16 Hypertension by Urvi Trivedi

SECTION 16

Hypertension 131.

Power to Control Systolic Blood Pressure-An Indian Evidence Tiny Nair

615

132.

High Altitude Systemic Hypertension (HASH) - A New Entity Yanamandra Uday, Velu Nair

618

133.

Alcohol and Hypertension Related Left Ventricular Systolic Dysfunction-Intergrated Approach Using Echocardiography Maninder Singh, Suraj Kumar Arora, Rohit Tandon

622

134.

Renovascular Hypertension R Chandni, R Gayathri

627

135.

Resistant Hypertension Kidiyur Jayakar Shetty, Manohar Kathige Nageshappa

631

136.

Vascular Remodeling in Hypertension Sanjay Jain, Srikanth Gopi

634

137

Secondary Hypertension: An Age-Based Approach to Diagnosis Amit A Saraf, Anoosha Bhandarkar

637

138.

Difficult to Treat Hypertension RK Singal, Vivek Pal Singh, AK Vardani

640

139.

Hypertension Urgencies & Emergencies Sekhar Chakraborty

643

140.

YOUNG Hypertensives: Do we Need to Look at them Differently? Sanjay Kalra, KVS Hari Kumar

650

141.

NCD Update: Connection between Chronic Kidney Disease and Cardiovascular Disease C Venkata S Ram

653

142.

Hypertension in CKD - Management Issues Pritam Gupta, Ankur Gupta

658

143.

Managing Blood Pressure in Acute Stroke : A Dilemma Bhupendra Chaudhary, Binay Karak

662

144.

Impact of Recent Hypertension Guidelines on Clinical Practice NK Soni, VB Jindal

665

145.

Best Practices in Hypertension-2017 PC Manoria, Pankaj Manoria, Piyush Manoria, SK Parashar

670

146.

Role of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Hypertension 2017 Santosh Bandopant Salagre

677

147.

Newer Beta Blocker in Hypertension Anita Jaiswal

680

148.

Hypertension Guidelines for 2017 – The Evidence So Far Uday M Jadhav, Amit Saraf

682

149.

Combination Drug Therapy in Hypertension AU Mahajan, Zohaib Shaikh

684

150.

Recent Advances in Ambulatory Blood Pressure Ashok L Kirpalani, Dilip A Kirpalani

690

151.

A Review of Nutritional Factors in Hypertension Management Ashok K Taneja, Tejinder Singh, Ashok Chandna

695

152.

Life Style Modification in Non Communicable Diseases BB Thakur, Smita Thakur

701

153.

Approach to the Patients with Hypertension BR Bansode

705

C H A P T E R

131

Power to Control Systolic Blood Pressure-An Indian Evidence

SYSTOLIC BLOOD PRESSURE

Systolic Blood Pressure (SBP) results from gradual decrease in diameter and stiffening of the proximal to the distal arterial vessels and mostly of the modification in the transit of wave reflections. The importance of central SBP (cSBP) is greater than brachial pressure as it is more closely associated with left ventricular hypertrophy and carotid atherosclerosis; it is a marker of end-organ impairment in hypertensive patients (Figure 1).

Tiny Nair

stroke and congestive heart failure (CHF) are also high in such population (supplementary hazards like diabetes mellitus, high body mass index (BMI) and physical inactivity are other contributing factors).

CHALLENGES IN CONTROLLING SBP

The main factors that hinder the control of high SBP in are: 1.

Stiffening of large arteries: The basic mechanism for the progressive rise in systolic blood pressure with age is the loss of distensibility and elasticity in the large capacitance vessels.

Reflected wave: As the pulse waves travel more rapidly and are reflected backwards from the periphery more quickly, a secondary boost is seen during systole in older patients. The early return of reflection increases pressure in late systole, leading to a progressive rise in systolic pressure,

Low renin activity: As people age, there is a progressive loss of functioning nephrons; therefore, the circulating renin level, measured as plasma renin activity typically falls in older people with hypertension

SIGNIFICANCE OF SBP

SBP has steadily gained importance in the last 10 to 15 years as many studies have revealed that it is a better indicator of cardiovascular disease in individuals above 50 years of age. The stiffening of the larger arteries in the elderly leads to elevation of SBP. The measurement of SBP is more precise than the measurement of diastolic blood pressure (DBP). If the hazards of high BP are concentrated on the former aspect, the clinicians will have greater clarity in measuring thresholds and setting objectives for their patients.

THE NEED FOR EMPHASIS ON SBP CONTROL

According to 2013 ESH/ESC Guidelines for the management of arterial hypertension, hypertension (HTN) is described as BP measurement ≥ 140/90 mmHg. SBP in individuals suffering from pre-hypertension is between 120-139 mmHg. The prospects of major cardiovascular events like myocardial infarction (MI),

Shortcomings in compliance to official guidelines- some clinicians give importance to only diastolic pressure when considering their patients’ health also hinders the control of SBP. The SF-36 questionnaire (a routine questionnaire for evaluating a patient’s health comprises of functional capacity, bodily pain, mental health etc.) evaluates the Health-Related Quality of Life (HRQoL) scores in hypertensive individuals with and without any existing complications. It has exhibited that the harshness of the resultant diseases due to HTN is directly involved in an individual’s QoL, rather than uncontrolled SBP itself.

THE POWER STUDY

Nair et al., conducted a trial with Indian patients to evaluate the response of hypertensive patients on a sustained release (SR) indapamide (1.5 mg) tablet as monotherapy along with the administration of various antihypertensive drugs. The parameters evaluated were minimisation of BP along with well-being of the patients.

Fig. 1: Raised systolic BP: accountable for the majority of hypertensive diagnosis

In this multicentric trial, 1545 Indian patients (between 40 and 70 years of age) were included after obtaining their written informed consent. The patients had uncontrolled HTN and were administered indapamide

616

34.3% 17.1% Improvement in emotional problem

15.4%

HYPERTENSION

Improvement in disturbed sleep

Improvement in lack of energy

P<0.001 N=1544

Fig. 3: Improvement in patient parameters after 90 days of treatment Fig. 2: SBP and DBP reduction in POWER trial SR 1.5 mg once-daily as monotherapy or along with the continuing medication for 90 days. The variation in well-being was evaluated using the Nottingham general health questionnaire. The entire patient population was re-evaluated after 30, 60 and 90 days of the treatment regimen. The treatment with Indapamide SR either as a monotherapy or over and above other existing anti-hypertensive agent lead to a reduction in SBP by 30 mmHg and a reduction in DBP by 15 mmHg, this reduction in BP was accompanied by overall improvement in well-being (Figures 2 & 3). The improvement in well-being was better in patients who could achieve the target BP.

INDAPAMIDE SR- AN IDEAL DRUG TO CONTROL SYSTOLIC BP

Indapamide is an antihypertensive medication belonging to the class of thiazide like diuretics. Indapamide SR is well-tolerated in humans with no effect on the metabolic pathways. The antihypertensive property is due to an increased arterial compliance along with inhibition of the total and arteriolar peripheral resistance and sub clinical diuresis. It controls BP for the entire 24-hour time period. Indapamide even diminishes the occurrence of microalbuminuria in hypertensive patients with type-2 diabetes. The ESH 2013 guidelines guidelines advocate the administration of diuretics as the initial treatment in hypertensive patients which include the elderly suffering from HTN, hypertensive patients who suffer from periodic strokes as well as heart failure patients who are at risk. The vascular action of indapamide involves the reduction of unusually high cardiovascular noradrenaline reactivity without inducing a corresponding increase in the adrenergic nervous activity. Hence, vasorelaxation occurs in hypertensive patients which decrease their BP. In the HYVET trial, Beckett et al included 3845 patients from Europe, China, Australasia and Tunisia (≥ 80 years of age) who were randomised into 2 groups: 1st group was administered indapamide SR (1.5 mg) and the 2nd group

was given a placebo. Perindopril (an ACEI) (2 or 4 mg) was also incorporated, if required, to attain BP of 150/80 mmHg. The trial results established that in very elderly individuals, antihypertensive treatment with indapamide (sustained release), with or without perindopril is beneficial as it causes reduction in the probability of deaths due to stroke by 39% and heart failure by 64%.

BENEFITS OF INDAPAMIDE OVER CHLORTHALIDONE

Indapamide SR 1.5mg has proven life-saving benefits, whereas chlorthalidone shows life saving benefits only when given in higher dosage (25mg and above), but at such high dose the risk of metabolic imbalance is also very high.

Indapamide is glucose neutral hence there is no risk of new-onset diabetes, whereas chlorthalidone increased the relative risk of new onset diabetes by 43% in ALLHAT. This can be a big risk in diabetes prone Indian hypertensive patients.

SBP results from the reduction in diameter and hardening of the arterial vessels. The probabilities of major cardiovascular events like MI and CHF increases in the hypertensive population. Indapamide is an antihypertensive thiazide like diuretic, which exhibits good tolerability in humans as it is metabolically neutral. Various studies have established the efficacy of indapamide in controlling SBP in hypertensive patients above 50 years (POWER study, HYVET trial etc.). Its benefits like long term protection from CV death, stroke etc and metabolic neutrality, give it an edge over chlorthalidone in the Indian market.

REFERENCES

Weber T, Wassertheurer S, Rammer M, et al. Validation of a Brachial Cuff-Based Method for Estimating Central Systolic Blood Pressure. Hypertension 2011; 58:825-832.

Sever P. The preeminence of systolic blood pressure measurement in the management of patients with high blood pressure. Medicographia 2010; 32:250-253.

Yadav S, Boddula R, Genitta G, et al. Prevalence & risk factors of pre-hypertension & hypertension in an affluent

north Indian population. Indian J Med Res 2008; 128:712720. 4.

Nicodѐme R, Albessard A, Amar J, et al. Poor blood pressure control in general practice: In search of explanations. Archives of Cardiovascular Disease 2009; 102:477-483.

de Gusmão JL, Mion Jr. D, Pierin AMG. Health-related quality of life and blood pressure control in hypertensive patients with and without complications. Clinics 2009; 64:619-29.

Nair T, Beckett N The Association between Blood Pressure Control and Well-being in Primary Care Practice: An Observational Study. J Pract Cardiovasc Sci 2016; 2:36-40.

Patwary MSR. Indapamide sustained release: Effective first step antihypertensive therapy. The ORION Medical Journal 2007; 26:419-421.

Nair T. Choosing a Diuretic in Hypertension: To Follow Instinct or Evidence. Medicine Update. Mumbai: The Association of Physicians of India, 2013: 78-80.

Beckett NS, Peters R, Fletcher AE, et al. Treatment of Hypertension in Patients 80 years of age and older. N Engl J Med 2008; 358:1887-1898.

617

10. Kaplan NM. Indapamide: Is it the better diuretic for Hypertension? Hypertension 2015; 65:983-984.

CHAPTER 131

C H A P T E R

132

High Altitude Systemic Hypertension (HASH) - A New Entity

INTRODUCTION

There are over 140 million people living worldwide at High Altitude (HA) of which 13 million are in Ethiopia, 1.7 million in Tibet (total 78 million in Asia), 35 million in the South America (Andes), and 0.3 million in Colorado Rocky Mountains. HA is defined in medical terms as an elevation of 2700 m above sea level. The numbers of people who reside or visit HA continue to rise. Troops of the Indian Army are stationed in the highest battlefield at Siachen glacier with altitudes varying from 15,000 to 23,000ft. HA tourism continues to be on the rise in India. The stays at these altitudes are fraught with multiple health/ medical issues known as High Altitude illnesses (HAI) such as high altitude pulmonary edema, high altitude cerebral edema, acute mountain sickness and chronic mountain sickness. The least described and minimally studied among these HAIs is the commonly occurring high altitude associated systemic hypertension (HASH).

CONCEPT BEHIND HASH: WHY SHOULD WE DEFINE A NEW ENTITY

Chronic intermittent hypoxia, as in obstructive sleep apnea, is known to cause systemic arterial hypertension (HTN), whereas, continuous hypoxia in healthy humans, as at HA, is known to mediate pulmonary arterial hypertension. In early reports of lowland sojourners at HA, systemic blood pressure (BP) was found to be elevated both in the un-acclimatized and the well acclimatized state. Submaximal and maximal exercise was found to further elevate the systemic BP at HA. There is a strong correlation between altitude and prevalence of systemic hypertension. The prevalence of systemic hypertension at HA has been reported from 37 - 62.4% in different series from Himalayas. Also, a study from India has demonstrated a higher prevalence of systemic hypertension in migrants as compared to natives born in Leh, Ladakh. Systemic hypertension occurring at HA is a type of secondary hypertension and might lead to increased long term morbidity and mortality. It is thus very important to define this highly prevalent entity for identifying these patients early and promptly managing them.

CARDIOVASCULAR CHANGES IN HA

HASH is a consequence of complex interplay of the cardiovascular changes in response to HA can be different in acute and chronic exposure. A brief summary of these changes are enumerated in Table 1.

Yanamandra Uday, Velu Nair

HASH AND ITS INCIDENCE

HASH is defined as presence of sustained hypertension (>150/90mm Hg; as per JNC criteria) in lowlanders at HA (>2700m). HASH is a type of secondary hypertension wherein stay at HA acts as the predisposing factor. There is paucity of data on HASH as lowlanders staying for prolonged periods in HA (2-3y) in great numbers outside the military/ occupational reasons is unusual. There is no literature available as on date to explain what happens to these individuals with HASH who continue to stay in HA with/ without treatment. In our experience, 4% of all subjects inducted to HA in a sample population and 34% of admissions to Medicine department in a secondary care center situated at HA were due to HASH in a two year period of 2012-13. Data from HA medical research center (HAMRC, India) by Singh SP et al revealed that seven percent of hospital admissions of lowland sojourners at 3300m from 2001-2008 were due to hypertension. In another study, the same group found 30.6 % of 316 subjects at 3300m to be hypertensive on screening by JNC VII criteria that were normotensive in plains.

PATHOPHYSIOLOGY OF HASH

Many theories have been proposed, pathophysiology being multifactorial with sympathetic activation, hormonal imbalance (Table 2) and endothelial activation playing crucial role.

Role of Sympathetic Activation

The role of the autonomic nervous system in controlling heart rate (HR) and cardiac output is well established. Short periods of exposure to hypoxia increase the concentration of epinephrine and nor epinephrine, which leads to hypoxia induced increase in HR and BP. These alterations in the autonomic nervous system might play some role in alteration of blood pressure at HA. In a study of 9 healthy Danish lowlanders after 9 weeks at 5260m, Calbet et al showed a 3.8 fold greater whole body noradrenaline (NA) release compared to sea-level values. Both the systolic and diastolic blood pressure (SBP, DBP) values were significantly higher than sea-level. Whether a sustained increase in whole body NA release occurs in sojourners at HA as demonstrated at extreme altitude is not known, although, Sharma et al had reported a return of urinary catecholamines to sea-level values by 90 days stay in sojourners at 3300m. In a study of lowland Han subjects working on the Lhasa railroad project Wu et al found 45 subjects who were normotensive at sea-level but developed HTN between 3486-4509m. While the BP settled by day 12-21 in 33 subjects, in the remaining subjects it

619

Table 1: Cardiovascular changes in HA Sustained Exposure

Elevation of HR in response to hypoxic challenge is attributed to the sympathetic stimulation and vagal withdrawal; however, intrinsic HR does not seem to be affected during acute exposure.

Resting HR seems to remain high despite acclimatization and does not reach sea level rates. Further increase in HR is seen with each increment in altitude. The decrease in plasma volume during the first few weeks in HA may unload the cardiopulmonary and arterial baroreceptors providing the continued stimulus to the sympathetic activation and at the same time causing vagal blockades leading to tachycardia.

Stroke volume:

Under acute conditions there seem to be no effects on the stroke volume. Classic studies at 4200m have documented up to 40% increase in cardiac outflow within days of ascent to HA. The magnitude of increase appears proportional to the hypoxia with no apparent increases below 700m of ascent.

Stroke volume is decreased and the reasons are manifold including decreased plasma volume, increased HR and more significantly diminished RV function consequent to increased pulmonary artery pressures. LV systolic function is rather unaffected at HA. The hypoxia tolerance of myocardium is attributed to heightened sympathetic drive, change of fuel to glucose/ lactate and transcriptional changes in mitochondrial nuclear genes. Consistent LV diastolic dysfunction has been noted with decreased distension; however, the volume depletion most probably masks the clinical manifestation of diastolic dysfunction.

Peripheral vascular resistance:

While the increase sympathetic drive on exposure to HA should have caused peripheral vasoconstriction, the hypoxia seems to override this phenomenon resulting in peripheral vasodilatation. This over-riding of the sympathetic stimulation by the local factors has been termed as functional sympatholysis.

The total sympathetic activity seems to increase with exposure to sustained hypoxia. The total peripheral resistance is the function of resistance in various regional vascular beds. The initial sympatholysis gradually decreases in response to improved CaO2 and subsequently the increased sympathetic drive seems to be the predominant factor.

Systemic blood pressure (BP):

The two diametrically opposite influences on the peripheral vascular resistance are increased adrenergic drive and functional sympatholysis, which determine the BP of the individual in HA. When BP is measured immediately on exposure to HA, there seems to be a slight hypotension. However over the next few hours there seems to be a modest increase in the BP due to reduction in plasma volume and subsequent increase in hemoglobin concentration. The regulation of the peripheral chemosensitive receptors by the total content of O2 rather than the PaO2 seems to be instrumental in this regard.

The BP measurements in lowlanders who are exposed to HA follow a pattern in which there is an immediate hypotension, followed by gradual rise in both diastolic and systolic BP as the functional sympatholysis response diminishes. However there is controversy over prolonged exposure (>90 days) to HA in that a few studies have reported return to sea level values, while others report sustained rise in BP.

CHAPTER 132

Acute Exposure HR (HR)

620

Table 2: Hormonal changes on exposure to HA

HYPERTENSION

Renin

Acute Exposure

Sustained Exposure

Decreased

Angiotensin II No major shifts, may be decreased in few individuals

No major shifts in the levels

Aldosterone

Decreased

Cortisol

No major change in hours

Increases secondary to hypoxic stress

Vasopressin

Decreased in initial hours

Increased over days to week and stabilizes in months

was significantly high even after 30-120 days. Descent to low altitude reduced the BP to pre-ascent values over 2-4 weeks but remarkably, eight of these subjects developed hypertension on each of four ascents leading to enforced descent and final removal from employment at HA. While their findings in the larger number of subjects are in consonance with the idea that sympathetic drive at HA settles with acclimatization the occurrence of repeated HTN in eight of their subjects on re-ascent to HA would suggest that a sub-set of healthy lowlanders are predisposed to sustained HTN with chronic systemic hypoxia at HA. Also study by Yanamandra et al revealed cardiac sympathetic-vagal imbalance in patients with HASH as evidenced by the abnormalities on heart rate variability (HRV) analysis.

Role of Endothelial Dysfunction

Endothelial dysfunction (ED) has been implicated in various HA illness (HAI) other than HASH previously. ED is also known to accentuate the risk of cardiovascular morbidity in various studies at sea level. ED can be determined by evaluation of endothelial markers, flow mediated dilation, intimal media thickness and lately by intra-arterial ultrasonography. In a study by the authors from India to elucidate role of endothelial dysfunction and HASH we found that the endothelial markers (sICAM and VCAM levels) were significantly higher in the patients with HASH when compared to the controls with similar duration of stay in HA. This rise could be either secondary to the inherent effect of the atherosclerosis in these individuals or the effect of the HA on unmasking the underlying ED. As we did not study the levels of cellular adhesion molecules (CAM) at sea level in these individuals so it is not possible to answer this question. Only conclusion which can be drawn from these results include that there is a significant difference in the above mentioned endothelial dysfunction markers between patients with HASH and controls. We also studied the flow mediated dilation in a group of patients with HASH in a case controlled fashion and found statistically significant differences.

Role of Conventional Risk Factors

Body fat content, is known to be associated with systemic hypertension at sea levels. A study conducted by the authors showed a significant relation between body mass index (BMI) and HASH. We also demonstrated a statistically significant correlation with obesity markers such as BMI, waist hip ratio (WHR) and actual body weight with HASH. The lipid profile revealed statistically higher cholesterol and LDL in patients with HASH against the controls but the values in either group were still in normal range. In another study by Singh SP et al from India revealed HASH subjects had a similar duration of stay, but had greater age, higher BMI and waist circumference than the control non-hypertensive population. 80.3% of the hypertensive patients were overweight/ obese by body fat criteria. Conventional risk factors for atherosclerosis would therefore appear to have a role in HASH. Another study from India by Kumar et al also found a greater BMI in eighteen subjects who developed HASH at 3300m compared to 28 who did not.

Role of Hormones In HASH

High altitude environment has a profound effect on most of the endocrine glands. Hypoxia is no doubt the major factor affecting endocrine function, but associated low temperatures and exercise are also factors affecting endocrine function. The hemodynamic and hormonal changes associated with HA exposure are illustrated in Table 2. Kumar et al from India, reported a significantly greater expression of the ACE D allele in subjects of HASH. This genetic expression was correlated to higher levels of ACE in these populations. In another study by us, patients of HASH displayed significantly greater levels of angiotensin II, norepinephrine, aldosterone/ARC and parathormone compared to normotensive subjects. All these factors are implicated to varying degrees in “essential” HTN in the plains too. It would therefore appear that at HA processes similar to those in the plains get accentuated in a sub-set of individuals resulting in development of HASH secondary to chronic hypoxia of HA. There was a definitive role of sympathovagal disturbance in the causation of HASH.

HOW TO DIAGNOSE?

The diagnosis is akin to the prevailing JNC guidelines in diagnosing hypertensive patients at sea levels, but for the necessity of continuous stay for more than 3 months at HA (>2700m) at the time of diagnosis in a lowlander. These definitions are arbitrary and primarily derived from studies conducted in HASH from India. Native highlanders with similar defining characters are not labelled HASH in the current studies as the data on the role of HA in such individuals is a topic of debate. There are studies to prove the benefit of ambulatory intermittent BP (AIBP) monitoring in diagnosing these patients earlier in HA. The lack of nocturnal dip in the BP is the earliest marker for these patients.

TREATMENT OF HASH

There are no guidelines on the management of the patients

Table 3: Take Home Message High altitude systemic hypertension (HASH) is a type of secondary hypertension following sustained exposure to high altitude.

•

Sympathetic activation, endothelial dysfunction and hormonal imbalance in patients with conventional risk factors can predispose to HASH.

•

Criteria for diagnosis are evolving and currently based on the criteria as defined in various clinical studies.

•

De-induction to lower altitude/ sea levels can reverse the pathology with recurrence on reinduction to HA. ACE inhibitors and calcium channel blockers are preferred agents in studies with no proven literature on the ideal agent.

with HASH, it being a naïve field. There is no literature available as on date to explain what happens to these individuals with HASH who continue to stay in HA with/ without treatment. Investigators have variably used beta blockers, ACE inhibitors and calcium channel blockers either in isolation or in combination. We suggest the use of ACE inhibitors followed by calcium channel blockers for the effective control of these patients. In our settings, patients are de-inducted to lower altitude on diagnosis of HASH. Most of these patients become normotensive after 3-4 months of descent. On re-ascent these individuals develop recurrent HASH, with time to onset being earlier than the previous episode.

CONCLUSION

The diagnosis of HASH is fraught with controversies and the scientific community is divided on the mere presence of such an entity. Many argue it to be an extended part of the physiological continuum of the acclimatization process to hypobaric hypoxia. The thin line dividing the raised BP due to physiological acclimatization and the pathological process causing morbidities secondary to sustained hypertension needs to be defined. A tremendous contribution from the research community is required in clearly defining these different aspects of HASH. (Take home messages have been tabulated as Table 3)

621

We would like to acknowledge O/o DGAFMS for providing support in carrying out studies on HASH and permission to present this paper. We also extend our heartfelt thanks to the staff of High Altitude Medical Research Centre and General Hospital at Leh for the administrative and logistic support in all our endeavors.

REFERENCES

Yanamandra U, Nair V. Emerging concepts in High Altitude Medicine. Text Book of Emergency Medicine. Editor: Velu Nair. Ed 2014. Wolters Kluwer Publications. ISBN: 9789351292470. Chapter 1.7; 51-4.

Menon AS, Yanamandra U, Nair V. Other High Altitude Related Illnesses. Text Book of Emergency Medicine. Editor: Velu Nair. Ed 2014. Wolters Kluwer Publications. ISBN: 9789351292470. Chapter 1.4; 37-43.

Sharma SC, Balasubramanian V, Mathew OP, Hoon RS. Serial studies of heart rate, blood pressure, and urinary catecholamine excretion on acute induction to high altitude (3,658 m). Indian J Dis Chest 1977; 19:16–20.

Mingji C, Onakpoya IJ, Perera R, Ward AM, Heneghan CJ. Relationship between altitude and the prevalence of hypertension in Tibet: a systematic review. Heart 2015; 101:1054-60.

Norboo T, Stobdan T, Tsering N, Angchuk N, Tsering P, Ahmed I, et al. Prevalence of hypertension at high altitude: cross-sectional survey in Ladakh, Northern India 2007– 2011. BMJ Open 2015; 5:e007026

Velasco A, Vongpatanasin W, Levine BD. Treating hypertension at high altitude: the quest for a magic bullet continues. Eur Heart J 2014; 35:3083-4.

Kumar R, Pasha MQ, Khan AP, Gupta V, Grover S, Norboo T, et al. Association of high-altitude systemic hypertension with the deletion allele-of the angiotensinconverting enzyme (ACE) gene. International journal of biometeorology. 2003; 48:10-4.

Ashraf MZ. Hypertension at high altitude: the interplay between genetic and biochemical factors in the setting of oxidative stress. Hypertens Res 2015 Dec 10.

Parati G, Ochoa JE, Torlasco C, Salvi P, Lombardi C, Bilo G. Aging, high altitude, and blood pressure: a complex relationship. High Altitude Medicine & Biology 2015; 16:97109.

10. Sique´s P, Brito J, Banegas JR, Le´on-Velarde F, de la CruzTroca JJ, Lope´z V, Naveas N, Herruzo R. Blood pressure responses in young adults first exposed to high altitude for 12 months at 3550 m. High Alt Med Biol 2009; 10:329–335.

CHAPTER 132

•

ACKNOWLEDGEMENT

C H A P T E R

133

Alcohol and Hypertension Related Left Ventricular Systolic DysfunctionIntergrated Approach Using Echocardiography Maninder Singh, Suraj Kumar Arora, Rohit Tandon

CASE REPORT

47 years old male, chronic alcoholic, drinking country made alcohol daily (25-30 drinks/week, 1 drink =60ml alcohol), came to OPD with dyspnoea and palpitations NYHA class II. General physical examination revealed mild bilateral pedal oedema, no icterus, clubbing. CVS: apical impulse in 6th intercostal space slightly lateral to mid-clavicular line. Normal heart sounds, no S3/S4, Soft systolic murmur grade III at apical region. Electrocardiogram: progression.

sinus

rhythm,

poor

wave

Echocardiography showed dilated cardiac chambers with global hypokinesia of left and right ventricle, eccentric LVH with moderate LV dysfunction and mild mitral regurgitation mildPAH (Figures 1 & 2). Long-term heavy alcohol consumption (of any beverage type) is the leading cause of a non-ischemic, dilated cardiomyopathy, herein referred to as alcoholic cardiomyopathy (ACM)1. ACM is a specific heart muscle disease of a known cause and is classified as a dilated cardiomyopathy,2,3 also frequently referred to as alcoholic heart muscle disease (AHMD).

specific immuno-histochemical, immunologic, or other criteria for the diagnosis of ACM and the diagnosis is often considered presumptive usually one of exclusion. The key factor to consider is a long-term history of heavy alcohol abuse.

INCIDENCE, PREVALENCE, AND MORBIDITY

Prevalence of ACM is variable ranges from 23 to 40%.4-6 It represents about 3.8% of all cardiomyopathy cases1. This statistic may seem rather insignificant; however, longterm heavy alcohol consumption is the second-leading cause of a dilated cardiomyopathy. Among ACM cases, men represent the larger percentage, whereas women represent approximately 14%1,7. In all races, death rates due to ACM are greater in men compared to women, and are greater in African-American men and women compared to white men and women with ACM.

WHAT DURATION AND LEVEL OF ALCOHOL CONSUMPTION IS ASSOCIATED WITH ACM?

