Nallamothu BK, Bates ER, Herrin J, Wang Y, Bradley EH, Krumholz HM. Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis. Circulation 2005; 111:761767. 7. Jollis JG, Roettig. 36. Gale CP, Manda SOM, Batin PD, Weston CF, Birkhead JS, Hall AS. Predictors of in-hospital mortality for patients admitted with ST-elevation myocardial infarction: a realworld study using the Myocardial Infarction National Audit Project (MINAP) database. Heart 2008; 94:1407-1412. 37. Iyengar SS, Nair T, Hiremath JS, Jadhav U, Katyal VK, Kumbla D, I. Sathyamurthy, R.K. Jain, M. Srinivasan et al. Pharmacologic reperfusion therapy with indigenous tenecteplase in 15,222 patients with ST elevation myocardial infarction - the Indian Registry. Indian Heart J 2013; 65:43641. 38. JJ Dalal,T Alexander,V.Dayasagar, S.S. Yengar, P.G. Kerkar, A. Mullasari, SP Sathe, G.S. Wander et al. 2013 Consensus Statement for Early Reperfusion and Pharmaco-Invasive approach in patients presenting with Chest pain Diagnosed as STEMI (ST Elevation Myocardial Infarction) in an Indian Setting JAPI Vol 62.June 2014. 39. Mehta Sameer, Oliveros E, Reynbakh O, Kostela J, Ossa MM, Zhang T, Botelho R, Rodriguez D, Botero M, Thomas J, Para D et al Thrombolytic Therapy in STEMI Interventions, CSI Cardiology Update 2014. 40. Peter R. Sinnaeve, Paul W. Armstrong, Anthony H. Gershlick,Patrick Goldstein, Robert Wilcox, Yves Lambert, Thierry Danays, ;Louis Soulat, Sigrun Halvorsen, Fernando Rosell Ortiz, Katleen Vandenberghe, Anne Regelin, Erich Bluhmki, Kris Bogaerts, Frans Van de Werf for the STREAM investigators ST–Segment-Elevation Myocardial Infarction Patients Randomized to a Pharmaco-Invasive Strategy or Primary Percutaneous Coronary Intervention Strategic Reperfusion Early After Myocardial Infarction (STREAM) 1-Year Mortality Follow-Up Circulation 2014; 130:1139-1145 41. Thomas Alexandera, Ajit S. Mullasari, Zuzana Kaifoszova, Umesh N. Khot, Brahmajee Nallamothu, Rao G.V. Ramana, Meenakshi Sharma, Kala Subramaniam, Ganesh Veerasekar, Suma M. Victor, Kiran Chand, P.K. Deb, K. Venugopal, H.K. Chopra, Santanu Guha, Amal Kumar Banerjee, A. Muruganathan Armugam, Manotosh Panja, Gurpreet Singh Wander, CSI Forum: Consensus Statement Framework for a National STEMI Program: Consensus document developed by STEMI INDIA, Cardiological Society of India and Association Physicians of India Indian Heart Journal 2015; 67:497–502
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Risk Stratification and Management Algorithm of NSTEMI
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Lekha Pathak, Ankur Jhavar
INTRODUCTION
A diagnosis of Non ST-segment elevation myocardial infarction (NSTEMI) can be made when the ischemia is sufficiently severe to cause myocardial damage that results in the release of a biomarker of myocardial necrosis into the circulation. In contrast, the patient is considered to have experienced Unstable Angina (UA) if no such biomarker can be detected in the bloodstream hours after the initial onset of ischemic chest pain. Unstable angina exhibits 1 or more of 3 principal presentations: (1) rest angina (usually lasting >20 minutes), (2) new-onset (<2 months previously) severe angina, and (3) a crescendo pattern of occurrence (increasing in intensity, duration, frequency, or any combination of these factors).1 Roughly two-thirds of patients with MI have NSTEMI; the rest have STEMI (Figure 1).2 Given the similarity in clinical presentation and the difficulty in distinguishing the 2 syndromes, the new guidelines favor the term non–ST-segment elevation acute coronary syndromes (NSTE-ACS) instead of UA or non–ST-segment elevation myocardial infarction.
Table 1: Risk Factors4 Major risk factors
Minor risk factors
High serum cholesterol level
Increasing age
Hypertension
Male gender
Diabetes mellitus
Family history
Cigarette smoking
Physical inactivity
PATHOPHYSIOLOGY4 (TABLE 1)
NSTEMI usually occurs by developing a partial occlusion of a major coronary artery or a complete occlusion of a minor coronary artery previously affected by atherosclerosis. The deposited cholesterol ultimately forms a plaque called atherosclerotic plaque.The most common mechanism of NSTEMI is rupture or erosion of an atherosclerotic plaque that triggers platelet aggregation, which leads to formation of a thrombus (blood clot) in a coronary artery (Figure 2).
CLINICAL PRESENTATION
History and Physical Examination Findings
Often located in the substernal region (sometimes the epigastric area), the chest pain or pressure frequently radiates to the neck, jaw, left shoulder, and left arm. Some patients may present with “anginal equivalent” symptoms include dyspnea, nausea and vomiting, diaphoresis, and unexplained fatigue.4 The 5 most important historyrelated factors that help identify ischemia due to CAD, ranked in order of importance, are the nature of the anginal symptoms (Table 2), a history of CAD, male sex, older age, and the number of traditional risk factors present.(8,9)
Electrocardiography
The ACC/AHA guidelines state that an experienced emergency physician should review the results of 12-lead ECG within no more than 10 minutes after the arrival in the ED of a patient with chest discomfort or other symptoms suggestive of ACS (Figure 3).3
Obesity Excess alcohol consumption Excess carbohydrates intake Social deprivation Diets deficient in fresh vegetables, fruit and polyunsaturated fatty acids Competitive and stressful lifestyle with type A personality
Fig. 1: Spectrum of Acute Coronary Syndromes
935
Thrombus (blood clot) within coronary artery Affected area of the heart by nstemi
Fig. 2: Partial thickness damage of heart muscle in NSTEMI(7)
ST-segment depression in nstemi
Fig. 3
T-wave inversion in nstemi
Findings on ECG associated with NSTEMI include STsegment depression, transient ST-segment elevation, T-wave inversion, or some combination of these factors; depending on the severity of the clinical presentation, these findings are present in 30% to 50% of patients.8,9 New ST-segment deviation, even of only 0.05 mV, is an important and specific measure of ischemia and prognosis.(11-13)
Cardiac Biomarkers of Necrosis
The advantages and disadvantages of the various biomarkers are shown in Table 3, and the timing of their release after acute MI is shown in Figure 3.
Early Risk Stratification
The management of patients with NSTE-ACS requires continuous risk stratification. Important prognostic information is derived from initial assessment, the patient’s course during the early days of management, and the response to anti-ischemic and antithrombotic therapy. The choice of stress test is based on the patient’s resting ECG and ability to exercise, local expertise, and available technologies. The exercise intensity of the treadmilltest (low level or symptom-limited) is used at the discretion of the attending clinician based on individual patient assessment. For invasively managed patients with residual nonculprit lesions, additional evaluation may be indicated to ascertain the significance of such lesions.
Noninvasive Test Selection
The goals of noninvasive testing in patients with a low or intermediate likelihood of CAD and high-risk patients
who did not have an early invasive strategy are to detect ischemia and estimate prognosis. Because of its simplicity, lower cost, and widespread familiarity with its performance and interpretation, the standard lowlevel exercise electrocardiographic stress test remains the most reasonable test in patients who are able to exercise and who have a resting ECG that is interpretable for ST shifts. There is evidence that imaging studies are superior to exercise electrocardiographic evaluation in women for diagnosis of CAD. Patients with an electrocardiographic pattern that would interfere with interpretation of the ST segment (baseline ST abnormalities, bundle-branch block, LV hypertrophy with ST-T changes, intraventricular conduction defect, paced rhythm, pre-excitation, and digoxin) should have an exercise test with imaging. Patients who are unable to exercise should have a pharmacological stress test with imaging.
Selection for Coronary Angiography
In contrast to noninvasive tests, coronary angiography provides detailed structural information for assessment of prognosis and appropriate management. When combined with LV angiography, it also provides an assessment of global and regional LV function. Coronary angiography is usually indicated in patients with NSTE-ACS who have recurrent symptoms or ischemia despite adequate medical therapy or who are at high risk as categorized by clinical findings (HF, serious ventricular arrhythmias), noninvasive test findings (significant LV dysfunction with EF<40, large anterior or multiple perfusion defects or wall motion abnormalities on echocardiography, high-risk Duke treadmill score ≤−11), high-risk TIMI or GRACE scores, or markedly elevated troponin levels. Patients with NSTE-ACS who have had previous PCI or CABG also should be considered for early coronary angiography, unless prior coronary angiography data indicate that no further revascularization is feasible. Before giving revascularization treatment, risk analysis
CHAPTER 204
Partial thickness damage of heart muscle in nstemi
CARDIOLOGY
936
Table 2: Likelihood that Signs and Symptoms Indicate an ACS Secondary to CAD Feature
High likelihood Any of the following
Intermediate likelihood Low likelihood Absence of high Absence of high-likelihood or intermediate-likelihood features features and presence of any of the but may have following
History
Chest or left arm pain or discomfort as chief symptom reproducing previously documented angina Known history of CAD. including Ml
Chest or left arm pain or discomfort as chief symptom Age ≥70 y Male sex Diabetes mellitus
Probable ischemic symptoms in absence of any of the intermediate-likelihood characteristics Recent cocaine use
Examination
Transient MR murmur, hypotension. diaphoresis, pulmonary edema, or rales
Extracardiac vascular disease
Chest discomfort reproduced by palpation
ECG
New, or presumably new, Fixed Q waves transient ST-segment deviation ST depression of 0.5-1.0 mm or (≥1 mm) or T-wave inversion T-wave inversion >1.0 mm in multiple precordial leads
T-wave flattening or inversion <1 mm in leads with dominant R waves Normal ECG tracing
Cardiac markers
Elevated cardiac Tnl, TnT, or CK-MB levels
Normal
Normal
ACS = acute coronary syndrome: CAD = coronary artery disease; CK-MB = muscle and brain fraction of creatine kinase; ECG= electrocardiography: Ml = myocardial infarction: MR = mitral regurgitation: Tnl = troponin 1: TnT = troponin T. Adapted from Agency for Health Care Policy and Research Clinical Practice Guidelines No. 10.45 in patients with NSTEMI should be done immediately after hospital admission. Several systems are available for risk stratification, but TIMI score and GRACE score are the best. These systems categorized the patients into low, medium and high risk groups.
combination of common therapies, including oxygen as needed, antianginal, antiplatelets and anticoagulants are initiated.
Oxygen
Medium to high risk patients should be considered for early coronary angiography and revascularization, either by PCI (percutaneous coronary intervention) or by CABG (coronary artery bypass grafting). Early medical treatment is appropriate in low risk patients, and coronary angiography and revascularization are reserved for those who fail to settle with medical treatment.
The role for routine O2 is much less clear than it was. O2 is a vasoconstrictor and as such may have detrimental effects Supplemental oxygen is indicated for patients who are hypoxic or at risk of hypoxia. For other patients a short period of O2 supplementation is reasonable during stabilisation. Unless the patient is in respiratory distress, has O2 saturation < 90% or high risk features of hypoxemia, oxygen is not indicated.2
Timi Score (Table 5)
Anti-anginals
The Thrombolysis in Myocardial Infarction (TIMI) Score is used to determine the likelihood of ischemic events or mortality in patients with unstable angina or non–STsegment elevation myocardial infarction (NSTEMI)
Grace Score (Table 6)
GRACE (Global Registry of Acute Coronary Events) score is used for risk assessment in ACS (acute coronary syndrome) which includes NSTEMI, STEMI and UA. This score is more accurate because it is derived from a multinational registry of unselected patients and includes hospitals in Europe, Asia, North America, South America, Australia and New Zealand. Risk assessment should be performed at the time of hospital admission and is important because it gives an idea about probability of in-hospital death and also guides the appropriate treatment plan in nstemi and unstable angina.
Management of NSTEMI
Once the patient is diagnosed with NSTE-ACS, a
Patients with ischemic chest pain and without contraindications to nitroglycerin should continue to get nitroglycerin for up to 3 doses. After 3 doses, IV Nitroglycerinis indicated, especially in the presence of 1) persistent chest pain, 2) hypertension and 3) heart failure.2 Relief of chest pain with nitroglycerin was seen in 35% of patients with NSTE-ACS compared with 41% without NSTE-ACS.10Therefore, resolution of pain with nitroglycerine is neither sensitive nor specific in the diagnosis ACS.
Morphine
One study has suggested an increased mortality associated with morphine use in NSTEMI patients. There were significant problems with this trial and further study needed; in the meantime the use of morphine has been downgraded from a class 1 to a class 2a recommendation. ie. may be useful.
Table 3: Biochemical Cardiac Markers for the Evaluation and Management of Patients with Suspected ACS but without ST Segment Elevation on 12-Lead ECG Advantages
Disadvantages
POC test Comment
Cardiac troponins
Yes 1. Powerful tool for 1. Low sensitivity risk stratification in very early phase of MI (<6 2. Greater h after symptom sensitivity and onset) and specificity than requires repeated CK-MB measurement at 8 3. Detection of to 1 2 h, if results recent Ml up to 2 are negative wk after onset 2. Limited ability to 4. Useful for detect late minor selection of reinfarction therapy
Data on diagnostic performance and potential therapeutic implications increasingly available from clinical trials
Useful as a single test for efficiently diagnosing NSTEMI (including minor myocardial damage), with serial measurements
Familiar to most clinicians
Previous standard and still acceptable diagnostic test in most clinical circumstances
5. Detection of reperfusion CK-MB
1. Rapid, cost1. Loss of specificity Yes efficient, accurate in setting of assays skeletal muscle disease or 2. Ability to detect injury, including early reinfarction surgery
Clinical recommendations
Clinicians should familiarize themselves with diagnostic â&#x20AC;&#x153;cutoffsâ&#x20AC;? used in their local hospital laboratory
2. Low sensitivity during very early Ml (<6 h after symptom onset) or later after symptom onset (>36 h> and for minor myocardial damage (detectable with troponins) Myoglobin
1. High sensitivity 2. Useful in early detection of Ml 3. Detection of reperfusion 4. Most useful in ruling out Ml
Yes 1. Very- low specificity in setting of skeletal muscle injury or disease 2. Rapid return to normal range limits sensitivity for later presentations
More convenient early marker than CK-MB isoforms because of greater availability of assays for myoglobin; rapid-release kinetics make myoglobin useful for noninvasive monitoring of reperfusion in patients with established Ml
ACS= acute coronary syndrome: CK-MB = muscle and brain fraction of creatine kinase; ECG = electrocardiography; Ml = myocardial infarction: NSTEMI = non-ST-segment elevation Ml: POC = point-of-care. From J.Am Coll Cardiol.42 with permission from Elsevier.
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Marker
937
938
Nitrates
CARDIOLOGY
Nitrates are routinely used to control Pain, CHF and Hypertension. Initially sublingually and then topically, orally or intravenously.needed. IV nitrates should be started at 10 mcg / min (= 6ml/hr of 25mg GTN in 250ml dextrose and titrated every 5 minutes according to symptoms and BP. Using ceiling dose is 600mcg/min
(=120ml per hour). SBP should not be allowed to fall rapidly or below 100mmHg It is advisable to change to an interrupted regime (oral/ topical) within 24 to 48 hrs if possible, in order to avoid tachyphylaxis.
Beta Blockers
Aggressive beta blockade is now less favoured than it was in the management of UA/NSTEMI patients. CHF/Poor LV function is probably now a stronger indication for the use of beta blockers. It may be harmful toadminister IV beta blockers toUA/NSTEMI patients who have contraindications to beta blockade, signs of HF or lowoutput state, or other risk factors for cardiogenic shock. The usual starting dose is short acting Metoprolol 25 mg tds, though 12.5mg tds may be more appropriate if there are concerns about tolerance. Aim for Metoprolol CR 95 mg daily by discharge but titrate slowly if there are concerns about haemodynamic stability or poor LV function. IV Metoprolol may be
Fig. 4: Timing of release of biomarkers after MI Table 4: Clinical Assessment and Initial Evaluation High-risk ACS
Intermediate-risk ACS
Lower-risk ACS
Prolonged chest pain cither > 20 min or ongoing, with one or more highrisk features:
No high-risk features, but one or more of:
No high- or intermediate-risk features
• Ongoing chest pain, yet no highrisk features
• Chest pain: single episode at rest, crescendo exertional angina
Transient ST-segment elevation • Crescendo angina preceding rest or pain depression > 0.5 mm • Borderline positive troponin: Sustained ST-scgmcnt depression e.g., troponin 1 level 0.4-2.0 ng4 > 0.5 mm • Previous intervention: T-wave inversion > 1 mm in > 5 percutaneous transluminal leads Deep (e.g., > 5 mm) T-wave coronary angioplasty / inversion coronary artery bypass surgery • Positive biochemical markers: • Increased baseline risk: e.g., Troponin level / CK-MB fraction diabetes, elderly clearly abnormal with 30-day rate of death or myocardial compatible history infarction: 4V8% • Recurrent myocardial ischemia with ECG ST-segment shift with or without pain
• FCG: normal or nonspecific abnormalities or unchanged from previous
• ECG
May include patients with history of known coronary artery disease or with risk factors for coronary artery disease 30-day rate of death or myocardial infarction: < 2%
• Acute myocardial infarction in past 4 weeks; pain with ECG ST abnormalities • Hemodynamic compromise with ongoing chest pin
heart failure / hypotension
30-day rate of death or myocardial infarction: 12%-30% ASA + heparin Glycoprotein lib/Ilia inhibitor Early cardiac catheterization
ASA + clopidogrel
ASA monotherapy
Heparin or low-molecular-weight heparin
No heparin
Decision for cardiac catheterization after stress testing
Observation for higher-risk indications
reasonable for initially persistent pain that fails to settle with nitrates.
Calcium Channel Blockers
These are not usual first line therapy. They should be considered in patients who cannot tolerate beta blockers or in whom a combination of nitrates and beta blockers does notcontrol symptoms.
Anti-platelets
If there are no contraindications, every patient presenting with NSTE-ACS should be given an initial dose of aspirin 162mg to 325mg, keeping in mind that higher doses are not more effective.(2,11,12) Giving aspirin as soon as possible produces up to 46% reduction in composite events of nonfatal MI, non-fatal stroke and vascular deaths in patients with NSTE-ACS.18 The first dose should be chewed or
Table 5: TIMI score Yes 1 point
No 0 points
Age ≥65 ≥3 risk factors for ACS; hypertension, hyperlipidemia, smoking, diabetes, family history Use of aspirin in last 7 days Prior coronary stenosis >50% >2 angina events in 24 hours or persisting discomfort ST-segment deviation of >0.05 mV on initial ECG Elevated cardiac biomarkers Total score Low risk
0-2
Intermediate risk
3-4
High risk
5-7
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Dual-Antiplatelet Therapy
In addition to aspirin, clopidogrel is part of the dualantiplatelet therapy and should be initiated regardless of definitive treatment of NSTE-ACS.(11) Having both aspirin and clopidogrel on board prevents platelet adhesion and aggregation, which are the earliest steps in coronary artery thrombus formation. The loading dose of clopidogrel is 300mg.
NOVEL ANTICOAGULANTS
Novel OACs, including dabigatran, apixaban, rivaroxaban and darexaban, have been studied for secondary prevention of ACS. The only one of these novel OACs to show a positive benefit–risk profile was a lowdose regimen of rivaroxaban. The results of the ATLAS ACS 2 TIMI 51 trial showed that in patients treated with standard antiplatelet therapy (thienopyridine plus ASA or ASA alone), treatment with rivaroxaban 2.5 mg twice daily led to a significant reduction in the composite of cardiovascular death, MI and stroke over 24 months compared with placebo (9.1% vs 10.7%; hazard ratio 0.84; p=0.02). As expected, the rate of major bleeding was significantly increased with rivaroxaban versus placebo (1.8% vs 0.6%; hazard ratio 3.46; p<0.001).However, in selected patients with elevated biomarkers and no history of stroke or transient ischaemic attack, the rate of fatal bleeding with rivaroxaban 2.5 mg twice daily was similar to placebo (0.1% vs 0.3%). Moreover, in this patient subgroup, treatment with rivaroxaban 2.5 mg twice daily significantly reduced cardiovascular mortality and allcause mortality (by 45% and 42%, respectively) compared with placebo. Based on this, rivaroxaban 2.5 mg twice daily has been approved in Europe (but not in the US) as an adjunct to standard antiplatelet therapy with thienopyridine plus ASA or ASA alone, for prevention of atherothrombotic events in patients who have experienced a recent ACS event and have elevated cardiac biomarkers and no history of stroke or transient ischaemic attack.(25) After an acute coronary syndrome, dual antiplatelet therapy with clopidogrel plus aspirin is still considered
Table 6: Grace Score Age
Points
HR
Points
SBP
Points
Cr
Points
Killip class
Points
<39
0
<70
0
<80
40
0.0-0.39
1
I
0
40-49
18
70-89
5
80-99
37
0.4-0.79
4
II
15
50-59
36
90-109
10
100-119
30
0.8-1.19
7
III
29
60-69
55
110-149
17
120-139
23
1.2-159
10
IV
44
70-79
73
150-199
26
140-159
17
1.6-1.99
13
Cardiac arrest
30
80-89
91
>200
34
160-199
7
2.0-3.99
21
Elevated cardiac markers
13
>90
100
-
-
>200
0
>4
28
ST-segment deviation
17
Low risk
1-88
Intermediate risk
89-118
High risk
>119
CHAPTER 204
Diltiazem is the preferred agent. Initially 30mg tds then slow release preparations. Amlodipine or Felodipine may be considered especially if the patient has poor LV function. They are safer if used in combination with beta blockers (less likely to induce tachycardia).
crushed to establish high blood levels quickly. Patients with contraindications to aspirin can be given 75 mg Clopidogrel as a substitute (Figure 5).11,12
myocardial infarctions in NSTE-ACS patients treated with fibrinolytics(17) and they are therefore are not indicated.(2)
940
Disposition
CARDIOLOGY
Optimal treatment for patients with NSTE-ACS is not as clear-cut as those with STEMI. After diagnosing NSTEACS and initiating treatment with anti-platelet, antianginal and anticoagulant medications, there are three pathways to definitively treat NSTE-ACS: 1.
Immediate invasive strategy, (angiography and revascularization) within 2 hours.
2.
Early-invasive treatment, (angiography followed by revascularization) within 24 hours.
3.
Ischemia-guided treatment involves maximal medical therapy with antiplatelet and anticoagulant agents.
Immediate-Invasive Treatment
Immediate-invasive treatment is indicated for the patient with NSTE-ACS that continues to have refractory angina despite intensive medical therapy, hemodynamic instability due to cardiogenic shock or overt heart failure, or sustained VT or VF, despite maximal medical therapy.(2) Within 2 hours, these patients should be taken to the catheterization lab or transfer to a facility with interventional capabilities.
Early-Invasive Treatment Fig. 5: Targets of available antithrombotic drugs a standard of care. However, new therapeutic approaches are increasingly being explored22,23 and, in particular, addition of a new oral anticoagulant (NOAC) to dual therapy (“triple therapy”) has been studied quite extensively. Even if one considers the most effective NOAC in combination with clopidogrel + ticagrelor, this triple therapy is not more effective than ticagrelor + aspirin. On the other hand, the increased risk of bleeding with triple regimens is well demonstrated. We therefore conclude that these triple regimens did not play any important roles in the patients experiencing an acute coronary syndrome.24
Anti-coagulation
Once antiplatelet treatment has been initiated, it is recommended that all patients should be started on anticoagulation, irrespective of treatment strategy. (2) Although, multiple anti-coagulants can be used, enoxaparin has the best evidence for use in decreasing recurrent cardiac events.(14,15,16). The ESSENCE trial found Enoxaparin to be more effective than unfractionated heparin in preventing death at 30 days.(14) The rates of recurrent ischemic events and invasive diagnostic and therapeutic procedures were also greatly reduced when enoxaparin was used over unfractionated heparin.(15)
Fibrinolytics
There is a higher incidence of intracranial hemorrhage and
When a patient with NSTE-ACS has any of the below features, they benefit more from early-invasive management:(2,17) 1.
GRACE Score >140, TIMI Score > 3
2.
Temporal change in Troponin or
3.
New or presumably new ST-depressions
Although these are the current recommendations, the decision for invasive management should be coordinated with the cardiologist.
Ischemia-guided Treatment
Formerly known as early-conservative treatment, ischemia-guided treatment involves maximum medical therapy withdual-antiplatelet therapy and anti-coagulants and is the preferred treatment for(2,17) 1.
TIMI score 0-2 (low risk) or GRACE Score < 109
2.
Low risk, Troponin-Negative Women
3.
Absence of high-risk features
Multiple studies have shown equivocal outcomes between early-invasive and ischemia-guided treatment in low-risk patients.(17,20,21) However, if the low-risk patient is in the emergency department and starts having recurrent chest pain or becomes hemodynamically unstable, then invasive management should be pursued (Figure 6).
CORONARY REVASCULARIZATION (FIGURE 7)1
Coronary revascularization (PCI or CABG) is carried out to improve prognosis, relieve symptoms, prevent
941
NSTE-ACS
Cardiac cath CAD
Oxygen PRN Nitrates Dual anti-platelet Anticoagulant Consult cardiologist
No
Discharge from protocol
Yes
CABG
Yes Left main disease No 1- or 2Vessel Disease
Risk Stratify: Clinical features TIMI/GRACE ECG Troponins
Medial Therapy, PCI or CABG
3- or 2-vessel disease with proximal LAD involvement
LV dysfunction or treated diabetes*
Development of refractory chest pain or hemodynamic instability
IschemiaGuided Treatment
High Risk
Early Invasive Treatment
Early Invasive Treatment
*Note that the evidence favors early invasive Treatment in Intermediate Risk
Fig. 6: Algorithm for Patients with UA/NSTEMI Managed by an Initial Conservative Strategy ischemic complications, and improve functional capacity. The decision to proceed from diagnostic angiography to revascularization is influenced not only by the coronary anatomy but also by a number of additional factors, including anticipated life expectancy, ventricular function, comorbidity, functional capacity, severity of symptoms, and quantity of viable myocardium at risk. These are all important variables that must be considered before revascularization is recommended. For example, patients with distal obstructive coronary lesions or those who have large quantities of irreversibly damaged myocardium are unlikely to benefit from revascularization, particularly if they can be stabilized on medical therapy. Patients with high-risk coronary anatomy are likely to benefit from revascularization in terms of both symptom improvement and long-term survival. The indications for coronary revascularization in patients with UA/NSTEMI are similar to those for patients with chronic stable angina.
CONCLUSIONS1
In general, the indications for PCI and CABG in UA/ NSTEMI are similar to those in stable angina. High-risk patients with LV systolic dysfunction, 2-vessel disease with severe proximal LAD involvement, severe 3-vessel disease, or left main disease should be considered for CABG. Many other patients will have less severe CAD that does not put them at high risk for cardiac death. However, even less severe disease can have a substantial negative affect on the quality of life. Compared with highrisk patients, low-risk patients receive negligible or very modestly increased chances of long-term survival with
*There is conflicting information about these patients. Most consider CABG to be preferable to PCI. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 20.
Fig. 7: Revascularization Strategy in UA/NSTEMI CABG. Therefore, in low-risk patients, quality of life and patient preferences are given more weight than are strict clinical outcomes in the selection of a treatment strategy. Low-risk patients whose symptoms do not respond well to maximal medical therapy and who experience a significant negative affect on their quality of life and functional status should be considered for revascularization. V. Hospital Discharge and Post–Hospital Discharge Care(1) The acute phase of UA/NSTEMI is usually over within 2 months. The risk of progression to MI or the development of recurrent MI or death is highest during that period. At 1 to 3 months after the acute phase, most patients resume a clinical course similar to that of patients with chronic stable coronary disease. Return to normal activities 1.
Appropriate advice will vary from patient to patient.
2.
Revascularised patients can return to activities sooner.
3.
Work – normally 2 weeks
4.
Sexual activity – normally 7-10/7
5.
Air Travel – normally 2 weeks
6.
Driving - normally 2 weeks post uncomplicated MI
Lifestyle Modification / Discharge considerations 1.
Encourage smoking cessation.
2.
Aim for regular daily exercise of 30-60 min
3.
Yearly influenza vaccination
4.
Screen and treat for depression
5.
Referral to cardiac CNS for cardiac rehabilitation
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CHAPTER 204
IschemiaGuided Treatment
Intermediate Risk
CABG
No PCI or CABG
Low Risk
Yes
M. Antman, John W. Beasley, Robert M. Califf, Melvin D. Cheitlin, Judith S. Hochman, Robert H. Jones et al
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24. New Oral Anticoagulants in Acute Coronary Syndrome: Is There Any Advantage Over Existing Treatments?Andrea Messori,1,* Valeria Fadda,1 Roberta Gatto,1 Dario Maratea,1 and Sabrina Trippoli1
13. Yusuf S, Zhao F, Mehta SR, et al. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with
25. Bayer Pharma AG. Xarelto® (rivaroxaban) Available at:http://www.ema.europa.eu/docs/en_GB/document_ library/EPAR_Product_Information/human/000944/ WC500057108.pdf [accessed 9 June 2015].
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205 Cardiac interventions have been a spectacular journey marked by undeterred outcome of genuinity, serendipity and proper channelization of scientific knowledge and skills. Cardiac catheterization began in 1711 with equine biventricular catheterization by Hales. However, the dramatic beginning was with Forsmann’s 1929 right heart self catheterization; Cournand, Richards and others unlocked the right heart in 1940’s; Zimmerman and others unlocked left heart in 1950’s and Coronaries were unlocked by Sones in 1958. Dotter’s accidental catheter recanalization of peripheral artery in 1963, followed by Gruentzig’s balloon angioplasty in mid 1970’s led to today’s panoply of devices used percutaneously for revascularization. Over the past decade, the focus of catheterization has changed dramatically from its primary diagnostic function to a conduit of therapies. Today, therapeutic catheterization techniques have replaced conventional surgery for many lesions. The percutaneous transcatheter procedures are broadly grouped as Dilatational (Septostomy, Valvuloplasty, Angioplasty and Endovascular Stenting) or as Occlusions (Vascular embolization and Device closure of defects). Cardiac Interventions can be used in dealing with diseases such as: 1. Coronary Artery Disease 2. Heart Valve Diseases 3. Congenital Heart Disease 4. Hypertrophic Cardiomyopathy 5. Heart Failure 6. Cardiac Arrhythmias
CORONARY ARTERY DISEASE
The treatment of Coronary artery disease has multiple facets. It is recognised increasingly that lifestyle changes -- a healthier diet, exercise, smoking cessation and advanced medical therapies including statins, beta blockers and antiplatelet therapy – are the cornerstones of such treatment. Percutaneous Coronary Intervention has become the preferred approach and has evolved substantially from early days of Plain Open Balloon Angioplasty (POBA) to Bare Metal Stent (BMS), Drug Eluting Stent (DES) and Bioabsorbable Vascular Scaffold ( BVS ), rotational atherectomy and other interventions for patients with acute coronary syndrome, limiting angina or significant ischemia with appropriate anatomy. The usage of advanced imaging techniques like fractional flow reserve (FFR), intravascular ultrasound (IVUS), optical
Cardiac Intervention Pawan K Suri
coherence testing (OCT) and infrared spectroscopy has not only enabled the clinician to facilitate more accurate navigation inside vessal but in proper and adequate stent deployment as well. Cardiac assist in the catheterization lab had its origins in the form of extracorporeal membrane oxygenators (ECMO), which were used to support children in respiratory failure With the clinical introduction of an Intra-aortic balloon pump (IABP) by Kantrowitz in 1968, cardiologists diagnosing and treating patients with acute coronary syndromes began applying IABP therapy in the catheterization lab but usually in concert with the surgeons. Cardiopulmonary support (CPS) systems were introduced in the 1970s, filling a void between what the IABP could provide in the catheterization lab and what full cardiopulmonary bypass provided in the surgical suite. Therefore, although the IABP gained widespread use in the catheterization lab based on its relative ease of insertion, its lack of hemodynamic impact leading to a reliance on inotropic drug support limited its ability to meet the ideals described previously. Development of cardiac assist in the catheterization lab has, therefore, progressed through a number of iterations during the last 50 years. With each generation, the technology has struggled with the challenges of becoming either easy to implant, safer for the patient, and/or more effective in providing circulatory support and myocardial protection. The Impella technology is the latest generation of cardiac assist and represents a significant step in the history of technology development described previously. Its design facilitates a support strategy that represents the ideal of cardiac assist—safe and simple use consistent with both elective and emergent clinical environments, while supporting systemic hemodynamics and protecting the myocardium from ischemic damage.
HEART VALVE DISEASES
Typical valvular stenosis is characterised by fusion, partially absent or commisured valves with small eccentric orifice that is visualised angiographically. The dilating balloon catheter is positioned over a wire across the valve and balloon is inflated many times till waist of the stenotic lesion disappears. Before 1984, when Inoue et al first described the clinical application of percutaneous mitral balloon valvuloplasty (PMBV), surgical mitral commissurotomy was the preferred option for patients who had severe mitral stenosis (MS). Since its introduction, percutaneous mitral commissurotomy has demonstrated good immediate and midterm results and has replaced surgical mitral
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commissurotomy as the preferred treatment of rheumatic MS in appropriate candidates. Multiple percutaneous approaches for the treatment of mitral regurgitation (MR) are under development and various percutaneous approaches aimed primarily at the treatment of functional or ischemic dysfunction include: (1) Direct annular plication simulating surgical suture annuloplasty, (2) Thermal remodeling of mitral annular collagen, (3) Left ventricular remodeling using a percutaneously placed transventricular device, (4) A transatrial system with anchors in the coronary sinus and interatrial septum, and (5) a novel percutaneous ring for the treatment of functional TR. Transcatheter aortic valve implantation (TAVI) was first applied in an early animal study by Danish cardiologist Anderson in his garage in 1992and approximately 8,000 patients have now been treated with this technology worldwide. The procedures have been predominantly performed using two different devices with almost equal frequency: the Edwards Lifesciences (Irvine, CA) Sapien systems and the Medtronic, Inc. (Minneapolis, MN) CoreValve system. Although both systems have been shown to be safe and clinically effective, albeit with a limited duration of follow- up thus far, the principal difference in design is that the Edwards systems have employed a balloon-expandable concept, whereas the CoreValve device is self expanding.
CONGENITAL HEART DISEASE
Transcatheter occlusion of intracardiac and extracardiac communications has been revolutionised by the development of Amplatzer devices. These are made from a cylindrical Nitinol wire mesh formed by heat treatment into different shapes. A sleeve with a female thread on the proximal end of the device allows attachment of a delivery cable with a male screw. The attached device can be pulled and pushed into the loader and delivery sheaths respectively. A family of devices has been produced to occlude ostium secundum atrial septal defect (ASD), patent foramen ovale (PFO), patent ductus arteriosus (PDA) and ventricular septal defect (VSD). While the four lesions described above constitute the bulk of adult structural heart disease practice, there are countless lesions that require treatment in this patient population on a less frequent basis. They include stent placement for coarctation of the aorta, stenting of stenotic pulmonary arteries, pulmonary or systemic veins, surgically created baffles used to treat transposition of the great arteries, or conduits from the ventricles to the great arteries to bypass inoperable subvalvular obstruction, pulmonary arteriovenous malformations. Coronary fistula closure is a regularly performed procedure. Pulmonary and aortic balloon valvuloplasty are not infrequently performed procedures for stenotic valves. With experience in device use and sophisticated techniques, closure of perivalvular leaks around mechanical valves, aortoatrial fistulas, aortic pseudoaneurysms, and ventricular septal defects of both congenital and post myocardial infarction etiology is possible.
HYPERTROPHIC CARDIOMYOPATHY
Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disease. It is defined by an increase in left ventricular wall thickness that is not solely explained by abnormal loading conditions. This disorder is caused by a mutation in cardiac sarcomere protein genes and is most frequently transmitted as an autosomal dominant trait. HCM has a variable presentation. Although not required for the diagnosis of hypertrophic cardiomyopathy, a diagnostic cardiac catheterization is useful to determine the degree of outflow obstruction, cardiac hemodynamics, the diastolic characteristics of the left ventricle and LV anatomy, and, of particular importance, the coronary anatomy. Cardiac catheterization is also reserved for situations when invasive modalities of therapy, such as a pacemaker or surgery, are being considered. Therapeutic cardiac catheterization interventions, utilized in well selected cases of hypertrophic cardiomyopathy, include transcatheter septal alcohol ablation to relieve the LV outflow obstruction by intentional infarction of a portion of the interventricular septum.
HEART FAILURE
Heart failure is now the great epidemic, and remains primarily due to hypertension, valve or coronary disease. Indeed, while we’ve been “up to our necks” in coronary intervention for some time now, we are certainly now at least “knee deep” in valvular disease and at least “dipping our toes” into hypertension. Medications will remain a mainstay of heart failure management, and rightly so, but they should ideally be complementary to other forms of treatment that further unload the heart or reverse the primary disorder. The time has come for interventional cardiology to take its rightful place in the comprehensive and multi-disciplinary management of patients with heart failure Interventional therapies may be able to improve cardiac function and reverse heart failure. Examples abound, and include (1) percutaneous cardiac assist device therapy to facilitate multi-vessel high-risk intervention and complete revascularization or as a bridge to recovery with reduced infarct size in acute myocardial infarction, with or without cardiogenic shock; (2) percutaneous aortic and mitral valve repair and/or replacement to reverse or halt negative remodeling and improve cardiac output; (3) stem cell and gene therapy delivery to improve ventricular function; (4) cardiac resynchronization (CRT) to improve stroke volume; (5) atrial septal defect closure, paravalvular leak repair, and other advanced congenital defect treatment such as coarctation repair; and (6) alcohol septal ablation for hypertrophic cardiomyopathy to reduce outflow tract obstruction and improve both mitral regurgitation and diastolic function. Together, perhaps we will not only prevent some forms of heart failure from developing, such as that which occurs after a large myocardial infarction, but produce robust and sustained cardiac function recovery in those who already suffer from the disease, such as those with chronic ischemia and ventricular dysfunction or ongoing
hemodynamic stress from valve dysfunction.
CARDIAC ARRHYTHMIAS
The treatment of bradyarrhythmias with permanent pacemaker implantation represents the first interventional therapy for patients with cardiac arrhythmias. Previously, patients with tachyarrhythmias could only be cured by open heart surgery utilising intraoperative map guided surgery and ablation of the arrhythmia. Catheter ablation has completely revolutionised the treatment of these patients. RF ablation has become the technique of choice to cure patients with recurrent paroxysmal SVT due to AV reentrant tachycardia using an accessory pathway, AV nodal re-entrant tachycardia, atrial tachycardia and atrial flutter. It is also used for AV nodal ablation followed by pacemaker insertion or AV nodal modification in patients with poorly controlled atrial fibrillation. Patients with idiopathic non-ischaemic VT arising from the left ventricle or right ventricular outflow tract can similarly be cured. For all these patients, RF ablation offers curative therapy, thus eliminating recurrent symptoms, life-threatening attacks, tachycardia cardiomyopathy and need for lifelong drug therapy. For patients with resuscitated sudden cardiac death or at high risk for sudden death, the implantable cardioverter defibrillator (ICD) is the only technique that has significantly improved survival from sudden cardiac death.. Thus the ICD can prevent sudden death, but the main limitation is the cost of the device and it is not suitable in patients who have severe heart failure. In conclusion, interventional electrophysiology represents a tremendous leap forward in the management of cardiac arrhythmias. With catheter ablation, it offers a safe curative therapy for patients with recurrent SVTs and VTs and with the ICD, prevents sudden cardiac death in patients who have been resuscitated from it or who are at risk for it.
CONCLUSION
“Innovation in medical technology is key to the advancement of medicine. The practice of interventional cardiology will undoubtedly be different in the next decade. Coronary intervention will remain the dominant procedure for the interventionalist, and the number of procedures will grow slowly as the population ages. The increase in peripheral interventions probably will be greater than for coronary, but the greatest and most profound change will be in the growth of valvular heart
However, during all this process of innovation, interventional cardiologists are exposed to radiation and need to wear heavy lead aprons. Studies show 60 percent of interventional cardiologists has spine issues and 51 percent have the beginnings of cataracts along with a significant increase in incidence of brain tumours. New technology is available to address radiation and taking the cath lab staff and the operator out of the radiation field by using robotic systems along with new radiation protection systems like RdPad and Trinity protection systems to help block radiation scatter. The Zero Gravity ceiling gantry mounted lead suit system that takes the weight of lead aprons off of physicians are also available.
REFERENCES
1.
Mullins CE. Transeptal left heart catheterization. In: Mullins CE (ed) Cardiac Catheterization in Congenital Heart Disease :Pediatric and Adult. Malden, MA: Blackwell Publishing, 2006, pp.223-54. 2. Moore JD, Doyle TP. Interventional catheter therapy in adults with congenital heart disease. Prog Pediatr Cardiol 2003; 17;61-71. 3. Lauten A, Engstrom AE, Jung C et al. Percutaneous left ventricular support with the Impella-2.5-assist device in acute cardiogenic shock: results of the ImpellaEUROSHOCK- registry. Circ Heart Fail 2013; 6;23-30 4. Koruth JS, Dukkipati S, Miller MA, Neuzil P, d’Avilla A, Reddy VY. Bipolar irrigated radiofrequency ablation: a therapeutic option for refractory intramural atrial and ventricular tachycardia circuits. Heart Rhythm 2012; 9:193241. 5. Moat NE, Ludman P, de Belder MA et al. Long term outcomes after transcatheter aortic valve implantation in high risk patients with severe aortic stenosis: the U.K. TAVI Registry. J Am Coll Cardiol 2011; 58;2130-8. 6. Borger MA, alaim A, Murphy PM, doenst T, David TE. Chronic ischemic mitral regurgitation: repair, replace or rethink? Ann Thorac Surg 2006; 81;1153-61. 7. Steinhoff G, Strauer BE. Heart . in: Regenerative Medicine. From Protocol to Patient. Berlin: Springer 2011; 745-772. 8. McKenna WJ, Camm AJ. Sudden death in hypertrophic cardiomyopathy; Assessment of patients at high risk. Circulation 1989; 80;1489-1492. 9. Scheinman MM. NAPSE survey on catheter ablation. Pacing Clin Electrophysiol 1995; 18;1474-1478. 10. Bradley DJ, Bradley EA, Baughman KL. Cardiac resynchronization and death from progressive heart failure: a meta analysis of randomised controlled trials. JAMA 2003; 289:730-740 11. Hian SK, Miller DL, Le Heron J, Padovani R, Vano E. A summary of recommendations for occupational radiation protection in interventional cardiology. Catheter Cardiovasc Interv 2013; 81:562-567. 12. Weisz G, Metzger DC, Caputo RP, Delgado JA, Marshall JJ, Vetrovec GW, Reisman M, Waksman R, Granada JF, Novack V, Moses JW, Carrozza JP. Safety and feasibility of robotic percutaneous coronary intervention. PRECISE (Percutaneous Robotically-Enhanced Coronary Intervention) Study. J Am Coll Cardiol 2013; 61:1596-6000.
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Cardiac arrhythmias can present as benign ectopics or as life-threatening arrhythmias and sudden cardiac death. Clinical cardiac electrophysiology is the study of the electrophysiology of the heart and all aspects of management of cardiac arrhythmias. The invasive electrophysiological study was initially purely diagnostic, but recent advances in technology has allowed us to intervene and hence the term interventional electrophysiology. The interventional therapies include permanent pacing for bradyarrhythmias, arrhythmia surgery for arrhythmias, percutaneous catheter ablation and implantable devices for tachyarrhythmias.
disease interventions. New technology and improved imaging will be necessary and likely. The interventional laboratory of the future will be a different one from today, and the interventionist of the future will need to be skilled in many more techniques than just coronary interventions.
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Recent Developments in Intensive Cardiac Care for Acute Cardiac Disorders Suraj Kumar Arora, Abhishek Goyal, Gurpreet S Wander
Intensive cardiac care includes a wide range of cardiac emergencies that can develop into rapidly evolving life-threatening situations requiring efficient and rapid interventions. In its original concept, the CCU was designed for arrhythmia monitoring and treatment of patients with acute coronary syndromes. In present scenario, the CCU has evolved into a critical care environment that delivers care both to patients with acute single-system cardiovascular illness and to patients with more co-morbidities and multisystem organ dysfunction. The field of cardiac intensive care continues to advance in tandem with disorders and complexity of procedures. There have been few major developments in critical care in terms of specific new treatments and substantial evidence exist regarding the use of certain strategies, though not always guidelines based. Certain older concepts have also changed in light of new data. Here we summarize what we believe to be the most important features of progress in cardiac intensive care in recent years.
IONOTROPES
Positive inotropic drugs are typically used to stabilize patients with acute decompensated heart failure in the intensive care unit, as a bridge-to-decision or bridge to
heart replacement therapy. Despite evidence that inotropic therapy may increase mortality, there are clinical settings where inotropic support may be life-saving measure, and where hypoperfusion of vital organs is obvious and the need for improved perfusion is immediate. Initial choice of vasopressor was used to based on individualexperience and institutional bias. Dopamine, the precursor for norepinephrine, was recommended as a first line agent. However, patients in shock have a diminished response to indirect-acting agents such as dopamine, because a large component of the response to dopamine is neuronal release of norepinephrine. When endogenous norepinephrine is depleted in shock states, dopamine is unable to produce adequate response. In patients with cardiogenic shock, norepinephrine (ι1&β1-adrenergicagonist), should be preferred over dopamine as the first-line vasopressor because a subgroup analysis from a major randomized trial found that patients with cardiogenic shock who received dopamine had a higher mortality than those who received norepinephrine. In addition, dysrhythmias were more common in the dopamine group.
Fig. 1: An illustration of options for Mechanical Circulatory Support : (A) IABP, (B) Impella, (C) TandemHeart
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Table 1: Current Guideline recommendations of IABP Indication
ACC/AHA guidelines
ESC guidelines
STEMI with cardiogenic shock
IIa/Ba [1]
IIb/Ba [2]
STEMI without cardiogenic shock
-
III/A [3]
Mechanical complication of AMI
IABP can used to provide temporary circulatory support [1]
I/C [3]
High- risk PCI
IIb/C [4]
-
High-risk CABG
IIa/B [5]
Given concerns about increased mortality with shortterm intravenous therapy with milrinone or dobutamine in patients with acute decompensated heart failure, these drugs are not to be used in the routine management of such patients. However, administration should be considered in patients with severe hemodynamic compromise with low cardiac output that is not adequately managed by diuretics and vasodilators. Calcium sensitizing agents such as levosimendan exert positive inotropic effects on the heart by increasing the contractile apparatus sensitivity to calcium. Therefore, such drugs have the advantage of driving contractile state without increasing cAMP or calcium, both of which have adverse effects. Despite improvement in hemodynamics, there is no clear evidence of short term or long term clinical benefit. Two randomized trials with levosimendan, REVIVE-II and SURVIVE, indicated no difference in mortality with levosimendan and use was associated with more adverse effects in form of hypotension. Newer drugs are still under intense investigation and are in clinical trials. Omecamtiv mecarbil is the first selective cardiac myosin activator and increases the efficiency of heart muscle contraction. ATOMIC AHF trial showed that the drug didnâ&#x20AC;&#x2122;t have the usual adverse effects (e.g., tachycardia and arrhythmia) of traditional inotropic agents. Omecamtiv mecarbil may not be an inotrope, but it does improve myocardial systolic performance. Istaroxime is a novel intravenous drug that inhibits Na/ K+ ATPase and stimulates SERCA2a. HORIZON-HF study assessed the hemodynamic effects of Istaroxime and showed reduction in PCWP and increase in systolic blood pressure but no effect on neurohormones, renal function, ortroponin levels. The quest to develop more effective and safer positive inotropic drugs is continuing. Additional targets may
include improved mitochondrial function through modulation of oxidative stress iron handling, and biogenesis. Newer positive inotropic agents will also have greater advantages if they can be given orally.
CIRCUILATORY ASSIST DEVICES
Intra-Aortic Balloon Pump
Major categories of circulatory assist devices include: IABP, non-IABP percutaneous mechanical circulatory assist devices, and ECMO (Figure 1). The intraaortic balloon pump is the device cardiologists are most familiar with and has been in clinical use for more than 4 decades, largely on the basis of favorable observational data as well as the beneficial effect on coronary blood flow, myocardial oxygen demand and hemodynamic support. It can be inserted easily and rapidly, is the least expensive of all the devices, and does not require continuous monitoring by technical support personnel. The use of IABP during high-risk PCI, acute myocardial infarction, and cardiogenic shock had been present with the paucity of adequately powered randomized controlled trials in these settings (Table 1). In a trial on patients with AMI and Cardiogenic Shock, in a comparison of IABP with standard therapy, no difference in 30-day mortality or in any key secondary end points (hemodynamic stabilization, length of stay in the ICU, lactate levels, dose and duration of catecholamine therapy, and RFT) was found. Although IABP was safe, there was no evidence that it wasassociated with hemodynamic improvement. CRISP-AMI trial randomised patients with high-risk anterior STEMI without shock to a routine strategy of IABP prior to PCI lasting at least12 hours after PCI
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ACC, American College of Cardiology; AHA. American Heart Association; CABG, coronary artery bypass graft; ESC, European Society of Cardiology; IABP, lntra-aortic balloon pump; LVEF. left ventricular ejection fraction; PCI. percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; 1. Oâ&#x20AC;&#x2122;Gara PT, Kushner FG, Ascheim DD, et al_ 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127:e362-e425; 2. Steg PG, James SK. Alar D. et al. ESC guidelines for the management of acute myocardial infarction m patients presenting with ST-segment elevation Eur Heart J 2012; 33:2569-2619; 3. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS), European Association for Percutaneous Cardiovascular Interventions. Guidelines on myocardial revascularization Eur Heart J 2010; 31: 2501-2555; 4. LevineGN. Bates ER. Blankenship JC. et al. 2011 ACCF/AHA/ SCAI Guideline for percutaneous coronary intervention A report of the Amencan College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011. 58:e44-el22; 5. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for coronary artery bypass graft surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the Amencan Association for Thoracic Surgery. Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011; 58:el23-e210; aRecently downgraded from Class I to Class II
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Fig. 2: Circuit configuration for VA and VV-ECMO compared with PCI alone. This strategy did not lead to a reduction in myocardial infarct size and clinicaloutcomes at 6 months were not significantly different between the 2 groups. However, 8.5% of patients in the PCI alone group crossed over to rescue IABP therapy. These findings thus support a standbystrategy (rather than routine use) of IABP during primary PCI in high-risk anterior STEMI patients. In patients undergoing high-risk PCI, IABP insertion was found to be effective in two observationstudies by Briguori et al. These results were not supported by the Balloon Pump Assisted Coronary Intervention Study (BCIS-1), which showed elective IABP insertion did not reduce the incidence of MACCE followingPCI and thus do not support a strategy of routine IABP placement before PCI in all patients with severe left ventricular dysfunction and extensive coronary disease. A recent meta-analysis on similar group of patients by Romeo et al., also highlighted the lack of benefit of prophylactic IABP at reducing inhospital mortality and MACCE. IABP is thus simplest to deploy circulatory assist device and to be used as an adjuvant treatment in presence of hemodynamic impairment. Table I shows the current recommendations.
Percutaneous Ventricular Support Devices
The limitations of IABP led to development of other percutaneous mechanical circulatory devices, in that they provide greater improvement in hemodynamic parameters. Short-term mechanical circulatory support devices are again designed to be used for a wide range of clinical conditions ranging from prophylactic insertion for high-risk PCI to management of cardiogenic shock, ADHF, or cardiopulmonary arrest. Percutaneously inserted LVADs, such as Tandem Heart and Impella, are potential options for short-term Mechanical Circulatory Support (MCS) in the acute setting. Tandem Heart is a percutaneous left atrial to aorta assist device and Impella microaxial flow device is
left ventricle to aorta assist device. In head-to-head randomized comparison between the Tandem Heart and IABP in patients undergoing primary PCI, hemodynamics were significantly improved in the pVAD group; however, there were more complications with similar 30-day mortality rates. Impella 2.5 have been evaluated in patients undergoing non emergent high-risk PCI in PROTECT II trial, which has shown no significant difference in the primary end point of major adverse events at 30 days between Impella 2.5 or IABP. The EUROSHOCK Registry, a retrospective study of patients with AMI with CS undergoing implantation of Impella 2.5, showed decrease in lactate levels at 48 hours suggesting improved organ perfusion, but with high 30day mortality at 64.2%.Patients who received Impella 2.5 support prior to primary PCI in the setting of AMI and cardiogenic shock, rather than after PCI, fared better. The Impella 2.5 has also shown beneficial LV remodeling and unloading in anterior STEMI patients without cardiogenic shock. Multiple factors must be considered when choosing MCS including: the hemodynamic condition of the patient, hemodynamic impact of the device, technical considerations including ease and rapidity of insertion, and the ultimate goals of support. In emergent situations, IABP is often selected as the quickest and most familiar way to obtain some degree of hemodynamic stabilization, especially in the setting of AMI with pump failure. The initial effects of the IABP on coronary blood flow may be particularly desirable in this setting as well. If hemodynamic compromise occurs despite appropriatemedicalmanagement and/or IABP, one may consider more powerful hemodynamic support devices such as an Impella.
EXTRACORPOREAL MEMBRANE OXYGENATION
Mechanical cardiopulmonary support can be delivered
in a more prolonged fashion in an intensive care unit, as extracorporeal membrane oxygenation (ECMO). There are two types of ECMO - venoarterial (VA) and venovenous (VV) (Figure 2). Both provide respiratory support like in severe ARDS with refractory hypoxemia and hypercapnia, but only VA ECMO provides hemodynamic support.
In patients with acute coronary syndrome who were unresponsive to conventional CPR, ECMO plus intraarrest PCI was associated with improved outcomes in patients who were unresponsive to conventional cardiopulmonary resuscitation. Long-term survivors of ECMO performed for cardiogenic shock have better general health, physical health, and social functioning than patients who require chronic hemodialysis, have advanced heart failure, or have recovered from ARDS. VA-ECMO is thus a strategy for supporting patients with cardiovascular collapse as a bridge to recovery or more definitive therapies, and provide a short-term and longterm survival advantage.
HIGH-DOSE DIURETICS VS ULTRAFILTRATION
Ultrafiltration should be reserved for patients with fluid overload who do not achieve an adequate response to an aggressive diuretic regimen (Class IIb recommendation). Initial studies supporting use of ultrafiltration in HF were small but provided safety and efficacy data in acute HF. Ultrafiltration ascompared with diuretic therapy resulted in a higher rate of sodium and volume removal, greater weight loss and less frequent rehospitalizations and thus can provide more effective relief of congestion than pharmacologic therapy can. CARRESS-HF challenged this understanding of the effectivenessof ultrafiltration and concluded that ultrafiltration did not result in greater weight loss or improved renal function as compared with pharmacologic therapy and was associated with a similar rate of death or rehospitalization for ADHF. Thus, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was also associated with a higher rate of adverse events.
NON-INVASIVE VENTILATION
Noninvasive positive pressure ventilation (NPPV) refers to positive pressure ventilation delivered through a noninvasive interface. There is high quality evidence from meta-analyses and randomized trials that NPPV decreases the need for intubation, hospital mortality and improves respiratory parameters (eg, heart rate, dyspnea,
However, Three Interventionsin Cardiogenic Pulmonary Oedema study (3CPO), compared modes of ventilation with standard therapy and each other, detected no differences in mortality or need for intubation, in contrast to most preceding studies (although it did find more rapid improvements in patient-reported dyspnea, acidosis, and hypercapnia).The limitation was that they excluded sick patients who required life-saving or emergency intervention, a population that is more likely to benefit from NIV. Sleep-disordered breathing is common in patients who have heart failure with reduced ejection fraction, with prevalence of 50-75%. Adaptive servo-ventilation is a noninvasive ventilatory therapy that alleviates central sleep apnea by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. In the SERVE-HF trial, however, there was no significant effect of adaptive servo-ventilation on the primary composite end point in the time-to-event analysis of the first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening heart failure. Unexpectedly, there was higher all-cause and cardiovascular mortality in the adaptive servo-ventilation group than in the control group. However, no safety concerns have been identified during the short term application of positive airway pressure in patients with decompensated heart failure and thus noninvasive ventilation is considered as adjunctive therapy in patients with acute cardiogenic pulmonary edema who have severe respiratory distress or whose condition does not improve with pharmacologic therapy.
CONCLUSION
The field of critical care cardiology has undoubtedly grown over the past several years. Patients in cardiogenic shock represent an extremely high risk group in whom mortality has remained high despite revascularization and pharmacologic therapies. Stabilization therapy often begins with intravenous inotropic agents. In the setting of profound cardiogenic shock, IABP is less likely to provide benefit than continuous flow pumps including the Impella and Tandem Heart. ECMO may also provide benefit, particularly for patients with associated impaired respiratory gas exchange and patients unresponsive to conventional CPR. Application of high quality, appropriate, evidence-based medicine to these complex, high-risk cardiac patients requires formal training in this field.
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Levy JH. Treating Shock-Old Drugs, New Ideas. N Engl J Med 2010; 362:841-42.
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Francis GS, Bartos JA,Adatya S. Inotropes. J Am Coll Cardiol 2014; 63:2069â&#x20AC;&#x201C;78.
3.
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: areport of
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VA-ECMO can provide acute support in cardiogenic shock or cardiac arrest. The first successful use of extracorporeal membrane oxygenation (ECMO) for treatment of cardiogenic shock was described in 1973. Observational studies and case series have reported increased survival rates among patients who received ECMO for cardiac arrest or severe cardiogenic shock as compared to conventional CPR.
hypercapnia, acidosis) in patients with cardiogenic pulmonary edema.
the American College of Cardiology Foundation/American Heart Association Task Force onPractice Guidelines. Circulation 2013; 128:e240–327.
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4.
Tang WH. Reconsidering Ultrafiltration in the Acute Cardiorenal Syndrome. N Engl J Med 2012;367:2351-52.
5.
Weng CL, Zhao YT, Liu QH, et al. Meta-analysis: Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema. Ann Intern Med 2010; 152:590-600.
6.
Ihdayhid AR, Chopra S, Rankin J. Intra-aortic balloon pump: indications, efficacy, guidelines and future directions. Curr Opin Cardiol 2014, 29:285–292.
7.
Gilotra NA, Stevens GR. Temporary Mechanical Circulatory Support: A Review of the Options, Indications, and Outcomes. Clinical Medicine Insights-Cardiology 2014; 8:75– 85.
8. Rihal CS, Naidu SS, Givertz MM, et al. 2015 SCAI/ACC/ HFSA/STS Clinical Expert Consensus Statement on the Useof Percutaneous Mechanical CirculatorySupport Devices in Cardiovascular Care. J Am Coll Cardiol 2015; 65:e7–26.