ACM is characterized by a dilated left ventricle (LV), normal or reduced LV wall thickness, and increased LV mass. Unlike other cardiomyopathies, there are no

Alcoholics can present with either a preclinical (asymptomatic) or symptomatic ACM (the latter is primarily distinguished from the former by signs and symptoms of heart failure). The duration and amount of alcohol consumed by asymptomatic alcoholics does not correlate with changes in myocardial structure and functions except for study by Urbano-Ma´rquez and colleagues8, who found the total lifetime dose of alcohol was correlated to an increase in LV mass and a decrease in

Fig. 1: A: Apical 4 chamber view showing dilated left atrium and left ventricle. B: Pulse wave Doppler at the level of mitral leaflet showing increased Left ventricle diastolic pressure (Type III diastolic dysfunction)

Fig. 2: Tissue Doppler Imaging at level of medial mitral annulus showing reduced systolic and diastolic velocities

Alcohol Alcohol consumption  > 90 gms > 5 years •

Apoptosis (either directly via alcohol or indirectly via  NE levels

•

 synthesis and / or accelerated degradation of contractile proteins

•

 myofilament Ca2+ sensitivity

•

Intrinsic mycocyte dysfunction due to mitochondrial and sarcoplasmic dysfunction (due to Ca2+ overload, fatty ethyl esters or NE) Cell drop out and weakly contracting myocytes  Decreased cardiac output 

•

LV dilation to increase EDV (preload) to compensate for  cardiac output, however this is may be accompanied by wall thinning due to cell drop out

•

Hypertrophy of normal myocytes to compensate for weakly contracting neighboring myocytes Continued drinking  >15 years

•

Progressive LV dilation and wall thinning

•

Activation of other neurohormonal systems

•

Signs and symptoms of heart failure

Fig. 3: Flowchart depicting pathogenesis of ACM. gms =grams, NE= Nor epinephrine. EDV- End Diastolic Volume ejection fraction (EF). In general, asymptomatic alcoholic patients with changes in cardiac structure and function had a history of consuming > 90 g/d of alcohol (some studies report> 200 g/d) for > 5 years(average 15 years). 1 standard drink=14 gram of alcohol= 250 ml of beer (7% alcohol) = 45 ml of whisky. The key variable linked to the development of heart failure appears to be the duration of heavy daily alcohol consumption.

MYOCARDIAL STRUCTURAL AND FUNCTIONAL CHANGES ASSOCIATED WITH ACM

How do clinicians distinguish asymptomatic from symptomatic ACM?

Symptomatic ACM is characterized by a greater degree of LV dilation and increased cardiac mass. LV EDD values and LV mass values were 40% and 60% greater, respectively, in symptomatic alcoholics compared to asymptomatic alcoholics, and LV ESD values were twice as large in the symptomatic patients. Impaired early filling of the LV due to delayed relaxation is common in asymptomatic alcoholics and may in fact be the earliest functional sign of preclinical ACM. LV dilation is a very early finding that precedes changes in LV mass and diastolic dysfunction.

WOMEN WITH ACM?

There are very few studies that have examined the incidence, clinical characteristics, or outcomes of women

623

Similar to men, ACM occurs in women of a relatively young age (45 to 50 years).7 The clinical features resemble those found in men, and include a dilated LV, modest degree of hypertrophy, and reduced systolic function.

BIOMARKERS FOR ALCOHOL ABUSE

Gamma glutamyl transferase (GGT) glycoprotein is neither a very sensitive marker, showing up in only 30–50 percent of excessive drinkers in the general population, nor is it a specific marker of chronic heavy alcohol use, because other digestive diseases, such as pancreatitis and prostate disease, also can raise GGT levels. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) are enzymes that help metabolize amino acids, the building blocks of proteins. They are an even less sensitive measure of alcoholism than GGT. ALT is the more specific measure of alcohol-induced liver injury because it is found predominantly in the liver, whereas AST is found in several organs, including the liver, heart, muscle, kidney, and brain. Very high levels of these enzymes (e.g., 500 units per litre) may indicate alcoholic liver disease.

TREATMENT

Abstinence from alcohol is the cornerstone for treating ACM. Abstinence after development of milder HF can stop progression, or even reverse symptoms in some cases, otherwise severe HF ensues leading to a poor prognosis. Without complete abstinence, the 4 year mortality for ACM approaches 50%.

HYPERTENSION RELATED LEFT VENTRICULAR SYSTOLIC DYSFUNCTION

Case report 2

45 years old male, known hypertensive since past 2 years, compliant with medications now presented with chief complaints of weakness of right upper and lower limbs when he woke up in the morning. No past history of diabetes mellitus, heavy cigarette smoking or alcohol intake. GPE was normal. Pulse: 70 beats/min.regular. BP: 170/100 mm Hg left arm supine. BMI: 27 kg/m2 Systemic examination: CNS: Broca’s aphasia present. Facial deviation towards left side. Grade 3/5 Power in Right upper and lower limbs. CVS: Apex beat in 5th ICS. Normal heart sounds,no murmur. ECG : LVH with LV strain 2D Echocardiography showed moderate eccentric LVH with global hypokinesia of left ventricle with moderate LV systolic dysfunction and Type I Diastolic dysfunction (Figures 3, 4 and 5). NCCT brain left MCA infarct.

CHAPTER 133



with ACM, and no study has considered the effects of oestrogen. However, similar to men, long term heavy alcohol consumption in women is associated with the development of a dilated cardiomyopathy.

624

Table 1: Markers of alcohol consumption with respective sensitivity and specificity Summary of State Markers for Alcohol Consumption

HYPERTENSION

Marker

Sensitivity (percent)

Diagnostic Specificity (percent)

Gamma-glutamyltransferase (GGT)

611

n/a

Chronic alcohol abuse

Yes

Alanine aminotransferase (ALT)

Method-dependent

n/a

Chronic alocohol abuse

Yes

Aspartate aminotransferase (AST)

561

N/A

Chronic alcohol abuse

Yes

26-832+

923

Heavy alcohol use**

Yes

N-acetyl-β-hex6 aminidase

942

912

Heavy alcohol use

Whole bloodassociated acetaldehyde (WBAA)

1004

954

Recent alcohol consumption as all levels; monitoring abstinence

Yes

Mean corpuscular volume (MCV)

421

n/a

Heavy alcohol use

Yes

Apolipoprotein J

n/a

Heavy alcohol use

5-hydroxylypotophol (5-HTOL)

n/a

Monitoring sobriety

Salsolinol

n/a

Chronic alcohol consumption

Fattty acid ethyl easters (FAEE)

1005

905

Recent heavy alcohol use

Ethyl glucotonide (EIG)

n/a

Method-dependent

Monitoring sobriety. Torensics

Carbohydratedeficient transferring (CDT)

Possible or Current Use

Used Clinically in U.S.?

*Depending on method and gender; **More than 60 grams per day (4-5 standard drinks); n/a – data not available; 1Anitla et al 2004; 2 Stowel et al. 1997.; 3Jevona and Johnson 2003; 4Bean et al 2001; 5Wurst et al 2004

Fig. 3 : Dilated ventricle with hypertrophied walls and mildly dilated aorta

Fig. 4: Pulse wave Doppler at mitral valve level showing diastolic dysfunction type I pattern

with normal EF. The excess risk persists after simultaneous adjustment for age and LV mass.

625

ROLE OF ELECTROCARDIOGRAM

Development of LVH or its persistence during antihypertensive therapy is associated with an increased risk of left ventricular systolic dysfunction after 3 years follow-up.

BIOMARKERS INDICATIVE OF INCIPIENT HEART FAILURE IN HYPERTENSIVE SUBJECTS

Hypertension is a potent risk factor for left ventricular systolic dysfunction. All hypertensive subjects without symptoms of CHF and without structural heart disease should be classified as belonging to stage A, which denotes a high risk for CHF, whereas those without symptoms of CHF but with left ventricular (LV) hypertrophy, should be classified as belonging to stage B. Development of overt CHF may be preceded by a phase of asymptomatic LV systolic dysfunction (ALVSD). Diagnosis of ALVSD is important because treatment with angiotensin-converting enzyme (ACE) inhibitors may delay progression toward overt CHF in these subjects.

PREVALENCE OF ASYMPTOMATIC LEFT VENTRICULAR SYSTOLIC DYSFUNCTION

In general population, prevalence of ALVSD has been estimated at 2% in most studies. In the PIUMA study Prevalence of ALVSD in hypertensive subjects was 3.6%, EF was 40% to 49% in 87% of subjects, 30% to 39% in 9% of subjects and 30% in 4% of subjects. According to the Framingham Heart Study, severe LVSD developed in 3% to 6% among hypertensive patients and the risk of heart failure is increased by 2-fold in men and by 3-fold in women.9

PATIENT CHARACTERISTICS

Compared with the subjects without ALVSD, those with ALVSD are more frequently men and current smokers. Office and 24-hour ambulatory BP levels and heart rate were significantly higher in the subset with than without ALVSD.

INCIDENCE OF HEART FAILURE HOSPITALIZATIONS

Hospitalizations for symptomatic CHF are 1.48 per 100 subjects per year in most of the studies. Age, LV mass on echocardiography and reduced systolic functions LVEF <45% are independent predictors of overt CHF with a 9-fold higher risk of hospital admission for CHF over a mean follow-up period of 6 years compared with those

LV SYSTOLIC FUNCTION PARAMETERS FROM LINEAR MEASUREMENTS IN HYPERTENSION

LV linear dimensions for the calculation of FS and EF by Teichholz or Quinones methods are widely used in hypertensive patients. The use of these measurements has been superseded by more accurate and reliable measures as these linear measurements are dependent on geometric assumptions so are not recommended for clinical use. [10] Mid-wall fractional shortening (MFS) is relatively independent of afterload and hypertensive patients with left ventricular hypertrophy and normal ejection fraction have abnormal MFS. Midwall Fractional Shortening is based on too many assumptions using M-mode and has a cumbersome formula.11 Inner shell= [(LVIDd+SWTd/2+PWTd/2)3 – LVIDd3 + LVIDs3 ] 1/3-LVIDs MWFS=([LVIDd+SWTd/2+PWTd/d] – [LVIDs + inner shell]) (LVIDd = SWTd/2 + PWTd/2) x 100

TWO-DIMENSIONAL MEASUREMENTS

Biplane method of discs (modified Simpson’s rule obtained from apical four- and two-chamber views) is the most accurate in abnormally shaped ventricles and combined with harmonic imaging it improves the reproducibility of LV volumes used in EF calculation. Whether observed LV pump function is representative of actual myocardial contractile performance is determined by measurement of end systolic stress(∂m) ∂m (dynes/cm2 ) = 1.35 x P(LVID)/4h(1+h/LVID) ∂m = end-systolic meridional wall stress. P = pressure in the LV at the end of systole (may substitute SBP) LVID=LV internal diameter h=end-systolic posterior wall thickness OR ∂m (dynes/cm2 ) = 1.33 x {BPsys(Am)/Ac} x 103 ∂m = end-systolic meridional wall stress ,Ac = LV cavity

CHAPTER 133

Fig. 5 : Reduced left ventricular longitudinal functions using speckle tracking based strain measurement in this case value of GLS is =-12%(normal >-20%)

N-terminal propeptide of procollagen type III (PIIINP) one of the biomarkers of extracellular matrix remodelling is the first early biomarker for the development of HF in patients with hypertension and normal resting echocardiography Unlike traditionally used biomarkers for overt heart failure BNP, NT pro BNP which lack specificity and sensitivity this new biomarker holds promise for clinical use in hypertensive patients with mild left ventricular systolic dysfunction.

626

area in the short axis view, Am = myocardial area BPsys = systolic blood pressure To eliminate the effects of LV afterload on FSmw, stress corrected FSmw is calculated through the following formula:

HYPERTENSION

cESS ¼ {[SBP × (LVIDs/2)2] × [1 + (LVIDs/2 + LV 2 PWs)2/ (LVIDs/2 + LV 2 PWs/2)2]}/{(LVIDs/2 + LV 2 PWs)2 2 (LVIDs/2)2}, where SBP represents systolic blood pressure. This correction has shown to discriminate hypertensive from physiological LV hypertrophy in athletes.12

THREE-DIMENSIONAL MEASUREMENTS

Transthoracic 3DE provides a rapid and accurate method for quantifying LV volumes and EF (LVEF) It showed a superior reproducibility to 2DE, with a closer correlation to CMR-derived volumes in previous studies.13 A recent meta-analysis of validation studies comparing 3DE and CMR demonstrated that considerable variability still exists in the measurement of LV volumes (+34 mL for EDV, +30 mL for ESV,and +12% for EF), although it is less than that observed between 2DE and CMR.13 Several sources of 3D volume acquisition and measurement error are difficulty in imaging the anterior and lateral walls because of interference from ribs, low line density (and therefore lower spatial resolution—which may be partly readdressed with the use of LV opacification), low temporal resolution(which may be addressed by using multiple subvolumes—but at the risk of stitching artefacts), and time-consuming off-line analysis.14

TISSUE DOPPLER ASSESSMENT OF SYSTOLIC FUNCTION

In hypertensive heart disease, main parameter for systolic performance by tissue Doppler evaluation is s′with measurements at six sites from the apical four-chamber, two-chamber and long-axis views (six-site average s′ . 5.4 cm/s has 88%sensitivity and 97% specificity for LVEF >50%).main limitation is reliability on detection of cardiac motion which may hamper correct estimation.

ASSESSMENT OF MYOCARDIAL FUNCTION BY STRAIN

Longitudinal strain corresponds to the function of the endocardial layer of myocardium, where longitudinal fibres are subjected to the negative impact of early development of fibrosis in hypertensive heart disease.it is useful in identifying sub clinical left ventricular systolic dysfunction.15

KEY MESSAGE

Echocardiography plays an important role in detecting complications related to hypertension and alocohol. LV systolic dysfunction can be earlier identified by simple reproducible measures of longitudinal LV function using advanced echocardiographic techniques like tissue Doppler and strain.

REFERENCES

Vital and Health Statistics. Hyattsville, MD: U.S. Department of Health and Human Services. Centers for Disease Control and Prevention, October 1995; 13(122).

Report of the World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Br Heart J 1980; 44:672–673.

Richardson P. Report of the 1995 World Health Organization/ International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 1995; 93:841–842.

Fauchier L, Babuty D, Poret P, et al. Comparison of long term outcome of alcoholic and idiopathic dilated cardiomyopathy. Eur Heart J 2000; 21:306–314.

McKenna CJ, Codd MB, McCann HA, et al. Alcohol consumption idiopathic dilated cardiomyopathy: a case control study. Am Heart J 1998; 135:833–837.

Gavazzi A, De Maria R, Parolini M, et al, on behalf of the Italian Multicenter Cardiomyopathy Study Group (SPIC). Alcohol abuse and cardiomyopathy in men. Am J Cardiol 2000; 85:1114–1118.

Ferna´ndez-Sola` J, Estruch R, Nicola´s J-M, et al. Comparison of alcoholic cardiomyopathy in women versus men. Am J Cardiol 1997; 80:481–485.

Urbano-Ma´rquez A, Estruch R, Navarro-Lopez F, et al. The effects of alcoholism on skeletal and cardiac muscle. N En J Med 1989; 320:409–415.

Paolo Verdecchia, Fabio Angeli,et al Asymptomatic Left Ventricular Systolic Dysfunction in Essential Hypertension Prevalence, Determinants, and Prognostic Value. Hypertension 2005; 45:412-418.

10. Agata Bielecka-Dabrowa, Marta Michalska-Kasiczak Biomarkers and Echocardiographic Predictors of Myocardial Dysfunction in Patients with Hypertension Scientific Reports 5, Article number: 8916 (2015) 11. Okin PM, Wachtell K, Gerdts E, Dahlöf B, Devereux RB Relationship of left ventricular systolic function to persistence or development of electrocardiographic left ventricular hypertrophy in hypertensive patients: implications for the development of new heart failure. J Hypertension 2014; 32:2472-8. 12. Fukuda S, Watanabe H, Daimon M, Abe Y, Hirashiki A, Hirata K et al. Normal values of real-time 3-dimensional echocardiographic parameters in a healthy Japanese population: the JAMP-3D study. Circ J 2012; 76:1177–81. 13. Muraru D, Badano LP, Peluso D, Dal Bianco L, Casablanca S, KocabayGet al. Comprehensive analysis of left ventricular geometry and function by three-dimensional echocardiography in healthy adults. J Am Soc Echocardiogr 2013; 26:618–28. 14. Jenkins C, Bricknell K, Hanekom L, Marwick TH. Reproducibility and accuracy of echocardiographic measurements of left ventricular parameters using realtime three-dimensional echocardiography. J Am Coll Cardiol 2004; 44:878–86. 15.

Takeuchi M, Nishikage T, Mor-Avi V, Sugeng L, Weinert L, Nakai H et al. Measurement of left ventricular mass by real-time three-dimensional echocardiography: validation against magnetic resonance and comparison with twodimensional and M-mode measurements. J Am Soc Echocardiogr 2008; 21:1001–5.

C H A P T E R

134

Renovascular Hypertension

INTRODUCTION

R Chandni, R Gayathri

PATHOPHYSIOLOGY

Renovascular hypertension (RVH) is the most important cause of secondary hypertension and it is often due to occlusive lesion of renal arteries. RVH is precipitated by a hemodynamically significant stenosis of a renal artery or arteries (that is, a stenosis greater than 75% of the vessel lumen or 50% with post- stenotic dilation). The frequency of renovascular hypertension is less than 1% in patients with mild to moderate elevation of blood pressure but in contrast the prevalence is much higher (10-25%) in patients with acute, severe or refractory hypertension. RVH is a potentially curable cause of hypertension and major advances in vascular imaging has lead to early and easy non invasive identification of vascular lesions. Effective and well tolerated antihypertensive drug therapy has lead to satisfactory medical management of RVH. Selected patients may need angioplasty, stenting or both.

The chief mechanism underlying renovascular hypertension involves two factors: 1) Activation of Renin Angiotensin Aldosterone System 2) Presence or absence of contralateral kidney.

AETIOLOGY

The clinical clues which suggest the presence of renal arterial disease as the cause of hypertension and CKD include

Atherosclerotic renal artery stenosis and fibromuscular dysplasia are the major causes of renovascular hypertension.

In unilateral renal artery disease, the ischemic kidney initiates hypersecretion of renin, which in turn accelerates conversion of angiotensin I to angiotensin II and there is aldosterone induced sodium and water retention. On the other hand, there is renin suppression and pressure diuresis by the non stenotic kidney, precluding volume retention from contributing to the angiotensin II mediated hypertension. By contrast, a solitary ischemic kidney or bilateral disease has little or no capacity to excrete sodium and water thus leading to volume retention playing an additive role in the hypertension.

WHEN TO SUSPECT FOR RENOVASCULAR HYPERTENSION

•

Age at onset of hypertension <30 years or >55years

Atherosclerotic renal artery stenosis (ARAS) is the most common cause of renal arterial compromise accounting for 70-90% of cases of renal artery stenosis. ARAS usually involves the ostium or proximal renal arteries. It is more common in older patients, patients with other CV risk factors and has poor prognostic implications.

•

Abrupt onset of hypertension

•

Acceleration of hypertension

•

Refractory hypertension

Fibromuscular dysplasia (FMD) on the other hand is not as common as ARAS and accounts for 10-30% cases. It is more common in young women. It affects the distal 2/3 of renal arteries and its branches. It may involve the intima, media or adventitia but most commonly involves the media. Genetic factors play a role. It is usually associated with good prognosis and progressive disease with total occlusion is rare.

•

Accelerated hypertensive retinopathy

•

Malignant hypertension

•

Systolic diastolic abdominal bruit

•

Flash pulmonary edema

•

Evidence of generalised atherosclerosis obliterans

•

Asymmetry in kidney size on imaging studies

•

Acute kidney failure on treatment with an ACE inhibitor or ARB.

Other nonatherosclerotic causes include aneurysms, congenital or traumatic arteriovenous fistulas, polyarteritis nodosa, takayasu arteritis, neurofibromatosis, trauma, acute arterial thrombosis or embolism, aortic/renal artery dissection, hypercoagulable states, congenital bands and radiation induced fibrosis. Transplant renal artery stenosis is the most common vascular complication following renal transplant and contributes to transplant failure.

previously

well

controlled

Because of the potential risks of invasive procedures, only those patients who have a high likelihood of getting benefit from the procedure should be tested for RAS which include severe hypertension with progressive renal insufficiency, refractory hypertension, accelerated or malignant hypertension, unexplained recurrent flash pulmonary oedema, hypertension with ACEI or ARB induced acute renal failure and severe hypertension with asymmetry of renal size.

628

Table 1: Computed tomographic angiography and Magnetic resonance angiography CTA

MRA

Sensitivity 94%

90%

Specificity 60-90%

100%

HYPERTENSION

Can detect small accessory No iodinated contrast renal arteries medium Can be used in implanted devices

Cannot be used in those with implanted devices

Can cause contrast induced nephropathy in those with impaired renal function

Gadolinium based contrast medium may lead to nephrogenic systemic fibrosis in those with moderate to end stage renal failure

Images difficult to interpret in heavily calcified arteries

No calcification artefact

Contraindicated in patients with contrast allergy

INVESTIGATIONS

Investigations should include tests which define the structural abnormalities like Duplex Doppler ultrasonography, computed tomographic angiography (CTA), magnetic resonance angiography (MRA) and conventional angiography and those that define functional status of the kidneys like captopril renography, renal vein renin levels and 99mTc-DTPA renography. Renal arteriography which is an invasive procedure is the gold standard for the diagnosis of renal artery stenosis. Commonly employed non invasive procedures include Doppler ultrasonography, CTA and MRA (Table 1). Other procedures are not usually used as a screening test due to their low sensitivity and specificity. Duplex Doppler ultrasonography is safe, inexpensive and easily available and forms the first line of investigation in most patients with renal artery stenosis. It aids in direct visualization of the main renal arteries (B-mode imaging) which is combined with measurement (Doppler) of a variety of hemodynamic factors. Stenotic lesions can be detected by comparing the systolic flow velocity in the renal artery to that in the aorta, since the velocity of flow increases as an artery narrows; end-diastolic velocity also may be increased distal to a stenotic lesion. But the result is operator dependent with an accuracy of 60-90% and the sensitivity and specificity of ultrasonography in detecting hemodynamically significant ARAS was 85% and 92% respectively. Renal arteriography: ARAS typically involves the proximal 1/3 of the renal artery at or near the renal artery ostium. Lesions may be either concentric or eccentric within the renal artery. Regarding FMD, medial hyperplasia is the commonest form and is characterised

by ‘string of beads’ appearance in angiography (Figures 1, 2 & 3). It involves the middle to distal portion of the artery in contrast to ARAS. Renal arteriography helps to determine the translesional pressure gradient across areas of stenosis thus estimating the hemodynamic significance before performing invasive therapeutic procedures like percutaneous transluminal renal angioplasty (PTRA) or stenting. It was found that those with a translesional gradient >20 mmHg were associated with a significant improvement in hypertension following therapeutic procedure (Figures 4, 5, 6, 7 & 8).

MANAGEMENT

Optimal antihypertensive therapy and reducing CV risk is the initial step in the management of RVH. Blockade of renin-angiotensin system with ACE Is and ARBs is the most essential part in the treatment of RVH. If blood pressure control and renal function can be maintained with optimal medical therapy, little more is gained by elaborate diagnostic procedures. On the contrary, failure of medical therapy points to a potential benefit of improvement with interventional procedures. Indications for invasive treatment of ARAS are controversial. Intervention should be done based on patient’s clinical symptoms and for hemodynamically significant stenosis defined as 1) Greater than 50% diameter stenosis or greater than 75% reduction in cross sectional area and 2) Systolic pressure gradient greater than 10% of systolic pressure or a pressure gradient of 20 mmHg. While stenting is superior to percutaneous renal artery transluminal angioplasty (PRTA) in ARAS, PRTA is the preferred treatment in FMD.

MANAGEMENT OF RENOVASCULAR HYPERTENSION

Antihypertensive Drug Therapy

Blockade of the Renin-Angiotensin System using ACEIs, ARBs Direct Renin Inhibitors (Aliskiren) Calcium Channel Blocking Agents Diuretics Mineralocorticoid Receptor Blockade Additional Classes: Beta-Blockade, alpha-receptor blockade, sympatholytic agents, vasodilators 2.

Cardiovascular Risk Reduction Removal of tobacco use Treatment of dyslipidemia Treatment of obesity: obstructive sleep apnea Management of glucose intolerance / diabetes

Renal Revascularization: Selected Cases Endovascular revascularization

•

PTRA: primarily fibromuscular dysplasia

•

PTRA with stenting: Atherosclerotic disease

629

Fig. 4: Tight stenosis at ostium of right renal artery

Fig. 5: Wire and distal protection device (to prevent embolization to distal end arteries)

Fig. 6: Balloon dilatation of RAS

Fig. 7: Placing unexpanded stent at ostium

Fig. 8: After stent deployment

Figures 4 – 8: Percutaneous transluminal renal angioplasty (PTRA) with stenting in RAS (Courtesy: Dr. G. Rajesh, Department of Cardiology, Government Medical College, Kozhikode) Surgical: Renal artery bypass / endarterectomy (now usually reserved for complex aorto-renal disease, aneurysmal disease, failed endovascular stent procedures)

CONCLUSIONS

Renovascular hypertension is the most important cause of secondary hypertension. It is generally due to renal artery stenosis caused by atherosclerotic arterial disease or fibro muscular dysplasia. It could be unilateral or bilateral. The evaluation should be restricted to high risk patients. Duplex Doppler ultrasound (US) is useful as a noninvasive screening test as it is a relatively inexpensive, that does not require contrast, and can be used in patients with any level of renal function, though it is operator dependent. The newer non-invasive imaging modalities

like CT or MR angiogram have made the evaluation easy though more expensive. Medical treatment remains the standard of care, which includes optimization of antihypertensive therapy along with CV risk reduction including lipid lowering and anti platelet therapy. Selected patients may need angioplasty, stenting or both. Surgical procedures are reserved for patients who have complex anatomical lesions of renal artery, for patients who require nephrectomy and those requiring surgery of aorta. As early recognition and treatment may result in reversal of the disease and control of blood pressure, a high index of suspicion is needed.

KEY WORDS

Renovascular hypertension (RVH), Atherosclerotic renal artery stenosis (ARAS), Fibromuscular dysplasia (FMD),

CHAPTER 134

Fig. 1 Fig. 2 Fig. 3 Fibromuscular Dysplasia: A 37 year old lady presented with hypertension, POVD with bilateral renal bruit. MRA showed string of beads appearance in left renal artery (Figure 1 & 2), with suprarenal aneurysmal dilatation of aorta and string of beads appearance in the other major arterial branches of aorta (Figure 3). Arterial biopsy from left dorsalis pedis was consistent with FMD. (Courtesy: Dr. Danish E, Department of Medicine, Government Medical College, Kozhikode)

630

ACE inhibitors, Angiotensin Receptor Blockers (ARBs), Angioplasty, Stenting

hypertension: prospective intraindividual comparison of color Doppler US, CT angiography, GD-enhanced MR angiography, and digital substraction angiography. Ren Fail 2007; 29:295-302.

HYPERTENSION

REFERENCES

Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med 2001; 344:431–442.

Gottam N, Nanjundappa A, Dieter R. Renal artery stenosis: pathophysiology and treatment. Expert Rev Cardiovasc Ther 2009; 7:1413–1420

Dworkin LD, Cooper CJ. Clinical practice. Renal-artery stenosis. N Engl J Med 2009; 361:1972

Textor SC, Lerman L. Renovascular hypertension and ischemic nephropathy. Am J Hypertens 2010; 23:1159.

Napoli V, Pinto S, Bargellini I, et al. Duplex ultrasonographic study of the renal arteries before and after renal artery stenting. Eur Radiol 2002; 12:796-803

Rountas C, Vlychou M, Vassiou K, et al. Imaging modalities for renal artery stenosis in suspected renovascular

Mangiacapra F, Trana C, Sarno G, et al. Translesional pressure gradients to predict blood pressure response after renal artery stenting in patients with renovascular hypertension. Circ Cardiovasc Interv 2010; 3:537-542.

Aaron Smith, Ron C.Gaba, James T.Bui,MD and Jeet Minocha. Management of Renovascular Hypertension. Tech Vasc Interventional Rad. online 3 June 2016.