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Five Recent Land Mark Trials in Cardiology: How have They Changed Our Practice VK Bahl, Anunay Gupta
Field of cardiology has undergone a paradigm shift over the last decade , from the use of bare metal stents to bio-absorbable stents and from surgical aortic valve replacement to percutaneous aortic valve in patients with aortic stenosis. Every year new trials are published which provide evidence to change the clinical management of our patients. In the past year, landmark trials which were published are Heart Outcomes Prevention Evaluation-3 (HOPE-3), PARTNER 2, The Systolic Blood Pressure Intervention Trial (SPRINT), ABSORB III , Dual Antiplatelet Therapy trial (DAPT) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin - Thrombolysis in Myocardial Infarction 54). In the current review, we will discuss these trials along with their clinical implications and how they have changed our clinical practice.
HOPE-3
It is well established that antihypertensive therapy and statins lowers cardiovascular risk in patients with high risk. However, their role in intermediate-risk patients (annual event rate of less than <1%) without established cardiovascular disease is uncertain. HOPE-3 trial was designed to answer this question. It consisted of more than 12,000 patients with a median follow up period of 5.6 years. It had 2x2 factorial design, hence had three arms – an antihypertensive regimen, a statin and a combination of two. In first arm, patients received BP-lowering treatment which consisted of candesartan 16 mg/day and hydrochlorothiazide 12.5 mg/day. These patients did not have significantly fewer occurrences of a composite of CV-related death, nonfatal MI, or nonfatal stroke (the first co-primary outcome) at a mean follow up of 5.6 years compared with those who received placebo (4.1% vs 4.4%, respectively). The second co–primary outcome, which was heart failure, cardiac arrest, or revascularization to the composite was also not statistically significantly different between two groups (4.9% vs 5.2%). In second arm, study participants were randomized to rosuvastatin 10 mg/day vs placebo. A significant reduction in the first coprimary event was seen in the rosuvastatin group (P = 0.002) with a 24% lower risk for CV events. Similarly, statistical significance was achieved for second coprimary event also (P<.001). The trial’s third arm which was combination of two therapy randomized patients to rosuvastatin plus
candesartan/hydrochlorothiazide vs rosuvastatin plus placebo vs candesartan/hydrochlorothiazide plus placebo vs two placebos It was seen that those who received both of the treatment drugs together had significantly lower rates of the first primary outcome vs the double-placebo group (3.6% vs 5.0%, respectively, P=0.005), as well as the second primary outcome (4.3% vs 5.9%, P=0.003). In conclusion, it was seen that in an intermediate-risk population, everybody was benefited with statins and that statins were found to be safe. But in terms of bloodpressure lowering, those without elevated BP do not derive any benefit.
PARTNER 2
Transcatheter aortic valve replacement (TAVR) has become treatment of choice in severe symptomatic aortic stenosis patients with prohibitive surgical risk. In patients with high surgical risk either TAVR or surgical aortic valve replacement is an option. PARTNER 2 assessed the role of TAVR in patients with intermediate surgical risk. PARTNER 2 randomized 2032 patients with severe symptomatic aortic stenosis who underwent TAVR with the balloon-expandable Sapien XT valve or surgery. The mean age was 81 years at the time of implantation. Patients were considered to be at intermediate risk after clinical assessment by a multidisciplinary heart team. The mean Society of Thoracic Surgeons score was 5.8%, with 81.3% patients had a score between 4% and 8%. At 2 years, the primary composite end point of all-cause death or disabling stroke occurred in 19.3% with TAVR and 21.1% with surgery in the intention-to-treat population (hazard ratio [HR] 0.89; P=0.25). TAVR met the threshold for noninferiority in intention-to-treat (P=0001) and astreated analyses (P<0.001). In the transfemoral-access group, the all-cause death or stroke rate was significantly lower with TAVR than surgery (HR 0.79; P=0.05). TAVR is a reasonable alternative to surgical aortic-valve replacement (AVR) in intermediate-risk patients and may be superior when using a transfemoral approach.
SPRINT TRIAL
Latest JNC 8 guidelines recommends treating to a target of 150/90 mm Hg for the patients 60 years of age and older and to 140/90 mm Hg in others. SPRINT compared the effects of antihypertensive treatment with a systolic blood pressure (SBP) target of <120 mm Hg (intensive treatment) versus <140 mm Hg (standard treatment).
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It randomized 9361 hypertensive adults ≥50 years of age who had an average SBP of 130–180 mm Hg and were at additional risk for cardiovascular disease (CVD). During follow-up, the mean SBP was 121.5 mm Hg in intensive treatment group and 134.6 mmHg in standard treatment group. Trial was stopped prematurely after a median follow-up of 3.26 years because primary composite outcome of myocardial infarction, non–myocardial infarction acute coronary syndrome, stroke, acute decompensated heart failure, and CVD death was reduced by ≈ 25% in intensive treatment group. All-cause mortality was also reduced by ≈ 27% in the intensive treatment group. Acute kidney injury or failure were more common in the intensive (4.1%) than in the standard (2.5%) arm. Electrolyte abnormalities were also more common in the intensive (3.1%) than in the standard (2.3%) arm. Hence SPRINT redefined blood pressure targets and questions J-shaped curve. For people at high cardiovascular risk, a systolic goal of less than 120 mm Hg is appropriate.
ABSORB III
Drug-eluting coronary stents (DES) have been associated with better clinical outcomes than bare-metal stents however, there is ongoing risks of stent thrombosis and restenosis. These late adverse events are due to permanent metallic stents. Fully bioresorbable stents i.e bioresorbable vascular scaffolds (BVS) have been developed which undergo complete bioresorption hence might be devoid of late adverse events. In ABSORB III trial 2008 patients with stable or unstable angina were randomized in a 2:1 ratio to receive an everolimus-eluting bioresorbable vascular (Absorb) scaffold or an everolimus-eluting cobalt– chromium (Xience) stent. At one year there was no significant difference between the Absorb group and the Xience group in rates of cardiac death, target-vessel myocardial infarction, or ischemia-driven target-lesion revascularization. However, stent thrombosis within 1 year occurred in 1.5% of patients in the Absorb group and in 0.7% of patients in the Xience group (P=0.13) which was numerically higher but statistically not significant. Hence , ABOSRB trial showed non inferiority of BVS to current generation available DES. But patient and lesion selection criteria which were used in this trial needs to be kept in mind. Similarly increased risk of stent thrombosis is alarming hence effective duration and need of dual antiplatelet therapy in these patients is currently not known.
DAPT with aspirin and ticagrelor, compared with aspirin alone in patients with prior history of myocardial infarction (MI). DAPT trial compared continuing thienopyridine therapy for 30 months as opposed to stopping it after 12 months in patients who were already taking aspirin after coronary stenting. About two-thirds of the study patients received clopidogrel, and one-third received prasugrel. Patients who had ischemia or bleeding during the first 12 months were excluded from the 12–30-month study. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis and major adverse cardiovascular and cerebrovascular events. The rate of myocardial infarction and death from any cause was was also lower. The rate of moderate or severe bleeding was increased with continued thienopyridine. PEGASUS-TIMI 54 trial randomized 21,162 patients who had had a MI 1 to 3 years prior to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. It was seen that over a three year follow up period both ticagrelor doses reduced, as compared with placebo the rate of the primary efficacy end point which was the composite of cardiovascular death, myocardial infarction, or stroke. However, rates of TIMI major bleeding were significantly higher with ticagrelor than with placebo. Hence above trial results demonstrate that in patients with history of ACS which are at high risk of further ischemic events may benefit from prolonged ticagrelor based DAPT but with slightly increased risk of bleeding. Similarly in patients who had undergone stent implantation extending therapy to 30 months reduced the risk of stent thrombosis and MI but also increased the risk of mild to moderate bleeding in patients with or without prior history of MI.
CONCLUSION
To summarize, these recent landmark trials showed benefit of statins in patients without CVD, TAVR emerging as preferred modality for intermediate and high risk severe aortic stenosis, lower BP targets against as recommended by current guidelines, bio-absorbable stents being noninferior to current generation DES and suggested benefit of extended duration of DAPT therapy in post PCI and ACS patients.
REFERENCES
1.
Cushman WC, Goff DC. More HOPE for Prevention with Statins. N Engl J Med 2016; 374:2085-7.
2.
Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 2016; 374:1609-20.
3.
Moat NE. Will TAVR Become the Predominant Method for Treating Severe Aortic Stenosis? N Engl J Med 2016; 374:1682–3.
4.
SPRINT Research Group, Wright JT, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015; 373:2103-16.
DAPT AND PEGASUS-TIMI 54
Dual antiplatelet therapy (DAPT) is standard treatment for patients with acute coronary syndromes (ACS) and in patients undergoing DES implantation and includes use of aspirin with either an irreversible thienopyridine P2Y12 inhibitor, clopidogrel or prasugrel, or ticagrelor. DAPT study assessed the benefit of extended Post-PCI DAPT in patients with or without acute coronary syndrome. PEGASUS-TIMI 54 examined the effects of long-term
Perkovic V, Rodgers A. Redefining Blood-Pressure Targets-SPRINT Starts the Marathon. N Engl J Med 2015; 373:21758.
9.
Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372:1791-800.
6.
Ellis SG, Kereiakes DJ, Metzger DC, Caputo RP, Rizik DG, Teirstein PS, et al. Everolimus-Eluting Bioresorbable Scaffolds for Coronary Artery Disease. N Engl J Med 2015; 373:1905-15.
7.
Byrne RA. Bioresorbable Vascular Scaffolds--Will Promise Become Reality? N Engl J Med 2015; 373:1969-71.
8.
Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371:2155-66.
10. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; doi:10.1016/j.jacc.2016.03.513.
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To Assess Predictive Value of Carotid Artery Intima Media Thickness as a Non-Invasive Marker for Coronary and Cerebral Artery Disease Gurmukh S Sainani, Mitul A Shah
INTRODUCTION
There is a great interest in identifying asymptomatic patients at high risk who might be candidates for more intensive, evidence based medical interventions that reduce cardiovascular disease (CVD) and cerebrovascular disease risk. Measurement of carotid intima media thickness (CIMT) with B-mode ultrasound is a noninvasive and reproducible technique for identifying subclinical vascular disease and for evaluating CVD risk. Earlier endothelium was thought to be a smooth, intact non-thrombogenic lining of the arterial wall but now it is known that the endothelium produces vasoactive factors which are divided into 2 groups. Endothelial derived relaxing factors (EDRF) eg nitric oxide (No) and prostacyclin (PG12) and Endothelial derive constricting factors (EDCF) like Endothelin-1 and Thromboxane A2 (TXA2). These factors balance the effects of vascular tone and vascular structure and preserve a smooth nonthrombogenic luminal surface. The alterations in these factors, if allowed to become chronic, are responsible for changes in vascular structure and growth and adhesions to platelets and leukocytes leading to atherosclerosis.1
ENDOTHELIAL CELL DYSFUNCTION CAN BE ASSESSED BY 3 METHODS
1.
Intima media thickness (IMT)
2.
Brachial artery flow mediated dilatation (FMD)
3.
Ankle brachial index (ABI)
Atherosclerotic vascular disease begins in childhood and progresses over decades. Symptomatic, clinical cardiovascular disease (CVD) events generally occur when atherosclerosis progresses to flow limiting disease that causes ischemia or when thrombus forms on an existing plaque as a result of rupture or erosion2. The greater the degree of subclinical atherosclerosis, the greater is the risk of future cardiovascular events3-7. To prevent morbidity and death from CVD, there is great interest in identifying asymptomatic patients at high risk who would be candidates for more intensive, evidence based medical interventions that reduce CVD risk. Measurement of carotid intima media thickness (CIMT) with B-mode ultrasound is a non-invasive, sensitive and reproducible technique for identifying and quantifying
atherosclerotic burden and CVD risk. It is a well validated research tool that has been translated increasingly into clinical practice8-12. Measuring CIMT and identifying carotid plaque can be useful for refining CVD risk assessment. CIMT testing can reclassify patients at intermediate risk, discriminate between patients with and without prevalent CVD and predict major adverse CVD events. CIMT measurements should be limited to the far wall of the common carotid arteries and should be supplemented by a thorough scan of the extra cranial carotid arteries for the presence of carotid plaque to increase sensitivity for identifying subclinical vascular disease. Carotid plaque is defined as the presence of focal wall thickening that is at least 50% greater than that of the surrounding vessel wall or at a focal region with CIMT greater than 1.5 mm that protrudes into the lumen which is distinct from the adjacent boundary. The presence of carotid plaque or CIMT greater than or equal to 75th percentile for patientâ&#x20AC;&#x2122;s age, sex, race and ethnicity are indicative of increased CVD risk and may signify the need for more aggressive risk reduction interventions. According to the recommendations of American Society of Echocardiography (ASE), patients with the following clinical circumstances also might be considered for CIMT testing: (1) Family history of premature CVD in a firstdegree relative (2) Individuals younger than 60 years with severe abnormalities with a single risk factor who otherwise would not be candidates for pharmacotherapy or (3) Women younger than 60 years of age with at least two CVD risk factors. This test can also be considered if the level of aggressiveness of therapy is uncertain and additional information about the burden of subclinical vascular disease or future CVD risk is needed.
AIMS AND OBJECTIVES
1.
To ascertain whether there is any correlation between the grade of CIMT and the severity of coronary artery disease. (CAD as assessed by coronary angiography).
2.
To ascertain whether there is any correlation between the CIMT and severity of cerebrovascular disease.
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Table 1: Group wise CIMT values RCCA Mean-Max CIMT (MM)
LCCA Mean-Max CIMT (MM)
Mean
Standard Deviation
Mean
Standard Deviation
Group A (CAD)
0.860
0.224
0.858
0.247
Group B (CVA)
0.752
0.183
0.808
0.222
Group C (Controls)
0.544
0.143
0.554
0.146
RCCA (right common carotid artery); LCCA (left common carotid artery); The mean CIMT (carotid intima media thickness) in RCCA and LCCA in coronary artery disease (CAD) and cerebrovascular disease (CVA) are significantly higher than controls.
To establish the range of CIMT in normal persons (controls).
MATERIAL AND METHODS
We carried out the study in a large accredited institute (Jaslok Hospital and Research Centre) serving as a tertiary care centre. The subject was approved by scientific committee and ethnical committee of Jaslok Hospital and Research Centre. Total 125 subjects in the age group of 30-75 years were selected from the inpatient and outpatient departments of the Jaslok Hospital and Research Centre, Mumbai. We selected 3 groups of subjects Group A (CAD) : Coronary artery disease patients â&#x20AC;&#x201C; These patients underwent coronary angiography and were documented as having coronary artery disease (50 cases) Group B (CVA): Cerebrovascular disease patients: Patients admitted with stroke (cerebrovascular accidents and confirmed by CT, CT-angio and/or MRI - 25 cases) Group C (Controls) â&#x20AC;&#x201C; These subjects were selected from health check-up, staff members of the hospital who had no complaints, no abnormal physical findings with normal BP, normal ECG and normal blood reports (50 subjects). All 125 subjects were studied as per the protocol enquiring about complaints, any history of smoking, tobacco chewing or alcohol intake, past history of hypertension, diabetes mellitus, dyslipidemia, coronary artery disease or cerebrovascular disease. After obtaining a written and informed consent from each individual selected for this project, carotid ultrasound study was performed in the department of ultrasonography at the Jaslok Hospital and Research Centre. We recorded age, sex, body mass index, pulse, blood pressure, fasting and 2 hours post lunch blood sugar, lipid profile, ECG, X-ray chest. Coronary angiographies for CAD cases and CT, CT angio and/or MRI for stroke cases were done. As recommended by Stein J H et al,3 while describing the consensus statement from the American Society of Echocardiography, Carotid Intima Media Thickness Task Force, the maximum CIMT (CIMT-Max) was measured in the far wall of the proximal, middle and distal segments of both common carotid arteries and the mean of the three CIMT-Max values or the highest value was taken
as the final Mean-Max CIMT. These measurements were supplemented by a thorough scan of the extra cranial carotid arteries for the presence of carotid plaque which is supposed to increase sensitivity for identifying subclinical vascular disease. Carotid plaque is defined as the presence of focal wall thickening that is at least 50% greater than that of the surrounding vessel wall or at a focal region with CIMT greater than 1.5 mm that protrudes into the lumen and is distinct from the adjacent boundary. The various parameters were analysed statistically. We studied the demographic distribution of the patients taken in the study and also compared the CIMT values among all three groups along with various cardiovascular disease (CVD) risk factors. We also studied whether the presence or absence of carotid plaque had any correlation with CAD or CVD along association with various CVD risk factors.
RESULTS
There was a significant increase in CIMT on both sides in those with CAD (Group A) as compared to the normal individuals (Group C) (P value 0.000) (Table 1). The group A (CAD) was further subdivided into three subgroups as per the number of coronary arteries involved (1 vessel, 2 vessels and 3 vessels) and the CIMT values were compared (Figures 1 & 2). It was found that there was a significant difference in the CIMT between those with 1 vessel and 3 vessels CAD on right side (p value <0.001). Also it was found that there was significant difference in the CIMT between those with 1 vessel and 3 vessels CAD and those with 2 and 3 vessels CAD on left side (P valve<0.001) Also a significant increase in CIMT was observed on either side in those with CVA (Group B) as compared to the normal individuals (Group C) (P value 0.000) (Table 1 and Figure 3). The number of hypertensive individuals in Group A and Group B were 37 and 15 respectively while the others were non-hypertensive. We found that there was a significant difference in CIMT on either side in hypertensive versus non-hypertensive individuals (P value 0.000 for both sides). The number of diabetic individuals in Group A and Group B were 18 and 10 respectively while the others were nondiabetics. Here also a significant difference was found in CIMT on either side in diabetic versus non-diabetic
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3.
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Comparison of RCCA Mean-Max CIMT (mm) as per no. of coronary arteries involved
Comparison of RCCA and LCCA Mean-Max CIMT (mm) among study groups
0.80 0.90
0.70 0.90
0.70 Median value
0.60 0.80
0.50
0.50 0.40 0.30
0.50
0.50
0.20 0.10
0.40
0.00
0.70
0.30
Group B
Group C
RCCA Mean-Max CIMT (mm)
0.20
CARDIOLOGY
0.80
0.60 Median value
0.80
0.80
0.10 0.00
One (1)
Two (2) Number of Vessels involved
Three (3)
Fig. 1: There was a significant difference in the CIMT between those with 1 vessel CAD and 3 vessels CAD on right side (P value <0.016) Comparison of LCCA Mean-Max CIMT (mm) as per no. of coronary arteries involved 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00
Group B
Group C
LCCA Mean-Max CIMT (mm)
Fig. 3: There was a significant increase in CIMT on either side in those with CVA as compared to the normal individuals (P value 0.000 for both sides) Cerebrovascular Accidents and CIMT
In a study performed by Sahoo R et al.,7 it was found that the CIMT was independently associated with the presence of carotid plaques and strokes. Thus the findings of our study that the CIMT is positively correlated with the presence of CVA are supported by the above study.
Hypertension and CIMT
individuals (P value <0.004 and <0.012 for right and left side respectively).
In a study conducted by Yarynkina et al8, the relationship between CIMT and other cardiovascular disease risk factors in 77 patients with mild and moderate essential hypertension (EH) was assessed and it was concluded that common carotid artery IMT changes are related with BP elevation, in part with pulsatile component of BP (Systolic BP, Pulse Pressure). In another study conducted by Sharma P et al9, the CIMT was evaluated in 203 hypertensive cases and 101 normotensive individuals (controls). Mean IMT was significantly high in hypertensive patients compared to the control group (p< 0.001). In addition they found a significant difference in IMT of bilateral common carotid arteries between the smokers and non-smokers hypertensive patients (p <0.02). In conclusion, the study revealed a strong correlation between IMT of common carotid arteries and hypertension. Thus, our observations are in echo with the above mentioned studies.
DISCUSSION
Diabetes Mellitus and CIMT:
Median value
1.00
0.70 0.60
One (1)
Two (2) Number of Vessel involved
Three (3)
Fig. 2: A significant difference in the CIMT was noted between those with 1 vessel CAD versus 3 vessels CAD and 2 vessels CAD versus 3 vessels CAD on left side (P value <0.001)
Coronary Artery Disease and CIMT
In the ARIC (Atherosclerosis Risk in Communities) Study conducted by Nambi V et al.4 it was concluded that adding plaque and CIMT to traditional risk factors improves CHD (Coronary Heart Disease) risk prediction. In another study conducted by Yoshida M at al5, it was concluded that Carotid IMT is a significant predictor of CVD (Cardiovascular diseases) in asymptomatic type II diabetic patients and the combination of Framingham Risk Score (FRS) and IMT improves the prediction of CVD in these patients. Bots ML et al.6 studied whether common carotid IMT is related to future stroke and myocardial infarction and found that an increased common carotid IMT is associated with future cerebrovascular and cardiovascular events.
Sainani G S and Khan N10, found a very strong correlation of diabetes mellitus and CIMT and they concluded that: (1) Post-prandial hyperglycemia is directly responsible for increase in CIMT and as the level of post-prandial blood sugar increases there is proportionate increase in the CIMT; (2) With increasing age, there is proportionate increase in CIMT in patients with post prandial hyperglycemia as compared to those without post prandial hyperglycemia; (3)There is increase in CIMT with increase in the duration of diabetes mellitus; (4) There is no gender bias in CIMT among patients with post prandial hyperglycemia; (5) Smoking and alcohol accelerate CIMT in patients with post prandial hyperglycemia. There is a study conducted by Inohara T et al11 in which they found CIMT >or=1.6 as the independent predictor of
coronary artery plaque and it was proven that the CIMT is a useful screening tool to detect coronary artery plaque in type II diabetic patients with Calcium Score of zero. In another study by Irie Y et al12, it was concluded that in type II diabetic patients without apparent cardiovascular disease, the addition of max-IMT to conventional risk factors substantially improves the risk stratification for CAD.
Carotid Plaque and its Various Associations:
CONCLUSIONS
1.
The mean CIMT in the normal healthy individuals (controls) in this study population on the right side is (0.544 ± 0.143) mm and on the left side is (0.554 ± 0.146) mm.
2.
CIMT is positively correlated with the presence of coronary artery disease, severity of coronary artery disease, presence of cerebrovascular accidents, presence of hypertension and diabetes mellitus.
3.
It was also found that the presence of carotid artery plaque has a very strong association with CAD and CVA.
REFERENCES
1.
Sainani GS, Bhatia MS, Sainani RG. Endothelial Cell Dysfunction-A Key Factor in Atherogenesis and its Reversal (laboratory and Clinical Study); Atherosclerosis, Hypertension and Diabetes; Edited by Pierce G N, Nagano Makoto, Zahradka P, Dhalla N S; Kluwer Academic Publishers; 2003; p. 27-51.
2.
Virman R, Burke AP, Farb A. Kolodgie FD – Pathology of the vulnerable plaque. J Am Coll Cardiol 2006; 47:C13-8
3.
Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement
4.
Nambi V, Chambless L, Folsom AR, et al. Carotid intimamedia thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk In Communities) study. J Am Coll Cardiol 2010; 55:1600 –7.
5.
Yoshida M, Mita T, Yamamoto R, Shimizu T, Ikeda F, Ohmura C, Kanazawa A, Hirose T, Kawamori R, Watada H. Diabetes Care 2012; 35:178-80.
6.
Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997; 96:1432–7.
7.
Sahoo R, Krishna MV, Subrahmaniyan DK, Dutta TK, Elangovan S. Neurol India 57:627-30.
8.
Yarynkina O, Svyshchenko E, Mishchenko L, Tchyrulneva N, Mospan M, Yegorushkin V. Relationship Between Carotid Intima-Media Thickness and Cardiovascular Risk Factors in Hypertensive Patients; Journal of Hypertension 28 e-–Supplement A:e592, June 2010.
9.
Sharma P, Lohani B and Chataut S P; Ultrasonographic evaluation of carotid intima-media thickness in hypertensive and normotensive individuals; Nepal Med Coll J 2009; 11:133-135.
10. Sainani G S, Khan N; Carotid Artery Intima Media Thickness – A Correlative Study of Diabetics with Postprandial Hyperglycemia versus Controls with Euglycemia; Medicine Update 2012; 22:298-303. 11. Inohara T, Niinuma H, Niwa K. J Am Coll Cardiol 2012; 59(13s1):E1155-E1155. doi:10.1016/S0735-1097(12)61156-5. 12. Irie Y, Katakami N, Kaneto H, Kasami R, Sumitsuji S, Yamasaki K, Tachibana K, Kuroda T, Sakamoto K, Umayahara Y, Ueda Y, Kosugi K, Shimomura I. Atherosclerosis 2012; 221:438-44. Epub 2012 Jan 21.
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Here we found that the presence of carotid plaque has a very strong association with the presence of CAD and CVA and is supported by previous studies.
from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. J Am SocEchocardiogr 2008; 21:93–111.
C H A P T E R
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Two-and Three-Dimensional Echocardiographic Assessment of the Aortic Valve Efstathia Andrikopoulou, Garima Arora, Navin C Nanda
Aortic valve (AV) is a semilunar valve composed of three cusps and its orifice normally measures 3 to 4 cm2. Degenerative calcific changes occurring in the elderly may lead to a stenotic orifice resulting in hypertrophy of the left ventricle and symptoms such as exertional dyspnea, angina and exertional syncope. In younger patients, rheumatic involvement may produce commissural fusion leading to stenosis. AV stenosis (AS) may be associated with varying degrees of regurgitation (AR). In approximately 1-2% of population the AV is congenitally bicuspid with only 2 leaflets. This has a greater predilection for developing stenosis in younger patients and may be associated with weakness of the ascending aortic wall leading to aneurysm formation and dissection, the so-called bicuspid AV syndrome. Other variants of AV
Table 1: Estimation of Aortic Valve (AV) Gradients (G) and Orifice Area (A) by Echo/Doppler A. Maximum and mean AV Gâ&#x20AC;&#x2122;s are estimated by converting maximum and mean AV velocities (V) obtained with continuous wave Doppler using the modified Bernoulli formula: G = 4 xV2 (mmHg). B. AVA is calculated using the Doppler principle (LVOT/AV flow= area x velocity) and continuity equation (flow volume same in LVOT and aortic root). Volume of flow in LVOT is calculated by multiplying LVOT area (obtained from 2D echo measured diameter assuming circular configuration) with velocity time integral (VTI) obtained by pulsed wave Doppler. AV VTI is obtained by continuous wave Doppler. AVA = 0.785 x (LVOT diameter) 2 x LVOT VTI/AV VTI. Since VTI is related to velocities, it can be substituted by either maximum or mean velocities in this equation. LVOT= left ventricular outflow tract.
including quadricuspid and unicuspid AV have also been reported but they are rare.
AV STENOSIS
This is most commonly assessed by two-dimensional transthoracic echocardiography (2DTTE) and Doppler. Tables 1-3 show the methods to do this and include pitfalls and several useful tips to overcome some of them. It should be stressed that the pressure gradients and the continuity equation are flow-dependent and thus only provide an indirect estimate of the AVorifice area (A) and the severity of AS. Under- or over-estimation of the severity of AS can be seen in up to 15% of patients. Underestimation often stems from errors in Doppler interrogation of the AV, whereas overestimation is usually seen in cases of significant pressure recovery. To overcome this, direct planimetry of the AV has been proposed as another method to obtain accurate measurement of the AV. 2D TTE planimetry is hampered by the difficulty in identifying the flow limiting tips of AV leaflets where the orifice would be smallest. This is specially the case in patients with poor acoustic windows and those with extensively calcified leaflets which makes it difficult to visualize the AV leaflets and their motion. Twodimensional transesophageal echoardiography (2D TEE) is more helpful in obtaining planimetry of AVA because of superior quality images provided by this modality but is less helpful in obtaining maximum pressure gradients because of the difficulty in aligning the Doppler beam parallel to the AS jet in the limited windows available in the transgastric approach which is commonly used to assess AS severity.
IMPORTANT SUBGROUPS OF AS
Low Flow Low Gradient AS
In some cases, both the pressure gradient across the AV
Table 2: Criteria for Determination of AS severity Degree of severity
AVA (cm2)
Mean AV gradient (mmHg)
Maximum AV velocity (m/s)
Dimensionless Index (DI)
Mild
>1.5
<20
<2
>0.50
Moderate
1-1.5
20-40
2-4
0.25-0.50
<1 (AVAi< 0.6 cm2/m2)
>40
>4
<0.25
Severe
2DTTE: Two-dimensional transthoracic echocardiography; AVAi: Aortic valve area indexed to body surface area; other abbreviations as in the previous table. Dimensionless index = LVOT VTI/ AV VTI. This is a useful index since it bypasses potential errors in the measurement of LVOT diameter.
Table 3: Pitfalls and Useful Tips in the Assessment of AS Severity by 2D TTE.
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1. Poor acoustic window, calcification of mitral and/or aortic valve annulus may preclude accurate assessment of LVOT diameter. Tip: Optimizing transducer angulation and gain settings may help in the latter case. 2. Poor acoustic window may preclude accurate assessment of AV pressure gradient. Tip: All windows which visualize the AV ((apical, left and right parasternal, suprasternal/supraclavicular and subcostal) should be utilized in a given patient to obtain maximum velocities. Consider TEE.