Kosmas IP, George H, Jenny MC et al. Atherosclerotic Renal Artery Stenosis: Association with emerging vascular risk factors. Nephron Clin Pract 2008; 108:c56-c66.

10. Amresh Krishna, Om Kumar, Mritunjay Kumar Singh. Renovascular hypertension: A review article. Clinical queries: Nephrology 2013; 2:38-43.

Resistant Hypertension

C H A P T E R

135

Kidiyur Jayakar Shetty, Manohar Kathige Nageshappa

INTRODUCTION

There have been considerable advances in the pharmacotherapy of hypertension, we now have a variety of antihypertensive drugs specifically targeting the different biochemical, hormonal and hemodynamic factors involved in the pressor mechanism. Despite this and the advances in our knowledge about the pathophysiology, we clinicians continue to face problems in attaining acceptable level of blood pressure control leading to serious target organ damage, followed by increased morbidity and mortality. Although the exact incidence of resistant hypertension is not known, with the population growing older and heavier it is only likely for it to go up. The importance of diagnosis of resistant hypertension also lies with the fact that we could sometimes unearth a reversible cause of hypertension. This article aims to update our present knowledge of what is called as resistant hypertension – its definition, aetiology, evaluation and management. Traditionally, resistant hypertension is defined as blood pressure that remains above goal in spite of the concurrent use of three antihypertensive of different classes, one of which should be a diuretic and all agents being used in optimal doses. By definition, the diagnosis also includes patients whose BP is controlled with the use of more than three medications. Uncontrolled hypertension is not synonymous with

Table 1: Drugs that contribute to treatment resistance • Nonnarcotic Analgesic – NSAID, COX 2 Inhibitors • Sympathomimetic agents – Decongestants, Cocaine • Stimulants – Methylphenidate, dexmethylphenidate, dextroamphetamine, amphetamine, methamphetamine, modafinil • Alcohol • Oral Corticosteroids – Especially cortisone and hydrocortisone which have the greatest mineralocorticoid effect • Oral Contraceptive • Cyclosporine • Erythropoietin • Herbal compounds – Ephedra or ma huang • Licorice – Ingredient in oral tobacco products, suppresses metabolism of cortisol. Most cases of true resistant hypertension are albeit due to secondary hypertension.

resistant hypertension. Before labeling as resistant hypertension based on the above criteria, the following provisions need to be applied and exclude uncontrolled hypertension due to •

Poor adherence,

•

Inadequate treatment regimen – the drug, its frequency and dosage,

•

Pseudo resistance.

Populations with resistant hypertension usually have multiple disease process and most have secondary hypertension. Presence of obesity, excessive salt intake, sleep apnea and renal diseases being particularly common factors. Strict implementation of therapeutic life style changes, reemphasizing compliance; recognition and treating the secondary causes of hypertension and judicious use of combination anti-hypertensives are imperative for successful treatment outcomes.

PREVALENCE

In our setting considering the prevalence of diabetes, increased salt intake, recurrent urinary tract infection, and abuse of NSAIDs – the renal parenchymal disease appears to play a major role. Additionally, in view of the increased prevalence of tropical aortoarteritis and the atherosclerosis – renal artery stenosis contributes to renovascular hypertension. A high index of suspicion and detailed clinical examination followed by specific hormonal test and imaging will help in identifying the endocrine causes of which primary aldosteronism is often missed and occasionally pheochromocytoma. The prevalence and the genetic assessment of patient with resistant hypertension are very limited.

PSEUDORESISTANCE

It is important to adhere to basic principles of medicine and advocate proper technique in measuring the blood pressure, consider white-coat effect and reemphasize and confirm adherence to treatment before labeling such of the patients as resistant hypertension. The three main parameters contributing to resistant hypertension are: •

Life style

•

Drugs (Table 1)

•

Secondary Hypertension (Table 2)

Life style factors like Obesity, excess ingestion of dietary salt, smoking and heavy alcohol indulgences are all associated with increased risk of resistant hypertension.

HYPERTENSION

632

Table 2: Clinical & Laboratory Clues of Secondary Hypertension Findings

Disorder Suspected

Further Diagnostic Studies

Snoring, daytime somnolence, obesity, unexplained fatigue

Obstructive sleep apnea

Polysomnography

Hypokalemia, hypernatremia

Aldosteronism

Ratio of plasma aldosterone to plasma renin activity, CT scan of adrenal glands

Edema, elevated blood urea nitrogen and creatinine levels, proteinuria

Renal parenchymal disease

Creatinine clearance, renal ultrasonography, Renal biopsy

Abdominal bruit

Renovascular disease

Magnetic resonance angiography, renal arteriography

Young adult, Headache, claudication in legs, Decreased or delayed femoral pulses, Murmurs in the precordium

Coarctation of aorta

CXR – Inverted Figure of 3 notching of ribs, Doppler or CT imaging of aorta

Weight gain, fatigue, weakness, hirsutism, amenorrhea, moon facies, dorsal hump, purple striae, truncal obesity, hypokalemia

Cushing’s syndrome

Iatrogenic Cushings commoner.

Paroxysmal hypertension, headaches, diaphoresis, palpitations, tachycardia

Pheochromocytoma

Dexamethasone-suppression test Urinary catecholamine metabolites (vanillylmandelic acid, metanephrines, normetanephrines) Plasma free metanephrines

Fatigue, weight gain, hair loss, diastolic hypertension, muscle weakness

Hypothyroidism

Thyroid Function Test

Heat intolerance, weight loss, palpitations, systolic hypertension, exophthalmos tremor, tachycardia

Hyperthyroidism

Thyroid Function Test

Kidney stones, osteoporosis, depression, lethargy, muscle weakness – the classical description of Bone, moan, stone, groan!

Hyperparathyroidism

Serum calcium, parathyroid hormone levels

Headaches, fatigue, visual problems, enlargement of hands, feet, tongue

Acromegaly

Growth hormone level

Table 3: Problems in measurement of BP When the patient has

BP appears higher by

Cuff over clothing & Wrong Cuff Size

10 – 40 mm of Hg

Full Urinary bladder

10 – 15 mm of Hg

Unsupported arm

10 mm of Hg

Unsupported back or feet

5 – 10 mm of Hg

Crossed legs

2 – 8 mm of Hg

EVALUATION

A detailed medical history is important and should include the documentation of duration, severity and progression of hypertension, with any target organ involvement. Detailed drug history including the response to prior medication including their adverse effects, if any, should be noted. Specific vital information could include the level of adherence and the intake of over the counter and other alternative forms of therapy, this piece of information is a bit tricky and to be elicited in a non judgmental fashion or with out being very critical, seeking the assistance of family members may clear some ambiguities but should be done in the presence of the patient. A history of snoring, and daytime somnolence increases

the possibility of sleep apnea, history of peripheral vascular disease or cardiovascular disease increases the possibility of renal artery stenosis; a labile hypertension associated with palpitation and diaphoresis suggests Pheochromocytoma. It will be seen from the above list, that a good proportion account for curable causes – Secondary hypertension, in contrast to the Primary or Essential hypertension, which can only be controlled but not curable

EXAMINATION

Strict adherence to basic technique of blood pressure measurement is essential. Common problems accounting for measurements are listed in Table 3.

inaccurate

The emerging strategies to asses hypertension includes Self-measured home BP and 24-hour – ambulatory blood pressure. These are useful adjuncts to office BP measurements especially in detecting •

‘White Coat’ hypertension and White coat worse’ hypertension

•

Assessing the nocturnal blood pressure which may be a more important predictor of cardiovascular events

Table 4: Summary • > 140/90; > 3 Drugs in optimal dose; One diuretic • BP Optimal Control but using > 3 drugs

Exclude Pseduoresistance

• Impoper Technique • Poor Compliance • White Coat Phenomenon

Reversible Factors

• Obesity, Physical Inactivity • Excess Salt consumption • Alcohol excess • Drugs - NSAIDs, OCPs, Sympathomimetics, Stimulants

Rule out Secondary HTN

Pharmacotherapy

•

• Obstructive Sleep Apnea .Primary Aldosteronism • CKD Renal Artery Stenosis • Phaeochromocytoma Cushings Syndrome • Coarctation of Aorta • Optimise diuretic therapy incuding the use of aldosterone antagonitst • Use agent with different yet complimentary mechanism of action • Specilist referral in compelling indications

Uncover ‘masked hypertension’

MANAGEMENT

Aim

Prompt and effective treatment with strict life style measures, judicious use of medications and or surgical interventions to quickly attain near normal blood pressure to prevent further target organ damage

Steps 1.

Advocating strict healthy life style measures like regular exercises, restriction of salt, weight reduction, moderation of alcohol intake and complete abstinence from smoking

Discontinuance of drugs likely to increase blood pressure

Screen for secondary causes of hypertension and institute specific treatment and possible cure

Judicious use of pharmacotherapy advocating effective combinations in optimal doses

In refractory cases renal sympathetic denervation and baroreceptor activation therapy have been tried but have not shown to be beneficial

Medications

If secondary hypertension is ruled out, we suggest the use of, the triple combination of an angiotensin-converting

If beta blockers are used, a vasodilating beta blocker, such as labetalol, carvedilol or nebivolol, may provide more antihypertensive benefit with fewer side effects compared to traditional beta blockers. Direct vasodilators hydralazine or minoxidil are reserved for patients who remain hypertensive despite the above approach. Prognosis depends on the •

Degree and duration of resistant hypertension

•

Extent of target organ damage

•

Curable secondary causes

CONCLUSION

When a clinician encounters a patient with uncontrolled hypertension it is advisable to exclude the common cause like inadequate drug regimen, noncompliance, and unhealthy life style before arriving at a diagnosis of resistant hypertension. This diagnosis necessitates a detailed historical, clinical, and investigative analysis to search for the underlying cause and address the same, which will be rewarding.

REFERENCES 1.

What is New in Indian Guidelines on Hypertension – III, © Supplement to JAPI 2013; 61.

Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. The Lancet 2010; 376:1903-1909

European Society of Hypertension- European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertension 2003; 21:1011-1053.

Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF, et. al Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hyperten 2004; 18:139-185. 10.

Bauchner H, Fontanarosa PB, Golub RM: Updated guidelines formanagement of high BP: Recommednations, review and responsibility. JAMA 2014; 311:477.

Resistant hypertension: Diagnosis, Evaluation and Treatemnt: A Scientific Statement From the American Heart Association Professional Edcuation Committee of the Council for High Blood Pressure Research. David A. Callhoun, Daniel Jones, Stephen Textor, David C. Goff, Timothy P. et al, Circulation 2008; 117:e510-e526.

633

CHAPTER 135

Confirm RHTN

enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), a long-acting dihydropyridine calcium channel blocker (usually amlodipine), and a long-acting thiazide diuretic is often effective and generally well tolerated. Further, addition of spironolactone can augment the effect. The more specific aldosterone blocker, eplerenone, does not induce the side effects seen with spironolactone. Among patients with an estimated glomerular filtration rate of less than 30 thiazide diuretics are less effective, and loop diuretics, such as furosemide and torsemide may be necessary for effective volume control. Torsemide with its more predictable absorption and longer duration of action may be preferred.

C H A P T E R

136

Vascular Remodeling in Hypertension

INTRODUCTION

The pathophysiology of systemic hypertension is complex and multifactorial. The main factors modulating the systemic arterial pressure are intravascular volume, sympathetic nervous system, renin-angiotensinaldosterone system and the functional and structural changes in vasculature. The diameter and the compliance of resistance vessels, that includes small arteries (100400 µm) and arterioles, predominantly determine the peripheral resistance and thus the arterial pressure. Two kinds of structural changes occur in microcirculation of hypertensive patients. One is rarefaction, defined as abnormally decreased spatial density of small arteries and arterioles. The other, termed vascular remodeling includes the structural modifications of resistance vessels causing reduction of their lumen size. In this article, we briefly review the basic concepts of remodeling, its pathophysiology and the effect of antihypertensive modalities on remodeling.

NOMENCLATURE

According to the terminology proposed by Mulvany et al, vascular remodeling includes any change in diameter in a fully relaxed vessel, as measured under standard intravascular pressure. The process of change in lumen without change in amount (wall cross sectional area) or characteristics of materials is called eutrophic remodeling. The process may involve increase (hypertrophic remodeling) or decrease (hypotrophic remodeling) in wall cross sectional area. Increase or decrease in lumen diameter is classified as external and internal remodeling respectively. For example, the increase in wall thickness, decrease in lumen diameter without any change in wall cross sectional area in resistance vessels of essential hypertension is termed as inner eutropic remodeling.

MECHANISMS OF REMODELING

Based on Laplace law, wall stress (force acting on unit cross sectional area) is calculated as P x r/h, where P is transmural arterial pressure, r is radius of lumen and h is wall thickness. In hypertension, the vascular smooth muscle cells of large elastic arteries are exposed to stretch from the elevated arterial pressure. To normalize the increased wall stress, large arteries like aorta undergo hypertrophy (outward hypertrophic remodeling) while maintaining the lumen size. On exposure to acute raise in arterial pressure, smaller arteries and arterioles undergo constriction through myogenic reflex, thus decreasing the lumen size and increasing the wall thickness so as to decrease R/h ratio and normalize the increased wall

Sanjay Jain, Srikanth Gopi

stress. Myogenic reflex is an intrinsic reflex that occur independent of neural innervation or endothelial function. Large arteries cannot autoregulate with constriction in case of raised arterial pressure and hence undergo hypertrophy. This reflex constriction in resistance vessels, when persistent, becomes permanent with structural changes in the form of inward eutropic remodeling. In inner eutropic remodeling, there is reduction in vascular lumen due to closer rearrangement of vascular smooth muscle cells in the extracellular matrix without any change in amount of wall material. This increases the media to lumen ratio (r/h ratio decreases) thus trying to normalize the wall stress. Intermediate sized arteries show features of both hypertrophy and reduction in lumen size in response to elevated pressures. The myogenic reflex, in resistance vessels, protects capillary bed from exposure to high pressures. Later inward eutropic remodeling does the same. When the reflex is impaired as in diabetes mellitus or in case the reflex is unable to compensate for accelerated hypertension, small arteries undergo inward hypertrophic remodeling. The same is observed in hypertension due to renovascular causes or primary aldosteronism. The cellular pathways involved in vascular remodeling are not completely understood. Vascular smooth muscle cells are attached to their extracellular protein components through the transmembrane proteins called integrins. Along with these integrins, the cellular response also depends on the components of the extracellular matrix. When extracellular matrix is exposed to increased wall stress, the stretch is transmitted through the integrins to the intracellular protein kinases like Src-family kinases, Focal adhesion kinases (FAK) as well as cytoskeletal proteins like talin, paxillin and actin. This initiates the intracellular pathways and leads to gene expression for vascular remodeling. Initial intracellular event is likely the phosphorylation of Src followed by activation of FAK proteins. This pathway downstream leads to activation of MAPK/ERK (mitogen-activated protein kinases / extracellular signal-regulated kinases) pathway, which leads to expression of proto-oncogenes like c-fos involved in remodeling. Platelet-derived growth factor and epidermal growth factor receptors augment this signaling pathway.

MEDIATORS OF REMODELING

Renin-Angiotensin-Aldosterone System (RAAS): The RAAS contributes to hypertension mainly via the vasoconstriction by angiotensin II (A II) and sodium

retention by aldosterone. Angiotensin II participates in the inflammation and remodeling of the small arteries, atherosclerosis of large arteries and contributes to vascular inflammation, fibrosis and other structural changes in target end organs. At cellular level, angiotensin II binds to angiotensin II type 1 receptors (AT1R) which leads to activation of tyrosine kinase receptors like epidermal growth factor receptor and platelet derived growth factor receptor and intracellular tyrosine kinases like Src family. It also activates NAD (P)H oxidase leading to production of reactive oxygen species (ROS), which in turn stimulate the MAP/ERK kinase pathway, growth promoting transcription factors like cytoplasmic nuclear factor κB (NFκB) and matrix metalloproteinases. Angiotensin II may down-regulate peroxisome proliferator-activated receptors (PPARs), which has anti-inflammatory effects. Angiotensin II also promotes expression of proinflammatory molecules like vascular cell adhesion molecule -1, intracellular adhesion molecule -1 etc. Aldosterone or mineralocorticoid receptor activation also plays a role in activation of inflammation and oxidative stress causing impairment of endothelial function and vascular remodeling. This occurs through complex molecular interactions of aldosterone on cellular pathways of angiotensin II and also by stimulation of mineralocorticoid receptor by angiotensin II. RAAS blockade can have positive impact on vascular remodeling. Apart from RAAS, increased endothelin 1 production also plays a role in vascular remodeling through its direct and indirect hypertrophic effects.

associated with obesity or impaired myogenic reflex in diabetes. Life style modifications to control these can have a favorable impact on remodeling.

Inflammation and Endothelial Dysfunction: Chronic persistent inflammation contributes to the pathogenesis of hypertension. Angiotensin II may be the major mediator of vascular inflammation by activating nuclear factor κB (NFκB), which up-regulates the cytokines, chemokines and the leucocyte adhesion molecules. It also causes oxidative stress and increased endothelin 1 synthesis leading to vasoconstriction. These all lead to endothelial dysfunction and vascular remodeling. Life style modifications and drugs blocking RAAS (independent of their vasodilation property) may reduce the vascular inflammation.

Anti-hypertensive agents ACE inhibitors, Angiotensin receptor blockers (ARBs), aldosterone antagonists and calcium channel blockers (CCBs) tend to decrease the arterial stiffness in both the large and small arteries. These effects are likely to be mediated through the down regulation of Transforming growth factor – beta (TGF-β) expression, thus displaying anti-fibrotic effect. ACE inhibitors, ARBs and CCBs can reverse the remodeling in small arteries and the effect may be primarily due to their vasodilatory action. Atenolol and likely other beta blockers do not reverse the remodeling in spite of their BP lowering effect, probably due to lack of vasodilatory action. Peroxisome proliferator-activated receptor γ (PPAR γ) agonists like rosiglitazone can prevent and reverse the remodeling in hypertension. Exercise training apart from its anti-inflammatory effects, can help to reduce the arterial wall thickness. Positive life style modifications to control the obesity and the metabolic syndrome improve the vascular remodeling associated with these conditions.

Obesity, Diabetes Mellitus and Metabolic Syndrome: These conditions can exhibit hypertrophic remodeling in small arteries even in normotensive. This may be attributed to the increased oxidative stress and inflammation

REMODELING AND CLINICAL IMPLICATIONS

Remodeling in large arteries increases the arterial stiffness and wave reflection that leads to an elevated pulse pressure and systolic blood pressure. Studies have shown that an increased arterial stiffness as measured by aortic augmentation index or pulse wave velocity is an adverse prognostic factor of cardiovascular disease. In hypertension, vascular remodeling may be the earliest evidence of target organ damage. Increased media to lumen ratio and increased hypertrophy are associated with elevated risk of cardiovascular morbidity. In retina, a decrease in lumen diameter is associated with an increased risk of cerebrovascular accident. The vascular remodeling in small resistance arteries and arterioles may have significant role and prognostic significance in ischemic heart disease, cerebrovascular disease and chronic kidney disease. Lowering of arterial BP alone may not be sufficient in improving outcomes in hypertension unless other factors involved in impaired vascular function and remodeling are corrected. Conditions like diabetes mellitus with impaired myogenic reflex or accelerated hypertension or renovascular hypertension, hypertrophic inward remodeling is seen instead of eutrophic remodeling and these conditions are at higher risk target end organ damage than seen in essential hypertension and needs early and aggressive intervention.

CONCLUSIONS

The pathophysiological effects and the prognostic importance of vascular remodeling in hypertension are under active research and the exact role of remodeling either as cause or consequence of hypertension needs to be clearly evaluated with further studies. A better understanding of the molecules and the cellular pathways involved in hypertension and remodeling may help in development of more targeted treatment options and better clinical outcomes.

CHAPTER 136

Immunity: Both the innate and adaptive immunity contribute to the low grade inflammation seen in hypertension. Effector T cells including Th1 lymphocytes, Th2 lymphocytes and Th 17 lymphocytes as well as T suppressor lymphocytes including regulatory T cells are involved in vascular remodeling, mediated through the action of angiotensin II and aldosterone. Th1 cells predominantly promote remodeling while T regulatory cells may exert protective effects through their antiinflammatory action of IL-10. The initiating stimulus for immune activation is not clear but neo-antigens produced by elevated arterial pressure or other stimuli are proposed as likely cause.

635

HYPERTENSION

636

REFERENCES 1.

Feihl F, Liaudet L, Waeber B, Levy BI. Hypertension: A Disease of the Microcirculation? Hypertension 2006; 48:1012–7.

Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, et al. Vascular remodeling. Hypertens Dallas Tex 1979 1996; 28:505–6.

Martinez-Lemus LA, Crow T, Davis MJ, Meininger GA. alphavbeta3- and alpha5beta1-integrin blockade inhibits myogenic constriction of skeletal muscle resistance arterioles. Am J Physiol Heart Circ Physiol 2005;289:H322329.

Prewitt RL, Rice DC, Dobrian AD. Adaptation of resistance arteries to increases in pressure. Microcirc N Y N 1994 2002; 9:295–304.

Sonoyama K, Greenstein A, Price A, Khavandi K, Heagerty T. Review: Vascular remodeling: implications for small artery function and target organ damage. Ther Adv Cardiovasc Dis 2007; 1:129–37.

Rice DC, Dobrian AD, Schriver SD, Prewitt RL. Src autophosphorylation is an early event in pressuremediated signaling pathways in isolated resistance arteries. Hypertens Dallas Tex 1979 2002; 39:502–7.

Duprez DA. Role of the renin-angiotensin-aldosterone system in vascular remodeling and inflammation: a clinical review. J Hypertens 2006; 24:983–91. Schiffrin EL, Touyz RM. From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension. Am J Physiol Heart Circ Physiol 2004; 287:H435-446.

12. Schiffrin EL. Immune modulation of resistance artery remodelling. Basic Clin Pharmacol Toxicol 2012; 110:70–2. 13. Grassi G, Seravalle G, Scopelliti F, Dell’Oro R, Fattori L, Quarti-Trevano F, et al. Structural and Functional Alterations of Subcutaneous Small Resistance Arteries in Severe Human Obesity. Obesity 2010; 18:92–8. 14. Stepp DW. Low-flow vascular remodeling in the metabolic syndrome X. AJP Heart Circ Physiol 2003; 286:964H–970. 15. Ecobici M, Voiculescu M. Importance of arterial stiffness in predicting cardiovascular events. Romanian J Intern Med Rev Roum Med Interne 2016 Aug 4; 16. Asmar RG, London GM, O’Rourke ME, Mallion JM, Romero R, Rahn KH, et al. Amelioration of arterial properties with a perindopril-indapamide very-low-dose combination. J Hypertens Suppl Off J Int Soc Hypertens 2001; 19:S15-20. 17. Park JB, Schiffrin EL. Small artery remodeling is the most prevalent (earliest?) form of target organ damage in mild essential hypertension. J Hypertens 2001;19:921–30. 18. Rizzoni D, Porteri E, Boari GEM, De Ciuceis C, Sleiman I, Muiesan ML, et al. Prognostic significance of small-artery structure in hypertension. Circulation 2003; 108:2230–5. 19. Izzard AS, Rizzoni D, Agabiti-Rosei E, Heagerty AM. Small artery structure and hypertension: adaptive changes and target organ damage. J Hypertens 2005; 23:247–50. 20. Wong TY, Klein R, Couper DJ, Cooper LS, Shahar E, Hubbard LD, et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet Lond Engl 2001; 358:1134–40.

Brown NJ. Aldosterone and Vascular Inflammation. Hypertension 2008; 51:161–7.

21. Cipolla MJ, Bishop N, Vinke RS, Godfrey JA. PPAR Activation Prevents Hypertensive Remodeling of Cerebral Arteries and Improves Vascular Function in Female Rats. Stroke 2010; 41:1266–70.

10. Schiffrin EL. Vascular remodeling in hypertension: mechanisms and treatment. Hypertens Dallas Tex 1979 2012; 59:367–74.

22. Thijssen DHJ, Cable NT, Green DJ. Impact of exercise training on arterial wall thickness in humans. Clin Sci 2012; 122:311–22.

11. Ghanem FA, Movahed A. Inflammation in high blood pressure: a clinician perspective. J Am Soc Hypertens 2007; 1:113–9.

C H A P T E R

137

Secondary Hypertension: An Age-Based Approach to Diagnosis

INTRODUCTION

Worldwide statistics show that one in three adults have hypertension. Most of these patients have no clear etiology and are classified as having essential hypertension. However, 5 to 10 percent have secondary hypertension, in which an underlying, potentially correctable etiology can be identified.

GENERAL APPROACH TO THE PATIENT

The physician should confirm that the patient’s blood pressure has been accurately measured using correct positioning with an appropriately sized cuff. Ambulatory blood pressure monitoring can be useful to rule out white coat hypertension, if suspected. It is also important to review the patient’s diet and medication use for other potential causes of elevated blood pressure. The clinical features of secondary hypertension are enumerated in Table 1. Many drugs affect blood pressure (Table 2) and a trial period off of a potentially offending medication may be all that is needed to reduce blood pressure. If these potential contributors to hypertension have been excluded and concern for secondary hypertension remains, the physician can investigate for potential physiologic causes.

MOST COMMON CAUSES OF SECONDARY HYPERTENSION BY AGE (TABLE 3)

Young adults (19 to 39 years of age) Renal artery stenosis

In young adults, particularly women, fibromuscular dysplasia is one of the most common causes of secondary hypertension. Patients with renal artery stenosis may have an audible high-pitched holo-systolic renal artery bruit. Although angiography is the diagnostic standard for detecting renal artery stenosis, it is invasive and should not be used as an initial diagnostic test. MRI with gadolinium contrast media and computed tomography (CT) angiography are equally accurate. If MRI and CT angiography are contraindicated, renal Doppler can be used.

Thyroid dysfunction

Hypothyroidism can cause an elevation in diastolic blood pressure, whereas hyperthyroidism can cause an isolated elevation of systolic blood pressure, leading to a widened pulse pressure. Although hypothyroidism is one of the more common secondary causes of hypertension in young adults, there is actually an increased incidence of hypothyroidism with age, peaking in a patient’s 60s. In

Amit A Saraf, Anoosha Bhandarkar

contrast, hyperthyroidism is significantly associated with elevated blood pressures in 20- to 50-year-olds. Thyroidstimulating hormone is a sensitive marker used for initial diagnosis of either condition.

MIDDLE-AGED ADULTS (40 TO 64 YEARS OF AGE)

Aldosteronism

Non–medication-induced hypokalemia should lead the physician to suspect aldosteronism, although this abnormality occurs in only 30 percent of patients. Aldosteronism affects 10 to 20 percent of patients with resistant hypertension, making it the most common cause of secondary hypertension in this subgroup. The best initial test for aldosteronism is measurement of the aldosterone/renin ratio. Ideally, aldosterone and renin levels should be measured in the morning at least two hours after waking and in the upright position. If the aldosterone/renin ratio is above 20 (when plasma aldosterone is reported in ng/dL and plasma renin activity in ng/mL/hour), and is accompanied by an aldosterone level above 15 ng/dL (416.10 pmol/L), the patient should undergo salt suppression tests.

Obstructive sleep apnea

Obstructive sleep apnea is a notable cause of secondary hypertension, particularly in 40- to 59-year-olds. The standard diagnostic test is polysomnography, but clinical assessment tools (e.g., Epworth Sleepiness Scale, Sleep Apnea Clinical Score) with night-time pulse oximetry may be sufficient for the diagnosis of moderate to severe obstructive sleep apnea. In patients with obstructive sleep apnea, the normal variation in blood pressure over 24 hours is impaired and it may be beneficial to perform ambulatory blood pressure monitoring on these patients to fully evaluate their circadian pressures.

Pheochromocytoma

Pheochromocytomas are rare tumors responsible for approximately 0.5 percent of cases of secondary hypertension. Patients typically present between 30 and 60 years of age. Diagnosis is important because of the cardiovascular sequelae and because the hypertension is largely reversible with surgery. Testing can be done by measuring metanephrines in a 24-hour urine sample, but measurement of plasma free metanephrines is easier for the patient and has a negative likelihood ratio close to zero, making it a good test to rule out the disorder.

Cushing syndrome

Most presentations of cushing syndrome (hypercortisolism) are iatrogenic from prescribed corticosteroids. Options for

638

Table 1: Clinical features of secondary hypertension Signs/symptoms

Possible secondary hypertension cause

Diagnostic test options

• Arm to leg systolic blood pressure difference > 20 mm Hg

Coarctation of the aorta

• Magnetic resonance imaging (adults)

• Delayed or absent femoral pulses

HYPERTENSION

• Murmur • Increase in serum creatinine concentration Renal artery stenosis (≥ 0.5 to 1 mg per dL after starting angiotensin-converting enzyme inhibitor or angiotensin receptor blocker • Renal bruit • Bradycardia/tachycardia

• Computed tomography angiography • Doppler ultrasonography of renal arteries • Magnetic resonance imaging with gadolinium contrast media

Thyroid disorders

• Thyroid-stimulating hormone

• Hypokalemia

Aldosteronism

• Renin and aldosterone levels to calculate aldosterone/renin ratio

• Apneic events during sleep

Obstructive sleep apnea

• Polysomnography (sleep study)

Pheochromocytoma

• 24-hour urinary fractionated metanephrines

• Cold/heat intolerance • Constipation/diarrhea • Irregular, heavy or absent menstrual cycle

• Daytime sleepiness • Snoring • Flushing • Headaches

• Sleep Apnea Clinical Score with nighttime pulse oximetry

• Plasma free metanephrines

• Labile blood pressures • Orthostatic hypotension • Palpitations • Sweating • Syncope • Buffalo hump

Cushing syndrome

• 24-hour urinary cortisol

• Central obesity

• Late-night salivary cortisol

• Moon facies

• Low-dose dexamethasone suppression

• Striae initial testing include 24-hour urinary free cortisol, lowdose dexamethasone suppression or late-night salivary cortisol tests.

Table 2: Select drugs that may elevate BP Drug class

Common examples

Estrogen

Oral contraceptives

Herbal

Ephedra, ginseng, ma huang

It should be suspected in those who develop hypertension after 50 years of age, have known atherosclerosis elsewhere, have unexplained renal insufficiency or have a rapid deterioration in kidney function when started on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

Illicit drugs

Amphetamines, cocaine

Nonsteroidal anti-inflammatory

Cyclooxygenase-2 inhibitors, ibuprofen, naproxen

Psychiatric medicines

Buspirone, carbamazepine, clozapine, fluoxetine, lithium, tricyclic antidepressants

Renal failure

Steroids

Methylprednisolone, prednisone

Sympathomimetic drugs

Decongestants, diet pills

OLDER ADULTS (65 YEARS AND OLDER)

Renal artery stenosis caused by atherosclerosis

Hypertension can be a major cause of renal parenchymal damage, particularly in older adults, which in turn leads to worsening hypertension. Alternatively, renal damage from another process, such as diabetes mellitus, can

result in hypertension. Evaluation for possible chronic renal failure should include calculating the estimated

Adolescents. Revised May 2005. NIH Publication No. 055267. http://www.nhlbi.nih.gov/health/prof/heart/hbp/ hbp_ped.pdf. Accessed July 16, 2014.

Table 3: Most common causes of secondary hypertension by age Age groups Percentage of Most common hypertension etiologies with an underlying cause 10 to 15

Young adults (19 to 39 years)

Renal parenchymal disease

Elliott WJ. Renovascular hypertension: an update. J Clin Hypertens (Greenwich) 2012; 10:522-533.

Zhang HL, Sos TA, Winchester PA, Gao J, Prince MR. Renal artery stenosis: imaging options, pitfalls, and concerns. Prog Cardiovasc Dis 2010; 52:209-219.

Rountas C, Vlychou M, Vassiou K, et al. Imaging modalities for renal artery stenosis in suspected renovascular hypertension: prospective intraindividual comparison of color Doppler US, CT angiography, GD-enhanced MR angiography, and digital substraction angiography. Ren Fail 2010; 29:295-302.

Elamin MB, Murad MH, Mullan R, et al. Accuracy of diagnostic tests for Cushing’s syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab 2011; 93:1553-1562.

Klein I, Danzi S. Thyroid disease and the heart [published correction appears in Circulation. 2011;117(3):e18]. Circulation 2007; 116:1725-1735

Myint KS, Watts M, Appleton DS, et al. Primary hyperaldosteronism due to adrenal microadenoma: a curable cause of refractory hypertension. J Renin Angiotensin Aldosterone Syst 2012; 9:103-106.

Viera AJ, Hinderliter AL. Evaluation and management of the patient with difficult-to-control or resistant hypertension. Am Fam Physician 2009; 79:863-869.

Funder JW, Carey RM, Fardella C, et al.; Endocrine Society. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2013; 93:32663281.

Coarctation of the aorta Thyroid dysfunction Fibromuscular dysplasia Renal parenchymal disease

Middleaged adults (40 to 64 years)

8 to 12

Older adults (65 years and older)

Aldosteronism Thyroid dysfunction Obstructive sleep apnea Cushing syndrome Pheochromocytoma Atherosclerotic renal artery stenosis Renal failure Hypothyroidism

glomerular filtration rate and obtaining a urinalysis to assess for albuminuria.

REFERENCES

U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and

10. Grossman E, Messerli FH. Secondary hypertension: interfering substances. J Clin Hypertens (Greenwich) 2009; 10:556-566.

CHAPTER 137

Adolescents (12 to 18 years)

639

C H A P T E R

138

Difficult to Treat Hypertension

INTRODUCTION AND EPIDEMIOLOGY

Treating high blood pressure is a common challenge faced in primary care practice. Hypertension is a significant risk factor for coronary artery disease, stroke, heart failure, and renal failure. About 33% urban Indian adults – or approximately 60 million people and 25% rural Indian adults – or approximately 90 million people are hypertensive. Only 38% percent of urban Indians are being treated for their HTN, whereas only 25% of rural Indians suffering from HTN are under treatment. Only one fifth of urban Indians and one-tenth of rural Indians suffering from hypertension have their BP under control. Even in the United States, less than 25 percent of patients with hypertension have their blood pressure under control. The major causes of uncontrolled hypertension are inadequate therapy, inappropriate therapy, patient noncompliance, and lack of patient education. Other major causes of unresponsiveness to antihypertensive therapy include “white coat” hypertension, pseudo-hypertension, obesity, volume overload, excess alcohol intake and sleep apnea, and unfavorable interactions with prescription and other drugs. In many patients, these factors must be dealt with before blood pressure can be controlled.

DEFINITIONS AND MANAGEMENT GOALS

Hypertension is defined as persons 18 years of age and above with a systolic blood pressure of 140 mm Hg or more or a diastolic reading of 90 mm Hg or more, or those taking antihypertensive medications. Between 9095% of cases are essential hypertension in which there is no identifiable cause. A considerable number of patients fail to reach target blood pressure ranges despite lifestyle advice and standard medical therapy. The blood pressure goal in uncomplicated patients is 140/90 mm Hg which could be relaxed to 150/90 mm Hg in patients greater than 60 years of age. A more appropriate treatment target in patients with end-organ damage is 130/80 mm Hg. Resistant hypertension (HTN) is defined as a blood pressure (BP) value >140⁄90 mm Hg or >130 ⁄ 80 mm Hg in patients with diabetes or renal disease despite adherence to a medical regimen that includes at least 3 anti-hypertensive medications, one of which is a diuretic. Difficult-to-treat HTN is somewhat less well defined. It includes patients who do not meet the strict criteria of resistant HTN, but nonetheless their BP is not controlled despite aggressive intervention that may not necessarily include diuretic therapy.

RK Singal, Vivek Pal Singh, AK Vardani

DIAGNOSIS

Blood pressure should be measured after a patient has been seated quietly for five minutes in a non-stressful environment, with his or her arm supported at heart level and with the use of a properly calibrated and sized cuff. If the cuff is too narrow or too short, readings may be erroneously high (typically by 5 to 15 mm Hg in the case of systolic pressure). The patient should be asked whether he or she has smoked a cigarette within the previous 15 to 30 minutes, since smoking can cause an transient elevation in systolic blood pressure of 5 to 20 mm Hg. Avoidance of coffee is also recommended, although the increase in systolic blood pressure after one cup of caffeinated coffee is usually only 1 to 2 mm Hg. The diagnosis is based on the findings of at least two or three elevated blood-pressure measurements. However, if the blood pressure is above 160/100 mm Hg, additional readings are not required for diagnosis. Some patients with difficult-to-treat hypertension have a normal blood pressure at home. This phenomenon has been attributed to “white-coat” hypertension in the physician’s office. Repeated home measurements or 24hour ambulatory monitoring may differentiate this type of hypertension from truly resistant hypertension. White coat hypertension should be suspected in patients who remain resistant to therapy in the absence of target organ damage (retinopathy, nephropathy, left ventricular hypertrophy), who manifest symptoms of over medications (orthostatic symptoms, persistent fatigue) and/or who report home blood pressure values significantly lower than values measured in the office. Because white coat hypertension is so common, all patients with hypertension should be encouraged to obtain home blood pressure values. Pseudo-hypertension is a falsely elevated blood pressure obtained by indirect cuff measurement secondary to loss of arterial compliance (sclerotic arteries in the elderly), requiring increased cuff pressure in order to compress the underlying artery. Pseudo-hypertension should be suspected in elderly patients whose blood pressures remain elevated despite therapy, who have little or no evidence of target organ damage or who manifest symptoms of over medications. The condition is suggested if the radial pulse remains palpable despite occlusion of the brachial artery by the cuff (the Osler maneuver), although this sign is not specific. The presence of this condition can be confirmed by intra-arterial blood-pressure measurement. Evaluation of the patient with difficult-to-control

Table 1: Checklist for difficult-to-treat hypertension Exclude pseudo-resistance by 24-h ABPM or home (or self) BP measurements

Step 2

Recheck for secondary causes (in particular renoparenchymal disease, renal artery stenosis, hyperaldosteronism)

Step 3

Maximize lifestyle changes (e.g., salt restriction, weight reduction, physical activity)

Step 4

Evaluate patient’s adherence

Step 5

Optimize pharmacologic therapy

Step 6

Consider renal denervation

hypertension should include an assessment of adherence to the prescribed management plan, including recommended lifestyle modifications (Table 1). Explaining to the patient that combination of the dietary modifications and low sodium intake can be as effective as a single antihypertensive medication may help motivate patients. Patients often do not persist in taking their antihypertensive medications. A once-daily regimen can improve adherence to antihypertensive treatment, as well as prescription of fixed-dose combination pills, because most patients require more than one class of antihypertensive medication. Asking about and addressing side effects may also improve adherence by enhancing patient’s understanding of treatment. Above all, the physician and the patient must be convinced that treating to reach a goal blood pressure level of less than 140/90 mm Hg is worthwhile. A very common reason for failure to reach blood pressure goal is suboptimal therapy. Physicians may prescribe inadequate doses of antihypertensives or have resistance to add additional agents. Greater blood pressure reduction is achieved by combining lower doses of drugs from different antihypertensive classes rather than increasing the dose of a single medication. Importantly, one of the drug classes should be a diuretic. The lower dose combination strategy is also more likely to minimize side effects.

PATIENT FACTORS

Obesity

Obese patients do not respond as well as leaner patients to antihypertensive medication. Thus, weight reduction is a particularly important adjunct to drug therapy in obese patients with difficult to treat hypertension. Progressively higher doses of antihypertensive drugs are required to control blood pressure as the body mass index increases. However, even lean patients with hypertension, glucose intolerance and hyperinsulinemia may require higher drug dosages, suggesting that obesity, a sedentary lifestyle, glucose intolerance and insulinemia, all of which are related to insulin resistance, may cause refractory hypertension.

Excess alcohol intake raises blood pressure in both treated and untreated patients with hypertension, and blood pressure either returns to normal or becomes easier to control when alcohol intake ceases.Alcohol abuse is also a frequent cause of non-compliance with medications. Other potentially interfering agents that should be considered in patients with difficult-tocontrol hypertension include cocaine, amphetamines, anabolic steroids, oral contraceptives, cyclosporine, antidepressants, herbal supplements (e.g.; ginseng) and nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs including cyclooxygenase-2 inhibitors not only raise blood pressure, but can interfere with the mechanism of nearly every antihypertensive drug class.

Sleep Apnea

Sleep apnea affects 2 to 4 percent of middle-aged adults, most of whom are unaware they have this disorder. Associations between sleep apnea and both diurnal hypertension and morbidity and mortality due to cardiovascular and cerebrovascular causes have been reported. The association between sleep apnea and diurnal hypertension is independent of obesity, age and sex, and appears to be related to stimulation of the sympathetic nervous system by repetitive upper-airway closure. A sleep study is indicated in patients with resistant hypertension and other signs and symptoms of sleep apnea, including obesity, large neck size (size 17 inches or greater in men and size 16 inches or greater in women), excessive loud snoring, interrupted sleep, daytime somnolence, polycythemia and carbon dioxide retention.

Volume overload

Whether related to excess sodium intake or inadequate/ inappropriate diuretic treatment, is the most common cause of resistant hypertension in patients who adhere to therapy. All patients with hypertension should be counseled to avoid foods high in sodium and to increase their consumption of fruits, vegetables and low-fat dairy products. These foods contain micronutrients that reduce the pressor effects of concomitant sodium intake. In patients with hypertension and normal renal function, thiazide diuretics are more effective than loop diuretics in lowering blood pressure. However a switch to a loop diuretic may be warranted in patients with renal dysfunction (glomerular filtration rate less than 30 mL per minute; serum creatinine approximately 3 to 4 mg per dL).

CONCLUSION

Using planned systematic approach achieving BP goals with appropriate combination therapy in most patients is possible. In addition to an appropriate antihypertensive treatment regimen, it is important to be aware off poor adherence and to monitor patients for the use of substances that interfere with antihypertensive therapy. Patients with white-coat hypertension can be recognized using ABPM. Patients with secondary hypertension due to conditions such as renal artery stenosis or renal

641

CHAPTER 138

Step 1

Alcohol abuse and other interfering exogenous substances

HYPERTENSION

642

parenchymal disease, can be identified with appropriate screening. In patients with difficult-to-treat hypertension, the regimen may be intensified but careful monitoring is mandatory.

REFERENCES

Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation 2008; 117:e510-526.

U.S. Department of Health and Human Services. National Heart Lung and Blood Institute. Your guide to lowering your blood pressure with DASH. http://www.nhlbi.nih. gov/health/public/heart/hbp/dash/. Accessed September15, 2016.

Frank J. Managing hypertension using combination therapy. Am Fam Physician 2008; 77:1279-1286.

Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 2001; 19:2271-2277.

Viera A J, Hinderliter A L. Evaluation and management of the patient with difficult-to-control or resistant hypertension. American Family Physician 2009; 79:863–869.

Ong KL, Cheung BM, Man YB, Lau CP, Lam KS. Prevalence, awareness,treatment, and control of hypertension among United States adults1999-2004. Hypertension 2007; 49:69-75.

Grogan JR, Kochar MS. Alcohol and hypertension. Arch Fam Med 1994; 3:150-154.

Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States [published correction appears in N Engl J Med. 2002;346(7):544]. N Engl J Med 2001; 345:479-486.

C H A P T E R

139

Hypertension Urgencies & Emergencies

INTRODUCTION

Hypertension is defined as the level of blood pressure beyond which the vascular risk has increased in general population.Over the last few decades the cut off limit of normal blood pressure has changed considerably.Last JNC guideline suggests the upper limit of normal blood pressure is 140/90mmHg below the age of 60years. As the prevalence of the hypertension is increasing for the last 3decades the hypertensive crisis is also increasing. It has been estimated globally that 1 -2 % of hypertensive populations suffer from hypertension urgencies & emergencies which parallels the distribution of primary hypertension. Uncontrolled hypertension beyond 180/120 mmHg can be classified as hypertensive urgency or emergency depending upon the end organ damage. The prompt recognition of hypertensive emergency & urgency with proper diagnostic test and triage may lead to prevention of end organ damage and fatal outcomes like myocardial infarction, stroke, renal failure, Coma and death.

Sekhar Chakraborty

Degree of BP elevation

The briskness /rapidity of increase of BP

The length of time of Hypertensive crisis

The degree of end organ damage.

Therefore Hypertensive crisis is classified into two types 1.

Hypertensive Urgency – defined as the elevated blood pressure more than 180/120 in the presence of target end organ damage

Patients may present with non progressive symptoms of headache, shortness of breath, epistaxis,pedal edema

Hypertensive emergency defined as severe HTN more than 220/140 mmHg with end organ damage. It may lead to acute MI, Hypertensive encephalopathy, intracranial hemorrhage, dissecting aneurysm, acute renal failure, pulmonary edema and so on. In case of pregnant females BP more than 169/109 mmHg is considered as hypertensive emergency

HISTORY

In 1914 The clinician Franz Volhard and pathologist Theodor Fahr coined the term malignant hypertension which we recognize today as hypertensive urgency.They described individuals with severe hypertension along with renal failure, retinopathy with papilledema,fibrinoid necrosis and death. In 1921 - Keith and Wagener identified similar patients having papilledema with retinopathy but no renal insufficiency. They introduced the term “Accelerated Hypertension”. In 1928 Oppenheimer & Fishberg described hypertensive encephalopathy in the back ground of Accelerated Hypertension. Currently it is defined as – 1.

Accelerated HTN – Severely elevated BP more than 179/109 mmHg associated with ocular hemorrhages,exudates but no papilledema (Grade III Kimmel Stiel – Wilson retinopathy)

Malignant HTN - Severely elevated BP more than 179/109 mmHg associated with ocular hemorrhages, exudates with papilledema (Grade IV Kimmel Stiel – Wilson retinopathy)

DEFINITION

The hypertensive crisis and its outcome depends on

EPIDEMIOLOGY

Hypertensive emergencies are common and occur 1% to 2% of hypertensive population. Hypertensive crisis affects 5 lakhs Americans every year. Zampaglione et al evaluated the prevalence of hypertensive crisis in emergency department for 1 year and frequency of end organ damage during the 1st 24 hours after presentation. They observed that the frequency of the hypertensive urgencies was 76% and hypertensive emergencies was 24%. They also found that the hypertensive crisis was more common in patients of renal disease. It is more prevalent in the elderly and men are affected 2 times more often than woman. It is also common in lower socioeconomic status and among those who are noncompliant. In South East Asia region 36% of adults have hypertension. In India, review of epidemiological studies suggest that the prevalence of hypertension has increased in both urban and rural subjects and presently 25% of the urban adults and 10 to 15% of rural adults are hypertensive. Among all Indian hypertensive 1 to 2 % present with hypertensive crisis.

ETIOLOGY

Common causes of Hypertensive Crisis 1.

Medication Noncompliance

HYPERTENSION

644

Table 1: Hypertensive Crises According to the Plasma Renin Level

Phencyclidine

MAO inhibitor with tiramine

Disorders with high renin

Malignant hypertension

Linezolid

Medium to high renin states

Unilateral renovascular hypertension

NSAIDS

Amphetamines

Renal vasculitis (scleroderma, lupus, polyarteritis)

Secondary causes hypertensive crisis

Renal trauma

Renal Disease

Endocrine Disorders-

Cushing Syndrome

Primary Hyperaldosteronism

Pheochromocytoma

Cerebro Vascular accident

Cardiac & Spinal Surgery

Spinal cord and Head injuries

Hypertension with pulmonary edema

SLE

TTP-HUS

Hypertension with acute myocardial infarction or unstable angina

Pregnancy

Renin secreting tumors Adrenergic crises: pheochromocytoma, cocaine abuse, clonidine 3

Probable medium to high renin states (PRA ≥ 0.65 ng/mL/h)

Sodium-volume overload, low renin states: PRA ≤ 0.65 ng/ mL/h

Hypertension with cerebral hemorrhage Hypertension with (impending) stroke

Perioperative hypertension

Lack of resources & medical insurance

Smoking

Diabetes

Obesity

Acute tubular necrosis Acute glomerulonephritis Urinary tract obstruction

Antihypertensive drug withdrawal

Renal Parenchymal disease

Reno vascular disease

Drugs (i.e. cocaine, PCP)

Collagen Vascular diseases

Cushing disease

Pheochromocytomas

Preeclampsia and eclampsia

10.

Postoperative state

The most common cause of Hypertensive crisis is chronic hypertension with its acute exacerbation. The followings drugs can precipitate hypertensive crisis in normotensive or hypertensive individuals. Cocaine

leads

Associated risk factors Lack of a primary care physicians

that

Low renin essential hypertension Preeclampsia/eclampsia

Oral contraceptives

hypertension

Dissecting aortic aneurysm

Primary aldosteronism

PATHOPHYSIOLOGY (FIGURE 1)

Precise mechanism of hypertensive crisis is not known. Two general theories, Pressure hypothesis and Humoral hypothesis suggest that pathologic events of hypertensive crisis develop when there is critical imbalance of pressure and humoral factors. In severe hypertension – 1.

Amplification of RAS Damage to endothelium of blood vessel and deposition of fibrin thrombi,

High vascular reactivity and elevated levels of vasoactive agents such as norepinephrine, angiotensin II and vasopressin  Natriuresis  Hypovolemia  More elevation of vasoactive agents  arteriolar fibroid necrosis  Endothelial damage  Plate late deposition and micro angiopathic hemolatic anemia. It leads to ischemia and further release of vasoactive agents.Thus the cycle continues

Elevation of asymmetric dimethyle arginine,endogenous NO synthase inhibitors.It is observed in preeclampsia.

CLINICAL PRESENTATION

Hypertension urgencies and emergencies may present asymptomatically. Silent HTN crisis has been found commonly in young black men.

645 NO

PGI2

NO ATII

TxA2

ADH

Platelet aggregation DIC

TxA2 NO

PGI2

ETI

Normotension or chronic hypertension

Fibrinogen

CAMs

Hypertensive Urgency

RBC Platelet

Fibrinoid necrosis Perivascular oedema

Hypertensive emergency

Fig. 1: Pathophysiology of Hypertensive emergencies

Fig. 2: Grade 1 : Hypertensive Retinopathy Signs and symptoms of hypertensive urgency

Headache --- 22%

End organ damage

Epistaxis ----17%

Cerebral infarction --- 24%

Faintness ---- 10%

Acute pulmonary edema --- 22%

Psychomotor agitation ---- 10%

Hypertensive encephalopathy --- 16%

Chest pain --- 9%

Congestive heart failure --- 12%

Dyspnea ---- 9%

Less Common symptoms are arrhythmias and paresthesias.

Less common presentation are intracranial heamorrhage, acute aortic dissection, acute MI, acute kidney injury and eclampsia.

Signs and symptoms of hypertensive emergency 1.

Chest pain ---- 27%

Dyspnea --- 22%

Neurologic deficits ---21%

Single organ involvement is observed in 83 % of patients Two organ involvement is observed in 14% of patients Multi organ involvement (> 3 organs) is observed in 3% of patients.

CHAPTER 139

CAT CAMs

HYPERTENSION

646

Fig. 3A

Grade 3 KWB Retinopathy •

Fig. 3B

Grade 3 and 4 highly correlated with progression to end organ damage and decreased survival

DIAGNOSIS

Clinical examination should include thorough history taking, physical examination and relevant investigation. History should include duration and severity of hypertension, previous BP records prior organ damage associated symptoms, recreational drug and alcohol use. Thorough auditing of list of medications particularly antihypertensive drugs and their dosing compliance with antihypertensive regimen. A.

Relevant Symptoms

Headache and chest pain

Dyspnea,edema and acute fatigue

Epistaxis

FUNDOSCOPIC EXAMINATION

Seizures

•

Lost art

Change in the level of consciousness

•

Keith-Wagener-Barker Classification

Palpitation, Diaphoresis and tremors suggestive of pheochromocytoma

Weight gain and thinning of skin suggestive of cushing’s syndrome.

History of comorbid condition

Fig. 4: Hypertensive Retinopathy Grade 4

Keith-Wagener-Barker Classification •

Grade 1 (Figure 2)

Mild narrowing of the arterioles

“Copper Wire”

•

Grade 2

Moderate narrowing - Copper wire and AV nicking

•

Changes associated with long standing essential hypertension

•

Grade 3 (Figure 3A & 3B)

Severe Narrowing - Silver wire changes, hemorrhage, cotton wool spots, hard exudates

•

Grade 4 (Figure 4)

Grade 3 + Papilledema

Diabetes, smoking, hyperlipidemia, chronic kidney disease C.

Medication and addiction

Physical Examination

Fell all peripheral pluses including uperlimbs, carotids, femoral and lower extremities

Measure the blood pressure using appropriate technique and proper BP cuff

Measure blood pressure both arms and at least one leg.

Hypertensive Emergency

Hypertensive Urgency

Admission to Hospital Observation to general ward IPD admission for those having comorbidities like Diabetes,stroke, IHD or noncompliant to drugs Immediate admission to ICU for prompt BP control once stabilized patient may be shifted to general ward

Goal

Gradual BP control over 1248 Hrs. reduce BP to 160/100 mmHg over hours

BP should be reduced effectively within minutes to one hour Goal is to reduce BP <25% within 2-6 Hrs. & stabilized to 160/100 mmHg then 25% within 48 Hrs.

Table 2: differences in Management of HTN Urgency & Emergency

Labetalol,

Rapid acting antihypertensive agents

Parenteral titrable agents with continuous monitoring of BP, Neurological status,Urine output

Clevidipine

New Drug

Phentolamine

Enalapril

Less Use

Hydralazine

Fenoldapam,

Nitroglycerine,

Nicardipine

Aggressive reduction of BP may aggravate Hypoperfusion &worsening of end organ damage. However in patient of aortic dissection rapid reduction of BP <120/80mmHg should be achieved within 5-10mines initially with B blockers

BP Should not be lowered rapidly to their release Nifedipine normal base line. Parenteral route Clonidine, & high dose to be avoided to protect Prazosin, hypoperfusion Amlodepine of major arterial beds Esmolol,

Labetalol captopril extended

Low dose short acting drugs

Oral Medication

Precaution

Choice of Drugs

Selecting Drug

Route of Medication

Can be discharged to be followed up after 48Hrs. at OPD

Discharge & follow up

BP reading in supine and sitting and standing positions are required to measure volume status.

5. A comprehensive cardiovascular examination is of value.

6. Elevated jugular venous pressure, Pedal edema, third heart sound, gallop, crepitations, provide the evidences of heart failure

7. A prominent and displaced apical impulse or a harsh intrascapular murmur is suggestive of coarctation of aorta.

8. Auscultation of carotids and abdominal bruits.

9. Fundoscopic examination – Presence of hemorrhages, exudates, papilledema – confirms hypertensive emergency.

10. N e u r o l o g i c a l examination – to assess stroke, somnolence, stupor, visual loss, focal neurological deficits, seizures or coma.

11. Check for mental status.

12. Look for target organ damage.

E. Relevant Investigation

1. Initial evaluation

a. Electrocardiogram – ST, T wave changes, evidence of LVH, ischemia, arrhythmia

b. Hematocrit, total leucocyte count and peripheral blood smear

Renal function test

Urinalysis with microscopic examinationhematuria and proteinuria

Chest radiograph – cardiomegaly and pulmonary congestion

Thyroid function test

Non contrast CT of head

Echocardiogram

(LV

CHAPTER 139

4. 647

HYPERTENSION

648

Table 3: Drugs for hypertensive urgencies Agent

Dose

Onset of action

Comment

Captopril

12.5-25 mgPO

15-60 min

Can precipitate acute renal failure in patients with bilateral renal artery stenosis

Nifedipine (extended release)

10-20 mgPO

20 n i i n

Avoid short-acting or sublingual nifedipine due to risk of sudden hypotension, stroke, cardiac event

Labetalol

200-400 mg PO

20 120 min

Heart failure, bradycardia, bronchospasm

Clonicline

0.1-0.2 mgPO

30-60 min

Rebound hypertension due to abrupt withdrawal

Prazosin

l-2 mgPO

2-4 h

First-dose hypotension, syncope, tachycardia

Amlodipine

5-10 mg

30-50 min

Headache, tachycardia, flushing

MANAGEMENT

Table 4: Parenteral Agents used in the Management of Various Hypertensive Crises Primary Condition

Therapy

Acute aortic dissection

Labctalol or nicardipine + esmolol, nitroprusside + esmolol

Hypertensive encephalopathy

Labetalol, nicardipine, fenoldopam, clevidipine

Acute myocardial ischemia

Nitroglycerin ± esmolol, fenoldopam, labetalol

Congestive heart failure

Enalaprilat, loop diuretic

Eclampsia

Hydralazine, nicardipine, labetalol

Pheochromocytoma

Phentolamine, labetalol

Acute pulmonary edema

Sodium nitroprusside. nicardipine, fenoldopam. loop diuretic, nitroglycerin

Acute ischemic stroke/ intracerebral bleed

Nicardipine, fenoldopam, labctalol, clevidipine

Acute renal failure/ MAHA

Nicardipine, fenoldopam

Proper management of hypertensive crisis is essential to prevent end organ injury of brain, heart, kidneys & vascular system. Understanding of treatment goal appears to be of parament importance (Tables 3, 4 & 5).