4. The LVOT velocity profile is assumed to be laminar and flat. Tip: Does not appear to cause any significant error in clinical practice. 5. Doppler cursor may not be aligned with the jet core leading to underestimation of the severity of AS. Tip: Use color Doppler guidance for alignment with AS jet flow and multiple transducer angulations. 6. Difficulty in differentiating LVOT velocity by pulsed wave Doppler from higher velocity flow acceleration. Tip: Keep pulsed wave Doppler sample volume just outside the flow acceleration area identified by color Doppler, measure diameter in mid-systole. 7. Continuity equation gives only indirect measurement of AVA. Also, overestimates AS severity in many patients especially if the LVOT is narrow or borderline narrow (around 20 mm). Tip: Preservation of A2 by auscultation, large AVA by 2D TTE/3D TTE planimetry and good opening of AV leaflets help exclude severe AS. Beware patients with congenital AS where the domed leaflets may appear to open normally because stenosis is located at the AV tip which may not be identified by 2D TTE. 3DE is helpful in these cases. 8. Eccentric AS jet may preclude parallel alignment of the Doppler cursor in measurement of maximum AV velocity. Tip: Use multiple transducer angulations to obtain maximum jet velocity. 9. Jet originating from mitral regurgitation may be mistaken for or “contaminate” jet of AS. Tip: Timing of onset of LVOT waveform in relation to the QRS complex of the EKG would be same as AS jet. MR jet would originate earlier. 10. Low stroke volume may underestimate severity of AS. Similarly, high cardiac output may lead to its overestimation. Tip: Use low dose Dobutamine when low stroke volume or flow rate as explained in the text and mentioned in Figure 1. Evaluate for underlying significant anemia. 11. Pressure recovery may lead to overestimation of severity of AS. Tip: Correction factors have been suggested but need further validation. Beware small LVOT and aorta as explained in the text. 12. Co-existing supra or sub-valvular pathology of the AV may impact accurate assessment of severity of AS since CW Doppler will give the maximum gradient but cannot localize its origin. Tip: Planimetry by 2D/3D TTE will help differentiate. 3DE: Three-dimensional echocardiography; other abbreviations as in previous tables.
and the AVA (as calculated by the continuity equation) may be low. This is seen in patients with underlying low cardiac output and low ejection fraction (EF), such as significant left ventricular (LV) systolic dysfunction, mitral stenosis and dilated cardiomyopathy. In these cases, it is best to proceed with low dose Dobutamine stress test (maximum dose of 20 mcg/kg/min) to assess for underlying contractile reserve and distinguish between truly severe AS and pseudosevere AS (Figure 1).
Low Gradient Severe AS with normal LV function
Severe AS by the continuity equation may also be seen in association with paradoxically low gradients in a subgroup of patients with normal LV function and EF, especially elderly women with small and severely
hypertrophied LV’s and advanced diastolic dysfunction. This is attributed to low transvalvular stroke volume and low flow rate (<200mL/sec) across the AV which accounts for low gradients. In these cases also, low dose Dbutamine stress echocardiography can be used to distinguish true from pseudosevere AS (Figure 1).
Pressure Recovery
Occasionally, Doppler and invasive gradients may be discordant (Doppler-high, catheterization-normal-low) and this could be due to the phenomenon of pressure recovery. This phenomenon is based on the principle of conversion of potential energy (pressure) to kinetic energy (velocity), which occurs at the level of the stenosis. Some of the energy is also lost as heat, turbulence, friction
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3. Assumption that the LVOT is circular and its cross-sectional area remains constant throughout systole (when using the continuity equation). Tip: May consider using LV-Aortic junction for LVOT measurement since it does not change in size during the cardiac cycle and appears circular.
CARDIOLOGY
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Fig. 1: Algorithm for approaching patients with severe aortic stenosis (AS) and mismatch between their aortic valve (AV) orifice area (A) and pressure gradient. When peforming a Dobutamine stress test in patients with AS, the presence (or absence thereof) of contractile reserve, defined as an increase in the stroke volume by >20% with Dobutamine, is an important prognostic marker, especially in patients undergoing evaluation for surgical replacement of the AV. Since AVA derived from the continuity equation is not reliable in many situations as explained in the text, it may be useful to assess it by two- or three- dimensional echo planimetry, preferably the latter. EF: left ventricular ejection fraction or eddy currents. Distal to the stenosis, velocity is once again converted back to pressure (“pressure recovery”). Invasive assessment of pressure (catheterization) is always done at some distance from the stenosis (AS), which is after “pressure recovery” has already occurred. This is in contrast to Doppler measurements which are done at the level of stenosi, correlating with maximal drop in pressure. It should be noted that it is Doppler that gives the correct estimate of the gradient across the stenotic valve, however, the afterload “seen” by the LV more accurately correlates with the distal pressure as measured invasively, and therefore, catheterizationderived gradient may be more physiologic. Pressure recovery phenomenon is most often seen in patients with small LVOT (≤20mm), small diameters of the aorta (≤30mm at the level of the sinotubular junction), with long tubular AS (not discrete ones) and when there is systolic doming of the AV. Of note, in some rare cases, AS might be severe by Doppler gradients, but not by catheterization and pressure recovery is not significant. In these cases, Doppler may be detecting focal areas of high gradients, through the heavily calcified AV. To best resolve these cases, one can directly measure the AVA by three-dimensional echocardiography (3DE) either 3D TTE or 3D TEE or even 2D-TEE and thus grade AS severity.
INCREMENTAL VALUE OF 3DE
A major advantage conferred by 3D echo over the 2D modality is its ability to acquire the entire extent of the AV and its surrounding structures in the 3D data set which facilitates cropping and sectioning using multiple planes
and at any desired angulation including obtaining en face views of the AV. On the other hand, 2D provides only thin sections of the AV and its surrounding structures at any given time precluding comprehensive and accurate assessment. Because of this advantage, 3D provides more accurate assessment of AV morphology especially in patients with bicuspid valves with a prominent raphe which could be mistaken for a tricuspid AV on 2D imaging. Because of the ability to systemically and comprehensively section the AV data set, the flow limiting tips of the AV can also be more easily and reliably identified and the orifice area planimetered by 3D echo as compared to the 2D technique resulting in more accurate assessment of AVA. 3D TEE provides superior quality images as compared to 3D TTE but TEE is semi-invasive and not entirely devoid of risk and discomfort to the patient.
AORTIC REGURGITATION
AR can arise from abnormalities of the AV itself (degenerative calcification, bicuspid AV) or from primary dilation of the aortic root and proximal ascending aorta. In the developing world, rheumatic heart disease remains a common cause of AR. AR is primarily a state of volume overload, which over time leads to eccentric LV hypertrophy and initially an increased LV EF. As the LV slowly fails to continue adapting to the excess volume, pressure overload also develops, LV EF begins to drop and patients develop symptoms, commonly exercise intolerance and dyspnea. Much like AS, 2DE and 3DE are the mainstay for the assessment of the presence and severity of AR. In clinical practice, this is most often done qualitatively by observing
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Table 4: Echo Criteria for Grading Aortic Regurgitation (AR) Severity. Degree of severity
Mild
Severe
VC* (cm2)
PHT** (msec)
EROA*** (cm2) by PISA method
RV+ (mL)
RF+
Holodiastolic LV flow reversal dilation## in isthmus/ proximal descending aorta#
Density and contour of AR jet###
<25%
<0.3
>500
<0.1
<30
<30
No
No or mild Low density, faint or incomplete contour
25%-59%
0.3-0.6
200-500
0.1-0.29
30-59
3049
No
Mildmoderate
Higher density compared to mild, more completely filled contour
>60%
>0.6
<200
≥0.3
≥60
≥50
Yes, Also prominent.
Severe
Similar to moderate, high density, contour spherical to triangular (very severe)
EROA: estimated regurgitant orifice area; LV: left ventricular; PHT: pressure half-time; PISA: proximal isovelocity surface area; RF: regurgitant fraction; RV: regurgitant volume. VC: vena contracta; other abbreviations as in previous tables. *VC measurements can be obtained by 3DE for greater accuracy. Add VCs if more than one jet. Potentially VC method ideal but suffers from many institutions not having 3D transducers. ** More useful in acute than chronic AR. Difficult to keep the ultrasonic beam parallel to AR jet throughout diastole and hence correct PHT may not be obtained. Also, affected by LV compliance. *** Suffers from inaccuracy because a mostly incorrect assumption is made that the flow acceleration is hemispherical. + Inaccurate in the presence of moderate/ severe MR. #Useful to confirm severe AR found by the jet width/LVOT width method and in cases with eccentric AR or where the AR jet is not well visualized. Color Doppler should be used to place the pulsed wave Doppler sample volume in the middle of the reversed flow signals (red in color) at the level of the aortic isthmus which is the junction of the aortic arch with the descending thoracic aorta (at the level of origin of the left subclavian artery) using suprasternal examination approach. Beware: pandiastolic backflow may be seen in patients with patent ductus arteriosus and other systemic arterio-venous shunts. Proximal abdominal aorta may be used if the suprasternal window is poor or unavailable but is less sensitive. ## Dilation of the LV may be seen in other conditions. ### Density and contour depend on the direction of the jet (inaccurate for eccentric AR) and their appearance might overlap for moderate-severe AR.
the proximal AR jet width in relation to LV outflow tract (OTO) diameter. Quantitative estimation requires more sophisticated 2DE and 3DE methods (See Tables 4 and 5).
segments and detect aneurysm or dissection which could be causing AR.
TEE IN THE EVALUATION OF AR
As mentioned above, 3DE allows for direct, en face, visualization of the AV, which helps in reliable assessment of AV morphology. 3DE is superior to 2DE in evaluating other causes of AR such as vegetations, perforations and aortic fibroelastomas. 3DE has also been found more accurate in identifying mostly benign lesions such as Lambl’s excrescences and thickened nodules of Arantius which can mimic tumor masses. In addition, it may facilitate grading the severity of AR by direct measurement of the area of AR vena contracta (VC), which essentially represents the “hole” or defect in the AV through which AR occurs. 3DE may also provide more
TEE supplements TTE when the transthoracic acoustic window is poor and in the intra-operative setting. The TEE criteria used for severity assessment are essentially similar to TTE except the proximal jet width tends to be somewhat larger because of the higher resolution provided by the higher frequency TEE transducer.. Similar to AS, it is more challenging to properly align the Doppler beam and thus obtain reliable estimates of AR velocity needed for calculating, ARt volume and fraction.. However, use of TEE may improve visualization of different aortic
INCREMENTAL VALUE OF 3DE
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Moderate
AR Jet width/ LVOT width
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Table 5: Pitfalls and Tips in the Assessment of AR Severity by 2DTTE using AR Jet Width/LVOT Width Ratio
CARDIOLOGY
• Most widely used method in clinical practice. • Preferably use parasternal long axis view since LVOT width is usually maximum in this view. Measure jet width at the origin of AR from AV (essentially the vena contracta, VC) and measure LVOT inner width in the same frame. AR jet may fan out immediately after its exit from the AV hence important not to measure the width further downstream otherwise overestimation will occur. • Keep Nyquist limit in low fifties. Increasing the Nyquist limit which also changes the color filter tends to decrease AR jet width leading to underestimation of AR severity. Conversely, lower Nyquist limits will increase AR jet width leading to overestimation. • Similar to the Nyquist limit, standardize color gain. Increase color gain till noise and artifacts appear, then slowly reduce it till they just disappear and use that setting for grading AR severity. Use very high Nyquist limits in eccentric jets to visualize origin and course of AR jet. • Use multiple acoustic windows to optimize AR visualization. Short axis view not recommended to grade AR severity because cardiac motion makes it difficult to accurately identify AR jet origin. • Severe AR found by this method may be further confirmed by suprasternal examination (see Table 4) to increase the confidence level. • AR jet origin may be difficult to visualize in the presence of AV vegetations which may disperse the jet. Also, AR severity may be underestimated by one grade in the presence of aortic root aneurysm. In these cases, try different acoustic windows. Suprasternal examination would help in excluding severe AR Abbreviations as in previous tables.
accurate quantification of LV volumes when following patients with chronic AR and trying to determine timing for surgery. Lastly, it might have potential in estimating the AR volume by quantifying the left and right sided stroke volumes. 3DTEE is also increasingly used in patients with prior AV replacement, both surgical and transcatheter, to more accurately diagnose paravalvular leaks by clearly demonstrating their location and size. In conclusion, judicious use of multiple echocardiographic modalities including 2DE/Doppler, 3DE and low dose Dobutamine helps in the comprehensive assessment of the AV for stenosis and regurgitation.
REFERENCES
1.
Nanda NC (Ed): Comprehensive Textbook of Echocardiography. New Delhi, India: Jaypee Brothers Medical Publishers (P) Ltd, 2014
2. Nanda NC, Karakus G, Değirmencioğlu A (Eds): 4.Manual
of Echocardiography. New Delhi, India: Jaypee Brothers Medical Publishers (P) Ltd, 2016. 3.
Nanda NC, Hsiung MC, Miller AP, Hage FG: Live/ Real Time 3D Echocardiography. Oxford, U.K.: WileyBlackwell, 2010.
4. Nanda NC and Domanski M: Atlas of Transesophageal Echocardiography. 2nd edition. Baltimore: Lippincott, Williams and Wilkins, a Wolters Kluwer business, 2007 5.
Enriquez-Sarano M, Tajik AJ. Clinical practice. Aortic regurgitation. N Engl J Med 2004; 351:1539-46.
6.
Hachicha Z, Dumesnil JG, Bogaty P, Pibarot P. Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival. Circulation 2007; 115:285664.
7.
Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr 2009; 22:1-23; quiz 101-2.
8.
Zamorano JL, Badano LP, Bruce C, Chan KL, Goncalves A, Hahn RT, et al. EAE/ASE recommendations for the use of echocardiography in new transcatheter interventions for valvular heart disease. J Am Soc Echocardiogr 2011; 24:93765.
9.
Pibarot P, Dumesnil JG. Improving assessment of aortic stenosis. J Am Coll Cardiol 2012; 60:169-80.
10. Pibarot P, Dumesnil JG. Low-flow, low-gradient aortic stenosis with normal and depressed left ventricular ejection fraction. J Am Coll Cardiol 2012; 60:1845-53. 11. Bartko PE, Heinze G, Graf S, Clavel MA, Khorsand A, Bergler-Klein J, et al. Two-dimensional strain for the assessment of left ventricular function in low flow-low gradient aortic stenosis, relationship to hemodynamics, and outcome: a substudy of the multicenter TOPAS study. Circ Cardiovasc Imaging 2013; 6:268-76. 12. Perez de Isla L, Zamorano J, Fernandez-Golfin C, Ciocarelli S, Corros C, Sanchez T, et al. 3D color-Doppler echocardiography and chronic aortic regurgitation: a novel approach for severity assessment. Int J Cardiol 2013; 166:640-5. 13. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, 3rd, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg 2014; 148:e1-e132. 14 Capoulade R, Pibarot P. Assessment of Aortic Valve Disease: Role of Imaging Modalities. Curr Treat Options Cardiovasc Med 2015; 17:49. 15. Senior R, Chahal NS, Drakopoulou M et al.Resting arotic valve area at normal transaortic flow rate but not at normal stroke volume reflects the true valve area in patients with low gradient severe aortic stenosis: implications for obviating the need for stress echocardiography in such patients. British-Cardiac-Society (BCS) Annual Conference on Hearts and Genes. Publisher: BMJ Publishing Group. Pages: A55-A55, ISSN: 1355-6037. 16. Chahal NS, Drakopoulou M, Gonzalez-Gonzalez AM, et al. Resting aortic valve area at normal transaortic flow rate reflects the true valve area in suspected low gradient severe aortic stenosis. JACC Cardiovascular Imaging 2015; 8:113339.
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Management of Atrial Fibrillation in Indian Scenario Saumitra Ray, Amitava Mazumdar
INTRODUCTION
Atrial Fibrillation (AF) is the most prevalent sustained arrhythmia. Overall global prevalence of AF is 1-2% in the adult population with prevalence increasing with increasing age. AF increases overall and cardiovascular mortality. 20 to 30% of all strokes and left ventricular dysfunction are associated with AF. AF is also associated with high rate of hospitalization and poor quality of life. AF must be aggressively diagnosed and managed to reduce the high mortality and morbidity associated with that.
EPIDEMIOLOGY
In developed countries almost 25% of middle aged persons are expected to have AF in their lifetime. In the European Union annual incidence of AF is 120000 to 215000. After the age of 65 years, the prevalence of AF reaches almost 6%. The United Nation Population Fund has projected a 326% increase of people aged between 60 to 80 years in India over next decade. Non-valvular AF (NVAF) is associated with a 500% increased risk of stroke. The AF related strokes are more severe. The risk of stroke in AF increases with age, being 1.5% at 50 to 59 years of age to 23.5% at 80 to 89 years. Valvular AF is associated with a 17 fold increased risk of stroke. The West Birmingham Atrial Fibrillation project showed a prevalence of 0.6% in the Indian subset. However, there is paucity of epidemiological data to
Table 1: Classification of AF Name
Description
First diagnosed AF
when detected first, irrespective of suspected duration and symptoms
Paroxysmal AF
when terminated of its own or by cardioversion within 7 days of onset
Persistent AF
when lasted for more than 7 days, even if terminated later on
Long standing persistent AF
when persisting more than a year but planned to be converted
Permanent AF
when cardioversion option is abandoned.
determine the true incidence and prevalence of AF in India. Recently the Indian Heart Rhythm Society - Atrial Fibrillation (IHRS-AF) registry, REALIZE-AF and Indian subgroup analysis (unpublished) of trials of the newer oral anticoagulant (NOAC) have thrown light on the AF scenario in India. The prevalences of paroxysmal AF in the RE-LY (Randomised Evaluation of Long term anticoagulant therapY), REALISE-AF, and IHRSAF study were 38%, 43% and 19.5% respectively and prevalence rates of permanent AF were 18.6%, 34.3% and 33.7% respectively.
DIAGNOSIS AND CLASSIFICATION OF AF
AF is suspected on the basis of pulse examination and confirmed by a 12 lead ECG with a rhythm strip. Sometimes a prolonged (72 hours) ECG monitoring is required. Also it is important to interpret data from implanted pacemakers and ICDs for episodes of AF. AF may be classified as per the duration. This is described in Table 1. In RealiseAF Survey from India it was found that 28.6% patients had paroxysmal AF, 22.6% had persistent AF and 34.3% had permanent AF. AF is also classified on the basis of its pathogenesis: AF secondary to structural heart disease (eg, heart failure, left ventricular hypertrophy), focal AF, polygenic AF, monogenic AF, post operative AF, AF with mitral stenosis or prosthetic heart valve and AF in athletes. Risk factors for developing AF include heart failure (both with reduced and preserved ejection fraction), hypertension, valvular heart disease, diabetes, obesity, chronic obstructive airway disease, hyperthyroidism, hypertrophic cardiomyopathy, sepsis, and chronic kidney disease. Detection and control of the risk factors are essential for AF management.
TREATMENT OF ACUTE (FIRST DIAGNOSED) AF
Acute AF may present with hemodynamic instability, hemodynamically stable but symptomatic and hemodynamically stable and asymptomatic. Hemodynamic instability is usually associated with severe mitral or aortic stenosis, hypertrophic cardiomayopathy, sepsis etc. Direct Current (DC) cardioversion with 150-200 Joules is usually employed. Pharmacological cardioversion may be done with intravenous class Ia (quinidine), Ic (flecainide, propafenone) antiarrhythmic drugs (AAD) if there is no structural heart disease or with amiodarone in presence of structural heart disease. Due to more wide spread availability amiodarone is commonly
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used in India in all situations. Ibutilide and vernakalant are other options. Cardioversion must be done under anticoagulation coverage, like heparin or low molecular weight heparin.
CARDIOLOGY
If the patient is hemodynamically stable and has AF for more than 48 hours, then patient should wait for 3 weeks on adequate oral anticoagulation (VKA or NOAC) before cardioversion and the anticoagulation should continue for at least 4 weeks after the cardioversion. Maintenance of sinus rhythm after successful cardioversion is done with long term AAD use. If there is no structural heart disease dronedarone, propafenone, flecainide and sotalol are recommended. In associated stable coronary artery disease without heart failure, dronedarone is recommended. In presence of heart failure, amiodarone is the drug of choice. AAD should not be used in presence of sinoatrial or atrioventricular node dysfunction without pacemaker backup. Catheter ablation may be contemplated in experienced centres. Pulmonary vein isolation surgery is sometimes effective in paroxysmal AF whereas biatrial maze procedure is suitable for persistent AF. In chronic AF both the physician and patient should decide together whether cardiversion will be attempted or rate control strategy with stroke prevention measures will be accepted. In the later situation, the AF is termed as permanent AF.
RATE CONTROL IN AF
Whether rhythm control has survival benefit over rate control in chronic AF is still controversial. Both acute and long term AF needs ventricular rate control for symptomatic benefit. Beta blockers, verapamil, diltiazem and digoxin, either alone or in combination, are recommended for this purpose. Though controversial, a resting heart rate below 110 per minute may be an initial target. Stricter control is required for patients remaining symptomatic. None of these has any mortality benefit in AF (even beta blockers lose their mortality benefit for heart failure with reduced ejection fraction in presence of AF). Recalcitrant cases may require atrioventricular node ablation in conjunction with permanent pacemaker implantation. Amiodarone may be used in selective cases for rate control. Verapamil and diltiazem are not indicated if left ventricular ejection fraction is below 40%. In RealiseAF Survey from India it was found that 46.1% patients received rate control treatment, 35.2% rhythm control treatment and 18.4% received no drugs for AF. Amiodarone was the most commonly prescribed drug (39.2%) followed by beta blockers (38.5%) and digitalis (31.9%). class I drugs are rarely prescribed.
STROKE PREVENTION IN AF (SPAF)
20-30% of all strokes are due to AF. Many idiopathic stokes are found to be due to silent paroxysmal AF. Stroke risk needs to be assessed in all patients with AF and to be updated in every clinical visit. CHA2DS2-VASc
score is the standard risk estimator. Oral anticoagulant (OAC) has clear benefit in all men with CHA2DS2-VASc score of 2 or more, and all women with CHA2DS2-VASc score of 3 or more. A score of 1 in men and 2 in women may also merit OAC therapy. Other patients do not need OAC, and specifically antiplatelets have no role in SPAF. But in India almost half of AF patients received antiplatelets only. Bleeding risk scores like HASBLED should also be assessed to tailor therapy in individual patient. Broadly, there are two groups of OAC, vitamin K antagonists (VKA) and non vitamin K antagonist newer OAC (NOAC). In moderate to severe mitral stenosis and with mechanical heart valve prosthesis, only VKSs are recommended. In all other cases both groups can be used interchangeably if there is no specific contraindication to one agent or other. VKA (warfarin, acenocoumarol) drugs have multiple drug-drug and drug-food interactions, need close monitoring of INR, have a narrow therapeutic window, are slow in onset and offset of action, and have higher risk of intra cranial bleeding. The TTR (time in therapeutic range) should be kept as high as possible while on VKA. The optimum is above 60% whereas in India it is found to be around 30% in various substudies. The NOACs are generally preferred on these accounts, but they are expensive and they do not have easily available antidotes. The substudies including Asian populations of the original trials of each of these drugs. Catheter based left atrial appendage (LAA) occlusion and surgical LAA exclusion are considered for patients not suitable for OAC therapy. In stable coronary artery disease patients with AF only OAC is recommended without any antiplatelet agent. In ACS patients and in those with coronary stents, and with low bleeding risks, 6 months triple therapy (aspirin 75 mg daily, clopidogrel 75 mg daily and OAC) followed by another 6 months of dual therapy (clopidogrel and OAC) and then lifelong OAC monotherapy is recommended. In patients with high bleeding risk, the respective durations of triple, dual and monotherapy are 1 month, 11 months and lifelong. If a patient on VKA has minor bleeding, the dose of VKA is to be delayed till INR comes below 2. For moderate bleeding, symptomatic treatment, treatment of cause and in some cases intravenous vitamin K are given. For severe bleed, prothrombin complex concentration or fresh frozen plasma is needed. In minor bleeding on NOAC one day or one dose is skipped. For moderate bleeding, along with symptomatic treatment oral charcoal is given if the last dose is taken recently. Specific antidotes are available for severe bleeding. When OAC needs to be stopped for planned operations, bridging therapy with heparin or low molecular weight heparin proved be of no use unless there is mechanical heart valve prosthesis.
UPSTREAM THERAPY OF AF
In people with high risk for developing AF because of
presence of risk factors, it has been shown in some studies that treatment with ACEI, ARB, statin or ranolazine may prevent the first attack of AF.
CONCLUSION
In India burden of AF is huge. Early detection, proper patient counseling and guide line based tailor made therapy go a long way to reduce the loss of productive life. Standardizations of pathological laboratories, patient education and most importantly providing the treatment at affordable costs are high in priority for effective management of AF in India. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
2.
The Indian consensus guidance on stroke prevention in atrial fibrillation: An emphasis on practical use of nonvitamin K oral anticoagulants. Jamshed Dalal, Abhay Bhave,.Saumitra Ray, et al. SPAF Academy India experts. Indian Heart Journal volume 67, supplement 2, December 2015, page S13-S34.
3.
2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology (2014), doi: 10.1016/ j.jacc.2014.03.021.
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REFERENCES
1.
Paulus Kirchhof, Stefano Benussi, Dipak Kotecha,et al, on behalf of Authors/Task Force Members. DOI: http://dx.doi. org/10.1093/eurheartj/ehw210 ehw210 First published online: 27 August 2016.
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Heart Failure in Young and Elderly – Management Strategies
ABSTRACT
Cardiovascular disease is one of the leading cause of death today, of which over half is attributable to ischemic heart disease. Congestive heart failure, ischemic heart disease and atrial fibrillation are the three most common cardiac disorders encountered in an elderly population. Heart failure is a life threatening disease and addressing it should be considered a global health priority. At present, approximately 26 million people worldwide are living with heart failure. Despite of burdens that heart failure imposes on society, awareness of the disease is poor. As a result, many premature deaths occur. This is in spite of the fact that most types of heart failure are preventable and that a healthy lifestyle can reduce the risk. Compliance with clinical guidelines is also associated with improved outcomes for patients with heart failure. It is time to ease the strain on healthcare system through clear policy initiatives that prioritize heart failure prevention and champion equality of care for all.
INTRODUCTION
Heart Failure (HF) is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/ or elevated intra-cardiac pressures at rest or during stress1. HF is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. The guidelines underscore that “it is largely a clinical diagnosis that is based on a careful history and physical examination.” As HF is a syndrome and not a disease, its diagnosis relies on a clinical examination and can be challenging. The prevalence of HF depends on the definition applied, but is approximately 1–2% of the adult population in developed countries, rising to ≥10% among people >70 years of age 2, 3. The lifetime risk of HF at age 55 years is 33% for men and 28% for women18. The most common cause of HF remains an ischemic insult. This insult initiates a cascade of events mediated by neurohormonal influences that adversely affect the heart.
CLASSIFICATION OF HEART FAILURE
The main terminology used to describe HF is historical and is based on measurement of the LVEF. HF comprises a wide range of patients, from those with normal LVEF [typically
Brian Pinto, Chetan Rathi, Ankeet Dedhia
considered as ≥50%; HF with preserved EF (HFpEF)] to those with reduced LVEF [typically considered as,>40%; HF with reduced EF (HFrEF)]. Patients with an LVEF in the range of 40–49% represent a ‘grey area’, which we now define as HFmrEF (Table 1). Differentiation of patients with HF based on LVEF is important due to different underlying aetiologies, demographics, co-morbidities and response to therapies4. Most clinical trials published after 1990 selected patients based on LVEF [usually measured using echocardiography, a radionuclide technique or cardiac magnetic resonance (CMR)], and it is only in patients with HFrEF that therapies have been shown to reduce both morbidity and mortality. The diagnosis of HFpEF is more challenging than the diagnosis of HFrEF. Patients with HFpEF generally do not have a dilated LV, but instead often have an increase in LV wall thickness and/or increased left atrial (LA) size as a sign of increased filling pressures. Most have additional ‘evidence’ of impaired LV filling or suction capacity, also classified as diastolic dysfunction, which is generally accepted as the likely cause of HF in these patients (hence the term ‘diastolic HF’). However, most patients with HFrEF (previously referred to as ‘systolic HF’) also have diastolic dysfunction, and subtle abnormalities of systolic function have been shown in patients with HFpEF. Hence the preference for stating preserved or reduced LVEF over preserved or reduced ‘systolic function’. In previous guidelines it was acknowledged that a grey area exists between HFrEF and HFpEF5. These patients have an LVEF that ranges from 40 to 49%, hence the term HFmrEF. Identifying HFmrEF as a separate group will stimulate research into the underlying characteristics, pathophysiology and treatment of this group of patients. Patients with HFmrEF most probably have primarily mild systolic dysfunction, but with features of diastolic dysfunction. Patients without detectable LV myocardial disease may have other cardiovascular causes for HF (e.g. pulmonary hypertension, valvular heart disease, etc.). Patients with non-cardiovascular pathologies (e.g. anaemia, pulmonary, renal or hepatic disease) may have symptoms similar or identical to those of HF and each may complicate or exacerbate the HF syndrome.
HEART FAILURE IN YOUNG
The importance of heart failure in young is that there was a striking difference in signs and symptoms during presentation in younger patients versus older patients.
Younger patients presented with less dyspnea, reflected by a lower New York Heart Association functional class, and they less often had peripheral edema and/or rales. In contrast, they frequently presented with signs of paroxysmal nocturnal dyspnea, increased jugular venous pressure, and hepatomegaly. These findings are important for clinicians who have to diagnose HF, because mild dyspnea and absence of peripheral edema and/or rales might easily lead to a missed diagnosis of HF in younger patients, in particular because of its low prevalence.