PROGNOSIS

Studies have shown that patients are not being evaluated properly at the emergency room during the time of hypertensive crisis. Fundoscopic examination is the most neglected clinical examination in emergency setting and studies revealed that 2/3rd of patients evaluated for hypertensive crisis did not have fundoscopic examination done. Serum biochemistry is not properly obtained along with other investigation. Data regarding the outcome of hypertensive crisis is very poor.In a study of 315 patients of malignant hypertension,40% were alive after 33months. The most common causes of death were renal failure (39.7%), stroke (23.8%), MI (11.1%) & heart failure (10.3%).

Adapted from Varon et al.47 MAHA indicates microangiopathic hemolytic anemia.

dysfunction, valve abnormalities, wall motion abnormalities) i.

Lipid profile

Tests to be done once the patients is stabilized

Renal artery imaging – Renal artery stenosis

Urinary VMA /Metanephrines/ Pheochromocytoma

Plasma cortisol and dexamethasone suppression test – Cushing’s syndrome.

HIAA

The main predictors of survival in hypertensive crisis were found to be known duration of HTN & procuring the serum level at presentation. In one study 1year, mortality rate has been found 79% in untreated hypertensive emergences and 5years survival rate in all treated hypertensive crisis is 74%.This study indicates categorically the benefits of managing hypertensive crisis effectively.

CONCLUSION

Physicians should be prompt enough to perform – 1.

Complete evaluation of patients of hypertensive crisis including fundoscopic examination & suggestive proper laboratory investigation.

To manage effectively to reverse the crisis

To correct underlying trigger, so that such event should not happen in future.

To improve long-term outcome.

–

The differences in management of hypertensive emergencies and urgency are given in Table 2.

649

Table 5: Drugs for hypertensive emergencies Hydralazine Dose: 10-20 mg IV holus may be repeated every 30 min till goal BP is reached or unacceptable tachycardia develops Onset/duration of action after discontinuation: 10-30 min/2-4 h Comments Direct arteriolar vasodilator Reflex tachycardia, flushing Avoid in patients with increased ICP, ischemic heart disease, and aortic dissection (without β-blockade) Sodium nitroprusside Dose: 0.25-10 mcg/Kg/min IV infusion Onset/duration of action after discontinuation: seconds/2-3 min Comments Arterial and venodilaior with rapid onset and offset of action Preferred agents for most hypertensive emergencies Titrate to goal BP Infusion bag and delivery set must be light resistant or covered Nausea, vomiting, muscle twitching on prolonged use (>24-48 h) Thiocyanate/cyanide intoxication, metabolic acidosis in patients with renal impairment Thiocyanate level >10 mg/dL should be avoided Phentolamine Dose: 5-15 mg IV bolus, repeat every 5-15 min Infusion: 0.2-5 mg/min Onset/duration of action after discontinuation: 1-2 min/10-30 min Comments Pure α-blockade Reflex tachycardia, orthostatic hypotension Used in syndromes with excess catecholamine (pheochromocytoma) Enalapril Dose: 1.25 mg every 6 h Onset/duration of action alter discontinuation: 15-30 min/6-12 h Comments Mainly afterload reduction Contraindicated in pregnancy, renal artery stenosis Useful in patients with CHF

Ref: ICU protocols, A Step wise approach, ISCCM –Chawla and Todi.

CHAPTER 139

Labetalol Dose: 10-80 mg IV bolus every 10 min to a maximum dose of 300 mg Infusion: 0.5-2 mg/min Onset/ : 5-10 min duration /3-6 h Comments Combined α- and β-blockade Bradycardia, bronchospasm Avoid in congestive heart failure (CHF). bronchial asthma Commonly used in pregnancy-induced hypertension Esmolol Dose: 500 mcg/Kg IV bolus can be repeated after 5 min Infusion: 50-200 mcg/Kg/min Onset/duration of action after discontinuation: 1-5 min/15-30 min Comments Avoid in patients with heart block, CHF, asthma Short-acting cardioselective β-blocker Bradycardia. CHF, heart block, may precipitate bronchospasm Nicardipine Dose: 5 mg/h IV infusion; titrate up by 2.5 mg/h every 20 min up to maximum dose of 15mg/h Onset/duration of action after discontinuation: 15-30 min/1-4 h Comments Dihydropyridine calcium channel blocker Reflex tachycardia Avoid in acute heart failure Useful in subarachnoid hemorrhage Fenoldopam 0.1 mcg/Kg/min IV infusion, titrate up every 15 min to a maximum of 0.8 mcg/Kg/min Onset/duration of action after discontinuation: 3-5 min/30 min Comments Selective peripheral dopamine-1 receptor agonist Arterial vasodilator Improves renal perfusion, useful in patients with hypertensive emergencies with renal failure Contraindicated in glaucoma Nitroglycerine Dose: 5-100 mcg/min IV infusion Onset/duration of action after discontinuation: 2-5 min/5-15 min Comments Mostly venodilator with modest arterial dilation Headache, tachycardia, flushing, vomiting Develops tolerance with prolonged use Methemoglobinemia Useful in emergencies with cardiac failure or ischemia

C H A P T E R

140

YOUNG Hypertensives: Do we Need to Look at them Differently?

YOUNG HYPERTENSION

The definition of young adults is a matter of debate. While the American motion picture “Young Adult” features a 37-year-old lady as its heroine, the Framingham Offspring Study on ‘young’ hypertension includes 2027 men and 2267 women aged 20 to 49 years.1 We therefore use the same age group to define ‘young”, in the context of adult hypertension. Young hypertensives have unique biomedical, psychological and social attributes, which are important determinants of their risk factors, clinical features, motivational cues, and therapeutic outcomes. A thorough understanding of these issues is important to ensure appropriate screening, diagnosis and management of young adults with hypertension.

PATIENT- CENTRED APPROACH

Patient centricity is encouraged by management guidelines on diabetes and dyslipidemia, but not by current hypertension treatment recommendations. In blood pressure care, patient centeredness implies active involvement of patients in their own care, by using modern technology such as ambulatory blood pressure monitoring and home blood pressure monitoring. There has been no use of the phrase “patient centered choice of targets” in blood pressure treatment recommendations. Hypertension management, especially in young persons, needs patient centered goals, strategies and targets. The Eighth Joint National Committee (JNC 8) panelists2 write: “{their} recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient”. This suggestion forms the noesis of this chapter. Both American Diabetes Association (ADA)3 and European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)4 convey the message of choosing patient-centered targets and goals while managing hypertension. The general target for blood pressure may be made more stringent for ‘younger’ individuals with longer life expectancy and additional risk factors (smoking, obesity, dyslipidemia); high risk of stroke or progression of albuminuria. Such a step should be contemplated only if therapy is well tolerated, and does not pose an unacceptable cost or bill burden upon the patient. Younger patients who complain of symptoms suggestive of high blood pressure, such as headache, anger and irritability, may benefit from lower blood pressure levels,

Sanjay Kalra, KVS Hari Kumar

provided they remain asymptomatic, and enjoy better quality of life. Asymptomatic patients may be managed using conventional targets (<140/90 mm Hg).

DIAGNOSIS

The diagnostic criteria for various grades of hypertension are similar in younger and older adults.2,4 The methods of evaluation and diagnosis are similar. It must be noted, however, that many forms of secondary hypertension, such as renal hypertension (renal artery stenosis) adrenal disorders (pheochromocytoma, Conn’s syndrome) and other endocrine disorders (acromegaly, hyperthyroidism, hypothyroidism, hyperparathyroidism, hypogonadism, polycystic ovary syndrome) are more common, or are first diagnosed in, young adulthood. Thus, young hypertensives need thorough evaluation prior to being labeled as having essential hypertension.

RISK FACTORS

Hari Kumar et al have described the Ominous Octet of S’s which are risk factors for the development of noncommunicable disease are in general, and cardiovascular diseases in particular. These include sex, salt, sugar, sleep, smoking, stress, sunlight and sedentary behavior.5 The same authors have added saturated fat to complete the Nasty Nine, and prolonged sitting to create the list of Terrible Ten. Some of the terrible ten have a bidirectional relationship with high blood pressure, others contribute to or are risk factors for hypertension, and yet others are worsened by hypertension. Understanding of these associations helps in chalking out preventive and therapeutic strategies for hypertension. Rates of hypertension are higher among young men than among women,1 increasing threefold from the second to the fifth decade in men and eight-fold in women. Under age 40, men are twice as likely as women to develop hypertension, but after age 40, 8-year incidence rates were similar in men (14.2%) and women (12. 9%). Adiposity (P < 0.01), heart rate (P < 0.01), and triglyceride (P < 0.05) are significant independent predictors of hypertension in men, while adiposity (P < 0.001), heart rate (P < 0.01), hematocrit (P < 0.05), and alcohol consumption (P < 0.05) are independent contributors in women. Adiposity is a major modifiable contributor to hypertension. In modern medicine, asymptomatic organ damage is assessed for risk stratification. Four markers (micro albuminuria, increased pulse wave velocity, left ventricular hypertrophy and carotid plaques) are considered important risk prognosticators. Among

investigations, echocardiography with Doppler is considered to have the highest predictive value, while electrocardiography, estimation of glomerular filtration rate, micro albuminuria, carotid intima-media thickness, arterial stiffness, ankle-brachial index and fundoscopy are considered useful, reproducible, easily available, and cost-effective alternatives.

THERAPEUTIC TARGETS AND TOOLS

In all persons aged ≥ 18 years, with either diabetes or chronic kidney disease (CKD) (till age 70) the threshold of ≥140/90 mm Hg, and target of ≤ 140/90mm Hg will apply. JNC 8 reiterates that a person who has lower blood pressure should not modify therapy, as long as it is well tolerated. JNC 8 panelists do recommend ethnicity based choice of therapy including thiazide type diuretic or calcium channel blocker (CCB) for the general black population (including those with diabetes), and ACEi or ARB for blacks with CKD. However, no specific guidance is provided for South Asians. ADA suggests a target of <140/90 mm Hg for all people with diabetes, but advocates lower targets in “younger patients”, those with albuminuria, and/or those with one or more additional atherosclerotic cardiovascular disease risk factors (dyslipidemia, obesity, and smoking). Such targets are proposed only if they can be achieved ‘without undue treatment burden”. Lower targets are especially important in persons with a high risk of stroke (systolic blood pressure control) or worsening of albuminuria, and ‘long life expectancy”. The threshold for beginning nonpharmacological intervention is also lower, at > 120/80 mm Hg. ADA favors the use of renin angiotensin system (RAS) inhibitors. Mention is made of outcome benefits with perindopril + indapamide6 and benazepril + amlodipine combinations. ACEi and ARB may be substituted for each other, if one class is not tolerated. Serum creatinine/eGFR and serum potassium levels should be monitored during long term of RAS blockers. ADA suggests administration of one or more antihypertensive medications at bed time. The 2013 ESH/ESC guidelines suggest institution of pharmacotherapy above a threshold of 140/90 mm Hg, in all patients with low-moderate cardiovascular risk, or previous stroke/transient ischemic attack, or coronary heart disease or diabetic/non-diabetic kidney disease. The only exception is made for the elderly (who are offered a higher systolic target) and for diabetes (who are given a lower diastolic target).

651

In the modern world, young adults face high stress levels. Whether related to domestic, work or travel issues, stress is a ubiquitous part of today‘s life; and is a major contributor to young hypertension. Treatment strategies need to take this into account.7 Busy and erratic schedules also mean that drugs with long half –lives, which can be administrated at any time of the day, without regards to the clock or to meal timing are preferred.

PERCEIVED COMPLICATION RISK

Hypertension needs to be managed not only for symptom relief, but also for maintenance of vascular health.8 Prevention or delay of vascular events such as stroke and myocardial infarction are important motivating factors for elderly persons with high blood pressure. Such illnesses may appear remote or unlikely to a young person. However, more immediate, and more worrisome, is the possibility of complications such as sexual dysfunction. Counselling regarding the role of good blood pressure control in maintaining sexual function, and prescription of “sexually neutral” drugs are important in this regard.9 Such counseling and choice of drugs may help improve adherence to prescribed anti-hypertensive therapy.

TOLERABILITY OF DRUGS

While efficacy of drugs is taken for granted today, emphasis is laid upon tolerability. Various classes of drugs may be associated with side effects such as edema, increased micturition, fatigue, cough, postural hypertension, and sexual dysfunction. The young hypertensive may find these side effects intrusive and inconvenient. Discussing these issues prior to prescription of therapy, and choosing management strategies and goals in a patient- centered manner will help improve acceptance of drug treatment.

NON-PHARMACOLOGICAL THERAPY

Strong emphasis should be laid on non-pharmacological therapy in young persons with hypertension.9 Regular physical activity, a healthy diet low in salt and saturated fat, avoidance of tobacco, excessive alcohol and abuse of drugs, stress management and adequate sleep are important components of such therapy. Yoga and meditation may be encouraged in such persons.10

PHARMACOLOGICAL THERAPY

The choice of anti -hypertensive drugs is similar in young and relatively older individuals. As per current guidelines, diuretics, calcium channel blockers and renin angiotensin system (RAS) blockers are drugs of choice.2-4 A patient–centered approach should be followed while choosing drugs for blood pressure management. Low dose thiazide diuretics, like indapamide SR and chlorthalidone, or thiazides in relatively higher dose, such as hydrochlorothiazide are economical choices, but increase urine output. Calcium channel blockers are effective blood pressure lowering drugs, but can cause edema. Angiotensin converting enzyme (ACE) inhibitors, especially enalapril and ramipril, may be associated with a high incidence of cough. Because of these factors, tolerability plays an important role in choice of therapy.

CHAPTER 140

In the general population, the blood pressure threshold for initiating pharmacologic treatment is ≥ 140/90 mm Hg in those aged less than 60 years, and ≥150/90 in those aged 60 or above. While the therapeutic target is a blood pressure of < 140/90 mm Hg or <150/90 mm Hg respectively, persons who are asymptomatic on therapy which achieves lower levels do not require adjustment of medication.

PSYCHOSOCIAL FACTORS

652

Efficacy is equally important, too there is a trend towards preference of once daily drugs with longer half –lives, which are able to achieve both day time and nocturnal normotension.

HYPERTENSION

PRO-METABOLIC THERAPY

A large number of young persons with hypertension have comorbid conditions such as diabetes,2 obesity, dyslipidemia and hyperuricemia. The choice of antihypertensive drug should be such that it should preferably improve, and at the least be neutral to, other metabolic parameters. Renin angiotensin system blockers, for example, are able to enhance insulin sensitivity, and thus possibly attenuate the dysfunction noted with metabolic syndrome. The 2013 ESH/ESC authors list metabolic syndrome and glucose intolerance as possible contraindications for thiazide diuretics and beta-blockers, but refrain from describing these contraindication as compelling.

support adherence to treatment by reminding the user to take his /her medication regularly. Tele-health projects offer counseling services related to various aspects of hypertension, enhancing patient and community awareness, and offer simple advice which facilitates patient empowerment and appropriate decision making. The YUVA helpline, recently launched from Hyderabad, is one such useful service (phone 07097066606).

REFERENCES

Garrison RJ, Kannel WB, Stokes J, Castelli WP. Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Preventive medicine. 1987; 16:235-51.

James PA, Oparil S, Carter BL, Cushman WC, DennisonHimmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507-20.

American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes—2016. Diabetes Care 2016; 39(Suppl. 1):S52–S59

Some JNC 8 panelists recommend initiation of combination therapy (2 or more drugs) when blood pressure is > 160/100 mm Hg or when it is > 20/10 mmHg above goal. Titration of drug treatment can be done by maximizing dosage, adding a second medication, or starting a fixed dose combination. They reiterate that more than one class of drugs will frequently be necessary and advocate use of thiazide-like diuretics, ACE or ARB and CCB, in varying combinations. Only if these three classes prove inadequate, along with lifestyle modification, do they recommend addition of beta blockers, aldosterone antagonists or other classes. Fixed dose combination (FDCs) of rational and complementary molecules are helpful in such cases. Examples include FDCs of RAS blockers, amlodipine and diuretics, in dual or triple combination.

Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood Pressure 2013; 22:193-278.

Sharma R, Hari Kumar KVS, Kalra S. The ominous octet of ‘S’ in noncommunicable disease. Accepted in J Soc Health and Diabetes

Patel A, ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. The Lancet 2007; 370:829-40.

Appel LJ, Champagne CM, Harsha DW, Cooper LS, Obarzanek E, Elmer PJ, Stevens VJ, Vollmer WM, Lin PH, Svetkey LP, Young DR. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA: Journal of the American Medical Association 2003.

Group UP. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. British Medical Journal 1998; 703-13.

TECHNOLOGY

Al Khaja KA, Sequeira RP, Alkhaja AK, Damanhori AH. Antihypertensive Drugs and Male Sexual Dysfunction A Review of Adult Hypertension Guideline Recommendations. Journal of Cardiovascular Pharmacology and Therapeutics 2016; 21:233-44.

COMBINATION THERAPY

Monotherapy may not be sufficient to normalize blood pressure in many patients, especially those with comorbid conditions such as diabetes, chronic kidney disease, and stress. A combination of drugs is required in such cases. The maximum time frame for intensification of therapy (either by up titration of dose or addition of an extra drug), if goals are not achieved, is one month.

The average young hypertensive is more technology savvy that his elder counterparts. Blood pressure care provides digital health solutions for preventative and curative interventions, as well as non-pharmacological and drug related therapies. Mobile applications and gadgets which monitor diet and physical activity patterns,

10. Manchanda SC, Madan K. Yoga and hypertension. J Prev Cardiol 2013; 2:361-4.

NCD Update: Connection between Chronic Kidney Disease and Cardiovascular Disease

C H A P T E R

141

C Venkata S Ram

(Adapted from the Special issue of the Hypertension Journal 2016, Number 1 (pp. 33-38) with permission from Jaypee Brothers Medical Publishers) The burden and consequences of chronic disease are increasing rapidly throughout the world with no end in sight. Cardiovascular disease (CVD) is progressing relentlessly in all communities and is responsible for excessive morbidity and premature mortality. The spectrum of CVD ranges from asymptomatic ischemia in vital organs to the development of systemic vascular disease. Thus, the manifestations of CVD include coronary artery disease (CAD), congestive heart failure (CHF), left ventricular hypertrophy (LVH), transient ischemic attack (TIA), cerebrovascular disease (CeVD), aortic aneurysms, and peripheral arterial disease (PAD). Therefore, the impact of CVD on life expectancy is of critical importance. The risk factors for CVD are well established and the disease occurrence and progression can be interrupted by early identification and aggressive control of the risk factors. The prevalence of CVD is quite high in patients with chronic kidney disease (CKD). Unfortunately, CVD and CKD are closely inter-connected, often co-exist, and can initiate and perpetuate the morbidity. The CVD-CKD circuit is a vicious cycle. The onset of CVD in patients with CKD occurs much earlier and more extensively compared to the general (non-CKD) population. It is clear that CVD

Table 1: Confluence of traditional and non-traditional CVD risk factors in CKD

can be extensive and extremely dangerous in patients with CKD. From a patho-physiological point, CKD is a powerful risk factor and a signal for the development of CVD. The CVD-CKD connection is of serious importance in clinical medicine. For a practicing clinician, CKD should, therefore, be considered as a precursor for CVD. The diagnosis of CKD signifies simultaneous presence of CVD. It has been postulated that for every 10 mL/ min decrease in glomerular filtration rate (GFR), the risk of mortality from CVD increases by 6%! (1). In patients with end-stage renal disease (ESRD), CVD is the principal reason for premature death, excess morbidity, and hospitalization.

RISK FACTORS AND MARKERS OF CVD IN PATIENTS WITH CKD

The pathophysiological risk factors for CVD in patients with CKD in many ways are similar to the patients without CKD. However, uremic toxins likely play an additional role in “igniting” and “fuming” CVD in patients with CKD. Beyond the traditional risk factors for CVD, patients with CKD have other adverse factors such as --- hemodynamic volume overload, anemia, oxidative stress, vascular inflammation, uremia, calcium-phosphate product, endothelial malfunction, enhanced activity of the sympathetic nervous system (SNS), renin-angiotensinaldosterone system (RAAS), and insulin resistance. Hence, the traditional and in non-traditional risk Figure: both Pathophysiology of CVD CKD factors contribute to the burden of CVD in the presence

Traditional risk factors

Non-Traditional risk factors

Traditional

Non-Traditional

Male gender

Anemia

Family history

Uremia

Physical inactivity

Volume overload

Obesity

Oxidative Stress

Hypertension

Vascular inflammation

Hyperlipidemia

Calcium-Phosphate Product

Diabetes

Catabolic State

Tobacco use

Endothelial dysfunction

Excessive alcohol consumption

 Activity of SNS and RAAS

↑ CVD in CKD

 Thrombogenic factors

Fig. 1: Pathophysiology of CVD in CKD

HYPERTENSION

654

of CKD. In patients with ESRD, the cardiovascular milieu is further deranged and becomes complex. While it is possible to demonstrate cardiovascular risk markers such as C-reactive protein (CRP), IL-6, TNF-α, asymmetric dimethyl arginine, and endothelial dysfunction, clinical utilization of these indices in patients with CKD is not widely available. Thus, the focus on CVD prevention in patients with CKD remains on tackling the conventional risk factors (Table 1 and Figure 1).

PREDISPOSING RISK FACTORS FOR CVD IN PATIENTS WITH CKD

Hypertension

Patients with CKD are likely to have antedating chronic hypertension which is aggravated with declining renal function. More than 90% of patients with CKD have hypertension. The pathophysiology of blood pressure elevation in CKD includes but not limited to---sodium retention, volume expansion, and enhanced activities of SNS and RAAS. In the elderly patients with CKD, renovascular resistance is increased.2 As CKD worsens, the blood pressure control mechanisms get deranged and patients have significant nocturnal hypertension (non-dipping).3 Persistence of nocturnal hypertension aggravates target organ damage---LVH, CHF, and atherosclerosis. In patients with ESRD, systolic blood pressure increases disproportionately causing systolic hypertension and the wide pulse pressure poses a significant hazard.4 Uncontrolled hypertension worsens CKD progression and enhances CV mortality. Aggressive blood pressure control may halt the progression of CKD (5). While the recommended blood pressure targets should be aimed for in patients with CKD, even a modest reduction in the blood pressure level may be helpful to lower the CVD burden.6

Dyslipidemia

Elevated level of LDL and a lower level of HDC---are attributable to CVD risk in the general population. The association between dyslipidemia and CVD is particularly strong and fully expressed in patients with CKD.7-9 While there is an agreement about the CV risk from dyslipidemia in patients with CKD, routine use of statins has not been advocated. Therapy therefore, has to be individualized. Fibrates are relatively contra-indicated in patients with CKD due to the risk of rhabdomyolysis. The pathophysiology of lipid metabolism in patients with CKD is extremely complex. For example, uremia decreases the activity of triglyceride lipase which leads to retention of triglycerides and lipoprotein lipase activity is also impaired in CKD. Additionally, dialyzer membrane dialysate itself, and heparin use alter lipid catabolism in patients with CKD. Urea accumulation (in CKD) causes formation of carbamylated LDL which is an independent risk factor for systemic vascular disease.10 The benefits of statin therapy to prevent CVD in patients with CKD have not been conclusively demonstrated. For example, atorvastatin showed no composite benefits on CVD in patients with ESRD;11 in the Aurora study,

rosuvastatin reduced the LDL in patients with ESRD but had no significant effect on CVD outcomes.12 However, in the SHARP trial13 statin therapy (along with ezetimibe) reduced the CV events in ESRD patients. Meta-analysis provides sufficient evidence for the ultimate benefits of statin therapy in patients with ESRD.14 Statin therapy reduced CV morbidity and mortality in kidney transplant patients.15 The AHA/ACC guidelines recommend (highintensity) statin therapy for patients with CKD except in ESRD.16

Diabetes

Diabetes is a paramount risk factor for nephropathy and CKD. A majority of patients with diabetes also have hypertension. Therefore, diabetes by itself or any combination with hypertension leads to CKD and its progression to ESRD. The vascular pathology in diabetes is likely mediated in part by advanced glycation end products (AGEs). AGEs accumulate in the vascular wall and provoke inflammation leading to atherosclerosis. AGE deposition in the vessel subsequently causes crossbridging of the proteins, matrix formation, collagen synthesis, loss of elasticity and an increase in the arterial stiffness. These abnormal biophysical pathways triggered by AGEs causes vascular dysfunction in diabetes and CKD.17,18 The resultant endothelial damage may be responsible for proteinuria in patients with diabetic renal disease. CV mortality goes up steeply after the onset of proteinuria. Microalbuminuria correlates with manifestations of CVD-LVH, increased intima-media thickness, and CAD.19-21 Patients with microalbuminuria/proteinuria might also have other CV risk factors. Diabetes causes endothelial dysfunction, coagulation abnormalities and vascular inflammation.22-24 Microalbuminuria predicts transformation to proteinuria and progression of CKD.25

Tobacco Consumption

Smoking is known to cause CVD but increases the risk of CKD. Tobacco causes hemodynamic and intra-renal abnormalities.26 SNS activation may play a contributory role in the development of CKD. Kidney response to increasing levels of blood pressure may be impaired in people who smoke cigarettes.27 Tobacco abstinence should be recommended to prevent CKD in the community.

Obesity

High body mass index and obesity increase the CV event rates in patients with CKD.28,29 Metabolic syndrome imparts CVD risk in general population and this association may also be applicable to patients with CKD. Adiponectin is an established biomarker for CV risk in metabolic syndrome. Lower levels of adiponectin were noted in CKD patients with cardiovascular mortality.30

Deranged Calcium/Phosphate metabolism

Hyperphosphatemia and hyperparathyroidism cause vascular stiffness and calcification. These abnormalities cause LVH, systolic hypertension, and myocardial ischemia. These biological and biophysical abnormalities

are present in patients with CKD making them easily vulnerable to CVD.31

Anemia

Inflammation

CKD typifies an example of vascular inflammation.34-36 Vascular inflammation has a pathogenetic role in CV syndromes in patients with CKD. Progression of CKD is associated with endotoxemia and CVD burden37 C-reactive protein (CRP) mediates critical processes in the pathogenesis of atherosclerotic disease. IL-6 excess in patients with CKD is a potent stimulus for CRP.38 There appears to be a close correlation between the degree of vascular inflammation and CKD stages.39 High levels of CRP are associated with increased mortality in patients with CKD. It is not clear whether possible benefits of statin therapy in CKD are due to their anti-inflammatory actions. A high ratio of neutrophil-to-lymphocyte is an indirect marker of vascular inflammation. Patients with CKD demonstrate a high neutrophil-to-lymphocyte indicating the underlying contributory role of inflammation in the clinical outcome of patients with CKD.40 CKD by the virtue of its manifold mechanisms (including inflammation) unfolds the patho-physiology of CVD. Oxidative stress is linked to vascular inflammation. Uremic solutes like cysteine, homocystein, β2- microglobulin, and AGEs promote oxidative stress in CKD.41 In some studies, antioxidants have been shown to reduce CVD events.42,43 However, guidelines do not comment on the role of antioxidants in CKD patients to reduce the CVD burden.

SPECTRUM OF CVD IN PATIENTS WITH CKD

The strong link between CVD and CKD is not surprising because of shared predisposing risk factors for both the entities. However, CKD by itself is an independent risk factor for CVD. On the other hand CVD presence portends a decline in the renal function. Thus the CVD-CKD loop is a vicious cycle.44,45 Atherosclerotic lesions in patients tend to be extensive, heavily calcified, and more unstable. The morphologic features of atherosclerosis in patients with CKD are distinctive and “malignant” in nature. A common cardiac structural abnormality of patients with CKD is LVH. As the renal function declines there is a reciprocal increase in LVH.46 A majority of patients with CKD demonstrate LVH. It is a important to recognize that LVH is a strong and independent risk factor for CVD burden in patients with CKD.

CHF is a major pathophysiological and clinical problem in patients with CKD. While the predisposing factors for CHF in patients with CKD are conventional in nature, LVH, declining GFR, and anemia further contribute to the development of CHF in patients with CKD/ESRD. Sudden cardiac arrest is a highly feared (and prevalent) complication in patients with CKD. Renal disease increases the risk of sudden cardiac arrest. There is an inverse relationship between GFR and sudden cardiac arrest.48,49

CONCLUSIONS

Clinical experience prospective and retrospective studies, and outcome observations confirm and reinforce the critical importance of CVD in patients with CKD. Evidence suggests that the intensity of CVD in patients with CKD is due to the confluence of traditional and nontraditional clustering of risk factors. The prognosis of CVD in patients with CKD is considerably poor compared to patients without CKD. The entire spectrum, breadth, length, and depth of CVD are maximally expressed in patients with CKD. CKD and its progression cause an exponential increase in the CVD burden. Recognition of this adverse association essential to formulate evidence based preventive and therapeutic strategies at the community level. It is imperative to identify and control the traditional and nontraditional CV risk factors in patients with CKD while acknowledging that CKD by itself is an independent powerful risk factor for CVD. A broad approach, therefore, is to diagnose and manage the risk factors for CVD and CKD in an aggressive manner and the community clinical practice level. This mandates public awareness and medical education to combat the horrible consequences of CVD in patients with CKD.

REFERENCES

McCullough PA, Li S, Jurkovitz CT, et al. Chronic kidney

655

CHAPTER 141

Renal insufficiency leads to chronic anemia due to decreased synthesis of erythropoietin. Anemia is a common feature of CKD and is implicated in the pathogenesis of LVH. Correction of anemia may cause regression of LVH in patients with CKD.32 Paradoxically, however, full correction of anemia has been associated with increased CV mortality in CKD patients with CAD or CHF.33 Higher iron stores may have an adverse effect on coronary perfusion. The current guidelines recommend correction of anemia but not overshoot the normal hemoglobin level.

The manifestations of CVD (CAD, LVH, CHF, hypertension, atrial fibrillation, ventricular arrhythmias, cardiomyopathy, and sudden cardiac death) are accentuated and fully expressed in CKD patients. CVD mortality in ESRD patients is 20-30 times higher compared to the general population. CAD in patients with CKD tends to be severe and “violent” with high mortality. Unfortunately, ACS may be missed in patients with CKD because chest pain may be absent and EKG may be misleading due to LVH. The Uremic milieu drastically reduces the success of coronary and other vascular interventions in patients with CKD. Herein lies the deadly paradox--- CVD is not only extensive in patients with CKD but also less responsive even to aggressive and early therapeutic options. Ironically, patients with CKD may have ischemic heart disease (without visible occlusive coronary artery disease) due to microcirculatory disturbances and LVH. Another structural pathologic lesion--- arterial calcification---is frequent in patients with CKD. A high coronary artery calcification is common in patients with CKD.47

disease, prevalence of premature cardiovascular disease, and relationship to short-term mortality. Am Heart J 2008; 156:277-83.

HYPERTENSION

656

Fliser D, Franek E, Joest M, et al. Renal function in the elderly: impact of hypertension and cardiac function. Kidney Int 1997; 51:1196-204.

Farmer CK, Goldsmith DJ, Cox J, et al. An investigation of the effect of advancing uraemia, renal replacement therapy and renal transplantation on blood pressure diurnal variability. Nephrol Dial Transplant 1997; 12:2301-7.

Klassen PS, Lowrie EG, Reddan DN, et al. Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis. JAMA 2002; 287:1548-55.

Shulman NB, Ford CE, Hall WD, et al. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-up Program Cooperative Group. Hypertension 1989; 13(suppl): 180-93.

Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT Study Group. Lancet 1998; 351:1755-62.

Liu Y, Coresh J, Eustace JA, et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 2004; 291:451-9.

Shoji T, Nishizawa Y, Nishitani H, et al. Impaired metabolism of high density lipoprotein in uremic patients. Kidney Int 1992; 41:1653-61.

Shoji T, Nishizawa Y. Plasma lipoprotein abnormalities in hemodialysis patients---clinical implications and therapeutic guidelines. Ther Apher Dial 2006; 10:305-15.

10. Apostolov EO, Basnakian AG, Ok E, Shah SV. Carbamylated low-density lipoprotein: nontraditional risk factor for cardiovascular events in patients with chronic kidney disease. J Ren Nutr 2012; 22:134-8. 11. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238-48. 12. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009; 360:1395-407. 13. Baigent C, Landray MJ, Reith C, et al. On behalf of the SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011; 377:2181-92. 14. Hou W, Lv J, Perkovic V, et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Eur Heart J 2013; 34:1807-17. 15. Fellstrom B, Holdaas H, Jardine AG, et al. Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial. Kidney Int 2004; 66:154955. 16. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American

Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; pii:S0735-1097(13)06028-2. 17. Raj DS, Choudhury D, Welbourne TC, Levi M. Advanced glycation end products: a nephrologist’s perspective. Am J Kidney Dis 2000; 35:365-80. 18. Brownlee M, Cerami A, Vlassara H. Advanced products of nonenzymatic glycosylation and the pathogenesis of diabetic vascular disease. Diabetes Metab Rev 1988; 4:437-51. 19. Mykkanen L, Zaccaro DJ, O’Leary DH, et al. Microalbuminuria and carotid artery intima-media thickness is nondiabetic and NIDDM subjects. The Insulin Resistance Atherosclerosis Study (IRAS). Stroke 1997; 28:1710-16. 20. Suzuki K, Kato K, Hanyu O, et al. Left ventricular mass index increases in proportion to the progression of diabetic nephropathy in type 2 diabetic patients. Diabetes Res Clin Pract 2001; 54:173-80. 21. Stephenson JM, Kenny S, Stevens LK, et al. Proteinuria and mortality in diabetes: the WHO Multinational Study of Vascular Disease in Diabetes. Diabet Med 1995; 12:149-55. 22. Stehouwer CD, Lambert J, Donker AJ, et al. Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovasc Res 1997; 34:55-68. 23. Stehouwer CD, Nauta JJ, Zeldenrust GC, et al. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet 1992; 340:319-23. 24. Festa A, D’Agostino R, Howard G, et al. Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: the Insulin Resistance Atherosclerosis Study. Kidney Int 2000; 58:1703-10. 25. Mann JF, Gerstein HC, Yi QL, et al. Development of renal disease in people at high cardiovascular risk: results of the HOPE randomized study. J Am Soc Nephrol 2003; 14:641-7. 26. Grassi G, Seravalle G, Calhoun DA, et al. Mechanisms responsible for sympathetic activation by cigarette smoking in humans. Circulation 1994; 90:248-53. 27. Ritz E, Benck U, Franek E, et al. Effects of smoking on renal hemodynamics in healthy volunteers and in patients with glomerular disease. J Am Soc Nephrol 1998; 9:1798-804. 28. Kamimura MA, Carrero JJ, Canziani ME, et al. Visceral obesity assessed by computed tomography predicts cardiovascular events in chronic kidney disease patients. Nutr Metab Cardiovasc Dis 2013; 23:891-7. 29. de Mutsert R, Snijder MB, van der Sman-de Beer F, et al. Association between body mass index and mortality is similar in the hemodialysis population and the general population at high age and equal duration of follow-up. J Am Soc Nephrol 2007; 18:967-74. 30. Baigent C, Burbury K, Wheeler D. Premature cardiovascular disease in chronic renal failure. Lancet 2000; 356:147-52. 31. Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004; 15:2208-18. 32. Silberberg J, Racine N, Barre P, Sniderman AD. Regression of left ventricular hypertrophy in dialysis patients following correction of anemia with recombinant human erythropoietin. Can J Cardiol 1990; 6:1-4. 33. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients

with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339:584-90. 34. Stenvinkel P, Heimburger O, Jogestrand T. Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients: association with Chlamydia pneumoniae seropositivity. Am J Kidney Dis 2002; 39:274-82. 35. Yeun JY, Levine RA, Mantadilok V, Kaysen GA. C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 2000; 35:469-76.

37. McIntyre CW, Harrison LE, Eldehni MT, et al. Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6:133-41. 38. Ramkumar N, Cheung AK, Pappas LM, et al. Association of obesity with inflammation in chronic kidney disease: a cross-sectional study. J Ren Nutr 2004; 14:201-7. 39. Stenvinkel P, Alvestrand A. Inflammation in end-stage renal disease: sources, consequences, and therapy. Semin Dial 2002; 15:329-37. 40. Solak Y, Yilmaz MI, Sonmez A, et al. Neutrophil to lymphocyte ratio independently predicts cardiovascular events in patients with chronic kidney disease. Clin Exp Nephrol 2013; 17:532-40. 41. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 2002; 62:152438.

657

43. Tepel M, van der Giet M, Statz M, et al. The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a randomized, controlled trial. Circulation 2003; 107:992-5. 44.

Elsayed EF, Tighiouart H, Griffith J, et al. Cardiovascular disease and subsequent kidney disease. Arch Intern Med 2007; 167:1130-6.

45. London GM, Parfrey PS. Cardiac disease in chronic uremia: pathogenesis. Adv Ren Replace Ther 1997; 4:194-211. 46. Foley RN, Parfrey PS, Harnett JD, et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 1995; 47:186-92. 47. Matsuoka M, Iseki K, Tamashiro M, et al. Impact of high coronary artery calcification score (CACS) on survival in patients on chronic hemodialysis. Clin Exp Nephrol 2004; 8:54-8. 48. Goldenberg I, Moss AJ, McNitt S, et al. On behalf of the Multicenter Automatic Defibrillator Implantation TrialII Investigators. Relations among renal function, risk of sudden cardiac death, and benefit of the implanted cardiac defibrillator in patients with ischemic left ventricular dysfunction. Am J Cardiol 2006; 98:485-90. 49. Pun PH, Smarz TR, Honeycutt EF, et al. Chronic kidney disease is associated with increased risk of sudden cardiac death among patients with coronary artery disease. Kidney Int 2009; 76:652-8.

CHAPTER 141

36. Kato S, Chmielewski M, Honda H, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol 2008; 3:1526-33.

42. Boaz M, Smetana S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomized placebo-controlled trial. Lancet 2000; 356:1213-18.

Hypertension in CKD Management Issues

C H A P T E R

142 INTRODUCTION

Chronic kidney disease (CKD) is a worldwide public health problem. The prevalence of CKD has steadily increased over the past two decades in US.The prevalence of CKD in India is largely undetermined. A recent study from western India showed CKD was found in 20.93% and eGFR <60 mL/min/1.73 m2 was noted in 8.29% of participants. In India, it has been recently estimated that the ageadjusted incidence rate of end stage renal disease (ESRD) to be 229 per million population (pmp), and >100,000 new patients enter renal replacement programs annually. Hypertension (HTN) has been reported to occur in 85% to 95% of patients with CKD (stages 3–5). The relationship between HTN and CKD is cyclic in nature. Uncontrolled HTN, a risk factor for developing CKD, is associated with a more rapid progression of CKD, and is the second leading cause of ESRD in the U.S. Meanwhile, progressive renal disease can exacerbate uncontrolled HTN due to volume expansion and increased systemic vascular resistance. Multiple guidelines discuss the importance of lowering blood pressure (BP) to slow the progression of renal disease and reduce cardiovascular morbidity and mortality. However, in order to achieve and maintain adequate BP control, most patients with CKD require combination of antihypertensive agents; often up to three or four different medication classes.

PATHOPHYSIOLOGY

HTN - related mechanisms that are involved in the progression of renal damage include the systemic BP load, the degree to which it is transmitted to the renal microvasculature(i.e., renal autoregulation), and local susceptibility factors to barotrauma, which is the degree of damage for any degree of BP load. Among these proteinuria, glomerular hypertrophy, fibrogenic mediators, genetic factors, and age are the most important. Proteinuria is also important factor in progression of CKD. Therefore, drugs targeting proteinuria benefit in controlling HTN and overall retarding the progression of CKD. The potential benefits of lower BP include a decreased risk of both cardiovascular disease (CVD) and progression of CKD. To assess the likely benefit in a given patient, the clinician needs to consider such issues as the prior rate of CKD progression, the expected course of the specific disease, the level of urinary albumin excretion and the presence or absence of other risks of CVD. Potential

Pritam Gupta, Ankur Gupta

adverse effects generic to treatment used to lower BP include decreases in cerebral perfusion (contributing to dizziness, confusion and falls) and acute deterioration in kidney function.

BLOOD PRESSURE PATTERN IN CKD

Masked uncontrolled HTN is more prevalent among individuals with CKD with rates ranging from 40% to 70%. The likelihood of having masked uncontrolled HTN rises in proportion to kidney dysfunction and the extent of proteinuria. Without an assessment of ambulatory or home BP, masked uncontrolled HTN will be missed, and this group of individuals is at a high risk for both cardiovascular events and initiation of dialysis. In healthy individuals, BP falls by 10% to 20% during sleep. A fall in nocturnal BP characterises a normal circadian pattern of BP. Individuals whose BP fails to drop or, instead, rises at night are at an increased risk of death compared with dippers. In addition, mean nocturnal systolic BP predicts ESRD or death, and non-dipping is associated with the severity of interstitial fibrosis and tubular atrophy. Therefore, the findings from Hermida and colleagues, that dipping patterns are blunted in individuals with CKD is a concern and particularly relevant for management of HTN in patients with CKD.

SCREENING FOR SECONDARY CAUSES OF HYPERTENSION IN SPECIFIC GROUP OF CKD PATIENTS

Renovascular hypertesnion- In patients in whom fibromuscular dysplasia (FMD) is suspected, an MR angiogram of the kidney should be performed. Routine screening for atherosclerotic renovascular disease is not recommended.

Pheochromocytoma- Plasma-free metanephrines levels may be falsely high in advanced CKD. In patients with CKD 5, plasma catecholamines (epinephrine and norepinephrine) may be a more appropriate screening test for pheochromocytoma.

Primary aldosteronism-24-hr urine aldosterone >12 μg with a suppressed plasma renin activity in the setting of high dietary sodium intake along with MR of abdomen.

Glomerulonephritis- Urine microscopy should be performed in any patient who has sudden worsening of hypertension or renal functions.

TARGETS OF BP CONTROL

It is recommended that adults with CKD (diabetic/non-

The recent publication of the Systolic Blood Pressure Intervention Trial (SPRINT) has again opened the debate on optimal BP targets. This trial, enriched with patients of CKD and the elderly, indicated superior cardiovascular and survival outcomes from a target systolic BP< 120 mm Hg versus the usual systolic BP target of < 140 mm Hg. At many levels, from primary care to subspecialty providers including nephrologists, there are calls for modifying current guidelines to consider new lower BP targets.

MANAGEMENT

Individualise BP targets and agents according to age, coexistent CVD and other comorbidities, risk of progression of CKD, presence or absence of retinopathy (in CKD patients with diabetes) and tolerance of treatment.

Non pharmacological interventions to control blood pressure

Lifestyle modification offers the potential to lower BP in a simple, inexpensive, effective fashion while also improving a range of other outcomes (e.g., changes in lipid levels resulting from diet and exercise and liver function through moderation of alcohol intake). Various observational studies show that weight-loss strategies reduce BP in CKD patients. A BMI of 20-25 is recommended. High dietary salt intake not only exacerbates HTN in patients with CKD but also has the potential to directly worsen kidney function. Rats receiving a high salt diet show sustained increases in kidney levels of transforming growth factor-β, polypeptides associated with kidney fibrosis. High salt diet blunts kidney autoregulation, which exposes the glomerulus to higher filtration pressures. Over time, the high glomerular filtration pressure leads to glomerular sclerosis and nephron loss. Lowering salt intake reduces BP in the general population. In CKD patients with reduced GFR, salt retention is associated with an increase in BP. Lowering of salt intake to 90 mmol (2 g) per day of sodium (corresponding to 5 g of sodium chloride) is advisable unless there is contraindications. Two larger studies from the US Renal Data System found that CKD 5 patients on dialysis who are sedentary have a higher risk of death than those who are active. Therefore undertaking an exercise program compatible with cardiovascular health and tolerance, aiming for at least 30minutes 5 times per week is recommended. Consumption of alcohol in moderation with cessation of

cigarette smoking is advisable, though there is no direct data regarding this.

659

Pharmacological treatment

Data has shown that in CKD patients three or more agents are frequently needed for BP control. With the exception of ARBs or ACE-Is in CKD patients with high levels of urinary albumin or protein excretion, there is no strong evidence to support the preferential use of any particular agent(s) in controlling BP in CKD; nor are there data to guide the clinician in the choice of second- and thirdline medications. CKD patients have relatively poor cardiovascular outcomes relating to their non dipper and reverse dipper status. Atleast one of the antihypertensive drug is suggested to be given at night. Also, to have maximum adherence and less of side effects, combination of drugs to have minimum pill burden is recommended whenever possible.

RAAS BLOCKERS

ACE-Is and ARBs should be used with caution or even avoided in certain CKD subgroups, particularly in patients with bilateral renal-artery stenosis or with intravascular fluid depletion, because of the risk of a large reduction in GFR. The normal capacity of the kidney to auto-regulate GFR in the face of fluctuations in BP is impaired in CKD and further compromised by the use of ACE-Is or ARBs. If hyperkalemia occurs with them, then possible measures include lowering of potassium in diet, reducing dose or switching to fosinopril or trandolapril or adding potassium losing diuretic. The elderly diabetic patients should also be enquired about postural hypotension which may be increased by vasodilators and diuretics via volume depletion. Antihypertensive and anti-proteinuric effects of ACE-Is and ARBs are complemented by dietary sodium restriction or administration of diuretics. Co- administration of betablockers and calcium-channel blockers with ACE-Is or ARBs is also acceptable. Aldosterone antagonists like spironolactone and eplerenone have been shown to decrease urine albumin excretion when added to ACE-I or ARB therapy. Hyperkalemia is potential side-effect and plasma potassium levels and kidney function should be monitored closely during the introduction of aldosterone antagonists and during intercurrent illnesses, particularly those associated with a risk of GFR reduction, as occurs with dehydration.

DIURETICS

Salt and water retention are major factors contributing to high BP in CKD patients and to morbidity and mortality through systemic or pulmonary edema. Thus, diuretics potentially have an important role in the control of hypertension in this clinical setting. Thiazides or thiazide like agents like chlorthalidone or indapamide are recommended as addition to ACE-I or ARBs for BP control especially in setting of edema. As the GFR falls below about 30–50ml/min/1.73m2, thiazides might not be effective in reducing edema. Their dose needs to be increased or switch to a loop diuretic like frusemide or

CHAPTER 142

diabetics) with urine albumin excretion < 30 mg/day whose office BP is consistently >140mmHg systolic or > 90mmHg diastolic be treated with BP- lowering drugs to maintain a BP that is consistently <140 mm Hg systolic and <90 mm Hg diastolic. Also it is suggested that CKD (diabetic/nondiabetic) patients with urine albumin excretion >30mg/ day whose office BP is consistently >130mmHg systolic or > 80mmHg diastolic be treated with BP- lowering drugs to maintain a BP that is consistently <130 mm Hg systolic and <80 mm Hg diastolic. Furthermore, guidelines also recommend ACE-I or ARBs to be used as first line agents for such patients.

660

torsemide in patients with CKD 4, particularly if the BP is becoming resistant to therapy.

CCBS

HYPERTENSION

The major subclasses are the dihydropyridines (e.g., amlodipine, nifedipine, cilnidipine and lercanidipine), the non-dihydro-pyridine benzothiazepines (e.g., diltiazem) and the phenylalkylamines (e.g., verapamil). Studies have shown anti-proteinuric effect of cilnidipine. However, fluid retention, seen particularly with dihydropyridines, can be problematic in patients with CKD.

BETA BLOCKERS

In patients with CKD, the accumulation of beta-blockers or active metabolites could exacerbate concentrationdependent side effects such as brady-arrhythmias. Such accumulation occurs with atenolol and bisoprolol, but not carvedilol, propranolol, or metoprolol. They can be combined with ACE-I or ARBs but should not be combined with verapamil or diltiazem as such combination can lead to life threatening brady-arrhythmias.

ALFA BLOCKERS

Alpha-blockers reduce the symptoms of benign prostatic hyperplasia, which may be a co-morbidity to consider in older men with CKD. In general, alpha-blockers are not considered a first-line choice because of the common side effects of postural hypotension, tachycardia and headache. They should be commenced at a low dosage to avoid a first-dose hypotensive reaction.

CENTRALLY ACTING ALPHA-ADRENERGIC AGONISTS

They decrease sympathetic outflow from brain and cause vasodilatation.The main agents in use are methyldopa, clonidine, and moxonidine. They are often required for BP control when other agents fail. Their important sideeffect is fluid retention which often requires diuretic use.

DIRECT VASODILATORS

Minoxidil is needed in cases of resistant hypertension. Side -effects often limits its use. Hydralazine is used in hypertensive emergencies.

HYPERTENSION IN DIALYSIS POPULATION

There have been no trials establishing an optimal level of BP control in patients on dialysis, and guidelines extrapolate trials in other high risk patients (e.g. diabetics). UK renal association guidelines suggest a BP goal of < 130/80 mmHg in both HD (post-dialysis) and PD patients. Achieving BP targets in patients on HD is difficult: 1.

HTN is multifactorial.

Volume overload is a major problem.

Timing of measurement of BP is controversial (pre or post-dialysis). Interdialytic measurement or ambulatory blood pressure monitoring (ABPM), are probably more useful but not easy to achieve in practice.

Compliance with salt and water intake and polypharmacy are major issues.

It is possible to achieve excellent BP control without the use of any drugs by normalising extracellular fluid volume and maintaining dry weight with ultrafiltration on dialysis. Salt and fluid intake between dialysis sessions must be kept low. Doses of antihypertensives should be kept low to avoid hypotension.

BP CONTROL IN RENAL TRANSPLANT RECIPIENTS

HTN is well recognised as an important risk factor for both decline in transplant kidney function and development of CVD and an increased risk of graft loss and all-cause mortality. The aetiology of HTN in renal transplant is multifactorial: •

Native diseased kidneys

•

Calcineurin inhibitors (cyclosporine, tacrolimus)

•

Steroids

•

Pretransplant HTN

•

Donor HTN

•

Tranplant renal artery stenosis

•

Chronic allograft injury

It is suggested that adult kidney transplant recipients whose office BP is consistently >130mmHg systolic or >80mmHg diastolic be treated to maintain a BP that is consistently <130mmHg systolic and <80mmHg diastolic, irrespective of the level of urine albumin excretion. In adult kidney transplant recipients, choose a BPlowering agent after taking into account the time after transplantation, use of calcineurin inhibitors, presence or absence of persistent albuminuria, and other co-morbid conditions.

CONCLUSION

No single BP target is optimal for all CKD patients. It is encouraged to individualise treatment depending on age, the severity of albuminuria, and co-morbidities. In general, the available evidence indicates that in CKD patients without albuminuria the target BP should be ≤140 mmHg systolic and ≤90 mmHg diastolic. However, in most patients with an albumin excretion rate of ≥30 mg/ day (i.e., those with both micro- and macroalbuminuria), a lower target of ≤130 mmHg systolic and ≤80 mmHg diastolic is suggested. In achieving BP control, the value of lifestyle changes and the need for multiple pharmacological agents is acknowledged. Use of agents that block the RAAS is recommended or suggested in all patients with an albumin excretion rate of ≥30 mg/day. Recommendations are almost identical in CKD patients with and without diabetes.

REFERENCES

High prevalence of chronic kidney disease in a semi-urban population of Western India. Trivedi H, Vanikar A, Patel H, et al. Clin Kidney J 2016; 9:438-43.

Epidemiology and risk factors of chronic kidney disease in India—results from the SEEK (Screening and Early Evaluation of Kidney Disease) study. Singh AK, Farag YMK, Mittal BV, et al. BMC Nephrol 2013; 14:114–24.

Chronotherapy improves blood pressure control and reduces vascular risk in CKD. Hermida RC, Ayala DE, Smolensky MH, et al. Nat Rev Nephrol 2013; 9:358-68.

A European Renal Best Practice (ERBP) position statement on the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of blood pressure in non-dialysis-dependent chronic kidney disease: an endorsement with some caveats for real-life application. Verbeke F, Lindley E, Van Bortel L, et al. Nephrol Dial Transplant 2014;29(3):490-6.

Masked Uncontrolled Hypertension in CKD. Agarwal R, Pappas MK, Sinha AD. J Am Soc Nephrol 2016; 27:924-32.

Ambulatory and home blood pressure monitoring in people with chronic kidney disease. Time to abandon clinic blood pressure measurements? Ruiz-Hurtado G, Gorostidi M, Waeber B, Ruilope LM. Curr Opin Nephrol Hypertens 2015; 24:488-91.

Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard bloodpressure control. N Engl J Med 2015; 373:2103-16.

KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Taler SJ, Agarwal R, Bakris GL, et al. Am J Kidney Dis 2013; 62:201-13.

10. How Does SPRINT (Systolic Blood Pressure Intervention Trial) Direct Hypertension Treatment Targets for CKD? Taler SJ. Am J Kidney Dis 2016; 68:15-8.

661

CHAPTER 142

Kidney disease: Improving global outcomes (KDIGO) blood pressure work group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Becker, G.J.a, Wheeler, D.C.b, De Zeeuw, D.c, et al. Kidney International Supplements 2012; 2:337-414.

C H A P T E R

143

Managing Blood Pressure in Acute Stroke : A Dilemma

Hypertension is the most important modifiable risk factor for stroke. It is estimated that 25% or more of strokes may be attributable to hypertension. Because many patients with stroke have mild hypertension or prehypertension, we have shifted our focus and now think of stroke on a continuum of risk based on blood pressure (BP) level rather than on a threshold effect. Because high BP may not exist in isolation, a wider definition of hypertension has been proposed that also takes into account the absolute risk of cardiovascular events and associated metabolic factors or early disease markers. Several observations have demonstrated spontaneous elevation of blood pressure in the first 24-48 h after stroke onset with a significant spontaneous decline after a few days. Several mechanisms may be responsible for the increased blood pressure including stress, pain, urinary retention, Cushing effect due to increased intra cranial pressure and the activation of the sympathetic, reninangiotensin and ACTH-cortisol pathways. Despite of increased prevalence of hypertension following stroke, optimal management has not been yet established. Several arguments speak for lowering the elevated BP: risks of hemorrhagic transformation, cerebral edema, recurrence of stroke and hypertensive encephalopathy. On the other hand, it may be important to maintain the hypertensive state due to the damaged autoregulation in the Ischemic brain and the risk of cerebral hypoperfusion exacerbated by the lowered systemic blood pressure. Lowering BP reduces the risk of stroke. Epidemiological studies have shown that for each 10 mm Hg lower systolic blood pressure (SBP), there is a decrease in risk of stroke of approximately one third in persons aged 60 to 79 years. This association is continuous down to levels of at least 115/75 mm Hg and is consistent across sexes, regions, stroke subtypes, and for fatal and nonfatal events. Lowering diastolic blood pressure (DBP) was once the main target to achieve stroke and other cardiovascular event reduction, but SBP has now become the target. As recently shown, even the elderly with sustained SBP elevation may gain from BP reduction in relation to less fatal or nonfatal stroke, death, and heart failure. Although the role of longer-term BP control to improve outcomes in patients with stroke is undisputed, BP management immediately after a stroke remains controversial.

Bhupendra Chaudhary, Binay Karak

BLOOD PRESSURE MANAGEMENT AFTER INTRACEREBRAL HEMORRHAGE

Patients with intracerebral hemorrhage (ICH) often have elevated BP. Approximately one third of all patients with ICH presenting within 3 hours of symptom onset have a significant expansion of the hematoma over the next 20 hours. Initial hematoma volume and hematoma expansion are powerful predictors of mortality after ICH. Some studies have suggested an association between high BP and hematoma expansion and BP is often lowered under the assumption that high BP promotes hematoma expansion. Nonetheless, there may be other reasons to lower BP. Hypertensive patients with ICH may have heart failure or elevated cardiac troponin in which lowering BP might be helpful. The argument against lowering BP in acute ICH is based on the possible existence of a perihematomal ischemic zone. Recent studies, however, indicate that low blood flow around the hematoma may be a consequence of reduced cerebral metabolism in this area rather than a primary reduction of blood flow. In addition, chronic hypertensives (due to a shift in the autoregulatory curve) and patients with increased intracranial pressure (ICP; due to lowered cerebral perfusion pressure) may develop cerebral ischemia if BP is acutely lowered.