One due to volume overload of ventricle with preserved systolic function of the ventricle, the common example is heart failure secondary to a large left to right shunt shown in Table 2. The second group consists of pressure overload, persistent arrhythmias, dilated cardiomyopathy and certain systemic disorders where the contractile function of ventricle is reduced. Symptoms and signs of heart failure can be confusing or fairly non-specific in children. HF presenting on the first day of life are commonly due to metabolic abnormalities. Structural diseases that cause HF in neonates usually do not manifest on 1st day of life; rather it is the causes of fetal HF like Ebstein’s or abnormal heart rate/rhythm that predominate. About 90% of all cases of HF in children occur before the end of first year of life and reflect the preponderance of congenital heart disease (CHD) as a cause of HF. In the first week of life, obstructive and
Table 1: Classification of Heart Failure Classification
Ejection Fraction
I. Heart Failure with Reduced Ejection Fraction (HFrEF)
≤40%
II. Heart Failure with Preserved Ejection Fraction (HFpEF)
≥50%
III. Heart Failure with Mid-Range Ejection Fraction (HFmrEF)
41% to 49%
The myocardium perse is normal in most CHD and the heart failure, if not presenting in the first year, is unlikely to develop for the next 10 years unless complicated by infective endocarditis, anemia, infections or arrhythmias. Thus older children (usually beyond two years) are likely to have other causes for HF like acute rheumatic fever with carditis, decompensated chronic rheumatic heart disease, myocarditis, cardiomyopathies and palliated CHD (post Senning operation for transposition of great arteries or Fontan group of surgeries for univentricular hearts). Dilated cardiomyopathy remains the principal indication for cardiac transplantation in children worldwide throughout childhood, apart from infancy when congenital heart disease is a more common indication. The prognosis for dilated cardiomyopathy is around 60% at five years from presentation with a high attrition within six months of presentation.6 Supraventricular tachycardia (SVT) causing heart failure and tachycardia-induced cardiomyopathy (TIC) are often used interchangeably. Although SVT is the most common cause of TIC, it is a broad term that also includes heart failure caused by ventricular arrhythmias. Chronic tachycardia has long been linked to the development of congestive cardiomyopathy through chamber dilatation and ventricular dysfunction resulting from structural and cellular changes that occur as a result of the rapid heart rates. SVT-related TIC is a treatable and often reversible cardiomyopathy that is usually a diagnosis of exclusion, evaluation, and management of SVT causing heart failure. The most common supraventricular arrhythmias causing TIC are atrial fibrillation and atrial flutter. Standard workup for cardiomyopathies should include a thorough history and physical, laboratory assessment, echocardiogram, and ischemic evaluation. If initial workup is negative,
Table 2 I. Volume overload with preserved systolic ventricular function a. Large left to right shunt: Ventricular Septal Defect (VSD), Patent Ductus Arteriosus (PDA) b. Admixture lesions with high Pulmonary blood flow : Transposition of Great Arteries (TGA) , Total Anamolous Pulmonary Venous Connection (TAPVC), Truncus c. Regurgitant lesion : Mitral Regurgitation (MR), Aortic Regurgitation (AR)
II. Myocyte dysfunction with abnormal ventricular contractile function a. Pressure overload: Severe Aortic Stenosis (AS), Pulmonary Stenosis (PS) b. Muscular dystrophy, Dilated cardiomyopathy c. Inflammatory: Myocarditis, Chaga’s, HIV d. Tachycardiomyopathies secondary to Supraventricular tachycardia(SVT) e. Abnormal morphology: single ventricular (pre and post op) f. Ischemic: Anamolous origin of Left Coronary Artery from Pulmonary Artery(ALCAPA) g. Others: Sepsis, hypocalcaemia etc.
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Children and young adults can have diverse causes of heart failure depending on the age, geographical location, and many other factors. Hence a descriptive epidemiology of heart failure in children is not possible. The causes of HF can be broadly classified into two groups as in Table2.
duct-dependent lesions can present with HF or acute circulatory shock. Development of HF due to left-to right shunts usually waits the fall in pulmonary vascular resistance at 4-6 weeks, though large VSD, PDA and aorto-pulmonary window can cause HF by 2nd week of life. Isolated ASD are mostly asymptomatic in children and if an infant is diagnosed to have ASD and is in failure, the likely diagnosis is TAPVC.
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then TIC should be considered. Many patients with SVTrelated TIC present with signs and symptoms of heart failure, including exertional dyspnea, orthopnea, and edema. It can often be difficult to determine whether the tachycardia is the cause or the result of cardiomyopathy. The goal of treatment is to control the tachycardia through rate or rhythm control, thereby improving a patient’s symptoms, reversing ventricular dysfunction, and preventing future cardiomyopathy. Despite the apparent normalization of systolic function with control of the tachycardia, cellular and structural abnormalities of the myocardium may persist and cause early recurrence of cardiac dysfunction when optimal medical therapy of cardiomyopathy and heart failure is stopped. A small subset of treated SVT-related TIC patients had sudden cardiac death after resolution of ventricular dysfunction, supporting the observation of enduring cellular and molecular abnormalities Lymphocytic myocarditis accounts for around 10% of recent onset cardiomyopathy. Viruses are the main causes in developed countries, coxsackie B and adenovirus accounting for most cases; Chagas disease is the most common cause in Central and South America, and other infectious causes should be considered. The treatment of heart failure caused by myocarditis in children is supportive and not essentially different from dilated cardiomyopathy, although patients with fulminant myocarditis are more likely to be supported to recovery rather than transplantation. About half of all young adults who survive childhood cancer have received anthracyclines, particularly daunorubicin or doxorubicin. The number of young adult patients with potential heart muscle disease is therefore going to be larger than, for example, young adult survivors of tetralogy of Fallot, or transposition. Cardiotoxicity is dose related, and myocyte damage on biopsy has a linear relation with cumulative dose. The myocyte necrosis is irreversible, although echocardiographic improvement in systolic function and recovery from symptomatic heart failure can be seen with treatment in most cases. In children there is progressive, dose related impairment of afterload in asymptomatic individuals7
Investigations - Heart Failure in Young8 •
Echocardiography (including check for anomalous coronary)
•
ECG
•
Myocarditis: Tracheal aspirate for viral PCR, paired serology (including coxsackie, adenovirus, echo, influenza, parainfluenza, varicella, RSV, rubella, CMV, EBV, HIV, parvovirus, mycoplasma, and endemic infections depending on geography — for example, Chagas’ disease, dengue, diphtheria, Coxiella burnetti; many organisms cause myocarditis ), troponin T, blood count for lymphocytosis. Myocardial biopsy for histology and PCR. Consider toxins if suggested by history, and illegal drugs (for example, cocaine)
•
Autoimmune: Anti-Ro and Anti-La, full SLE screen including antinuclear antibody, double stranded DNA, rheumatoid factor, ESR. Autoantibody screen (availability varies)—for example, anti-mysosin β receptor antibodies
•
Mitochondrial: Carnitine, acyl carnitine, lactate, glucose, white cell count for neutropenia, urine amino acids for methylglutaconic aciduria, muscle biopsy if clinical suspicion of mitochondrial disease. Molecular genetic diagnosis of Barth syndrome is available in some centres
HEART FAILURE IN THE YOUNG: KEY POINTS
Myocarditis •
Coxsackie and adenovirus account for the majority of cases of viral myocarditis
•
Fulminant infections have a better prognosis than non-fulminant infections
•
Children can be bridged to recovery using mechanical support
•
Randomized studies have not shown any benefit from immune suppression
•
Immunoglobulin may reduce cytokines in heart failure and short term echo improvement may be attributable to this, not resolution of myocarditis
Apoptosis, cytokines, and regeneration • Apoptosis occurs in myocytes
• The nucleus is affected later in myocyte apoptosis and this may allow recovery with bridging • New myocytes can develop as shown by chimeric studies • Circulating cytokines such as tumour necrosis factor α are increased in heart failure
Heart failure treatment in children
• ACE inhibitors are widely used in children • Carvedilol is helpful in stable patients • Aspirin may oppose the action of ACE inhibitors and carvedilol
Treatment of Heart Failure in Young
Heart failure treatment in children is very similar to that of adults. However, because of lack of resources and a reluctance of the pharmaceutical industry to undertake trials, few of the proven treatments in adults are licensed in children and paediatric preparations are not available, leaving parents to grind and dissolve adult tablets. A principle of paediatric drug usage is that the therapeutic effect in children is likely to be similar to what it is in adults, but pharmacokinetics are different. For example, phosphodiesterase III inhibitors have been shown to have a deleterious effect on long term survival, milrinone having a 28% increase in mortality compared to placebo, yet oral phosphodiesterase inhibitors such as enoximone are still used by paediatric cardiologists.
Congestion at Rest
Identification of acute aetiology: acute Coronary syndrome Hypertension emergency Arrhythmia acute Mechanical causea Pulmonary embolism Fig. 1 : Aetiology of acute heart failure ACE inhibitors are widely used in children, but β blockers are less commonly used even though the adult evidence base is strong; carvedilol has been successfully used in New York Heart Association functional class III and IV patients9, and it has also been used in children10. They should only be introduced in stable patients and the dose increased slowly. β Blockers must be stopped if inotropes are needed. Spironolactone has been shown to be beneficial in heart failure.
No
Digoxin use remains controversial in adults and children, and although therapeutic benefits have been seen in adults with a reduced hospitalization rate, overall mortality is not reduced. Digoxin may not be helpful in acute myocarditis. Anticoagulation with warfarin is difficult in children, but those with severe heart failure are at risk of mural thrombus. There is now evidence that aspirin and other non-steroidal anti-inflammatory agents can exacerbate heart failure and may reduce the effect of the diuretics, ACE inhibitors, and β blockers. The mechanism probably involves the inhibition of prostaglandin synthesis, increasing peripheral resistance and decreasing renal perfusion. Angiotensin II receptor blockers may have a role in replacing ACE inhibitors when there is an unwanted effect such as a severe cough, but they do not convey a survival benefit in adults and experience of their use in children has been very limited.
Low Perfusion at Rest
A
No
YES
B
Warm & Dry
Warm & Wet
(Low Profile)
(Complex)
Cold & Dry
Cold & Wet
L
YES
C
Signs/Symptoms of Congestion:
Orthopnea / PND JV Distension Hepatomegaly Edema Rales (rare in chronic heart failure) Elevated est. PAsys Valsalva square wave Abd-Jugular Reflux
Possible Evidence of Low Perfusion: Cool extremities Narrow pulse pressure Hypotension with ACE inhibitor Sleepy / obtunded Renal Dysfunction (one cause) Low serum sodium
Fig. 2 : Clinical features of AHF and signs (i.e. pulmonary infection, severe anaemia, acute renal failure).
Yes
When AHF is confirmed clinical evaluation is mandatory to select further management.It is recommended that initial diagnosis of AHF should be based on a thorough history assessing symptoms, prior cardiovascular history and potential cardiac and non-cardiac precipitants, as well as on the assessment of signs/symptoms of congestion and/ orImmediate hypoperfusion by physical examination and further initiation confirmed by appropriate additional investigations such asof ECG, chest X-ray, laboratory assessment (with specific specific treatment biomarkers) and echocardiography. Typically, symptoms and signs of Acute Heart Failure reflect fluid overload (pulmonary congestion and/or peripheral oedema) or, less often, reduced cardiac output with peripheral hypoperfusion (Figure 2).
recommen Since the sensitivity andFollow specificitydetailed of symptoms and signs are often not satisfactory, careful clinical evaluation in the specific ESC Guidelin needs to be followed by these additional investigations MANAGEMENT STRATEGIES OF HEART FAILURE IN ELDERLY
Understanding the pathophysiology of heart failure allows one to achieve the goals of treatment, which are to relieve symptoms, avoid hospital admissions, and prolong life. The fact that several drugs for HF have shown detrimental effects on long-term outcomes, despite showing beneficial effects on shorter-term surrogate markers, has led regulatory bodies and clinical practice guidelines to seek mortality/morbidity data for approving/recommending therapeutic interventions for HF. However, it is now recognized that preventing HF hospitalization and improving functional capacity are important benefits to be considered if a mortality excess is ruled out.
Diagnostic work-up to confirm AHF cal evaluation to select optimal management DIAGNOSIS AND INITIAL PROGNOSTIC EVALUATION OF HEART FAILURE
The diagnostic workup needs to be started in the pre-hospital setting and continued in the emergency department (ED) in order to establish the diagnosis in a timely manner and initiate appropriate management. The greater benefit of early treatment is well established in ACS and now needs to be considered in the setting of HF. In parallel, coexisting life-threatening clinical conditions and/or precipitants that require urgent treatment/correction need to be immediately identified and managed (Figure 1). Typically, an initial step in the diagnostic workup of AHF is to rule out alternative causes for the patient’s symptoms
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C H A M P
No
969
The goals of treatment in patients with HF are -
to improve their clinical status
-
functional capacity
-
quality of life
-
prevent hospital admission
-
reduce mortality
CARDIOLOGY
970
•
Non-pharmacological management:
1.
Lifestyle modifications
2.
Salt & water restriction
3.
Weight reduction
4.
Physical activity as per tolerance of patient
•
Pharmacotherapy -
1.
B- Blocker
2.
ACEI/ARBs
3.
MRA
4.
Diuretics
5.
Digoxin
•
Novel Treatment -
1.
LCZ-696 - ARNI
2.
IF-Channel Inhibitor - Ivabradine
•
Interventional Modalities -
1.
CRT-P / D
2.
LVAD
3.
Cardiac transplantation
NON-PHARMACOLOGICAL TREATMENT /LIFE-STYLE MODIFICATION
Diet
All patients need support and dietary advice regarding maintenance of optimal weight. Obesity increases the workload on the heart, especially during physical activity. Weight reduction, through restriction of dietary fat and calories is imperative for those who are obese, and is advised for those who are overweight. In patients with coronary heart disease and raised lipids, a low fat diet may delay recurrence of significant cardiovascular events. Salt intake should be restricted as this may aggravate a patient’s condition. Salt should not be added during cooking or at the table. A reduction in dietary sodium intake of 2,000 mg per day alone may provide substantial hemodynamic and clinical benefits for heart failure patients. Patients should be referred to a registered dietitian if there are repeat episodes of edema or for comorbid conditions such as diabetes, dyslipidemia and renal failure. It is important to help patients prioritize dietary modifications. Formerly called herbals, any over-the-counter dietary supplement or vitamin product should be discussed with a health care clinician to make sure there is not an interaction with the disease condition or other medications
Fluid intake
Patients with heart failure often have an intense thirst, which can lead to excessive fluid intake and hyponatremia. Fluid intake should be limited where possible, to about 1 liter a day for most patients. During periods of hot
weather, diarrhea, vomiting or fever, fluid intake may be increased or the dose of diuretic reduced.
Alcohol intake
Since even moderate usage may be associated with decreasing ventricular systolic function, alcohol use should be discouraged, or at the least, saved for special occasions. One drink is considered 10 oz. of beer, 5 oz. of wine or 1.5 oz. of hard liquor. In severe heart failure or those with alcoholic cardiomyopathy, complete abstinence is recommended.
Smoking
Smoking increases the risk of many cardiovascular, pulmonary and other problems, including cancers, and must be avoided at all costs.
Exercise
Bed rest is an important part of the treatment of acute heart failure or decompensated chronic heart failure, though early mobilization is important. Otherwise regular, and moderate physical activity for the condition of the patient, should be encouraged. This has significant symptomatic and other benefits in patients with heart failure. Dynamic exercise activities such as walking, cycling, swimming, bowling, gardening, etc. should be continued at a pace that is comfortable for the patient. Exercise instruction should be included as a part of a comprehensive heart failure program. Referral to a cardiac rehabilitation program is recommended for exercise prescription and modeling and will contribute to patients’ compliance with exercise, functional improvement and quality of life. Participation in a formal program may also contain education and compliance monitoring of lifestyle management components for heart failure.
Vaccination
Heart failure may predispose to and be exacerbated by pulmonary infection, which is a common cause of hospitalization. Therefore, influenza and pneumococcal vaccinations are recommended.
PHARMACOLOGICAL TREATMENT
Beta blocker
Beta-blockers reduce mortality and morbidity in symptomatic patients with HFrEF, despite treatment with an ACEI and, in most cases, a diuretic11,12. There is consensus that beta-blockers and ACEIs are complementary, and can be started together as soon as the diagnosis of HFrEF is made. There is no evidence favoring the initiation of treatment with a beta-blocker before an ACEI has been started. Beta blockers should be initiated in clinically stable patients at a low dose and gradually up-titrated to the maximum tolerated dose. In patients admitted due to acute HF (AHF) beta-blockers should be cautiously initiated in hospital, once the patient is stabilized. Beta-blockers should be considered for rate control in patients with HFrEF and AF, especially in those with high heart rate Beta-blockers are recommended in patients
with a history of myocardial infarction and asymptomatic LV systolic dysfunction to reduce the risk of death. The MERIT HF study13 of metoprolol succinate compared to placebo showed a mortality reduction at one year in patients with NYHA Class II-IV heart failure and, recently, the COMET trial14 has shown carvedilol to produce an additional 17% risk reduction in mortality versus metoprolol tartrate.
needs over time. In selected asymptomatic euvolaemic/ hypovolemic patients, the use of a diuretic drug might be (temporarily) discontinued. Principles of using diuretics for heart failure – Use in moderation; avoid excessive doses of any single drug
•
Make use of synergy between different classes of drugs, especially in cases of diuretic resistance (the principle of sequential nephron blockade)
•
Monitoring of blood chemistry may help to avoid uremia, hypokalemia, and hyponatremia
•
Use in combination with an angiotensin converting enzyme (ACE) inhibitor and/or digoxin unless this is not tolerated
ACEIs are also recommended in patients with asymptomatic LV systolic dysfunction to reduce the risk of HF development, HF hospitalization and death. The equivalence of angiotensin receptor blockers to ACE inhibitors in reducing mortality from CHF remains to be confirmed. The addition of valsartan to an ACE-inhibitor may reduce heart failure hospitalizations particularly in those not on a beta-blocker.
Mineralocorticoid/aldosterone receptor antagonists
MRAs (spironolactone and eplerenone) block receptors that bind aldosterone and, with different degrees of affinity, other steroid hormone (e.g. corticosteroids, androgens) receptors. Spironolactone or eplerenone are recommended in all symptomatic patients (despite treatment with an ACEI and a beta-blocker) with HFrEF and LVEF ≤35%, to reduce mortality and HF hospitalization17, 18. Caution should be exercised when MRAs are used in patients with impaired renal function and in those with serum potassium levels high. Regular checks of serum potassium levels and renal function should be performed according to clinical status. Spironolactone in low doses (mean 26 mg/day) was investigated in the RALES Trial17 which enrolled a population of patients (mean age 65 yrs) with advanced (NYHA III-IV, LVEF 220 micromoles/l) or other significant co-morbidities. Spironolactone significantly reduced mortality by 30% and hospitalizations for worsening heart failure by 35%, and significantly improved NHYA functional class.
Diuretics
Diuretics are recommended to reduce the signs and symptoms of congestion in patients with HFrEF, but their effects on mortality and morbidity have not been studied in RCTs. Loop diuretics produce a more intense and shorter diuresis than thiazides, although they act synergistically and the combination may be used to treat resistant edema. However, adverse effects are more likely and these combinations should only be used with care. The aim of diuretic therapy is to achieve and maintain euvolaemia with the lowest achievable dose. The dose of the diuretic must be adjusted according to the individual
Angiotensin II receptor blockers
ARBs are recommended only as an alternative in patients intolerant of an ACEI. Candesartan has been shown to reduce cardiovascular mortality. Valsartan showed an effect on hospitalization for HF in patients with HFrEF receiving background ACEIs19. Therefore, ARBs are indicated for the treatment of HFrEF only in patients who cannot tolerate an ACEI because of serious side effects. The combination of ACEI/ARB should be restricted to symptomatic HFrEF patients receiving a beta-blocker who are unable to tolerate an MRA, and must be used under strict supervision.
Combination of hydralazine and isosorbide dinitrate
There is no clear evidence to suggest the use of this fixeddose combination therapy in all patients with HFrEF. A subsequent RCT conducted in self-identified black patients (defined as being of African descent) showed that addition of the combination of hydralazine and isosorbide dinitrate to conventional therapy (ACEI, beta-blocker and MRA) reduced mortality and HF hospitalizations in patients with HFrEF and NYHA Classes III–IV20. The results of this study are difficult to translate to patients of other racial or ethnic origins.
Digoxin and other digitalis glycosides
Digoxin may be considered in patients in sinus rhythm with symptomatic HFrEF to reduce the risk of hospitalization21. In patients with symptomatic HF and AF, digoxin may be useful to slow a rapid ventricular rate, but it is only recommended for the treatment of patients with HFrEF and AF with rapid ventricular rate when other therapeutic options cannot be pursued.
Renin inhibitors
Aliskiren (direct renin inhibitor) is not presently recommended as an alternative to an ACEI or ARB.
Oral anticoagulants and antiplatelet therapy
Other than in patients with AF (both HFrEF and HFpEF), there is no evidence that an oral anticoagulant reduces mortality/morbidity compared with placebo or aspirin13. Studies testing the (NOACs) in patients with HFrEF are currently ongoing. Patients with HFrEF receiving oral
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•
Angiotensin-converting enzyme inhibitors
ACEIs have been shown to reduce mortality and morbidity in patients with HFrEF and are recommended unless contraindicated or not tolerated in all symptomatic patients15, 16. ACEIs should be up-titrated to the maximum tolerated dose in order to achieve adequate inhibition of the renin–angiotensin–aldosterone system (RAAS).
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anticoagulation because of concurrent AF or risk of venous thromboembolism should continue anticoagulation.
neurohormonal activation, or inflammation, with no independent effect of atrial fibrillation on outcome.
n-3 polyunsaturated fatty acids
The control of ventricular rate and the prevention of thromboembolic events are essential elements of treatment of heart failure in patients with an underlying supraventricular arrhythmia. Beta-blockers and digoxin used either alone or in combination are the drugs of choice for achieving rate control.
n-3 polyunsaturated fatty acids (n-3 PUFAs) have shown a small treatment effect in a large RCT as an effect on the cumulative endpoint of cardiovascular death and hospitalization.
CARDIOLOGY
Calcium-channel blockers
Non-dihydropyridine calcium-channel blockers (CCBs) are not indicated for the treatment of patients with HFrEF. Diltiazem and verapamil have been shown to be unsafe in patients with HFrEF.
NOVEL THERAPY
Development of the ARNI/LCZ696
A new therapeutic class of agents acting on the RAAS and the neutral endopeptidase system has been developed [angiotensin receptor neprilysin inhibitor (ARNI)] 22. The first in class is LCZ696, which is a molecule that combines the moieties of valsartan and sacubitril (neprilysin inhibitor) in a single substance. By inhibiting neprilysin, the degradation of NPs, bradykinin and other peptides is slowed. High circulating A-type natriuretic peptide (ANP) and BNP exert physiologic effects through binding to NP receptors and the augmented generation of cGMP, thereby enhancing diuresis, natriuresis and myocardial relaxation and anti-remodelling. Selective AT1-receptor blockade reduces vasoconstriction, sodium and water retention and myocardial hypertrophy23. The >8000-person-strong PARADIGM-HF trial showed that patients with chronic HF treated with LCZ696 had a 20% decrease in Cardiovascular death or HF hospitalizations vs those treated with the ACE inhibitor enalapril, as well as a significant reduction in all-cause mortality24.
If-channel inhibitor (Ivabradine)
Ivabradine slows the heart rate through inhibition of the If channel in the sinus node and therefore should only be used for patients in sinus rhythm. Ivabradine reduced the combined endpoint of mortality and hospitalization for HF in patients with symptomatic HFrEF and LVEF ≤35%, in sinus rhythm and with a heart rate ≥70 beats per minute (bpm) who had been hospitalized for HF within the previous 12 months, receiving treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose), an ACEI (or ARB) and an MRA25.
TREAT SECONDARY CAUSES OF HEART FAILURE AND SIGNIFICANT COMORBID CONDITIONS AND RISK FACTORS
Atrial fibrillation in heart failure
Patients with heart failure are at increased risk for atrial fibrillation and constitute an important subgroup of all patients with this arrhythmia. Atrial fibrillation affects 10-30% of patients with chronic heart failure. Atrial fibrillation may be a marker of poor prognosis, in which the primary problem is poor ventricular function,
Cardiorenal Syndrome
Cardiorenal syndrome can be generally defined as a pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of the other. The characterization and classification of this syndrome may provide ideas for the testing of hypotheses regarding the pathogenesis of this syndrome and help in designing interventions for the management of cardiorenal syndrome. No interventions based on proposed mechanisms of the development of cardiorenal syndrome (CRS) have shown consistent advantage, and the work group does not have any specific recommendations. However, developing awareness, the ability to identify and define, and physiological understanding will help improve the outcome of these complex patients.
Anemia: Workup and Treatment for Iron Deficiency in Patients with Heart Failure
The prevalence of iron deficiency in congestive heart failure ranges from 5-21% and may be related to malabsorption, long-term aspirin, uremic gastritis, or reduced iron recycled in the reticuloendothelial system. The Ferric Iron Sucrose in Heart Failure (FERRIC-HF) trial of 35 heart failure patients with iron deficiency witnessed an improved global assessment score and significantly increased peak oxygen uptake in patients with anemia. Overall, IV iron in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity and quality of life. The side effect profile is acceptable.
RECOMMENDATIONS
•
Beta-blockers and digoxin should be used either alone or in combination for achieving rate control in atrial fibrillation in heart failure.
•
Blood transfusions are not recommended to treat anemia in heart failure.
•
Intravenous iron replacement may improve anemia symptoms specifically the six-minute walk test.
PRIMARY PREVENTION
Compared with amiodarone treatment, ICDs reduce mortality in survivors of cardiac arrest and in patients who have experienced sustained symptomatic ventricular arrhythmias. An ICD is recommended in such patients when the intent is to increase survival; the decision to implant should take into account the patient’s view and their quality of life, the LVEF (survival benefit is uncertain
when the LVEF is <35%) and the absence of other diseases likely to cause death within the following year26. An ICD is recommended1 to reduce the risk of sudden death and all-cause mortality in patients with symptomatic HF (NYHA Class II–III), and an LVEF < 35% despite of 3 months of OMT, provided they are expected to survive substantially longer than one year with good functional status, and they have: IHD (unless they have had an MI in the prior 40 days
•
DCM.
ICD implantation is recommended only after a sufficient trial (minimum 3 months) of optimal medical therapy (OMT) has failed to increase the LVEF to 35%. Patients with a QRS duration ≥130 ms should be considered for a defibrillator with CRT (CRT-D) rather than ICD. CRT improves cardiac performance in appropriately selected patients and improves symptoms27 and wellbeing and reduces morbidity and mortality. Of the improvement in quality-adjusted life-years (QALYs) with CRT among patients with moderate to severe HF, twothirds may be attributed to improved quality of life and one-third to increased longevity28. CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration >150 msec and LBBB QRS morphology and with LVEF < 35% despite optimal medical therapy in order to improve symptoms and reduce morbidity and mortality1. Cardiac contractility modulation (CCM) is similar in its mode of insertion to CRT, but it involves non-excitatory electrical stimulation of the ventricle during the absolute refractory period to enhance contractile performance without activating extra systolic contractions. CCM has been evaluated in patients with HFrEF in NYHA Classes II–III with normal QRS duration (120 msec).
PREVENTION AND SCREENING
Screening for heart failure and treatment of patients at increased risk of developing heart failure are useful if interventions can modify the natural history of the condition and are safe and evidence-based. Control of systolic hypertension in the elderly is important in the prevention of heart failure, especially in patients with a past history of myocardial infarction. The SHEP Trial30 demonstrated that the risk of heart failure could be significantly attenuated in such patients by blood pressure lowering with a thiazide diuretic as first line therapy and similar findings were obtained recently in ALLHAT31. The SOLVD Prevention Trial demonstrated that treatment of asymptomatic left ventricular systolic dysfunction (LVEF<35%) with an angiotensin-converting enzyme inhibitor (enalapril 10 mg BID) could delay the expression of symptoms of heart failure by an average of eighteen months, but patients over the age of eighty were not randomized into this study.32
REHABILITATION
Programs that offer intensive follow-up to ensure that the patient complies with lifestyle changes and medication regimens at home can reduce rehospitalization and improve survival. Patients without available rehabilitation programs should seek support from local and national heart associations and groups. A strong emotional support network is also important.
CONCLUSION
HEART TRANSPLANTATION
The incidence of heart failure is increasing. It is therefore incumbent on healthcare providers to evaluate their heart failure practices and to incorporate the most current knowledge of the pathophysiology, assessment, and treatment modalities for heart failure into their patient care. Current practice guidelines provide a basis for the treatment of patients with heart failure. Critical to the success of heart failure management is the discharge planning process and follow-up in the outpatient setting. Integration of medical care and patient education with close communication between inpatient and outpatient care providers is essential. Monitoring and enhancement of patient compliance are the responsibility of both in-hospital and outpatient heart failure team members. An integrated and innovative approach to the management of heart failure patients based on consensus recommendations can contribute to improved patient outcomes, including reduced morbidity rates, improved functional status and quality of life, enhanced compliance, reduced rates of rehospitalization, reduced costs, and prolonged survival.
While the risks of this procedure are high, the 1-year survival rate is about 88% for men and 77% for women.
1. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal doi:10.1093/eurheartj/ehw128
Ventricular assist devices are mechanical devices that help improve pumping actions. They are used as a bridge to transplant for patients who are on medications but still have severe symptoms and are awaiting a donor heart. In some cases, they may delay the need for a transplant. Heart transplantation is an accepted treatment for end-stage HF29. Apart from the shortage of donor hearts, the main challenges in transplantation are the consequences of the limited effectiveness and complications of immunosuppressive therapy in the long term (i.e. antibody-mediated rejection, infection, hypertension, renal failure, malignancy and coronary artery vasculopathy). The most important factor for heart transplant eligibility is overall health. Chronological age is less important. Most heart transplant candidates are between the ages of 50 - 64 years.
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REFERENCES
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Five years after a heart transplant, about 73% of men and 67% of women remain alive.
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2. Mosterd A, Hoes AW. Clinical Epidemiology of Heart Failure Heart 2007; 93:1137–1146.