DILEMMA ABOUT BLOOD PRESSURE MANAGEMENT AFTER ACUTE INTRACEREBRAL HEMORRHAGE

While treating the patient of acute intracerebral hemorrhage the question of controlling the blood pressure in domain of when, how and how much always remains in mind of internist. Despite of vast experience in treating such situation many times one find himself in a difficult way to deal such an emergency situation so.

WHAT BLOOD PRESSURE LEVEL IS CONSIDERED TO BE TOO HIGH AND REQUIRING IMMEDIATE REDUCTION?

Despite absence of definitive supportive evidence, some experts believe that a SBP of >180 mm Hg or a mean arterial pressure (MAP) of >130 mm Hg would warrant immediate lowering. In the presence of conditions such as acute heart failure, hypertensive encephalopathy, active cardiac ischemia, and so on, lower BP targets may be appropriate.

WHAT IS THE APPROPRIATE TARGET BLOOD PRESSURE IN PATIENTS WITH ICH?

HOW FAST SHOULD BLOOD PRESSURE BE LOWERED?

Results of small studies suggest that rapidly lowering MAP by approximately 15% does not lower cerebral blood flow, whereas reductions of >20% can do so. Therefore, if BP-lowering is considered, current guidelines suggest cautious lowering of BP by no more that 20% in the first 24 hours.

WHAT ANTIHYPERTENSIVE AGENTS ARE APPROPRIATE FOR USE IN THE ACUTE SETTING?

Short and rapidly acting intravenous antihypertensive agents are preferred. In the United States, labetalol, hydralazine, esmolol, nicardipine, enalapril, nitroglycerin, and nitroprusside have been recommended. Intravenous urapidil is also used in Europe. Large studies comparing various antihypertensives are not available. Sodium nitroprusside and nitroglycerin should be used with caution because these agents can potentially increase ICP. It is the target of BP lowering which is more important than the agent used.

BLOOD PRESSURE MANAGEMENT AFTER ACUTE ISCHEMIC STROKE

Although hypertension in the immediate post-stroke period is frequently observed, BP tends to spontaneously fall within the first hours and days following the acute event, with the pattern of blood pressure change varying with stroke subtype. Precipitous falls in BP have, however, been associated with poor outcome and should be avoided. A ‘U-shaped’ association between admission BP and stroke outcome has been identified, with very high and very low BP being associated with poor post-stroke outcome. Early recurrent stroke has been suggested as one possible mechanism by which elevated BP may be associated with poor outcome. Cerebral perfusion becomes dependent upon systemic arterial BP following stroke due to impairment of cerebral autoregulation, and therefore changes in systemic BP can directly influence cerebral perfusion. Hypertension may sustain cerebral perfusion to the ischemic penumbra, with BP having been shown to fall spontaneously in response to successful recanalization of cerebral vessels following thrombolytic treatment, perhaps suggesting the restoration of cerebral autoregulation. High prethrombolysis BP has also been shown to be associated with poor recanalization and sustained hypertension may

663

DILEMMA ON BP MANAGEMENT IMMEDIATELY AFTER AN ACUTE ISCHEMIC STROKE

Apart from managing the ischemic penumbra, the management of other parameters like hyperglycemia, hyperthermia, raised ICP and the accelerated HT are of paramount importance, of which the high blood pressure leads the situation.

SHOULD BLOOD PRESSURE BE LOWERED IN PATIENTS WITH ELEVATED BP AFTER AN ISCHEMIC STROKE?

As per the AHA/ASA guidelines, it is recommended that before intravenous thrombolytic treatment, BP should be lowered if >185 mm Hg systolic or >110 mm Hg diastolic. After thrombolytic treatment, SBP should be kept <180 mm Hg and DBP <105 mm Hg. Intravenous labetalol, nitropaste, nicardipine infusion, and, if BP remains elevated, sodium nitroprusside are the recommended agents. Despite the absence of supporting evidence, these recommendations are often applied to patients receiving other forms of reperfusion therapy (e.g., intraarterial thrombolysis, clot retrieval, and so on). Patients with other indications for BP-lowering such as acute heart failure, aortic dissection, and so on should have the BP lowered. One should be cautious about abruptly lowering BP in other patients due to the risk of worsening cerebral ischemia. Guidelines suggest withholding antihypertensive agents in these patients unless the DBP is >120 mm Hg or the SBP is >220 mm Hg and limiting the drop in BP during the first 24 hours by approximately 15%.

Should Blood Pressure Be Elevated to Improve Cerebral Perfusion in Patients With Ischemic Stroke?

A few small case series have shown neurological improvement with induced hypertensive therapy. Studies are underway to assess the usefulness of this form of therapy in patients with a diffusion-perfusion mismatch on MRI. In the meantime, it is reasonable to try volume expansion and/or vasopressors in patients with hypotensive stroke or in patients who have had a worsening of the neurological deficit in association with a drop in BP.

Should Patients on Antihypertensive Agents Have Their Medications Held or Continued?

The AHA/ASA guidelines recommend restarting antihypertensives at 24 hours in previously hypertensive neurologically stable patients unless contraindicated. At the end, the optimum post-stroke BP, and how to achieve it, is yet to be identified. Current clinical guidelines do not advocate the active reduction of hypertension in the immediate post-stroke period unless there is a concurrent indication to do so. If elevated BP is to be

CHAPTER 143

Immediately after an ICH, it is perhaps more appropriate to tailor the target BP to each patient rather than using a “one size fits all” approach. The possibility of increased ICP and a history of chronic untreated hypertension should be considered while choosing the target. Recognizing the absence of definitive data, the American Heart Association/American Stroke Association (AHA/ ASA) guidelines suggest maintaining a cerebral perfusion pressure of 60 to 80 mm Hg in patients with possible increased ICP and a BP of 160/90 or a MAP of 110 mm Hg in other patients.

contribute to worsening cerebral edema and hemorrhagic transformation following acute ischemic stroke. Cardiovascular complications as well as early stroke recurrence in patients with elevated post-stroke BPs have been proposed as possible mechanisms for poor outcome.

664

lowered in the acute post-stroke period, the reduction should be cautious.

Tsivgoulis G, Saqqur M, Sharma VK, et al. Association of pretreatment blood pressure with tissue plasminogen activator- induced arterial recanalization in acute ischemic stroke. Stroke 2007; 38:961-6.

Mai tic HP, Kappeler L, Arnold M, et al. Blood pressure and vessel recanalization in the first hours after ischemic stroke. Stroke 2005; 36:264-9.

Willmot, M, Leonardi-Bee J, Bath PM. High blood pressure in acute stroke and subsequent outcome. A systemic review. Hypertension 2004; 43:18-24.

Bath P, Chalmers J, Powers W, et al. International Society of Hypertension (ISH): statement on the management of blood pressure in acute stroke. J Hypertension 2003; 21:665-72.

REFERENCES

HYPERTENSION

Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44:870-947. Bhatia R, Singh H, Singh S, et al. A prospective study of inhospital mortality and discharge outcome in spontaneous intracerebral hemorrhage. Neurol India 2013; 61:244-8. Robinson TG, Potter JF, Ford GA, et al. Effects of antihypertensive treatment after acute stroke in the Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomised, open, blindedendpoint trial. Lancet Neurol 2010; 9:767-75.

C H A P T E R

144

Impact of Recent Hypertension Guidelines on Clinical Practice

The movement towards evidence-based healthcare has been gaining ground quickly over the past few years, motivated by clinicians, and management concerned about quality, consistency and costs. Clinical Practice Guidelines, based on standard best practice, have been shown to be capable of supporting improvements in quality and consistency in healthcare. Many have been developed, though the process is time as well as resourceconsuming. Many have been disseminated, though largely in the relatively difficult to use format of narrative text. As yet they have not had a major impact on medical practice, but their importance is growing. •

To describe appropriate care based on the best available scientific evidence and broad consensus;

•

To reduce inappropriate variation in practice;

•

To provide a more rational basis for referral;

•

To provide a focus for continuing education;

•

To promote efficient use of resources;

•

To Act as focus for quality control, including audit;

•

To highlight shortcomings of existing literature and suggest appropriate future research.

HYPERTENSION AND RECENT GUIDELINES

Hypertension is a major contributor to cardiovascular morbidity and mortality in India and worldwide. In view of our special geographical and climatic conditions, ethnic background, dietary habits, literacy levels and socioeconomic variables, there could be some areas where significant differences need to be addressed. About one third of adult in most communities in developed or developing world have hypertension. Most patients with hypertension have other risk factors as well. Despite well-established approaches to diagnosis and treatment, the success of treating hypertension has been limited. In most of the communities fewer than half of hypertensive patients have adequately controlled BP. There are several important guidelines with new editions recently for managing hypertension as The 2013 ESH/ESC Guideline for management of arterial hypertension 2014 Evidence Based Guideline for the management of high BP in Adults- JNC 8 Report Indian Guideline on hypertension III 2013

NK Soni, VB Jindal

Clinical Practice Guideline for management of hypertension in the community A consensus Statement by ASH and ISH 2013 NICE Guideline for Hypertension in Adults 2011 Hypertension Canada Guidelines 2015 Guideline for diagnosis and management of hypertension in adult by Heart Foundation of Australia 2016 We have taken three to be reviewed i.e. JNC 8 from US published in JAMA in Dec 2013,IGH 3 from India published in JAPI Feb 2013 and NICE guideline from UK with updates in 2011 most commonly used as reference for clinical practice in India.

WHAT IS NEW IN JNC 8

The 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in Adults, was developed by panel members appointed to the Eighth Joint National Committee (JNC 8) and was endorsed by the American Academy of Family Physicians. Firstly, the definitions of hypertension and prehypertension, which were well-defined in JNC 7 has not been addressed in JNC 8. Secondly, similar treatment goals have been defined for all hypertensive population and no distinction between uncomplicated hypertension and hypertension with comorbid conditions like diabetes or chronic kidney disease (CKD) has been made. Another difference was the choice of initial drug in patients without compelling indications. In contrast to JNC 7 where thiazides were recommended to be the initial choice in patients without compelling indications, no such recommendation has been made in JNC 8. In all JNC 8 made nine recommendations. These recommendations were categorized from grades A to E and Grade N depending upon the strength of the recommendations. Grade A means “strongly recommended,” Grade B means “moderately recommended,” Grade C means “weakly recommended,” Grade D means “recommendation against” and Grade E means “expert opinion” (i.e., there is insufficient evidence or evidence is unclear or conflicting, but this is what the committee recommends). Grade N means “no recommendation for or against.” First five of the nine recommendations dealt with the question of threshold BP at which treatment should be started and the target BP, which is required to be achieved with treatment.

HYPERTENSION

666

Recommendation 1 (Grade A recommendation) states that in the general population aged ≥60 years, initiate pharmacologic treatment if BP is ≥150/90 mmHg and treat to a goal BP of <150/90 mmHg.

As is clear from discussion, JNC 8 guidelines are evidence based, more simplified with clear-cut thresholds and target ranges, and will surely be handy at the hands of clinicians in managing hypertensive patients.

Recommendation 2 states that in the general population <60 years, initiate pharmacologic treatment to lower BP at diastolic blood pressure (DBP) ≥90 mmHg and treat to a goal DBP <90 mmHg (For ages 30-59 years Grade A recommendation; for ages 18-29 years Grade E recommendation).

WHAT IS NEW IN INDIAN GUIDELINES ON HYPERTENSION - III

Recommendation 3 (Grade E) states that in the general population <60 years, pharmacologic treatment should be initiated if systolic blood pressure (SBP) is ≥140 mmHg and treat to a goal SBP <140 mmHg. In the population aged ≥18 years with CKD or diabetes, treatment should be initiated if BP is ≥140/90 and treat to goal BP of <140/90 mmHg (recommendations 4 and 5, Grade E). Recommendation 6-8 addressed the issue of choice of the drug to be given to hypertensive patients. As per recommendation 6 (Grade B recommendation), in the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB). In the general black population, including those with diabetes, initial antihypertensive treatment should include a thiazidetype diuretic or CCB (recommendation 7, for general black population: Grade B recommendation; for black patients with diabetes: Grade C recommendation). As per recommendation 8 (Grade B recommendation), in all patients aged ≥18 years with CKD, regardless of race or diabetic status, initial (or add-on) antihypertensive treatment should include an ACEI or ARB to improve kidney outcomes. Recommendation 9 (Grade E recommendation) addressed the broader issue of the treatment plan in a hypertensive patient according to which the main objective of hypertension treatment is to attain and maintain goal BP. As per this recommendation if goal BP is not reached within a month of treatment, the dose of the initial drug should be increased or a second drug from one of the classes in recommendation 6 should be added. The clinician should continue to assess BP and adjust the treatment regimen until goal BP is reached. If goal BP cannot be reached with 2 drugs, third drug from the list provided should be added and titrated. Recommendation says that an ACEI and an ARB should not be used together in the same patient. If goal BP is not reached using only the drugs in recommendation 6 because of a contraindication or the need to use more than 3 drugs to reach goal BP; antihypertensive drugs from other classes can be used. Referral to a hypertension specialist may be indicated for patients in whom goal BP cannot be attained using the above strategy or for the management of complicated patients for whom additional clinical consultation is needed.

In consonance with the first and second guidelines, a revised format was evolved by the Core committee which was then reviewed by 300 physicians and specialists from across the country whose inputs have been incorporated. Like the previous guidelines, this document has also been studied, reviewed, and endorsed by the Cardiological Society of India (CSI), Hypertension Society of India (HSI), Indian College of Physicians (ICP), Indian Society of Nephrology (ISN), Research Society for Study of Diabetes in India (RSSDI) and Indian Academy of Diabetes (IAD). The health related toxic effects of mercury are recognized world over and mercury sphygmomanometers are being replaced by aneroid and digital sphygmomanometers. We intend to emphasize that the change is inevitable and Indian physicians should also move towards using these devices and wean off the use of mercury sphygmomanometers. For follow up of the patients, while in 2nd Indian guidelines use of home monitoring of blood pressure was discouraged. However with availability of better devices and newer data showing its usefulness for follow up of these patients, this is now encouraged. The new epidemiological data that is now available in the last five years has been included and reflects the increasing prevalence and poor levels of control of hypertension in India. The value of beta-blockers as first line agents in hypertension has receded and these are now recommended as agents for use only in young hypertensive with specific indications. For routine patients these are no longer recommended as first line agents. Diuretics are now considered at par with of ACEI’s or ARB’s and calcium channel blockers and not as preferred agents as in previous guidelines. Chlorthalidone is now available and shown to be better than Hydrochlorothiazide and its usage is to be preferred. When blood pressure is high by more than 20/10 mm of Hg systolic and diastolic it is now recommended to start with a combination of drugs. Monotherapy is not going to be effective in achieving target blood pressure. Certain combinations have been shown to be better than others in recent trials. Specially ACEI’s/ARB’s in combination with CCB’s forms a good combination. Treatment of hypertension even in octogenarians (more than 80 years) has been shown to be beneficial (newer data) and has been recommended. At the time of 2nd guidelines, it was felt that “lower the better policy” for target blood pressure was preferred.

However it has been realized now that a J shaped curve does exist specially for non revascularised coronary artery disease patients and caution has been advocated in trying to lower blood pressure to low target levels specially in these patients. Chronic kidney disease is now recognized as a common comorbidity and has been explained. Awareness and diagnosis of this entity will help recognize the high risk hypertensive individuals.

The term HFnEF (Heart Failure with normal Ejection Fraction) needs to be recognized by physicians and has been mentioned and explained for use in clinical practice. HFnEF is common among elderly hypertensive individuals and is diagnosed on the basis of symptoms of dyspnea, raised BNP levels and diastolic dysfunction on echo with normal ejection fraction. Orthostatic Hypotension and its clinical implications have been included. A new form of non-pharmacological, interventional sympathetic denervation therapy has become recently available and is being evaluated. Its place in treatment of these patients will evolve over a period of time.

WHAT NEW IN NICE GUIDELINE

NICE guidelines change how high blood pressure is diagnosed and treated In one of the biggest changes to NICE’s previous guidance, published in 2006, the new 2011 guideline recommends that a diagnosis of primary hypertension should be confirmed using 24-hour ambulatory blood pressure monitoring (ABPM) as gold standard rather than be based solely on measurements of blood pressure taken in the clinic. Furthermore the implementation of ABPM in diagnosis would be cost saving for the NHS. The Guideline also gives a framework for use of home blood pressure monitoring (HBPM). For the first time this change empowers patients to become more involved in the monitoring and care of their hypertension. The NICE guideline also recommends changing the priority of medicines used to treat hypertension in people over the age of 55, focusing upon calcium channel blockers, based on evidence of event reduction and importantly, cost-effectiveness. Thiazide-like diuretics represent an alternative for those with heart failure or the very elderly who are intolerant of calcium channel blockers. In addition, the evidence around the choice of thiazide-like diuretics suggests that chlortalidone or indapamide may be more effective than bendroflumethiazide. For the first time, the Guideline offers advice on treating hypertension in the very elderly (people aged over 80). New costeffectiveness analysis shows that the cost of treating hypertension is now cheaper than doing nothing.

667

Stage 1 hypertension Clinic blood pressure is 140/90 mmHg or higher and subsequent ambulatory blood pressure monitoring (ABPM) daytime average or home blood pressure monitoring (HBPM) average blood pressure is 135/85 mmHg or higher. Stage 2 hypertension Clinic blood pressure is 160/100 mmHg or higher and subsequent ABPM daytime average or HBPM average blood pressure is 150/95 mmHg or high. Severe hypertension Clinic systolic blood pressure is 180 mmHg or higher or clinic diastolic blood pressure is 110 mmHg or higher. Measuring blood pressure Because automated devices may not measure blood pressure accurately if there is pulse irregularity (for example, due to atrial fibrillation), palpate the radial or brachial pulse before measuring blood pressure. If pulse irregularity is present, measure blood pressure manually using direct auscultation over the brachial artery. When measuring blood pressure in the clinic or in the home, standardise the environment and provide a relaxed, temperate setting, with the person quiet and seated, and their arm outstretched and supported. Diagnosing hypertension When considering a diagnosis of hypertension, measure blood pressure in both arms. If the difference in readings between arms is more than 20 mmHg, repeat the measurements.If the difference in readings between arms remains more than 20 mmHg on the second measurement, measure subsequent blood pressures in the arm with the higher reading. If blood pressure measured in the clinic is 140/90 mmHg or higher:Take a second measurement during the consultation.If the second measurement is substantially different from the first, take a third measurement.Record the lower of the last two measurements as the clinic blood pressure. If the clinic blood pressure is 140/90 mmHg or higher, offer ambulatory blood pressure monitoring (ABPM) to confirm the diagnosis of hypertension. If a person is unable to tolerate ABPM, home blood pressure monitoring (HBPM) is a suitable alternative to confirm the diagnosis of hypertension. If the person has severe hypertension, consider starting antihypertensive drug treatment immediately, without waiting for the results of ABPM or HBPM. If hypertension is not diagnosed but there is evidence of target organ damage such as left ventricular hypertrophy, albuminuria or proteinuria, consider carrying out investigations for alternative causes of the target organ damage. If hypertension is not diagnosed, measure the person’s clinic blood pressure at least every 5 years subsequently, and consider measuring it more frequently if the person’s clinic blood pressure is close to 140/90 mmHg.

CHAPTER 144

Approach to Hypertension and Kidney Disease has been revamped and KDIGO Clinical Practice Guidelines for management of Blood Pressure in Kidney Disease have been included.

In this guideline the following definitions are used.

HYPERTENSION

668

When using ABPM to confirm a diagnosis of hypertension, ensure that at least two measurements per hour are taken during the person’s usual waking hours (for example, between 08:00 and 22:00).Use the average value of at least 14 measurements taken during the person’s usual waking hours to confirm a diagnosis of hypertension. When using HBPM to confirm a diagnosis of hypertension, ensure that:for each blood pressure recording, two consecutive measurements are taken, at least 1 minute apart and with the person seated and blood pressure is recorded twice daily, ideally in the morning and evening and blood pressure recording continues for at least 4 days, ideally for 7 days.Discard the measurements taken on the first day and use the average value of all the remaining measurements to confirm a diagnosis of hypertension. Assessing cardiovascular risk and target organ damage For all people with hypertension offer to test for the presence of protein in the urine by sending a urine sample for estimation of the albumin:creatinine ratio and test for haematuria using a reagent strip take a blood sample to measure plasma glucose, electrolytes, creatinine, estimated glomerular filtration rate, serum total cholesterol and HDL cholesterol, examine the fundi for the presence of hypertensive retinopathy, arrange for a 12-lead electrocardiograph to be performed. Monitoring treatment and blood pressure targets Use clinic blood pressure measurements to monitor the response to antihypertensive treatment with lifestyle modifications or drugs. Aim for a target clinic blood pressure below 140/90 mmHg in people aged under 80 years with treated hypertension. Aim for a target clinic blood pressure below 150/90 mmHg in people aged 80 years and over, with treated hypertension. For people identified as having a ‘white-coat effect’, consider ABPM or HBPM as an adjunct to clinic blood pressure measurements to monitor the response to antihypertensive treatment with lifestyle modification or drugs. When using ABPM or HBPM to monitor response to treatment (for example, in people identified as having a ‘white coat effect’ and people who choose to monitor their blood pressure at home), aim for a target average blood pressure during the person’s usual waking hours of: below 135/85 mmHg for people aged under 80 years below 145/85 mmHg for people aged 80 years and over. Choosing antihypertensive drug treatment Step 1 treatment Offer people aged under 55 years step 1 antihypertensive treatment with an angiotensin-converting enzyme (ACE) inhibitor or a low-cost angiotensin-II receptor blocker (ARB). If an ACE inhibitor is prescribed and is not tolerated (for example, because of cough), offer a low-cost

ARB Do not combine an ACE inhibitor with an ARB to treat hypertension Offer step 1 antihypertensive treatment with a calciumchannel blocker (CCB) to people aged over 55 years and to black people of African or Caribbean family origin of any age. If a CCB is not suitable, for example because of oedema or intolerance, or if there is evidence of heart failure or a high risk of heart failure, offer a thiazide-like diuretic If diuretic treatment is to be initiated or changed, offer a thiazide‑like diuretic, such as chlortalidone (12.5–25.0 mg once daily) or indapamide (1.5 mg modified-release once daily or 2.5 mg once daily) in preference to a conventional thiazide diuretic such as bendroflumethiazide or hydrochlorothiazide. For people who are already having treatment with bendroflumethiazide or hydrochlorothiazide and whose blood pressure is stable and well controlled, continue treatment with the bendroflumethiazide or hydrochlorothiazide Step 2 treatment If blood pressure is not controlled by step 1 treatment, offer step 2 treatment with a CCB in combination with either an ACE inhibitor or an ARB. If a CCB is not suitable for step 2 treatment, for example because of oedema or intolerance, or if there is evidence of heart failure or a high risk of heart failure, offer a thiazide-like diuretic.For black people of African or Caribbean family origin, consider an ARB in preference to an ACE inhibitor, in combination with a CCB. Step 3 treatment Before considering step 3 treatment, review medication to ensure step 2 treatment is at optimal or best tolerated doses. If treatment with three drugs is required, the combination of ACE inhibitor or angiotensin II receptor blocker, calcium-channel blocker and thiazide-like diuretic should be used. Step 4 treatment Regard clinic blood pressure that remains higher than 140/90 mmHg after treatment with the optimal or best tolerated doses of an ACE inhibitor or an ARB plus a CCB plus a diuretic as resistant hypertension, and consider adding a fourth antihypertensive drug and/or seeking expert advice. For treatment of resistant hypertension at step 4: Consider further diuretic therapy with low-dose spironolactone (25 mg once daily) if the blood potassium level is 4.5 mmol/l or lower. Use particular caution in people with a reduced estimated glomerular filtration rate because they have an increased risk of hyperkalemia. Consider higher-dose thiazide-like diuretic treatment if the blood potassium level is higher than 4.5 mmol/l. When using further diuretic therapy for resistant hypertension at step 4, monitor blood sodium and potassium and renal function within 1 month and repeat as required thereafter. If further diuretic therapy for resistant hypertension at step 4 is not tolerated, or is

contraindicated or ineffective, consider an alpha- or betablocker. If blood pressure remains uncontrolled with the optimal or maximum tolerated doses of four drugs, seek expert advice if it has not yet been obtained.

REFERENCES

Indian Guidelines Management of Hypertension 2001. Hypertension India 2001; 15:1-34

Hypertension / blood pressure control, Goals, Executive Summary : Standards of Medical Care in Diabetes-2013. Diabetes Care 2013; 36:Suppl.1,S6-S7.

2003 European Society of Hypertension- European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertension 2003; 21:1011-1053.

2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311;507-20

Hypertension / blood pressure control, Goals, Executive Summary : Standards of Medical Care in Diabetes-2013. Diabetes Care 2013; 36:Suppl.1,S6-S7.

Special issue on Hypertension (I.G.H.)-III. Supplement to JAPI 2013; 61

Siddharth Shah. Indian Hypertension Guidelines; Evolution and Key Lessons. Medicine Update 2016; 677-80

http://www.ash-us.org/Publications/ASH-Position-Papers. aspx

https://www.nice.org.uk/guidance/cg127

CONCLUSION

The aim of clinical guidelines is to improve quality of care by translating new research findings into practice. There is evidence that the following characteristics contribute to their use: inclusion of specific recommendations, sufficient supporting evidence, a clear structure and an attractive lay out. These guideline are almost covering all aspect of hypertension management including Epidemiology, Racial difference, Definition and classification, Diagnostic tools and method of Examination, Goal of Treatment, Patient Education, Non Pharmacological Treatment and drug Treatment to have wide impact on all aspect of Hypertension Management. Guidelines provide an essential bridge in communicating up-to-date information from clinical trials to clinicians in comprehensive form so that they can provide the best form of treatment for patients. Disparities in the recommendations do exist in various Guidelines we have to choose one of them for our Practice. The primary aim of these guidelines is to offer balanced information to guide clinicians, rather than rigid rules that would constrain their judgment about the management of individual adult patients, who will differ in their personal, medical, social, economic, ethnic and clinical characteristics. To promote their implementation, guidelines could be used as a template for local protocols, clinical pathways and inter professional agreements.”

10. http://www.nhlbi.nih.gov/health-pro/guidelines/current/ hypertension-jnc-7 11. http://bhsoc.org/latest-guidelines 12. h t t p s : / / h e a r t f o u n d a t i o n . o r g . a u / i m a g e s / u p l o a d s / publications/PRO-167_Hypertension-guideline-2016_ WEB.pdf 13. http://csc.cma.org.cn/attachment/2014315/1394885445745. pdf 14. h t t p : / / w w w . e s h o n l i n e . o r g / G u i d e l i n e s / ArterialHypertension.aspx

CHAPTER 144

669

C H A P T E R

145

Best Practices in Hypertension-2017 PC Manoria, Pankaj Manoria, Piyush Manoria, SK Parashar

ABSTRACT

Change is the way of life. Everything in this universe keeps on changing, so also the best practices for hypertension keeps on changing to further optimize the results. It is important to bear in mind that the mortality in controlled hypertensive is not similar to normotensive and is at least two times greater. Therefore the treatment of hypertension should not be BP centric but disease centric policy should be employed. Fibrosis which occurs in hypertensive patients in the heart, LA, aorta and small vessels is an important contributor to morbidity and mortality. It is important to bear in mind that the office based readings of BP represents only a snapshot in time with low reproducibility. The ambulatory blood pressure monitoring provides an idea about the 24 hr BP profile. Besides this, it also gives an idea about the dipping patterns of blood pressure, the morning surges and the BP variability which has substantial prognostic and therapeutic importance. The goals of BP control are 140/90 mm Hg. The Sprint trial did show benefits of additional lowering of BP to 120 mm Hg but it is important to bear in mind that BP measurement in this trial was unique and never done before ,i.e., unattended, automated, unobstructive with patient relaxing in an AC room for 5 minutes before recording the reading. Therefore the reading of SPRINT 120 mm Hg will be higher by 10-15 mm Hg, if we record BP in the conventional manner in the clinic. Therefore lower goal of 120 mm Hg systolic of SPRINT cannot be applied in real practice as such. Among drugs used for hypertension, CTD is preferred over hydrochlorthiazide, Azilsartan a new sartan, has additional advantages and CCB Cilnidipine had additional advantage over amlodipine in that it provides renoprotection and has minimal chance of edema. Atenolol is out and currently vasodilatory betablockers are used for treatment of hypertension particularly when it is associated with coronary heart disease and heart failure. Angiotensin Receptor Neprilysin inhibitor is undergoing evaluation in hypertension with lot of excitement. Spironolactone is the fourth preferred drug in resistant hypertension. A panoply of interventional techniques including renal denervation been evaluated for treatment of hypertension but none of them have been approved for clinical use. The last couple of years have witnessed spectacular advances in the field of hypertension, both in terms of enhanced understanding and in the availability of rich panoply of therapeutic options. Due to this, the best practices for hypertension keep on changing.