CARDIOLOGY
3. Redfield MM, Jacobsen SJ, Burnett JC, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 2003; 289:194– 202. 4. Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, Shah SJ, Ahmed A, Bonow RO, Cleland JGF, Cody RJ, Chioncel O, Collins SP, Dunnmon P, Filippatos G, Lefkowitz MP, Marti CN, McMurray JJ, Misselwitz F, Nodari S, O’Connor C, Pfeffer MA, Pieske B, Pitt B, Rosano G, Sabbah HN, Senni M, Solomon SD, Stockbridge N, Teerlink JR, Georgiopoulou VV, Gheorghiade M. Developing therapies for heart failure with preserved ejection fraction: current state and future directions. JACC Heart Fail 2014; 2:97–112. 5. McMurray JJ V, Adamopoulos S, Anker SD, Auricchio A, Bo¨hm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GYH, Maggioni A Pietro, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, Bonet LA, Avraamides P, Ben Lamin HA, Brignole M, Coca A, Cowburn P, Dargie H, Elliott P, Flachskampf FA, Guida GF, Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S, Parissis JT, Ponikowski P, Members AF, McMurray JJ V, Adamopoulos S, Anker SD, Auricchio A, Bo¨hm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GYH, Maggioni A Pietro, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, Guidelines ESCC for P, Reviewers D. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart. Eur J Heart Fail 2012; 14:803– 869. 6. Dilated cardiomyopathy in children: determinants of outcome. Burch M, Siddiqi SA, Celermajer DS, Scott C, Bull C, Deanfield JE. Br Heart J 1994; 72:246-50. 7. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP N. Engl J Med 1991; 324:808-15. 8. Heart failure in young. Michael Burch. Heart 2002; 88:198– 202. 9. Effect of carvedilol on survival in severe chronic heart failure. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL, Carvedilol Prospective Randomized Cumulative Survival Study Group. N Engl J Med 2001; 344:1651-8. 10. Carvedilol as therapy in pediatric heart failure: an initial multicenter experience. Bruns LA, Chrisant MK, Lamour JM, Shaddy RE, Pahl E, Blume ED, Hallowell S, Addonizio LJ. Canter CE J Pediatr 2001; 138:505-11. 11. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H,
Waagstein F, Kjekshus J,Wikstrand J, ElAllaf D, Vı´tovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus KL,Ja´nosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz J,Rickenbacher P, Ball S, Gottlieb S, Deedwania P. MERIT-HF Study Group. Effects of controlled-release metoprolol on total mortality, hospitalizations, and wellbeing in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF). JAMA 2000; 283:1295–1302. 12. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344:1651– 1658. 13. MERIT-HF--description of the trial. Basic Res Cardiol 2000; 95 Suppl 1:I90-7. 14. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. http://dx.doi.org/10.1016/ S0140-6736(03)13800-7 15. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995; 273:1450–1456. 16. SOLVD Investigattors. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325:293–302. 17. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709-717. 18. Zannad F, McMurray JJV, Krum H, Van Veldhuisen DJ, Swedberg K, Shi H,Vincent J, Pocock SJ, Pitt B. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364:11–21. 19. Cohn JN, Tognoni G. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345:1667–1675. 20. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. N Engl J Med 1986; 314:1547–1552. 21. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336:525–533. 22. Paradigm-HF: a Paradigm Shift in Heart Failure Treatment? Arq Bras Cardiol 2016; 106:77–79. 23. King JB, Bress AP, Reese AD, Munger MA. Neprilysin inhibition in heart failure with reduced ejection fraction: a clinical review. Pharmacother J Hum Pharmacol Drug Ther 2015; 35:823–837. 24. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med 2014; 371:993-1004. DOI: 10.1056/NEJMoa1409077 25. Swedberg K, Komajda M, Bo¨hm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L. Ivabradine and outcomes in chronic heart failure (SHIFT) : a randomised placebo-controlled study. Lancet 2010; 376:875–885.
26. Connolly SJ, Gent M, Roberts RS, Dorian P, Roy D, Sheldon RS, Mitchell LB, Green MS, Klein GJ, O’Brien B. Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000; 101:1297–1302. 27. Sohaib SMMA, Finegold JA, Nijjer SS, Hossain R, Linde C, Levy WC, Sutton R, Kanagaratnam P, Francis DP, Whinnett ZI. Opportunity to increase life span in narrow QRS cardiac resynchronization therapy recipients by deactivating ventricular pacing: evidence from randomized controlled trials. JACC Heart Fail 2015; 3:327–336.
29. Banner NR, Bonser RS, Clark AL, Clark S, Cowburn PJ, Gardner RS, Kalra PR, McDonagh T, Rogers CA, Swan L,
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30. Kostis JB, Davis BR, Cutler J, Grimm RH et al. Prevention of Heart Failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1997; 278:212-216. 31. The ALLHAT Investigators. Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981-97. 32. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 3.
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28. Cleland JGF, Calvert MJ, Verboven Y, Freemantle N. Effects of cardiac resynchronization therapy on long-term quality of life: an analysis from the Cardiac ResynchronisationHeart Failure (CARE-HF) study. Am Heart J 2009; 157: 457– 466.
Parameshwar J, Thomas HL, Williams SG. UK guidelines for referral and assessment of adults for heart transplantation. Heart 2011; 97:1520–1527.
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212
Cardiac Pacemakers: Indications, Choices and Follow Up
INTRODUCTION
Therapeutic cardiac stimulation by permanent pacemakers has revolutionized the field of cardiology. Since the implantation of first internal pacemaker, pacing technology has evolved a lot, including reduction in size of pulse generator, increase in longevity and complexity of devices. Latest technology is Leadless pacing system. Type of pacemakers: Current permanent pacing systems are of three types: Transvenous systems, Epicardial systems and Leadless systems. Pacing systems consist of two components: a pulse generator, which provides the electrical impulse for myocardial stimulation; and one or more electrodes (commonly referred to as leads), which deliver the electrical impulse from the pulse generator to the myocardium. Leadless systems contain pulse generator and lead in same unit. Transvenous systems: The vast majority of contemporary cardiac pacing systems utilize transvenous electrodes (leads) for transmission of the pacing impulses from the pulse generator (which is implanted most commonly in the infraclavicular region of the anterior chest wall) to the myocardium. Transvenous leads are usually placed percutaneously or with a cephalic cut down. Transvenous leads, however, are associated with a non-trivial rate of long-term complications, including: •
Infection
•
Venous thrombosis and resultant subclavian vein occlusion
•
Lead malfunction
•
Tricuspid valve injury (resulting in tricuspid regurgitation)
Epicardial systems — Epicardial cardiac pacemaker systems utilize a pulse generator with leads that are surgically attached directly to the epicardial surface of the heart. These systems have largely been replaced by transvenous systems for patients requiring longterm cardiac pacing, although there is still a role for the occasional patient with vascular access problems (eg, venous thrombosis, congenital anatomical variations, prosthetic tricuspid valve). The major role for epicardial pacing systems in current practice is for temporary pacing following cardiac surgery; such systems, however, are designed as temporary systems that must be removed within the first days to weeks following cardiac surgery. Leadless systems: In response to the limitations of both transvenous and epicardial pacing systems, efforts have been made to develop leadless cardiac pacing systems.
Sandeep Bansal, Praloy Chakraborty Initial leadless systems involved multiple components but were associated with high complication rates 1. Subsequent leadless systems have utilized a self-contained system which includes both the pulse generator and the electrode within a single unit that is placed into the right ventricle via a transvenous approach2. Indications of Permanent Pacemaker Implantation3: Indications of permanent pacemaker implantations include A.
Sinus Node Disease: Permanent pacemaker is indicated in all patients with symptomatic sinus node disease, symptomatic chronotropic incompetence and symptomatic drug induced sinus bradycardia when discontinuation of the offending agent is not possible (Class I). In minimally symptomatic patients with sinus bradycardia and chronic heart rate less than 40 bpm while awake permanent pacemaker may be considered (Class IIb). In a patient with unexplained syncope pacemaker implantation may be considered if sinus rate is less that 40 /min or electrophysiological testing has documented sinus node disease (Class IIa).
B.
AV nodal Disease: Permanent pacemaker implantation may be considered in all patients with complete heart block. Even if the patient is asymptomatic and ventricular heart rate is more than 40, permanent pacemaker implantation should be considered (Class IIa).Indication is stronger(Class I) if patients with complete heart block or advanced second degree AV block(blocking of 2 or more consecutive P waves with some conducted beats) have any of the following:
1.
symptoms of bradycardia/ heart failure
2.
bradycardia induced ventricular arrhythmias,
3.
pause ≥ 3 seconds(≥ 5 seconds in presence of atrial fibrillation)
4.
Ventricular rate less than 40
5.
Cardiomegaly or LV dysfunction
6.
Site of block is below AV node.
7.
Any block developing after catheter ablation of the AV junction
If a patient with asymptomatic second degree AV block does not have the above criteria, EP studies should be done. If site of block is documented below the level of AV node by EP studies, permanent pacemaker implantation is recommended (Class IIa).
When a patient with first degree or second degree AV block has symptoms similar to those of pacemaker syndrome, permanent pacemaker implantation is reasonable (Class IIa). C.
E.
Post Myocardial Infarction : The criteria for permanent pacemaker implantation in patients with MI and AV block do not necessarily depend on the presence of symptoms. The long-term prognosis for survivors of AMI who have had AV block is related primarily to the extent of myocardial injury and the character of intraventricular conduction disturbances rather than the AV block itself. For all patients of AMI and persistent and symptomatic second- or third-degree AV block pacemaker should be considered (Class I indication). In an asymptomatic patient with persistent second- or third-degree AV block, permanent pacemaker implantation is Class I indication if the site of block is infra-His by ECG (alternating bundlebranch block) or by Electrophysiological study. In patients with transient advanced second- or thirddegree AV block the indication remain same as in above mentioned group. Permanent pacing may be considered for persistent second- or third-degree AV block at the AV node level, even in the absence of symptoms (Class IIb). Neuromuscular Disorders: Conduction system disease with progression to complete AV block is a well-recognized complication of several neuromuscular disorders such as myotonic muscular dystrophy, Kearns-Sayre syndrome, Erb dystrophy (limb-girdle muscular dystrophy),and peroneal muscular atrophy. In most cases the progression of conduction disease is unpredictable. Hence, any degree of AV block(including first degree AV block) and Fascicular Block is considered as Class IIb indication for permanent pacemaker implantation irrespective of symptomatic status. If such patient has third degree and advanced
F.
Carotid Hypersensitivity syndromes: Permanent pacemaker implantation should be considered in patients with syncope and documented ventricular aystole of more than 3 seconds on carotid stimulation (Class I).
G.
Neurocardiogenic Syncope: In a patient with neurocardiogenic syncope permanent pacing may be considered if bradycardia documented spontaneously or at the time of tilt-table testing (IIb)
H.
Pacing For Hemodynamic indication: Multisite pacing, also known as Cardiac resynchronization therapy(CRT) may be considered for patients with heart failure, LVEF<35%, QRS duration >120 ms and sinus rhythm. If the patient has a QRS duration of >150 ms, LBBB on ECG, NYHA Class II-IV on optimal medical therapy, CRT should be considered (Class I). If above mentioned patient has QRS duration 120 to 149 ms with LBBB or >150 ms with Non-LBBB(patient is Class III,IV on OMT), CRT may also be considered(Class IIa). Patient with LVEF<35% may require CRT irrespective of QRS duration if, Pacemaker is required for other indication with expected ventricular pacing >40% or the patient has atrial fibrillation and requires pharmacological blockade of AV node/ Av nodal ablation requiring 100% ventricular pacing(Class IIa).
I.
Selection of Pacemaker Mode: In 1974 a combined task force from the American Heart Association and the American College of Cardiology proposed a three-letter code describing the basic function of the various pacing systems which was subsequently updated by a committee from the North American Society of Pacing and Electrophysiology (NASPE) and the British Pacing and Electrophysiology Group (BPEG). Currently this code has five positions and is known as NBG code for pacing (Table 1)4. The five positions are as follow:
A.
The first position reflects the chamber(s) paced.
B.
The second position refers to the chamber(s) sensed.
C.
The third position refers to how the pacemaker responds to a sensed event
D.
The fourth position reflects rate modulation, also referred to as rate responsive or rate adaptive pacing.
E.
The rarely used fifth position specifies only the location or absence of multisite pacing, defined as stimulation sites in both atria, both ventricles, more than one stimulation site in any single chamber, or a combination of these.
The fifth position of the code is rarely used. •
”O” means no multisite pacing
•
”A” indicates multisite pacing in the atrium or atria
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CHAPTER 212
D.
Chronic Bifascicular Block: Pacemaker implantation should be considered in patients with chronic bifascicular block (irrespective of symptoms), if the bifascicular block is associated with intermittent complete heart block, advanced second degree AV block , Type 2 second degree AV block or documented alternating bundle-branch block(Examples are right bundle-branch block and left bundle-branch block on successive ECGs or right bundle-branch block with associated left anterior fascicular block on 1 ECG and associated left posterior fascicular block on another ECG). In a patient with chronic bifascicular block and syncope, if none of the above findings are documented, EP study may be considered and permanent pacemaker implantation is recommended ventricular tachycardia (VT) has been excluded(Class IIa). All chronic bifascicular block with markedly prolong HV interval (≥100 ms) or documented infra-His block should also be considered for permanent pacemaker.(Class IIa)
second-degree AV block, the scenario is considered as class I indication.
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Table 1: Revised NBG code for pacing nomenclature Position
I
II
III
IV
V
Category
0 = None A = Atrium V = Ventricle D = Dual (A+V)
0 = None A = Atrium V = Ventricle D = Dual (A+V)
0 = None T = Triggered I = Inhibited D = Dual (T+I)
0 = None R = Rate modulation
0 = None A = Atrium V = Ventricle D = Dual (A+V)
Manufacturer’s designation only
S = Single (A or V)
S = Single (A or V)
CARDIOLOGY
Table 2: Different Mode of pacing of DDD Clinical Condition
Atrial response
Ventricular response
Sinus node is diseased but AV conduction is normal
Paced atrial rhythm
Intrinsic ventricular rhythm A paced V sensed or AAI mode
Sinus node is normal but AV conduction abnormal
Sensed atrial rhythm Paced ventricular rhythm
A sense V pace or VDD
Both sinus node function and AV nodal conduction abnormal
Paced atrial rhythm
Paced ventricular rhythm
A pace V pace or DDD
Atrial fibrillation with low ventricular rate
None
Paced ventricular rhythm
VVI(mode Switch)
•
”V” indicates multisite pacing in the ventricle or ventricles
•
”D” indicates dual multisite pacing in both atrium and ventricle
Depending on chamber sensed or paced, pacemaker can be classified in to three categories: A.
Single chamber pacemaker: Single chamber pacemaker can be of atrium based or ventricle based.
In atrial based or AAI pacemaker the single lead is located in right atrium (usually right atrial appendage). The response of the pacemaker to intrinsic atrial rhythm is inhibitory, if the pacemaker sense intrinsic sinus rhythm no stimulation is given by the pacemaker. If there is no intrinsic P wave after a specific time period after sensed or paced P wave (the specific time depends on the lower rate of pacemaker, i.e. if the lower rate is 60 , the time period is 1000 ms), the pacemaker will pace the atrium and a pacing artefact will be followed by P wave. This pacemaker is a preferred mode in presence of sinus node dysfunction; however concomitant AV nodal dysfunction is contraindication for this pacing.
In Ventricle based or VVI pacing the lead is poisoned in right ventricle (apex, septum or outflow). The response of the pacemaker is same as AAI except the fact that it senses the R wave and pace the ventricle and pacing response is pacemaker artefact followed by R wave. In absence of intrinsic R wave the ventricle is paced in a fixed rate irrespective of atrial contraction, the AV synchrony is not maintained. This is a preferred mode of pacing where AV synchrony is not required ie: in presence of permanent atrial fibrillation.
Mode of Pacemaker
B.
Double Chamber pacemaker: In double chamber pacemaker, the leads are located in Right atrium and ventricle. The Classical double chamber pacemaker is DDD pacemaker.
In absence of intrinsic sinus rhythm for specific period, the atrial lead paced the right atrium. Following the sensed or paced P wave the ventricular lead waits for a specific period(AV delay), if the intrinsic R wave occurs, the ventricular lead sense it and ventricular pacing is inhibited(Inhibitory response). However in absence of intrinsic ventricular contraction after specific AV delay, the Ventricle is paced by ventricular lead(Trigger response). The Pacing protocol of a DDD pacemaker in different electro pathological conduction is described in table 2.
C.
In Multisite pacing apart from RA and RV lead, another lead is placed in coronary sinus to pace the left ventricle. As this pacemaker stimulates both LV and RV it is also known as biventricular pacemaker. This pacemaker is indicated in patients with heart failure
Pacemaker Follow-UP5, 6: A meticulous follow-up after pacemaker implantation is required for early detection and management of pacemaker related complications (pacemaker site infections, troubleshooting), optimizing the usage of pacing system, maximizing generator life and early assess battery status to predict end-of-life (EOL) of the pulse generator in order to permit timely elective generator replacement. Besides a pacemaker follow-up is used to provide patient and family support and education. Within 72 h of implantation, the main purpose of early post implant assessment is for inspection of the operative site and to confirm satisfactory pacemaker system
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Table 3: Patient and device assessment 1. Patient assessment A. Items to determine in a cardiovascular history
• • •
B. Items to determine in a focused physical examination:
•
Heart rate and rhythm (ECG with and without magnet) Heart sounds, breath sounds, signs of cardiac failure Wound and site assessment
Device assessment A. items to determine in a device history
• •
B. Data from available telemetry (varies with manufacturer and model)
• •
C. Check list of automatically available diagnostic data • (varies with manufacturer and model) •
D. If not available automatically function. Usually the capture threshold shows a slight rise within 2-6 weeks of the implantation followed by a decrease and then a chronic plateau value. Hence a follow-up visit with the cardiologist at approximately 12weeks time allows output reprogramming of the pacemaker settings to optimize safety margin and reduce battery drain. Thereafter till a period when the battery can be expected to deplete significantly or till about 7 to 10 years after the implant depending on the manufacturers recommendation and expected battery longevity. After that period 6 monthly follow-up is required till ERI is achieved. Once the ERI is achieved, a more intensified follow-up (3-6 monthly) is required. As per CSI/IHRS practice guidelines, factors tabulated in Table 3, should be included in pacemaker follow-up protocol. Auricchio A, Delnoy PP, Butter C, et al. Feasibility, safety, and short-term outcome of leadless ultrasoundbased endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study. Europace 2014; 16:681
2.
Reynolds D, Duray GZ, Omar R, et al. A Leadless Intracardiac Transcatheter Pacing System. N Engl J Med 2016; 374:533
3.
Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, et al; American College ofCardiology/American Heart
Programmed settings including last programmed date Battery status (cell impedance, voltage, energy, charge,current drain)
• •
Percentage of pacing and sensing in each chamber Counter of ventricular arrhythmias and atrial tachycardia(using useredefined criteria for data collection) Lead impedance trends over time Capture and sensing thresholds over time
•
capture and sensing threshold assessment Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation ofCardiac Pacemakers and Antiarrhythmia Devices); American Association for ThoracicSurgery; Society of Thoracic Surgeons. ACC/ AHA/HRS 2008 Guidelines forDevice-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American college of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Updatefor Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008; 117:e350-408.
4.
Bernstein AD, Daubert JC, Fletcher RD, et al. The revised NASPE/BPEG generic code for antibradycardia, adaptiverate, and multisite pacing. North American Society of Pacing and Electrophysiology/British Pacing and Electrophysiology Group. Pacing Clin Electrophysiol 2002; 25:260.
5.
Roberts P R, Follow-up and Optimisation of Cardiac Pacing Heart 2005; 91:1229-1234
6.
Rajgopal S, Kapoor A, Bajaj R, Vora A et al; CSI/IHRS practice guidelines on follow-up of patients with permanent pacemakers: A Cardiology Society of India/Indian Heart Rhythm Society task force report on practice guidelines on follow-up of patients with permanent pacemakers. Indian Heart J 2012; 64:S12–S17.
REFERENCES
1.
Time since implant of the lead/s and the pulse generator Previous hardware complications (e.g., advisory hardware,lead fracture, abandoned leads)
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• •
Dizziness, syncope, palpitations, dyspnoea, fatigue, angina Any significant clinical event (hospitalization etc.) since last visit Medication review
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213
Sudden Cardiac Death in Young People: Can it be Prevented Harendra Kumar
INTRODUCTION
Sudden Cardiac Death (SCD) is defined as unexpected natural death from a cardiac cause within short period, generally less than one hour from the onset of symptoms in a person without any prior condition that would be fatal1. But death in young and previously healthy individuals with no identifiable cause at autopsy, termed sudden arryhthmic death syndrome (SIDS), contributes upto 5% of SCD in general population aged 16-64 years and approximately 25-35% in less than 40 years of age group2. SCD occurs in those who have a substrate in presence of triggering factors. This chapter deals with mainly those people who are not known patients of cardiac diseases.
AETIOLOGY
22,000 population in Andhra Pradesh, there was autopsy incidence of SCD in 10-17% population.5 Based on US data of 1996 which showed 0.16% incidence of SCD in total US population6 , if we apply same incidence of 0.16% in 110 crore population of India, it was projected to be 17.6 lacs in India.7 Since, 60% of world’s heart disease is expected to occur in India by the end of decade, the incidence of SCD is expected to rise proportionately.8
FACTORS INFLUENCING SCD
Age : Increasing age enhances chances of SCD. In men of 50 years of age, the incidence of SCD was 100 per one lac people, which increased to 800 per lac in 75 years old i.e. 8 times higher.9 Sex : Women have less incidence of SCD.10 Smoking: Smokers have 2-3 times higher risk of SCD.
1.
In those over 50 years of age
•
CAD: responsible for 75-80% of SCD
•
Cardiomyopathies, Myocarditis
ECG: ECG change of myocardial infarction (MI) are well known.
•
Aortic Stenosis
Prolonged and short QT interval enhance chances of SCD.
•
Drug and Toxins : which is same for those below 50 years of age.
LBBB an LVH: Enhance 1.5 times risk of SCD. LVH is an independent predictor of SCD.
2.
In persons below 50 years of age
•
Premature CAD
Hypertension: Hypertension can cause SCD due to LVH and Resultant arrythmia.
•
Anomalous coronaries
Others : Low Socio-economic status11
•
Hypertrophic Cardiomyopathy (HCM)
Social Isolation
•
Left ventricular Hypertrophy (LVH) due to any cause
Psychiatric illnesses etc.
•
Long QT Interval
•
Short QT Interval
•
Catacholaminergic Tachycardia (CPVT)
•
Myocarditis
•
Dilated CMP
•
Valvular Heart Disease
•
Drugs and Toxins
Many young people develop premature CAD and MI and so they have chances of SCD. The bad thing about CAD is that in about 30% cases, SCD may be first symptom of MI. The risk of SCD in those patients who have developed in MI, is enhanced during first month and it gradually decreases with passage of time. However, with considerable remodeling and Scar formation, patient may be vulnerable to ventricular arrhythmia, the so called scar VT.12,13 The risk of SCD also increases if patient develops heart failure and ischaemic events recur. The patients of CAD who are of older age, male, hypertensive, diabetic, smokers, obese having increased cholesterol have comparatively more chances of SCD. The other concomitant features such as heart failure, L.V. dysfunction, LVH, Tachycardia, other abnormalities in ECG, poor functional status enhance chances of SCD.1,14,15
INCIDENCE
Polymorphic
Obesity: Also enhances risk of SCD.
Ventricular
In USA, the incidence of SCD was 53/100000 population.3 In China, the incidence of SCD was 41.8/100000 in a study on 678718 persons.4 In India, a small study on over
SCD IN CAD
INHERITED CARDIAC DISEASES
EARLY REPOLARIZATION SYNDROME
Many people dying suddenly and autopsy being normal, raised curiosity to find out the cause of death. Many such people were thought to have natural death unfortunately. In these victims of SCD with normal autopsy, postmortem genetic testing showed that about 20-35% deaths were due to inherited arrhythmic disorders.16-18
It is a common ECG finding in 2-5% population. It was considered a benign ECG finding for over half century. It can cause life threatening ventricular arrhythmia in some cases.24So, those persons who have early repolarization form of ECG and ventricular arrhythmia and unexplained syncope, 24 hour ECG, EP study should be done.
HYPERTROPHIC CARDIOMYOPATHY (HCM)
Brugada syndrome
Prevention of SCD
Beta-blockers and amiodarone are being used for a long time, but there is no improvement in survival. ICD is a better option. These patients should avoid intense physical activity, competitive sports and alcohol use.
Catacholaminergic Polymorphic Ventricular Tachycardia (CPVT)
It is not uncommon. The presenting feature is syncope/ ventricular arrhythmia in children and young adults, triggered by physical or mental stress. CPVT may be suspected by PVCS on exertion or by their appearance during exercise testing. 24 hour ECG may also help. CVPT accounts for 14-21%. Of SCD observed in young adults.20
LONG QT SYNDROME
Prolonged QT means QTC is >480 ms, when QTC prolongation is over 500 ms, then the risk of SCD is markedly increased due to ventricular arrhythmia like VT/VF, torsades. Risk of SCD is increased when there is unexplained syncope/cardiac arrest, documented lethal arrhythmias like VT/VF. Incidence of SCD in long QT syndrome may be 2.3 to as high as 5 times.21
Triggering factors to be avoided are :
Acute mental and physical stress, hypothermia etc. Some drugs are known to prolong QT interval: Terfenadine, Cisapride, Lithium, Qunidine, Sotalol, Amiodarone, Domperidon, Clarithromycin, Haloperidol etc.
Prevention of SCD in long QT •
Offender drug should be stopped
•
Beta-Blocker drugs are most preferred drugs for prevention of arrhythmia and syncope.
•
ICD may be needed when beta blockers are not sufficient.
ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY/DYSPLASIA (ARVC)
In this disease right ventricle is affected and is replaced by fibrofatty tissue, but L.V. can also be affected. It is a genetically determined heart muscle disease.22,23 It can cause syncope, VT and in some case SCD. It can be diagnosed by Echo. Symptomatic patients may need ICD.
Brugada syndrome can also cause SCD below 50 years of age, but it is rarely seen. The typical ECG pattern is ST elevation in lead V1 –V3 with RBBB. Death is due to polymorphic VT or VF.25
TRIGGERING FACTORS OF SCD
These are important because avoidance and taking care of these may prevent SCD.
MENTAL STRESS
Stress not only causes MI, but also triggers life threatening arrhythmias. It is already known that about 75-80% SCD is due to CAD. The INTER HEART study26 has shown that diverse stressful life events like death or major illness of spouse or a close family member, major self-illness, conflict among family members, loss of job etc. can cause SCD. Disasters like earthquake is known to cause miseries in the form of displacement from house, increase in mental stress immensely. In such a study of earthquake victims, the cardiac death was enhanced by 2-5 times even they had no physical trauma by earthquake.27Mental stress is also known to prolong QT interval.28
PHYSICAL STRESS
There is data that physical exertion was responsible for collapse and cardiac arrest of 11-17% persons.29 In an athlete meet in USA, SCD was found to be a leading cause of death.30 In fact many SCDs occur during competitive sports, run for job for recruitment in police or military, vigorous physical activity by a person who is spending sedentary life. In most of these situations, there must be some substrate in the form of CAD or genetic cardiac disorders or structural heath disease.
ELECTROLYTE IMBALANCE
Hypokalemia, Hypomagnesemia, Hypocalcemia can also trigger SCD.
WHAT ARE WARNING SIGNS
•
Undiagnosed syncope
•
History of cardiac arrest
•
Family history of SCD
•
History of VT/VF
•
Warning sign of ECG
•
Echo evidence of disease
•
History of Angina on effort
These persons should be meticulously investigated. Simple tests like ECG, Echo, exercise test, 24 hour ECG, ELR should be done first and EPS, coronary angiography,
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It is the commonest cause of SCD in this group. In those with history of pain chest, syncope, cardiac arrest, VT, family history of SCD, then one must be alerted. Echocardiography shows LV wall thickness (>30mm in high risk case) and LV outflow obstruction may be present.19
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CT Angio etc. should be done whenever required. With increasing awareness about genetic cardiac diseases, more and more causes of SCD/Cardiac arrest are being diagnosed. Earlier many cases were dumped as idiopathic VF. Many young victims of SCD were thought to die a natural death. The CASPER trial31 has shown the path, as cause of cardiac arrest was detected in 70% people.
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REFERENCES
1.
Zipes Douglas P, Wellens Hein JJ. Sudden Cardiac Death. Circulation 1998; 98:2324-2351.
2.
Priori SG, Wilde AA, Horie M et al. Executive summary: HRS/EHRA/APHRS Expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Europace 2013; 15:13891406.
3.
Chugh SS, Jui J, Gunson K. et al. Current burden of sudden cardiac death: Multiple score surveillance versus retrospective death certificate â&#x20AC;&#x201C; based review in large US community. J Am Coll Cardiol 2004; 44:1268-1275.
4.
Hua W, Zhang LF, WU YF et al. Incidence of sudden cardiac death in China: Analysis of 4 regional populations. J Am Coll Cardiol 2009; 54:1110-1118.
5.
Rao BH, Sastry BK, Chugh SS et al. Contribution of sudden cardiac death to total mortality in India. A Population study. Int J Cardiol 2012; 154:163-167.
6.
Zheng ZJ, Croft JB, Giles HW et al. Sudden cardiac death in United states in 1989-1996 (ABSTR) Circulation 2000; 102:11-841.
7.
Kumar H. Sudden cardiac death in apparently healthy young person: is it preventable: J Preventive Cardiology 2014; 4:654-660.
8.
Mohan V, Deepa R, Rani SS et al. Prevalence of Coronary artery disease and its Relationship to Lipids in a selected population in South India. The Chennai urban population study (CUPS No.5) J Am Coll Cardiol 2001; 38:682-687.
9.
Becker LB. Han BH, Meyer PM et al. Racial differences in the incidence of cardiac arrest and subsequent survival. The CPR Chicago project N Engl J Med 1993; 329:600-606.
10. Kannel WB, Wilson PWF, Dâ&#x20AC;&#x2122;Agostino RB et al. Sudden coronary death in women. Am Heart J 1998; 136:205-212. 11. Mansah GA, Mokdad AH, Ford ES et al. State of disparities in Cardiovascular health in the United States. Circulation 2005; 111:1233-1241. 12. Adabag AS, Themeau TM, Gersh BJ et al. Sudden death after myocardial infarction. JAMA 2008; 300:2022-2029. 13. Solomon SD, Zelenkofske S, Mamurray JJ et al. Valsartan in acute myocardial infarction trial (valiant) investigators. Sudden death in patients with myocardial infarction and left ventricular dysfunction, Heart failure or both. N Engl J Med 2005; 352:2581-2588. 14. Hallstrom AP, Omato JP, Weisfeldt M et al. Public access defibrillation and survival after out of Hospital cardiac arrest. N Engl J Med 2004; 351:637-646. 15. Buxton AE. Risk stratification for sudden death in patients with coronary artery disease. Heart rhythm 2009; 6:836-847.
16. Tester DJ, Auckerman MJ. The role of Molecular autopsy in unexplained sudden cardiac death. Currropin cardiol 2006; 21:166-172. 17. Ackerman MJ, Priori SG, Willems S et al. HRS/EHRA Expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the heart rhythm society (HRS) and The European Heart Rhythm Association (EHRA). Europace 2011; 13:1077-1109. 18. Klaver EC, Versluijs GM, Wilders R. Cardiac ion channel mutations in the sudden infant death syndrome. Int J Cardiol 2011; 152:162-170. 19. Musumeci MB. High risk for sudden death identified by electrocardiographic loop recording in a patient with hypertrophic cardiomyopathy without major risk factors. Am J Cardiol 2011; 107:1558-1560. 20. Lambardi R. Genetics and sudden death. Curr Opin Cardiol 2013; 28:272-281. 21. Chugh SS, Renier K, Singh T et al. Determinants of prolonged QT interval and their contribution to sudden death risk in coronary artery disease. The Oregon sudden unexpected death study. Circulation 2009; 119:663-670. 22. Marcus FI, Mckenna WJ, Sherrill D et al. Diagnosis of Arrhythmogenic right ventricular cardiomyopathy/ dysplasia: Proposed modification of the task force criteria. Circulation 2010; 121:1533-1541. 23. SenChowdhry S, Syrris P, Prasad SK et al. Left dominant arrhythmogenic cardiomyopathy: An under-recognized Clinical Entity, JACC 2008; 52:2175-2177. 24. GVSSAK I, Antzelevitch C. Early repolarization syndrome: Clinical characteristics and possible cellular and ionic mechanisms. J Electrocardiol 2000; 33:299-309. 25. Brugada R. Sudden Death: Managing family, the role of genetics. Heart 2011; 97:676-681. 26. Yusuf S, Hawkin S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (The INTER-HEART study) case control study. Lancet 2004; 364:937-952. 27. Kloner RA, Leo RJ, Poole WK et al. Population based analysis of the effect of the North-Ridge Earthquake on cardiac death in Los Angeles Country, California. J Am Coll Cardiol 1997; 30:1174-1180. 28. Andrassy GI, Szabo A, Ferencz G et al. Mental stress may induce QT interval prolongation and T wave notching. Ann Non invasive Electrocardiol 2007; 12:251-259. 29. Cobb LA, Weaver WD. Exercise : A risk factor for sudden death with coronary Heart disease. J Am Coll Cardiol 1986;7:215-219. 30. Harmon KG, Asif IM, Klossner D et al. Incidence of sudden cardiac death in National Collegiate Association Athletes. Circulation 2011; 123:1594-1600. 31. Krahn AD, Healey JS, Chauhan V et al. Systematic Assessment of patients with unexplained cardiac arrest: Cardiac arrest survivors with preserved ejection fraction registry (CASPER). Circulation 2009; 120:278-285.
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Update in Preoperative Cardiovascular Evaluation and Perioperative Cardiovascular Medical Management Michael A Mikhail, Arya B Mohabbat, Amit K Ghosh
INTRODUCTION
Major adverse cardiac events (MACE) are among the most common causes of perioperative mortality and morbidity. As such, the most recent key updates in perioperative medicine are related to perioperative cardiovascular risk assessment and management. The 2014 and 2016 American College of Cardiology/American Heart Association perioperative guidelines provide expert consensus on these topics. These guidelines include new definitions of operative urgency and risk, as well as more direction regarding perioperative cardiovascular testing and medical management. Patient-specific plus procedure-specific risk factors are crucial to determine an individualâ&#x20AC;&#x2122;s perioperative risk profile. Clinical judgement remains a core principle. Close communication among care teams also is essential.1
PREOPERATIVE CARDIOVASCULAR RISK STRATIFICATION
intrathoracic surgery; major orthopedic surgery; and open urologic surgery.1 The risk of perioperative major adverse cardiac event (MACE) may be estimated by compilation of patientspecific and procedure-specific risk factors through the Revised Cardiac Risk Index (RCRI) score, NSQIP score, or other similar scoring method.2,3,1 A patient is deemed of low perioperative cardiovascular risk if the risk of perioperative major adverse cardiovascular event (MACE) is less than 1%. A patient is of elevated perioperative cardiovascular risk if the risk of perioperative major adverse cardiovascular event (MACE) is greater than 1%. The combination of urgency of procedure, patient-specific risk, and procedure-specific risk is used to determine need for preoperative cardiovascular testing and perioperative cardiovascular medical management.1
PREOPERATIVE CARDIOVASCULAR TESTING
The first step of preoperative cardiovascular evaluation is to determine the urgency of the proposed non-cardiac procedure.(1) An emergency procedure is needed in less than six hours, to mitigate threat to life or to limb; in this situation, very limited preoperative evaluation is necessary. An urgent procedure is needed within 6-24 hours, to mitigate threat to life or limb; some preoperative cardiovascular evaluation may be feasible, if warranted. A time-sensitive procedure is necessary within 1-6 weeks; more preoperative testing may be feasible, if indicated; further delay for evaluation and significant changes in management will negatively affect outcome. An elective procedure may be delayed up to one year; this allows greatest time for preoperative evaluation and intervention, if needed.1
A screening preoperative electrocardiogram (ECG) is indicated in the setting of one or more patient-specific perioperative risk factors plus an elevated-risk procedure. A screening preoperative ECG is not clearly warranted in a stable patient undergoing a low-risk procedure, even in a patient with known cardiovascular disease or multiple cardiovascular risk factors. Age alone is not a well proven independent indication for preoperative ECG.1
From a cardiovascular perspective, procedures may be categorized as low procedure-specific risk or elevated procedure-specific risk.1 Low cardiovascular risk procedures are those which confer less than 1% risk of major adverse cardiac event (MACE). Common examples include endoscopic procedures, superficial procedures, cataract surgery, most breast surgery, and ambulatory surgery. Key examples of elevated cardiovascular risk procedures (risk of MACE greater than 1%) include emergent major operations, particularly in elderly patients; aortic and other major vascular surgery; prolonged procedures with large fluid shifts and/or blood loss; head and neck surgery; intraperitoneal and
Resting echocardiography is indicated or reasonable if clinically-suspected moderate or greater cardiac valvular disease (particularly if no echocardiography within one year, or if significant change in clinical status or physical exam); in adults who meet standard indications for cardiac valvular intervention (replacement or repair), on basis of symptoms and severity of valvular stenosis or regurgitation; if dyspnea of unknown origin; or if heart failure with worsening dyspnea or other decline in clinical status. Resting echocardiography may be considered in a clinically stable patient with history of LV dysfunction, if no such assessment within one year; however, this recommendation is weaker, and is most applicable if results will affect management.(1)
For non-cardiac surgery, routine screening with noninvasive cardiovascular testing is not useful for patients at low cardiovascular risk. If a patient has a functional capacity greater than 10 METs, even with known cardiovascular disease, then additional screening preoperative cardiac testing is not indicated.1
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Preoperative cardiac stress testing is indicated if perioperative MACE risk is greater than 1% and results will affect management. This is particularly true in the setting of poor functional capacity (less than 4 METs) or unknown functional capacity, plus an elevated-risk procedure. If a cardiac stress test is warranted even in the absence of non-cardiac surgery, then it should be obtained prior to non-emergency noncardiac surgery.1 Exercise ability, comorbidities, baseline ECG, and institutional expertise influence the choice of a cardiac stress study. Cardiac stress test selection entails selection of a cardiac physiologic stress modality, plus selection of a cardiac functional assessment modality.1,4-6 These are summarized further as follows:
COMMON CARDIAC PHYSIOLOGIC STRESS MODALITIES
Exercise4-6
Exercise should be utilized in cardiac stress testing, when possible. Poor exercise capacity or inability to achieve > 85% predicted maximal heart rate is associated with 24% risk of postoperative cardiac event, independent of ischemic ECG changes. However, exercise may not be feasible in the context of orthopedic limitation, neurologic deficit, poor pulmonary function, severe to critical vascular disease, and/or other exercise limitations.
Adenosine, Regadenoson, and Dipyridamole4-6
These are vasodilators that cause a coronary “steal” phenomenon. They may be options for physiologic cardiac stress in some patients with exercise limitations. Major adverse effects of these agents include hypotension, atrioventricular block, and bronchospasm. Adenosine. regadenoson, and dipyridamole should be avoided in patients with low systemic blood pressure, high-grade A-V block, known poor cardiac reserve, severe to critical cerebrovascular disease, or substantial bronchospastic disease. Theophylline and caffeine also decrease the effectiveness of the vasodilators.
Dobutamine4-6
Dobutamine is an adrenergic agent. It may be an option for physiologic cardiac stress in some patients with exercise limitations. Major adverse effects of dobutamine include cardiac dysrhythmias and severe hypertension. Dobutamine should be avoided in patients with baseline significant dysrhythmias or poorly-controlled systemic hypertension. Theophylline and caffeine do not impede the efficacy of dobutamine.
CARDIAC FUNCTIONAL ASSESSMENT MODALITIES
Stress ECG Alone1,4-6
Stress ECG alone confers high sensitivity and moderate specificity for risk of perioperative major adverse cardiovascular event (MACE). It is widely available, does not involve ionizing radiation, and is relatively inexpensive. Stress ECG may be non-diagnostic if certain baseline ECG abnormalities are present (including left bundle branch block, electronic ventricular pacing, left ventricular hypertrophy with repolarization abnormalities, ventricular preexcitation, baseline
ST depression greater than 1 mm, digoxin effect, prior myocardial infarction, percutaneous coronary intervention, and coronary artery bypass surgery). Stress ECG, without cardiac imaging, is a reasonable option for preoperative cardiac stress testing, when feasible, based upon balance of these considerations.
Stress Echocardiography1,7,8,4-6
Stress echocardiography (with exercise or pharmacologic stress) is highly sensitive and specific for detection of myocardial ischemia or infarction. Image quality can be impaired by obesity or “barrel chest;” this limitation may be overcome in some patients by the use of saline contrast. Baseline cardiac regional wall motion abnormality or left bundle branch block can lead to falsely-positive stress echocardiography results. Stress echocardiography is relatively widely available and entails no ionizing radiation exposure, but is moderately costly.
SPECT Myocardial Perfusion Imaging (Technetium or Thallium)1,7,4-6
SPECT myocardial perfusion imaging (technetium or thallium) confers high sensitivity and specificity for detection of myocardial ischemia or infarction. The specificity of SPECT is slightly less than that of stress echocardiography. Image quality of SPECT myocardial perfusion imaging can be impaired by obesity, “barrel chest,” or breast artifact (especially with thallium imaging). SPECT myocardial perfusion imaging is relatively widely available, does entail ionizing radiation exposure, and is costly. It is preferred over stress echocardiography in patients with known regional wall motion abnormalities.
Cardiac PET Imaging5,6
Cardiac PET imaging is useful to assess cardiac perfusion in patients with severe obesity. It is not widely available, entails ionizing radiation exposure, and is very costly.
PERIOPERATIVE ANTIPLATELET THERAPY
As with other aspects of perioperative medicine, decisions regarding perioperative management of antiplatelet therapy entail consideration of patient-specific and procedure-specific risk factors.1 In the POISE-2 Trial, Devereaux et al identified increased perioperative bleeding within 30 days, among patients undergoing noncardiac surgery who received perioperative aspirin (4.6% aspirin vs. 3.8% placebo), with no significant difference in risks of myocardial infarction or mortality. However, in that study, only 23% of patients had known coronary artery disease; patients with recent coronary intervention (defined as PCI with bare metal stent placement within 6 weeks, PCI with drug eluting stent placement within 12 months) were excluded. Aspirin vs. non-aspirin patients had no significant difference in life-threatening bleeding.9 Other outcomes have been noted in surgical patients who are at increased cardiovascular risk. In a 2006 metaanalysis by Biondi-Zoccai et al, involving 50,279 surgical patients at elevated cardiovascular risk, perioperative discontinuation of aspirin was associated with threefold increased risk of major adverse cardiac events
Much attention has been devoted to antiplatelet therapy in the setting of coronary artery disease, including in the context of noncardiac surgery. Related care recommendations have been clarified through the, “2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease.” For patients with stable ischemic heart disease (SIHD) who have undergone cardiac stent placement, elective noncardiac surgery should be postponed and dual antiplatelet therapy maintained for more than 30 days after bare metal stent placement and for more than six months after drug-eluting stent placement, to reduce the risk of major adverse cardiac event (MACE). However, if the risk posed by delay of noncardiac surgery is greater than the risk of stent thrombosis, discontinuation of clopidogrel may be considered after a minimum of three months. Secondary-prevention aspirin should be continued if at all possible. Clopidogrel should be resumed as soon as possible following surgery, once adequate hemostasis is confirmed. Elective noncardiac surgery should be delayed more than twelve months after acute coronary syndrome (ACS), whether the ACS has been addressed by medical therapy alone, PCI with bare metal stent (BMS) placement, PCI with drug-eluting stent (DES) placement, or coronary artery bypass graft (CABG).1,12 If noncardiac surgery must be performed within those periods after initial invasive or non-invasive treatment of coronary artery disease, then dual antiplatelet therapy should be maintained perioperatively unless the risk of major bleeding exceeds the risk of perioperative major adverse cardiac event (MACE). Key examples of reasons to hold dual antiplatelet therapy include active lifethreatening major bleeding (massive gastrointestinal tract hemorrhage that does not respond to non-surgical measures, life-threatening intracranial hemorrhage) and urgent or emergency intracranial surgery. Primaryprevention antiplatelet therapy should be held preoperatively, unless the risk of major adverse cardiac event (MACE) is deemed greater than the risk of major perioperative bleeding with antiplatelet therapy.1,12 These are guidelines, not mandates. Urgency of procedure, major adverse cardiac event (MACE) risk, bleeding risk, and overall clinical judgement remain essential.1,12
PERIOPERATIVE BETA BLOCKADE
Patient-specific and procedure-specific considerations
remain important to the complex topic of perioperative beta blockade. Perioperative beta blockade is associated with reduced risk of perioperative MACE, though increased risk of bradycardia, hypotension, and stroke. Perioperative beta blockade is associated with increased mortality in patients with zero or one RCRI risk factor, while also associated with decreased mortality in those with three or more RCRI risk factors. Ultimately, the decision regarding perioperative beta blockade is based on a balance of these.13, 1 The 2014 American College of Cardiology/American Heart Association Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery includes expert consensus on perioperative use of beta blocker therapy. According to that guideline, perioperative beta blockade is recommended if a patient already chronically takes a beta-blocker agent, reasonable if a patient has known or strongly-suspected clinically significant coronary artery disease, and reasonable if a patient has three or more Revised Cardiac Risk Index (RCRI) risk factors for perioperative major adverse cardiac event (MACE) plus a planned elevated-risk procedure.1 RCRI risk factors, as defined in 1999 by Lee et al, include high-risk surgery (intraperitoneal, intrathoracic, or suprainguinal vascular surgery), history of ischemic heart disease, history of heart failure, cerebrovascular disease, insulin-requiring diabetes mellitus, and serum creatinine level > 2.0 mg/dl.2 The 2014 ACC/AHA perioperative guideline supports greatest benefit from at least one week to one month titration of beta-blockade preoperatively (if indicated), continued at least one month postoperatively. Beta blockade should not be initiated on the day of surgery.1 More cardioselective beta blocker agents (such as bisoprolol and atenolol) might confer lower stroke and mortality risk than less cardioselective agents (such as metoprolol).13,1 COPD, without severe bronchospastic disease, is not a clear contraindication to cardioselective beta blocker therapy. (14, 15) Many patients who warrant perioperative beta blockade have long-term indications for such therapy; this is best addressed by each patient’s primary care provider.1
PERIOPERATIVE STATIN THERAPY
Studies of perioperative statin therapy mostly are small, and/or retrospective, and/or limited to cardiac surgery or peripheral vascular surgery. Despite these limitations, perioperative “statin” therapy is associated with deceased perioperative major adverse cardiac event (MACE) risk, particularly in elevated perioperative cardiovascular risk situations. Plausible mechanisms for these benefits include coronary artery plaque stabilization, anti-inflammatory effects, and potentially decreased thrombogenesis.1 Studies in 2003 and 2004 demonstrated reduced allcause mortality, cardiac mortality, and non-fatal cardiac events in patients who received perioperative statin therapy vs. placebo.16-19 In 2006, a large meta-analysis of 15 trials, including more than 223,000 total patients, demonstrated a significant reduction in perioperative
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(MACE).10 In a 2005 meta-analysis by Burger et al, including 41 studies, secondary-prevention aspirin was associated with a 1.5-fold increased risk of perioperative bleeding, but perioperative discontinuation of aspirin preceded 10% of all acute coronary events; there was no significant difference noted in the severity of bleeding between aspirin and non-aspirin patients, except in the context of intracranial surgery and possibly in the context of transurethral resection of the prostate. Burger et al concluded that aspirin should not be discontinued perioperatively, unless the risk of major perioperative bleeding exceeds the risk of cardiovascular events.11
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mortality in patients on statin therapy who underwent cardiac surgery, peripheral vascular surgery, and noncardiovascular surgery.20 A 2009 randomized controlled trial of statin-naĂŻve patients undergoing vascular surgery revealed a significant reduction in perioperative myocardial infarction and cardiovascular death.21 Based on available evidence, the 2014 American College of Cardiology/American Heart Association perioperative guideline supports perioperative continuation of statin therapy, perioperative initiation of statin therapy in patients undergoing cardiac and vascular surgery, and perioperative initiation of statin therapy in patients at elevated cardiovascular risk who undergo elevated-risk procedures.1
OTHER PERIOPERATIVE CARDIOVASCULAR MEDICATION MANAGEMENT
Perioperative management of angiotensin converting enzyme-inhibitor (ACE-I) and of angiotensin receptor blocker (ARB) therapy has been controversial. In a 2012 retrospective study of over 79,000 patients who underwent non-cardiac surgery, ACE-I therapy was associated with higher rates of intraoperative hypotension, but was not significantly associated with other cardiovascular outcomes (death, myocardial infarction, and stroke). (22) Two trials of ACE-I and ARB therapy in vascular surgery patients demonstrated significantly more hypotensive events with these agents, but no difference in other cardiovascular outcomes.23,24 In a large observational study, preoperative administration of ACE-Is and ARBs was associated with more frequent intraoperative hypotension, but no difference in rates of postoperative myocardial infarction or of renal failure.25 A 2008 metaanalysis demonstrated a 50% incidence of perioperative hypotension in patients taking ACEI-s or ARBs, but no significant difference in other major perioperative cardiovascular outcomes.26 Two trials addressed the effects of discontinuation of ACE-Is and ARBs prior to non-cardiac surgery. These studies demonstrated no specific harm associated with discontinuation of ACE-Is and ARBs preoperatively. However, patients with poorly controlled hypertension or heart failure were not included in those studies.24, 27 Overall data demonstrates that ACE-Is and ARBs do increase the risk of transient intraoperative hypotension, but without clearly proven significant adverse effect on other perioperative cardiovascular outcomes. The 2014 American College of Cardiology/American Heart Association perioperative guideline supports either continuation or withholding of ACE-I and ARBs preoperatively, based on clinical judgement. This guideline further indicates that, if ACE-Is or ARBs are held preoperatively, that it is reasonable to restart them as soon as feasible postoperatively.(1) A reasonable approach is as follows: Continue ACE-I or ARB therapy perioperatively in patients with uncontrolled hypertension or with congestive heart failure; withhold ACE-I or ARB therapy preoperatively in patients with satisfactory blood pressures and no known congestive
heart failure, but resume these agents postoperatively once stable hemodynamic status and renal function are confirmed. The use of clonidine in the perioperative setting also has been controversial. A 2014 multicenter randomized control trial, which involved over 10,000 non-cardiac surgery patients, revealed no significant difference in perioperative mortality or myocardial infarction with clonidine compared to placebo.28 However, in that study, clonidine was associated with substantially-elevated incidence of clinically significant hypotension and of non-fatal cardiac arrest.28 Based upon this data, the 2014 American College of Cardiology/American Heart Association perioperative guideline includes recommendation against prophylactic use of alpha-2 agonists in the perioperative setting.1 Initiation of clonidine for treatment of perioperative hypertensive emergency is indeterminate; if clonidine is used in this context, extreme caution and strong consideration of other antihypertensive therapies should be employed. Maintenance clonidine therapy should be continued perioperatively, if well-tolerated, due to risks of rebound hypertension and tachycardia if clonidine is discontinued abruptly.1, 29
PERIOPERATIVE MANAGEMENT OF OBSTRUCTIVE SLEEP APNEA
In patients with obstructive sleep apnea (OSA) or obesity hypoventilation syndrome, CPAP or BiPAP begun at least four to six weeks preoperatively is associated with several anatomic and physiologic benefits. These include reduced tongue volume, increased oropharyngeal volume, improved ventilatory drive, and improved cardiac function.30-32 In the setting of uncontrolled obstructive sleep apnea or uncontrolled obesity hypoventilation syndrome, elective noncardiac surgery should be delayed to allow optimal CPAP or BiPAP therapy for at least four to six weeks preoperatively, if possible. If such delay is not feasible (e.g.: urgent or emergency surgery), then CPAP or BiPAP should be initiated as soon as possible postoperatively.30-32
CONCLUSION
Major adverse cardiac events (MACE) remain among the most common causes of perioperative mortality and morbidity. The most recent major updates in perioperative medicine are related to perioperative cardiovascular risk assessment and management. The 2014 and 2016 ACC/ AHA perioperative cardiovascular guidelines include new definitions of operative urgency and risk, as well as more direction regarding perioperative cardiovascular testing and medical management. Patient-specific risk factors, procedure-specific risk factors, and clinical judgement remain crucial to determine a perioperative risk profile and subsequent perioperative care. Close communication among care teams also is essential.1,12
SAMPLE CASES
1.
A 72 year-old female awaits removal of a nodular basal cell carcinoma of her right maxillofacial region. Her additional history is noteworthy for
coronary artery disease, myocardial infarction, hypertension, hyperlipidemia, ten pack-years of cigarette smoking ended 40 years ago, and COPD. She is clinically stable, including regular ambulation of several blocks per day without problem. Medications include bisoprolol, lisinopril, simvastatin, and aspirin. Vital signs are normal. Physical examination findings are noncontributory. Based upon the 2014 ACC/AHA perioperative guideline, which of the following is recommended, to complete this patient’s preoperative evaluation? ECG within past 12 months
B.
ECG within past 6 months
C.
ECG within past 30 days
D.
ECG within past 7 days
E.
Preoperative ECG not indicated
Correct Answer: E) Preoperative ECG not indicated. This patient is medically stable, with a good functional capacity, and pending low-risk procedure. 2.
A 58 year-old male awaits elective left total hip arthroplasty, due to advanced osteoarthritis. He walks several blocks at a time, limited only by chronic left hip pain. His additional history is noteworthy for obesity. His only medication is ibuprofen twice daily as needed. Vital signs are normal. Physical examination findings are noteworthy for obese habitus (BMI 38 kg/m2), remainder noncontributory.
Which of the following is most helpful to further stratify this patient’s perioperative cardiovascular risk? A.
Resting transthoracic echocardiography
B.
Exercise electrocardiography
C.
Dobutamine stress echocardiography
D.
Adenosine-Tc sestamibi myocardial perfusion study (SPECT)
E.
Cardiac PET myocardial perfusion study
Correct Answer: C) Dobutamine stress echocardiography. This patient awaits an elective, elevated risk procedure. He has known cardiovascular disease with a poor functional capacity, limited by exertional dyspnea and chest discomfort. A cardiac pharmacologic stress test is indicated. The patient has known COPD with bronchospasm and clinical evidence of cerebrovascular disease; therefore, acute vasodilator agents should be avoided in him. The patient has no known contraindication to dobutamine. Although either stress echocardiography or stress myocardial SPECT would be reasonable in this situation, stress echocardiography confers high sensitivity and specificity, involves no ionizing radiation, and is feasible with his BMI. Based upon all of these considerations, dobutamine stress echocardiography is preferred in this case. 4.
Based upon the 2014 ACC/AHA perioperative guideline, which of the following is recommended, to complete this patient’s preoperative evaluation?
A 64 year-old female awaits elective bladder suspension, due to urinary incontinence. Her additional history is noteworthy for hypertension and hyperlipidemia. She is clinically stable, including regular ambulation of several blocks per day without problem. Medications include lisinopril, atorvastatin, and aspirin. Physical examination findings are noncontributory.
A.
ECG within past 12 months
B.
ECG within past 6 months
C.
ECG within past 30 days
D.
ECG within past 7 days
Which of the following is the best choice for perioperative management of aspirin in this case?
E.
Preoperative ECG not indicated
A.
Continue aspirin perioperatively
Correct Answer: E) Preoperative ECG not indicated. This patient awaits an elevated-risk procedure, but has adequate functional capacity and no known perioperative cardiovascular risk factor (RCRI or NSQIP).
B.
Hold aspirin for at least 3 days preoperatively
C.
Hold aspirin for at least 7 days preoperatively
D.
Hold aspirin for at least 14 days preoperatively
3.
E.
Hold aspirin for at least 30 days preoperatively
A 70 year-old male awaits elective ventral hernia repair. His additional history is noteworthy for coronary artery disease, hypertension, 50 packyears of cigarette smoking through the present, COPD with bronchospasm, and obesity. He is unable to ambulate more than one block, due to exertional dyspnea and diffuse chest discomfort. His medications include atenolol, lisinopril, simvastatin, aspirin, combination fluticasone/ salmeterol diskus, and albuterol inhaler as-needed. His vital signs are normal. Physical examination is remarkable for obese habitus (BMI 32 kg/m2),
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Correct Answer: C) Hold aspirin for at least 7 days preoperatively. This patient takes aspirin for primary prevention and awaits a procedure which entails increased bleeding risk. In this situation, aspirin should be held at least 7 days preoperatively. 5.
A 64 year-old male awaits open surgical repair of an asymptomatic 5.5 cm diameter abdominal aortic aneurysm. His additional history is noteworthy for coronary artery disease, myocardial infarction 6 years ago, percutaneous coronary intervention (PCI)
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A.
carotid pulses diminished bilaterally, pulmonary sounds diffusely diminished, and a large nonreducible ventral hernia.
with drug-eluting stent (DES) placement 2 months ago for treatment of acute coronary syndrome, HTN, 30 pack-years of cigarette smoking ended 10 years ago, COPD with bronchospasm, and chronic kidney disease. He has been clinically stable since PCI with DES placement, including regular ambulation of several blocks at a time without problem. His medications include diltiazem, isosorbide mononitrate, clopidogrel, aspirin, fluticasone/salmeterol diskus, and albuterol MDI as needed. Physical examination is noncontributory.
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How soon should elective AAA repair be performed? A.
As soon as possible, if no clopidogrel for at least 7-14 days before surgery.
B.
3 months after PCI/stent placement
C.
6 months after PCI/stent placement
D.
More than 12 months after PCI/stent placement
E.
Elective AAA repair should not be performed in this patient
Correct Answer: D) More than 12 months after PCI/stent placement. Based upon the 2016 ACC/AHA update on antiplatelet therapy, elective non-cardiac surgery should be delayed more than 12 months after treatment of acute coronary syndrome (whether ACS is addressed by medical therapy alone or by invasive therapy), if possible. 6.
In this same patient, if open surgical repair of abdominal aortic aneurysm must be performed within one month, due to rate of increase of aneurysm size, which of the following is the best choice for perioperative antiplatelet therapy management?
continued for more than 12 months after PCI with DES placement in the setting of acute coronary syndrome (ACS), more than six months after PCI with DES placement in the setting of stable ischemic heart disease (SIHD). If major surgery must be performed within those time periods, dual antiplatelet therapy should be continued perioperatively, if approved by the surgical team. Close communication among involved medical and surgical teams, and with patient, is especially important in such situations. 7.
A 74 year-old female awaits elective revision left shoulder arthroplasty, due to failed prosthesis. She walks several blocks at a time, without problem. Her additional history is noteworthy for obesity, type II diabetes mellitus, hyperlipidemia, 40 pack-years of cigarette smoking ended 10 years ago, and osteoarthritis. Her medications include lisinopril, metformin, atorvastatin, aspirin, and acetaminophen. Vital signs are normal. Physical examination findings are noteworthy for obese habitus (BMI 34 kg/m2), remainder noncontributory.
Which of the following is recommended, to reduce this patient’s risk of perioperative major adverse cardiac event (MACE)? A.
Add bisoprolol 1week preoperatively, continue through at least 1 week postoperatively
B.
Add bisoprolol 1 week preoperatively, continue through at least 1 month postoperatively
C.
Add bisoprolol 2 weeks preoperatively, continue through at least 1 month postoperatively
D.
Add bisoprolol 2 weeks preoperatively, continue through at least 1 month postoperatively Perioperative beta blockade not indicated in this case
A.
Continue clopidogrel and aspirin perioperatively, if approved by Vascular Surgery team
E.
B.
Hold clopidogrel for at least preoperatively, but continue aspirin
C.
Hold both clopidogrel and aspirin perioperatively
D.
Hold both clopidogrel and aspirin perioperatively, add unfractionated heparin IV as perioperative “bridge” therapy
E.
Hold both clopidogrel and aspirin perioperatively, add therapeutic-dose low molecular weight heparin as perioperative “bridge” therapy
Correct Answer: E) Perioperative beta blockade not indicated in this case. This patient’s risk of MACE likely is less than 1%. She does not already take beta blockade, does not have known or strongly suspected coronary artery disease, and does not have three or more RCRI risk factors for perioperative major adverse cardiac event. Based upon the 2014 ACC/AHA perioperative guideline and supporting literature, perioperative beta blockade is not indicated in this situation.
7-14
days
Correct Answer: A) Continue clopidogrel and aspirin perioperatively, if approved by Vascular Surgery team. This is a very challenging scenario. Aortic surgery certainly poses high risk of major perioperative bleeding. However, the risk of life-threatening in-stent coronary artery thrombosis is prohibitively high, if dual antiplatelet therapy is discontinued within six months after coronary artery stent placement. In the absence of absolute contraindication to antiplatelet therapy (such as lifethreatening gastrointestinal hemorrhage or intracranial hemorrhage), dual antiplatelet therapy should be
8.
A 65 year-old female awaits elective bilateral femoral-popliteal artery bypass, due to atherosclerotic peripheral artery disease with progressively worsened claudication. She walks two blocks at a time, without other problem. Her additional history is noteworthy for type II diabetes mellitus, hyperlipidemia, 60 pack-years of cigarette smoking ended 15 years ago, and osteoarthritis. Her medications include lisinopril, metformin, aspirin, and acetaminophen. She discontinued atorvastatin 5 years ago. The patient has had no known medication adverse effect. Vital signs
are normal. Physical examination findings are noteworthy for absent pulses throughout bilateral lower extremities, dependent rubor and elevation pallor of bilateral lower extremities, remainder noncontributory. Which of the following is recommended, to reduce this patient’s risk of perioperative major adverse cardiac event (MACE)? Initiate atorvastatin preoperatively
as
early
B.
Initiate atorvastatin on the morning of surgery
C.
Initiate atorvastatin immediately postoperatively
D.
Initiate atorvastatin postoperatively
E.
Do not initiate atorvastatin perioperatively
within
as
possible
one
week
Correct Answer: A) Initiate atorvastatin as early as possible preoperatively. This patient has known atherosclerotic peripheral artery disease and awaits major peripheral vascular surgery (an elevated-risk procedure). “Statin” therapy is warranted in this situation, both perioperatively and long-term. Although the optimal timing of perioperative statin therapy has not been established, initiation of such therapy as early as possible preoperatively is recommended, when indicated. 9.
10.
A 70 year-old male awaits elective robotic-assisted radical prostatectomy, due to biopsy-proven adenocarcinoma of the prostate. He walks several blocks at a time, without problem. His additional history is noteworthy for obesity, congestive heart failure, hypertension, type II diabetes mellitus, hyperlipidemia, 30 pack-years of cigarette smoking ended 10 years ago, and osteoarthritis. His medications include atenolol, lisinopril, metformin, simvastatin, aspirin, and acetaminophen. Vital signs are noteworthy for heart rate of 58 beats per minute, blood pressure 154/86 mm Hg, remainder normal. Physical examination findings are noteworthy for obese habitus (BMI 36 kg/m2), remainder noncontributory.
Which of the following is the best choice to reduce this patient’s risk of perioperative major adverse cardiac event (MACE)? A.
Begin clonidine now
B.
Begin clonidine on the morning of surgery, if blood pressure still elevated
C.
Begin clonidine postoperatively, if blood pressure still elevated
D.
Begin clonidine postoperatively, hypertension becomes symptomatic
E.
Avoid clonidine perioperatively, if possible
Hold simvastatin perioperatively
B.
Hold lisinopril perioperatively
C.
Hold lisinopril perioperatively only if the patient develops acute kidney injury
D.
Hold both simvastatin and lisinopril perioperatively
E.
Continue simvastatin and lisinopril perioperatively, if these remain well-tolerated
Correct Answer: E) Continue simvastatin and lisinopril perioperatively, if these remain well-tolerated. Established “statin” therapy should be continued perioperatively, as long as it is well-tolerated. Also, this patient has a history of congestive heart failure and of hypertension,
only
if
Correct Answer: E) Avoid clonidine perioperatively, if possible. Perioperative use of clonidine can increase the risk of non-fatal cardiac arrest and of clinically-significant hypotension. This medication should be avoided perioperatively, if possible. 11.
Which of the following is the best choice for perioperative cardiovascular medication management in this case? A.
A 64 year-old male awaits removal tomorrow of a chronically-infected right knee arthroplasty prosthesis. His additional history is noteworthy for coronary artery disease, myocardial infarction 4 years ago, HTN, 30 pack-years of cigarette smoking ended 10 years ago, COPD with bronchospasm, and chronic kidney disease. He has been clinically stable, including regular ambulation of several blocks at time, limited only by right knee pain and stiffness. His medications include diltiazem, lisinopril, atorvastatin, aspirin, fluticasone/salmeterol diskus, albuterol MDI as needed, and acetaminophen. Vital signs are remarkable for systemic blood pressure of 178/90 mm Hg, remainder of vital signs normal. Physical examination is noteworthy for apparent inflammation and decreased range of motion of the right knee, remainder noncontributory.
A 74 year-old male awaits elective lumbar spinal decompression. Additional history is noteworthy for morbid obesity (BMI 46), CAD with MI six years ago (asymptomatic), HTN, hyperlipidemia, type II DM, OSA (untreated), tobacco smoking, OA, and lumbar spinal stenosis with chronic neuroclaudication. His functional capacity is > 4 METs. Medications include bisoprolol, lisinopril, rosuvastatin, metformin, ASA, and APAP. Examination is remarkable for morbidly obese habitus and apparent widespread osteoarthritic changes (most prominent in the lumbar spine).
Which of the following is the best choice for perioperative management of this patient’s OSA? 1.
Elective surgery should be canceled, due to multiple comorbidities.
989
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A.
with currently-elevated systemic blood pressure. It is most appropriate to continue ACE-inhibitor therapy perioperatively in this situation, as long as it remains well-tolerated.
CARDIOLOGY
990
2.
Proceed with surgery; start CPAP immediately postoperatively.
3.
Initiate CPAP at least 4-6 weeks preoperatively, then proceed with surgery.
4.
Initiate CPAP at least one week preoperatively, then proceed with surgery.
Correct Answer: 3) Initiate CPAP at least 4-6 weeks preoperatively, then proceed with surgery. In patients with OSA or obesity hypoventilation syndrome, CPAP or BiPAP begun at least four to six weeks preoperatively is associated with several anatomic and physiologic benefits. This is preferred before proceeding with elective surgery, if feasible.
REFERENCES
1.
2.
3.
4.
Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014. Online ISSN: 1524-4539.
Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999; 100:1043. Gupta PK, Gupta H, Sundaram A, et al. Development and validation of a risk calculator for prediction of cardiac risk after surgery. Circulation 2011; 124:381. Kertai MD, et al. Which stress test is superior for perioperative cardiac risk stratification in patients undergoing major vascular surgery? Eur J Vasc Endovasc Surg 2002; 24:222-229.
5.
Askew JW, Chareonthaitawee P. Selecting the optimal cardiac stress test. Up To Date 2014.
6.
Mikhail, MA. Preoperative Cardiac Evaluation. Ask Mayo Expert 2010.
7.
Shaw et al. Meta-analysis of intravenous dipyridamolethallium-201 imaging (1985-1994) and dobutamine echocardiography for risk stratification before vascular surgery. JACC 1996; 27:787-98.
8.
Bach DS, Eagle KA. Dobutamine stress echocardiography: stressing the indications for preoperative testing. Circulation 1997; 95:8-10.
9.
Devereaux PJ, Mrkobrada M, Sessler DI, et al. POISE-2 Investigators. Aspirin in patients undergoing noncardiac surgery. N Engl J Med 2014; 370:1494-1503.
10. Biondi-Zoccai G, Lotrionte M, Agostoni P et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50 279 patients at risk for coronary artery disease. European Heart Journal 2006; 27:26670-2674. 11. Burger W, Chemnitius JM, Kneissl GD, Rücker G. Lowdose aspirin for secondary cardiovascular prevention - cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation - review and meta-analysis. J Intern Med 2005; 257:399-414. 12. Levine GN , Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation 2016; 134:123-155 13. Mushtaq M, Cohn SL. Perioperative beta-blockers in noncardiac surgery: The evidence continues to evolve. Clev Clin J Med 2014; 81:501-512. 14. Salpeter SR, et al. Cardioselective B-blockers in patients with reactive airway disease: a meta-analysis. Ann Intern Med 2002; 137:715-725. 15. Short PM, Lipworth SIW, Elder DHJ, Schembri S, Lipworth BJ. Effect of B blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ 2011; 342:d2549. 16. Poldermans D, Bax JJ, Kertai MD, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003; 107:1848. 17. Lindenauer PK, Pekow P, Wang K, et al. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med 2005; 353:349. 18. Kertai MD, et al. Association between long-term statin use and mortality after successful abdominal aortic aneurysm surgery. Am J Med 2004; 116:96-103. 19. Durazzo AE, Machado FS, Ikeoka DT, et al. Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial. J Vasc Surg 2004; 39:96 20. Hindler K, Shaw AD, Samuels J, Fulton S, Collard CD, Riedel B. Improved postoperative outcomes associated with preoperative statin therapy. Anesthesiology 2006; 105:1260-72; quiz 1289-90. 21. Schouten O et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med 2009; 361:980. 22. Turan A, You J, Shiba A, et al. Angiotensin converting enzyme inhibitors are not associated with respiratory complications or mortality after noncardiac surgery. Anesth Analg 2012; 114:552–60. 23. Coriat P, Richer C, Douraki T, et al. Influence of chronic angiotensin-converting enzyme inhibition on anesthetic induction. Anesthesiology 1994; 81:299. 24. Bertrand M, Godet G, Meersschaert K, et al. Should the angiotensin II antagonists be discontinued before surgery? Anesth Analg 2001; 92:26–30. 25. Kheterpal S, Khodaparast O, Shanks A, et al. Chronic angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy combined with diuretic therapy is associated with increased episodes of hypotension in noncardiac surgery. J Cardiothorac Vasc Anesth 2008; 22:180. 26. Rosenman DJ, McDonald FS, Ebbert JO, et al. Clinical consequences of withholding versus administering renin-angiotensin-aldosterone system antagonists in the preoperative period. J Hosp Med 2008; 3:319–25. 27. Brabant SM, Bertrand M, Eyraud D, et al. The hemodynamic
effects of anesthetic induction in vascular surgical patients chronically treated with angiotensin II receptor antagonists. Anesth Analg 1999; 89:1388â&#x20AC;&#x201C;92. 28. Devereux PJ, Sessler DI, Leslie K, et al. Clonidine in patients undergoing noncardiac surgery. N Engl J Med 2014; 370:1504-13. 29. James PA, Oparil S, Carter BL et al. 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in Adults: Report from the Panel Members Appointed to the Eight Joint National Committee (JNC8). JAMA 2014; 311:507-520.
30. Ryan CF, Lowe AA, Li D, Fleetham JA. Magnetic resonance imaging of the upper airway in obstructive sleep apnea before and after chronic nasal continuous positive airway pressure therapy. Am Rev Respir Dis 1991; 144:939.
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31. Cartagena R. Preoperative evaluation of patients with obesity and obstructive sleep apnea. Anesthesiol Clin North America 2005; 23:463. 32. Dorkova Z, Petrasova D, Molcanyiova A, et al. Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome. Chest 2008; 134:686.
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Transcatheter Aortic Valve Implantation (TAVI)
“asymptomatic” when they are actually very limited in functional Vivek Gupta, Alain Criber class. In addition, patients can perceive temporary improvement in symptoms after medical therapy.3 All of the above reasons emphasize underuse of surgical treatment: aortic valve replacement. The first procedure was BACKGROUND the major issue in thesurgical No medical therapy is available for successfully treating performed by Prof Alain Cribier in 1985 in severe Aortic an incomplete of the true surgical risk. shock. Later stenosis in a sick patient with cardiogenic calcific aortic stenosis. understanding Treatments that have been used to slow the progression of coronary artery disease have failed to prevent the progression of aortic stenosis or to reverse the damage. The primary treatment for severe aortic stenosis is aortic valve replacement surgery. The survival rate at 3 years in patients with symptomatic aortic stenosis who undergo surgery is 87%; in those who do not have surgery it is 21% (P <0.001). The operative mortality rate in the surgical treatment of aortic stenosis is less than 5%, but at least 30% to 40% of patients with severe aortic stenosis go untreated.1,2
on with time it became clear It provides symptomatic benefits for only a limited time (a few months) because of restenosis. When the hemodynamic effects of balloon aortic valvuloplasty and bioprosthetic aortic valve replacement are compared at 1 year, the latter affects a larger orifice area (2.07–2.1 cm2 vs 0.78–0.09 cm2) and has a more favorable mean gradient effect (5.8–6.5 mmHg vs 28.2–30 mmHg).4
Balloon aortic valvuloplasty is not an alternative to surgical aortic valve replacement. The first procedure was performed by Prof Alain Cribier in 1985 in severe Aortic stenosis in a sick patient with cardiogenic shock. Later on with time it became clear It Although surgical aortic valve replacement has been provides symptomatic benefits the formainstay onlyof atherapy limited (a few for severetime aortic stenosis, transcatheter aortic valve implantation (TAVI) is now an Surgical treatment of severe aortic stenosis has been months) because of restenosis. When the hemodynamic effects acceptable standard of care for patients with symptomatic underused for many reasons. Patients are thought to be too old, or they have left ventricular dysfunction or aortic stenosis who are not eligible for surgery or who are of balloon valvuloplasty bioprosthetic aortic valve at very high risk for surgical treatment. The development comorbidities thataortic affect the surgical scores. Alternatively, and of transcatheter devices has progressed rapidly during patients are not referred for surgery because they are replacement compared at 1 the year, theandlatter affects asurgical larger last decade, this approach challenges misdiagnosed (that are is, the severity of the aortic stenosis repair as the preferred or 2 2 only option for treating severe is underestimated) or are considered “asymptomatic” orifice area (2.07–2.1 cm vs 0.78–0.09 cm ) and has a more symptomatic aortic stenosis. when they are actually very limited in functional class. In addition, patients can perceive temporary improvement favorable mean gradient effectDEVELOPMENT (5.8–6.5 vsVALVE28.2–30 OF NONmmHg SURGICAL AORTIC AND FIM in symptoms after medical therapy. All of the above Dr. Cribier followed the saying of Edwin Land Don’t 4 reasons emphasize the major issue in the underuse of mmHg). undertake a project unless it is manifestly important and surgical treatment: an incomplete understanding of the 3
nearly impossible »
true surgical risk.
Balloon aortic valvuloplasty is not an alternative to
The challenge was Implanting a valve prosthesis within
20mm Balloon First case of BAV 1985
993
2002
1985
CHAPTER 215
Highly challenging of Valvular calcification Surounding Highly challenging because of Valvularbecause calcification Surounding Balloon Aortic Transcatheter structures: Coronary arteries, Mitral valve, IV septum (His structures: Coronary arteries, Mitral valve, IV septum (His bundle) and major clinical issues were Coronary occlusion Mitral Valvuloplasty Aortic Valve bundle) and major clinical issues were Coronary occlusion Mitral valve injury, Permanent AV block, Stroke, Aortic regurgitation, valve the injury, Permanent AVvalve, block, Stroke, Aortic regurgitation, diseased calcific aortic on the beating observed that a balloon expandable stent with high Prosthesis migration, Nonheart, lastingwas results Prosthesis migration, catheter Non lasting results using percutaneous based techniques” radial force might keep the valve open and a valvular Birth of the concept of stented valve structure in Aortic would Stenosis: observed haveIttowas be attached within the stent.
challenging becausevalve of Valvular Birth ofHighly the concept of that stented in Aortic calcification Stenosis: wasradial observed a balloon expandable stent withIthigh force might keep the valve Surounding structures: Coronary arteries, Mitral valve, A challenging combination of balloon expandable frame that a balloon expandable stent with high radial forcewould mighthave keeptothe valve open and a valvular structure be attachedwas within the stent. in order to keep IV septum (His bundle) and major clinical issues were and valve structure to be innovated open and a valvular structure would have to be attached within the stent. challenging combination of AV balloon expandable frame and valve Coronary occlusionAMitral valve injury, Permanent the stenosed valve open. A challenging combination of balloon expandable frame and structure was Prosthesis to be innovated in order to valve keep the stenosed valve block, Stroke, Aortic regurgitation, migration, Company PVT in year 1999 took undertook the task of structure be innovated in order to keep the stenosed valve open Non was lastingtoresults animal experimentation which validated the concept of open Birth of the concept of stented valve in Aortic Stenosis: It stented valve as shown in figures (Figures 1-4).
Dr. Cribier followed the saying of Edwin Land Don’t undertake a project unless it is manifestly important and nearly impossible » FIRST IN MAN CASE
In 2002, Alan Cribier led the team that performed the first percutaneous transcatheter implantation of an aortic valve prosthesis in a patient with calcific aortic stenosis. They used an antegrade transseptal approach with a 23mm balloon-expandable valve.5 In performing the first clinical retrograde transcatheter implantation of an aortic
The challenge was Implanting a valve prosthesis within the diseased calcific aortic valve, on PVT the beating heart, using Valve Design Concepts percutaneous catheter based techniques”
Extensive laboratory testing Animal program (sheep model) Acute and chronic studies
Fig 1
Fig 1
Rouen Autopsy Study Fig 2 Fig. 3: PVT Valve Design Concepts Fig.France-1994, 1
Rouen France-1994, Autopsy Study Fig 2
Post-BAV 23mm
Fig 3
Optimal dimensions of the frame Coronary ostia
Post-BAV 23mm
Post-Stent 23mm
Diameter Post-Stent
Fig. 2: Rouen France-1994, Autopsy Study
Post-Stent 23mm
Post-Stent Heigth:
Optimal dimensions of the frame 994
PMC full text: Tex Heart Inst J. 2013; 40(3): 298–301. Copyright/License ► Request permission to reuse
Next >>
Coronary ostia Diameter
Fig 4
Company PVT in year 1999 took undertook the task of animal experimentation which validated the concept of stented valve as shown in figures (Fig 1-4)
CARDIOLOGY
<< Prev
Heigth: 14/16
Fig. 1: Valves used in transcatheter aortic valve implantation procedures.
Fig. 1 Valves used in transcatheter aortic valve implantation procedures. A) The Edwards SAPIEN® valve is made of bovine pericardium in a trileaflet configuration. The valve is mounted on a highly resistant, stainless-steel, balloon-expandable stent that is 14 mm long ×23 or 26 mm wide and is delivered via a 24F to 26F (internal diameter) system. B) The SAPIEN® XT valve has a cobalt–chromium alloy frame and is compatible with lower-profile delivery systems. C) The Medtronic CoreValve® is made of single-layer porcine pericardium in a trileaflet configuration. The valve is mounted on a self-expandable nitinol frame, with inflows of 26, 29, and 31 mm. It is suitable for annulus diameters from 20 to 29 mm and is delivered thatusing an 18F catheter. Reproduced with permission from J Am Coll Cardiol 2012;60(6):483–92.
study). At the 1-year follow-up, there was an absolute reduction in mortality rate of 20% and an 18.3% reduction in the combined endpoint of death or stroke in patients FIRST IN MAN CASE In 2002, Alan Cribier led the team who underwent TAVI. Of TAVI patients, the number performed the first percutaneous transcatheter implantation of to article treat (NNT) in order to prevent a death was Images in this an aortic valve prosthesis in a patient with calcific aortic stenosis.needed IV Septum They used an antegrade transseptal approach with a 23-mm5 and the NNT to prevent a death or a major stroke balloon-expandable valve.5 In performing Mitral the first clinicalwas 5.5. In comparison with patients who received only (His bundle) retrograde transcatheter implantation of an aortic valvemedical therapy, TAVI patients experienced a significant prosthesis,Fig. 4: Optimal dimensions of the frame reduction in all-cause mortality at 2 years (43.3% vs 68%; hazard 95% Click on the ratio=0.56; image to see a larger version.confidence interval [CI], 0.43–0.73; valve prosthesis. P <0.001).7Furthermore, TAVI significantly improved quality-of-life measures over 1 year.
The incremental cost-effectiveness for TAVI—computed on the basis of the cost per quality-adjusted life-year (QALY), compared with standard therapy—was $61,889. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709202/figure/f1-21/[01-12-2016 The calculated QALYs were14:34:12] 1.4 for TAVI versus 0.4 for medical therapy.8 Because of this strong evidence, TAVI is now considered the standard of care for patients with severe symptomatic aortic stenosis who have a life expectancy of more than 1 year and who are ineligible for surgical aortic valve replacement.
30 min postimplantation
8 days post-
THE EDWARDS SAPIEN® VALVE
The Edwards SAPIEN® valve (Edwards Lifesciences, LLC; Irvine, Calif) that is used in the United States is made of bovine pericardium in a trileaflet configuration and is mounted on a 14mm × 23- or 26-mm stainlesssteel, balloon-expandable stent (Figure 1A) that is highly resistant to radial stress. The internal diameter of the delivery system is 24F to 26F. In Europe, the XT system has smaller delivery catheters (a 16F eSheath for the 23mm valve, up to a 20F eSheath for the 29-mm valve) (Figure 1B). In addition, the newer SAPIEN 3 valve is being tested in clinical trials. The Edwards SAPIEN® valve is made of bovine pericardium in a trileaflet configuration. The valve is mounted on a highly resistant, stainless-steel, balloonexpandable ... Strong evidence supporting the use of TAVI comes from the investigation of the Edwards SAPIEN valve in the landmark Placement of Aortic Transcatheter Valves (PARTNER) trial, in which patients with severe, symptomatic aortic stenosis who were not candidates for surgery were randomized to medical therapy or percutaneous aortic valve implantation (PARTNER 1B
Transcatheter aortic valve implantation has also been studied in high-risk surgical patients. Results of the PARTNER trial (cohort A) showed that the all-cause mortality rate at 2 years was similar in TAVI patients and surgical patients (33.9% vs 35%, respectively; P=0.78),9 indicating that TAVI might be an appropriate strategy in this group. On the basis of information gleaned from the Kansas City Cardiomyopathy Questionnaire, patients treated w i t h transfemoral TAVI had a greater improvement in health status at 1 month than did patients treated surgically (difference of 9.9 points; 95% CI, 4.9%–14.9%; P <0.001); similar findings were seen at 6 and 12 months. The QALY data suggested that TAVI was less expensive and more effective than surgical treatment. The same was not true for the transapical approach, which resulted in worse quality-of-life scores than did surgery, and cost more.10
CASE REPORT
84 year old diabetic, hypertensive follow up case of Coronary artery bypass surgery 10 years back with severe aortic valve stenosis (PG of 70 and mean gradient of 55 mm of Hg) was treated with implantation of Edwards XT valve in association with Dr Alain Cribier in the cath lab of Hospital Charles Nicolle, Rouen France in Nov 2011. Because of co morbid condition of Bypass Surgery, mild
995
Extreme Risk for SAVR Inoperable
High Risk for SAVR
TAVI Edwards SAPIEN
TAVI Edwards SAPIEN Or CoreValve Continued Access (No randomization)
TAVI CoreValve Continued Access (No randomization)
Fig. 2: Transcatheter aortic valve implantation (TAVI) for severe symptomatic aortic valve stenosis. Flow chart shows how patients are allocated for TAVI at the Texas Heart Institute, Heart Valve Center Nephropathy and respiratory disease patient was refused by cardiac surgeons in Delhi for surgical Aortic Valve replacement. Patient was evaluated with us in Delhi with MR / angio to know the size of annulus and also to assess the size of femorals and external iliac arteries. Patient was flown to France and treated with TAVI under conscious sedation. The procedure time was 40 minutes with minimalist environment. The peak gradient was reduced to 25 and mean gradient of 10 mm of Hg. The patient had trivial AR. The patient was discharged on day third. It has been 5 years now and the patient is doing well. Recent 2 D echo had similar findings 5 years follow up of First Edwards valve treatment in France done in Nov 2011.
surgical repair (randomized vs TAVI). Enrollment has been completed, and event-driven follow-up is ongoing. Nevertheless, the CoreValve Continued Access and Expanded Use trials have also been launched and are evaluating TAVI in patients whose conditions would have excluded them from randomized trials. The Medtronic CoreValve ADVANCE Study is one of the largest multicenter transcatheter valve trials to date11; the study group comprises 1,015 patients (mean age, 81 yr) who were consecutively treated at 44 experienced TAVI centers in 12 countries. Clinical endpoints in the trial were calculated according to definitions standardized by the Valve Academic Research Consortium.12 In the ADVANCE trial, the survival rates were high at both 30 days (95.5%) and 6 months (87.2%). The procedural success rate was 97.8%, and overall complication rates were low: stroke rates of 2.9% and major adverse cardiac and cerebrovascular events (MACCE) rates of 8.3% at 30 days. Valve function improved significantly in the study patients; the mean gradient decreased from 45.6 mmHg at baseline to 9.3 mmHg at 30 days. The 1-year mortality rates seen in ADVANCE13 compare favorably with the 24.2% 1-year all-cause mortality rate in TAVI patients in the PARTNER trial (cohort A). They are also similar to the 1-year results of the SAPIEN valve from the SOURCE registry, in which the 1-year survival rate was 76.1% in the overall cohort (although the survival rate was higher in the transfemoral subgroup, at 81.1%).13
THE MEDTRONIC COREVALVE® SYSTEM
The CoreValve® (Medtronic, Inc.; Minneapolis, Minn) is a porcine pericardial tissue valve that is sutured into a selfexpanding nitinol frame, which is designed for supraannular positioning to optimize hemodynamics (Figure 1C). The system uses an 18F catheter delivery system and has 3 valve sizes (26, 29, and 31 mm). In the United States, the CoreValve system is limited to investigational use. The CoreValve PIVOTAL study is currently examining its use in patients who are at high risk or ineligible for
Since 2012, a successful TAVI program has been in effect at the Texas Heart Institute at St. Luke’s Episcopal Hospital. In a collaborative effort between cardiologists and cardiovascular surgeons, both the SAPIEN and CoreValve protocols are available for patients, in accordance with their anatomy, annular size, and best routes of access (for example, transfemoral, transapical, and direct aortic) (Figure 2).
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No TAVI Due to anatomic or medical reasons
996
Table 1: The Hype and the Hope Hype for TAVI
Hope for TAVI
Used for all patients
Better risk stratification
Used in moderate-to lowrisk patients
Expanded access
As safe as or safer than surgical replacement
New, smaller, safer devices
Improves outcomes for all
Cost-effective
CARDIOLOGY
TAVI=transcatheter aortic valve implantation
FUNDAMENTAL MESSAGES, SUMMARY, AND UNSOLVED ISSUES
Currently, the only proven, long-term effective treatment for patients with severe symptomatic aortic stenosis is surgical valve replacement. However, many patients with severe symptomatic aortic stenosis remain untreated, often because of the operative and perioperative risks associated with surgical repair. This group of 30% to 60% of patients with untreated aortic stenosis has a high mortality rate and needs to be served by the medical community. The use of a multidisciplinary team of cardiologists, cardiovascular surgeons, and supporting groups (for example, imaging specialists, neurologists, geriatricians, social workers, and rehabilitation specialists) benefits patients and has enabled TAVI to become the standard of care for inoperable patients with severe aortic stenosis. The available results indicate that TAVI is an acceptable alternative to surgery in selected highrisk patients. Future randomized studies should focus on lower-risk patients who are candidates for operation. Vascular-access complications associated with TAVI are expected to decrease as the design and performance of new devices improve. A major complication of the TAVI procedure is stroke; common causes include balloon valvuloplasty, the passage of stiff catheters through an often-calcified aortic arch, the positioning and implantation of the valve itself, and postdilation (if used). In more recent studies,14 the incidence of stroke is lower than it was in previous reports, probably because of the use of more flexible and smaller delivery systems. The CoreValve can be implanted without prior valvuloplasty, and that alone might reduce the rate of embolization. Embolization-protection devices and deflectors that can redirect emboli from the arch downstream are being developed and evaluated, but no data support the clinical benefit of these devices. The clinical durability of the valves used for TAVI is unknown. In preclinical fatigue tests, the transcatheter valves have shown the same excellent performance as standard biological valves; this applies both to the leaflets and to the stents. The structural failure rate of the current generation of transcatheter valves in clinical trials is very low. Long-term follow-up data are of course lacking. Finally, another controversial issue is the use of TAVI in a younger, lower-risk population. In many centers, TAVI has become a routine procedure, and the results
of recent trials show improved outcomes and safety of the approach.15 However, the incidence of paravalvular leak and stroke, and the unknown durability factor are lingering concerns. On the basis of the data from the studies described above, trials in younger, lower-risk patients are justified. For now, the 2012 European Society of Cardiology/European Association for Cardio-Thoracic Surgery Guidelines for Heart Valve Disease clearly restrict the indication for TAVI to a high-risk population, as do the U.S. Food and Drug Administration-approved guidelines. As we learn more about the issues and challenges of TAVI, we hope to have available a better risk stratification for TAVI procedures and to identify the populations that benefit (Table 1). We also hope that access to TAVI will improve as smaller and safer devices become available, but TAVI must continue to be cost-effective. We should be cautious in our hype regarding the use of TAVI and not apply it prematurely to other patient groups; and we should be realistic about the risks associated with the procedure (Table 1).
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