Hypertension is the biggest global cause of mortality. It is important to wear in mind that control of hypertension is not self sufficient because the mortality in a controlled hypertensive is at least two times that of normotensive. This occurs due to two reasons: 1.

Hypertension is self sufficient to initiate and perpetuate atherosclerosis. This is classically illustrated in specimen of aorta of coarctation in children who usually do not have risk factors for atherosclerosis. The aorta below the coarct segment is normal but there is extensive atherosclerosis above it. Moreover atherosclerosis continues unabated even after control of blood pressure. Interestingly the HOPE-31 trial has shown that when candesartan is used with rosuvastatin there is a statically significant reduction in the primary end point cardiovascular death, MI and stroke compared to the group receiving candesartan alone.

Fibrosis develops in various parts of the cardiovascular system which has detrimental effects as mentioned below.

Fibrosis in myocardium: The fibrosis in the myocardium can be beautifully seen with Late Gadolinium Enhancement (LGE) on Cardiac Magnetic Resonance (CMR). This makes the ventricle vulnerable for development of heart failure and is also a risk factor for development of ventricular arrhythmias and sudden cardiac death.

Fibrosis in the left atrium: This predisposes for development of atrial fibrillation (AF) and stroke. This can be beautifully seen by LGE on CMR and is also utilized in conjunction with CHA2DS2-VASc score for prediction of stroke in AF. Moreover those patients who have left atrial fibrosis, the recurrence after Radio Frequency Ablation (RFA) for rhythm control is high. In fact, most of the electrophysiologist before attempting RFA in AF, visualize fibrosis in left atrium by CMR.

Fibrosis in the Aorta: In normal young individuals, the aorta is compliant and the aortic Pulse Wave Velocity (PWV) is about 8 meters / sec. but if there is fibrosis in the aorta, this result in decrease compliance and the aortic PWV is increased. In normal individuals the pulse wave after travelling from aorta to periphery comes back to aorta in diastole and this result in augmentation of diastolic

Table 1 : Criteria for diagnosing hypertension Category

SBP

DBP

Subset

Office BP Criteria Office BP

≥90

Daytime

≥135

≥85

Nightime

≥120

≥70

24-H

≥130

≥80

≥135

≥85

Ambulatory BP Criteria

Home BP Criteria blood pressure and increase in coronary filling but in aortopathy because of increase in aortic PWV, the pulse wave traverses fast from aorto to periphery and comes back to aorta in systole itself. This exerts several deleterious effects on the aorta. i.

Increased central aortic systolic pressure.

ii.

Increased LV after load.

iii.

Increased pulsatile strain with chances of plaque rupture

iv.

No diastolic augmentation.

Decreased coronary perfusion.

Criteria Nocturnal BP fall

Night to day time BP ratio

Normal dippers

>10%

0.8 to 1

Extreme dippers

>20%

<0.8

Non dippers

No fall

>1.0

 BP during night

Reverse dippers

defined as the average variation of BP throughout 24 hrs. quantitated as the SD of ABPM readings and is usually around 10-15 mm Hg for the day and 5-10 mm Hg for the night time. If the BP variability is increased, this is associated with increased incidence of cardiovascular events. Interestingly, the use of calcium channel blockers like amlodipine is associated with decreased cardiovascular events. Moreover the effect of BP lowering medicines is best assessed by 24 hour ABPM13-14

Hypertension and vascular disease

Aortopathy is a very important predictor of future cardiovascular events in hypertension

Hypertension no doubt is associated with increased macrovascular disease in coronary, cerebral and peripheral arteries but what is not being realized by many that hypertension is also a very important cause of cognitive decline due to microvascular disease in the brain particularly when it is associated with diabetes.

BLOOD PRESSURE RECORDING

Goals of blood pressure control:

For several years we have been utilizing office blood pressure for diagnosis and treatment of hypertension but it is important to remember that the office based readings represent only a single snapshot in time with low reproducibility. The Ambulatory Blood Pressure Monitoring (ABPM) provides an idea about the 24 hour BP profile2-4 (Table 1). Besides this, it also gives vital information regarding several parameters mentioned below. Nocturnal blood pressure: Normally the blood pressure falls in the night by 10% .If it does not dip in night than it is called non dipper pattern and this is associated with increased morbidity and mortality5-9. There are several types of nocturnal BP patterns as mentioned in (Table 2). The important causes of non dippers include obesity, Obstructive Sleep Apnoea (OSA), high salt intake in salt sensitive subjects, orthosthatic hypotension, autonomic dysfunction, Chronic Kidney Disease (CKD), old age, diabetic neuropathy, old age etc. a.

Morning surges of blood pressure: Normally the BP starts rising 90 minutes before your expected arousal and then rise, the maximum rise being less than 35 mm Hg. If the surge is more than 35 mm Hg, this is associated with increased incidence of cardiovascular events10-12.

Blood pressure variability: The BP variability is

The goals of BP are decreasing over the years (Figure). In JNC 4/5 the goal of SBP was 160, it decreased to 150 in JNC 6 and further dropped to 140 mm Hg in JNC 7. Interestingly the SPRINT trial15 showed that 120 SBP was better than 140 mm Hg .The trial showed a 25% reduction in the primary end point of MI, ACS (non-MI), stroke, heart failure or CV death, the all cause mortality and CV mortality decreased by 27 and 43 % respectively. The hospitalization for heart failure was decreased by 38%. The SPRINT trial did show benefits of additional lowering of BP to 120 mm Hg but is is important to bear in mind that the technique of BP measurement in this trial was unique and never done before, i.e., unattended, automated, unobstructive with patient relaxing in an AC room for 5 minutes before recording the reading. Therefore the reading of SPRINT 120 mm Hg will be higher by 10-15 mm Hg, if we record BP in the conventional manner in the clinic. Therefore lower goal of 120 mm Hg of this trial cannot be applied as such in real practice The 2016 European Guidelines on CVD prevention in clinical practice therefore has not directly endorsed SPRINT trial but it says based on current data, it may still be prudent to recommend lowering SBP/DBP to values within the range 130-139/80-85 mm Hg, and possibly close to the lower values in this range, in all hypertensive. The SPRINT trial also has several limitations.

CHAPTER 145

≥ 140

Home BP

671

Table 2: Criteria for different types of dippers

HYPERTENSION

672

Table 3: Targets for blood pressure in diabetes with hypertension

Table 4: Targets for blood pressure in chronic kidney disease and hypertension

Guideline

Subset

BP Goal

Guideline

Subset

BP Goal

ACC/AHA 2014

Diabetes

<140/90

ASH/ISH 2014

Diabetes

<140/90

Initial drug treatment option

ESH/ESC 2013

Diabetes

<140/85

CKD

<140/90

ACEI/ARB

ADA 2016

Diabetes

<140/90

ACC/AHA 2014 ASH/ISH 2014

CKD

<140/90

ACEI/ARB

ESH/ESC 2013

CKD no proteinuria CKD + proteinuria

<140/90 <130/90

ACEI/ARB ACEI/ARB

CHEP 2013

CKD

<140/90

ACEI/ARB

It is an open label study

It represents only 20% of total hypertensive population as patients with diabetes, congestive heart failure, proteinura >1 gm/day, eGFR < 20 were excluded

The SPRINT trial cannot be applied to diabetics as the ACCORD BP16 and ACCORDION trial carried out in diabetic were negative

It cannot be applied to frail elderly.

The big question is therefore why diabetics do not benefit from intensive narrowing. Perhaps, diabetics have microvascular disease and greater BP lowering decreases perfusion pressure and increases cardiovascular events. Pre-diabetics may benefit

Effect of lowering BP in target organs

Curiously enough, different organs behave differently to decrease in BP. a.

Brain: The dicta for brain is lower is better i.e. lower the BP, less is the incidence of stroke as shown by ACCORD BP16 and INVEST trial17.

Heart: As the coronary arteries are filled in diastole, lower diastole blood pressure below 70 to 80 increases the incidence of acute myocardial infarction and this results in a J-shaped curved. Thus in patients with coronary artery disease, the blood pressure should be carefully lowered.

Kidney: In kidneys, it is the intraglomerular pressure that matters more than the BP in the renal arteries. If the intraglomerular pressure is increased, this results in proteinuria which adversely affect the kidneys. Therefore in renal hypertension, drugs which decrease intraglomerular pressure like ACEI / ARBS are preferred.

between 130-140 mm Hg. It also showed that if systolic blood pressure lowered below 120 it results in an increase in mortality.

Chronic Kidney Disease and Hypertension:

The goals of blood pressure are outlined Table-4 the cutoff point is 140/90 mm Hg. if there is proteinuria lower BP goal i.e. 130/90 is beneficial. The AASK trial18 showed no benefit in the primary outcome of progression of kidney disease in patients of CKD with hypertension but when the data was analysed on the basis of PC ratio, the subset of patient with PC ratio >0.22 showed benefit.

Drugs for treatment for hypertension

Commonly four groups of drugs are used for treatment of hypertension. a.

Diuretics: Chlorthalidone (CTD) is preferred over hydrochlorthizide (HCTZ) which we have been using for several decades. This is because CTD produces greater reduction in BP including nocturnal BP and is associated with decrease in the cardiovascular events (CVE). HCTZ has never been shown to reduce CVE. Indapamide is also a good diuretic with no metabolic side effects.

RAAS Blockers: There are 4 types of RAAS blockers as mentioned below :

Angiotensin Converting Enzyme Inhibitors (ACEIs): These agents although they produce incomplete RAAS inhibition but have excellent outcome data.

ii.

Angiotensin Receptor Blockers (ARBs): Telmisartan in the ONTARGET trial was found equivalent to ACE inhibitor Rampril and is approved for clinical use like the ACEI Rampril.

Diabetes and Hypertension

The cut off point for control of blood pressure is outlined in Table 3. The ACCORD, ACCORDION and INVEST trial failed to show that lower blood pressure is better for diabetes. The ACCORD trial showed no difference in the primary end point of MI stroke and cardiovascular death between the groups of patients with systolic blood pressure 140 vs. 120 mm Hg. The INVEST trial showed that there was a trend towards greater all cause mortality in the subset of patients with systolic blood pressure of <130 mm Hg. i.e. tight control compared to usual control i.e. blood pressure

Azilsartan is a new sartan and has the advantage over other sartan that besides blocking AT1 receptors, it also activates ACE2 Angiotensin (17) mass pathways and provides vasculoprotective and vasodilatory effects. In terms of blood pressure reduction it is therefore more potent than the other

673

Table 5: Ongoing trials of LCZ696 in hypertension Patient population

Brief title

Comparator

NCT01785472

Essential hypertension

Efficacy and Safety of LCZ696 in Comparison to Olmesartan in Asian Patients With Essential Hypertension

Olmesartan

NCT01599104

Essential hypertension

Efficacy and Safety of LCZ696 in Comparison to Olmesartan in Japanese Patients With Essential Hypertension

Olmesartan

NCT01870739

Essential hypertension

A Study to Evaluate the Effect of LCZ696 on Aortic Stiffness in Subjects With Hypertension

Olmesartan

NCT01615198

Essential hypertension

Efficacy and Safety of LCZ696 in Comparison to Olmesartan in Elderly Patients With Essential Hypertension

Olmesartan

NCT01681576

Salt-sensitive hypertension

Assessment of LCZ696 and Valsartan in Asian Patients With Salt-sensitive Hypertension

Valsartan

NCT01256411

Essential hypertension

A Long-term (12 Months) Safety, Tolerability and Efficacy Study of LCZ696 in Patients With Essential Hypertension

NCT01601470

Mild-to-moderate hypertension

Evaluation of Drug-drug Interaction Between LCZ696 and Sildenafil in Subjects With Mild to Moderate Hypertension

Sildenafil

NCT01353508

Hypertension; heart failure and healthy volunteers

Sodium Excretion of LCZ696 in Patients With Hypertension; Heart Failure and Healthy Volunteers

Valsartan

NCT01692301

Hypertension

Study of the Safety and Efficacy of LCZ696 on Arterial Stiffness in Elderly Patients With Hypertension

Olmesartan, Amlodipine, Hydrochlorthiazide

NCT01663233

Essential hypertension

Efficacy and Safety of LCZ696 200 mg + Amlodipine 5 mg in Comparison With Amlodipine 5 mg in Hypertensive Patients Not Responding to Amlodipine

Amlodipine

NCT01646671

Severe hypertension

Safety and Tolerability and Efficacy of LCZ696 in Japanese Severe Hypertensive Patients

NCT01631864

Hypertension, concurrent obesity

Evaluation of the Metabolic Effects of LCZ696 and Amlodipine in Obese Hypertensive Subjects

Amlodipine

ISRCTN11958993

Chronic kidney disease

Randomized multicentre pilot study of LCZ696 vs. Irbesartan in patients with chronic kidney disease: UK Heart And Renal Protection (HARP)-III

Irbesartan

CHAPTER 145

Trial number

HYPERTENSION

These data are important because lowering systolic and pulse pressure in older people with stiffened arteries is an unmet need in our endeavor to reduce the risk of cardiovascular disease and heart failure in older people. The results suggest that ARNI has been able to achieve more in this regard than existing treatments and indeed this is an exciting advance.

sartans and provides good blood pressure control.

674

iii.

Direct Renal Inhibitors (DRI): These drugs despite a sound theoretical basis failed to produce outcome data in various trials and therefore they are not preferred.

iv.

Angiotensin Receptor Neprilysin Inhibitors (ARNI): This drug has already been approved for clinical use in patients with heart failure with reduce ejection fraction as Class-I (B) recommendation in various guidelines. The valsartan in ARNI produces RAAS blockade and the neprilysin inhibition with sacubtril results in increased bioavailability of natriuretic peptides, bradykinin and substance P,which produces natriuretic, vasodilatory and anti-proliferative effects.

The holy grail of systolic hypertension therapy is to achieve a ‘destiffening’ effect. The fact that release of BNP was reduced for ARNI provides indirect evidence that this may be occurring. Currently studies are under way using MRI to directly measure changes in arterial distensibility following ARNI treatment. Although ARNI has shown impressive reduction in systolic and diastolic blood pressure, the longterm antihypertensive efficacy of ARNI has not been fully evaluated. Moreover the effect of ARNI on cardiovascular outcomes in patients with hypertension is unknown. It is also to be seen whether ARNI also confers long-term prognostic benefits in patients with hypertension. Further studies need to be conducted to elucidate the role of ARNI in hypertensive patients with (i) diabetes, (ii) chronic kidney disease (iii) elderly (iv) resistant hypertension. Since blacks were underrepresented in the published hypertension trials, future trials should also include adequate black population. Most importantly, studies needs to be conducted comparing antihypertensive efficacy and outcome of ARNI with other drug classes such as ARBs, calcium-channel blockers and diuretics.

ARNI is now being evaluated for treatment of hypertension. The PARAMETER study19 showed favourable effects. This 52-week multi-center study randomized 454 patients with hypertension aged ≥60 years with a mean sitting systolic blood pressure (SBP) of ≥150 to <180 and a pulse pressure of >60 mm Hg to once daily ARNI (200 mg) or olmesartan (20 mg) for four weeks, followed by a forced titration to double the initial doses for the next eight weeks. At 12–24 weeks, if the BP target had not been attained, amlodipine (2.5–5 mg) and subsequently hydrochlorothiazide (6.25–25 mg) were added. The primary and secondary endpoints were changes from baseline in central aortic systolic pressure and central aortic pulse pressure at week 12, respectively. Results showed that after 12 weeks, patients treated with ARNI had a 3.77 mmHg greater reduction in central aortic systolic pressure and a 2.4 mm Hg greater reduction in central aortic pulse pressure from baseline compared to patients treated with olmesartan. Additionally, the 24 hour ambulatory brachial and central SBPs were significantly reduced from baseline to 12 weeks in both treatment arms, with ARNI lowering brachial SBP by an additional 4.1 mmHg and central SBP by an additional 3.3 mmHg compared to olmesartan. This finding was most pronounced during the nighttime. In other findings, a greater percentage of patients treated with olmesartan (47 percent) required additional hypertension medication at weeks 12–24 compared to patients in the ARNI group (32 percent). Investigators also noted that an exploratory analysis of the carotid-to-femoral pulse wave velocity indicated a trend toward greater improvement in a subgroup of ARNI treated patients with the stiffest arteries at baseline. PARAMETER is the first randomized study demonstrating the ability of ARNI to significantly reduce central blood pressure and pulse pressure compared to an ARB in high-risk older patients with systolic hypertension and a wide pulse pressure.

Besides PARAMETER trial, several other clinical trials are ongoing (Table 5). c.

Calcium channel blockers (CCBs): Amlodipine is a time tested CCB for treatment of hypertension and has been tested in several large scale trials with beneficial results. But the the main problem with amlodipine is pedal edema. Of late the fourth generation CCB is now commercially available. It has the advantage that it not only acts on the L-type calcium channel blockers but also blocks the N-type calcium channels which suppresses excess norepinephrine release from the sympathetic nerve endings. This provides cardio-protection20 as it does not increase heart rate and cardiac contraction and also provide renal protection by decreasing proteinuria21. It also produces venodilation and decreases chances of pedal edema22.

Beta blockers:: For several years beta blockers like atenolol has been commonly used for treatment of hypertension but the meta analysis by Carlberg23 showed that it increases all cause mortality and CV mortality by 13% and 16%. It increased MI by 17% and curiously enough the strokes were increased by 30%. As a result the NICE guidelines

for hypertension in 2011 degraded beta blockers to number four. Currently vasodilatory beta blockers like Nebivolol, carvedilol are used for treatment of hypertension. This has minimal side effects but long terms trials are lacking with these agents are lacking.

resistance. This is associated with venous stenosis in 25% of patients but this can be treated by venodilatation. c.

Combination Therapy

Most patient of hypertension in the long run requires combination therapy24. The desirable combinations are ACEI / ARB + Diuretics, CCB + Diuretics, ACEI / ARB + CCB, ACE / ARB + CCB +Diuretics. Hypertension uncontrolled (>140/90 mm hg) with triple combination i.e., ACEI/ARB +CCB + CTD is categorized as resistant hypertension. Depending on the population examined and the level of medical screening, the prevalence of resistant hypertension has been reported to range from 5–30% of the overall hypertensive population, with figures less than 10% probably representing the true prevalence. Resistant hypertension is associated with a high risk of CV and renal events25-28. But before labeling somebody as resistant hypertension, one should rule out the possibility of apparently difficult to control hypertension due to inappropriate cuff size, pseudohypertension, non-adherence to drug therapy, unknowingly taking large amount of salt, inadequately prescribed dosage or improper combination, white coat hypertension, drug induced hypertension etc. if true resistant hypertension is present, one should exclude obstructive sleep apnoea (OSA), hypothyroidism, renovascular hypertension, primary aldosteronism, aortoarteritis, endocrinal hypertension etc.

What should be the fourth drug if blood pressure is not controlled with ACE/ARB, CCB/Chlorthalidone i.e. resistant hypertension ?

This was tested in the PATHWAY 2 trial29 which showed that spironolactone was distinctly superior to bisoprolol and doxazosin and therefore this should be the fourth drug of choice.

But we should not forget that the major battle for hypertension is to be fought outside the clinics and hospitals because the major chunk of hypertensive patients is still out of reach. This can never be done merely by the medical fraternity but requires cohesive efforts by the government, voluntary agencies, paramedical workers, electronic and print media etc.

SUMMARY

Hypertension is the commonest cause of cardiovascular morbidity and mortality throughout the globe including our country. Prevention should be the goal and indeed it is possible. For hypertensive patients, we have panoply of powerful antihypertensive drugs to control it. But for optimum treatment, a disease centric approach should be employed rather than merely a BP centric approach.

REFERENCES

Salim Yusuf, Jackie Bosch, Gilles Dagenais, et. al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. NEJM 2016; 374:2021-2031

O’Brien E. Ambulatory blood pressure monitoring: 24-hour blood pressure control as a therapeutic goal for improving cardiovascular prognosis. Medicographia 2010; 32:241-9.

Several interventions have been used for treatment of hypertension like carotid baroreflex activation, Iliac AV anastomosis and renal sympathetic denervation.

Stenehjem AE, Os 1. Reproducibility of blood pressure variability, white-coat effect and dipping pattern in untreated, uncomplicated and newly diagnosed essential hypertension. Blood Press 2004; 13:214-224.

Baroreflex activation: It decrease blood pressure by vagal stimulation but the problem with this technique is that carotid stenosis is seen about 60% of patients and we do not know how to prevent it ?

Pickering TG, Shimbo D, Haas D. Ambulatory bloodpressure monitoring. N Engl J Med 2006; 354: 2368-74.

White WB, Larocca GM. Improving the utility of the nocturnal hypertension definition by using absolute sleep blood pressure rather than the “dipping” proportion. Am J Cardiol 2003; 92:1439-41.

Iliac AV anastomosis: In this external iliac artery connected to external iliac vein by a device. It decreases blood pressure by decreasing vascular

Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis. Stroke 1998;29:992-6.

de la Sierra A, Redon J, Banegas JR, et al. Prevalence and

Other drugs that can be used include betablockers like nebivolol or bisoprolol, alpha blockers, like prazosin ,direct vasodilators like hydralazine, minoxidil, centrally acting drugs like clonidine, moxonidine etc

Interventional therapy in hypertension

CHAPTER 145

Resistant hypertension

Renal sympathetic Denervation: This was a very promising technique and the initial results with SYMPLICITY-1 and 2 were exciting but distressingly enough the SIMPLICITY HTN-3 trial30 although it met the safety end point, it failed to show any reduction in blood pressure compared to the Sham control group. Therefore it has not been approved for clinical use. The failure of the trials was attributed to several reasons like operator inexperience / failure, fault with the catheter and patient in the late stage of disease with burnt out sympathetic activity. The problem with the technique is that there is no parameter to document success of renal denervation/ technical failure. New improved catheters for the procedure are being designed with circumferential denervation of renal artery and its branches and the initial result are exciting. It seems renal sympathetic denervation is still alive and not dead and may bounce back in future.

675

factors associated with circadian blood pressure patterns in hypertensive patients. Hypertension 2009; 53:466-72.

HYPERTENSION

676 8.

O’Brien E. Sleepers v non-sleepers: a new twist in the dipper/non-dipper concept. Hypertension 2007; 49:769-70.

Mancia G, Facchetti R, Bombelli M, Grassi G, Sega R. Long-term risk of mortality associated with selective and combined elevation in office, home, and ambulatory blood pressure. Hypertension 2006; 47:846-53.

10. Kario K, Pickering TG, Umeda Y, Hoshide S, Hoshide Y, Morinari M, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation 2003; 107:1401-1406. 11. White WB. Circadian variation of blood pressure: clinical relevance and implications for cardiovascular chronotherapeutics. Blood Press Monit 1997; 2:47-51. 12. Kario K, White WB. Early morning hypertension: what does it contribute to overall cardiovascular risk assessment? J Am Soc Hypertens 2008; 2:397-402. 13. 2013 ESH/ESC Guidelines for the management of arterial hypertension. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Mancia et al. Journal of Hypertension 2013; 31:1281-1357. 14. O’ Brien E, Asmar R, Beilin L, Imai Y, Mancia G, Mengden T, et al. Practice guidelines of the European Society of Hypertension for clinic, ambulatory and self blood pressure measurement. J Hypertens 2005; 23:697-701. 15. A randomized trial of intensive versus standard blood pressure control. The SPRINT Research Group. NEJM 2015; 373:2103-16. 16. Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. The ACCORD Study Group. NEJM 2010; 362:1575-1585 17. Rhonda M. Cooper-DeHoff, Yan Gong, Eileen M. Handberg, et al. Tight Blood Pressure Control and Cardiovascular Outcomes Among Hypertensive Patients With Diabetes and Coronary Artery Disease. JAMA 2010; 304:61–68. 18. Lawrence J. Appel, Jackson T. Wright, Tom Greene, et al. Intensive Blood-Pressure Control in Hypertensive Chronic Kidney Disease for the AASK Collaborative Research Group. NEJM 2010; 363:918-929. 19. Williams, B, Cockcroft JR, Kario K, et al. Principal results of the prospective comparison of angiotensin receptor

neprilysin inhibitor with angiotensin receptor blocker measuring arterial stiffness in the elderly (PARAMETER) study. European Society of Cardiology 2015 Congress; August 31, 2015; London, UK. Abstract 4143. 20. Chika Ogura, Koh Ono, Shoichi Miyamoto, et al. L/T-type and L/N-type calcium-channel blockers attenuate cardiac sympathetic nerve activity in patients with hypertension. Blood Pressure 2012; 21:367-371. 21. Hatta T, Takeda K, Shiotsu Y, et al. Switching to an L/N-type calcium channel blocker shows renoprotective effects in patients with chronic kidney disease: the Kyoto Cilnidipine Study. J Int Med Res 2012; 40:1417-28. 22. Ranjan Shetty, G Vivek, Kushal Naha, et al. Excellent Tolerance to Cilnidipine in Hypertensives with Amlodipine - Induced Edema. N Am J Med Sci 2013; 5:47–50. 23. Bo Carlberg, Ola Samuelsson, Lars Hjalmar Lindholm. Atenolol in hypertension: is it a wise choice? Lancet 2004; 364:1684-89. 24. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25:1105–1187. 25. Fagard RH. Resistant hypertension. Heart 2012; 98:254–261. 26. De la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension 2011; 57:171–174. 27. Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Maragolis KL, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation 2012; 125:1635–1642. 28. Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension 2011; 57:1076–1080. 29. Bryan Williams, Thomas M MacDonald, Steve Morant, et. al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drugresistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015; 386:2059-2068. 30. Deepak L. Bhatt, David E. Kandzari, Willam W. O’Neill et al. A controlled trial of renal denervation for resistant hypertension, for the SIMPLICITY HTN-3 investigators. N Engl J Med 2014; 370:1393-1401.

C H A P T E R

146

Role of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Hypertension 2017 Santosh Bandopant Salagre

INTRODUCTION

After the Framingham study first established hypertension as a risk factor of coronary artery disease, the objective of treating hypertension, as recommended by various hypertension guidelines, has been to reduce cardiovascular morbidity and mortality. Worldwide, annually 7.5 million deaths (13% of all deaths) are attributable to high blood pressure (BP)-related diseases, particularly cardiovascular diseases (CVD). Angiotensin Converting Enzyme Inhibitors (ACEIs) or Angiotensin Receptor Blockers (ARBs) are generally recommended by major hypertension guidelines as a first line of treatment, more so for younger, white hypertensive patients (below 55 or 60 years of age) in whom renin tends to be higher and Calcium Channel Blockers and Diuretics are more effective in old or black persons, in whom renin levels are generally lower. As reflected in the flow chart (Figure 1), A refers to drugs that interrupt the renin-angiotensin system (ACEIs/ ARBs/renin inhibitor) and C and D refer to those that do not(calcium channel blockers and thiazide type diuretics). Combination of drugs from these groups is likely to be more potent in lowering blood pressure than combination within a group.

RENIN ANGIOTENSIN ALDOSTERON SYSTEM (RAAS) AND IT’S ROLE IN PATHOPHYSIOLOGY

The RAAS represents a cascade of enzymatic reactions. The huge precursor molecule of Angiotensin II (Ang II), Angiotensinogen, is cleaved by renin, resulting in Summary of antihypertensive treatment recommendation

Step 1

Age < 55 years

Age > 55 years Or Black person of African or Caribbean origin of any age

ACEI or low cost ARB

CCB (use thiazide-like diuretic, if oedema or high risk/evidence of HF)

Step 2

ACEI + CCB / Thiazide-like diuretic

Step 3

ACEI + CCB + Thiazide-like diuretic

Step 4

Resistant hypertension Consider adding apironolactone / increase the dose of Thiazide-like diuretic / alpha or beta - blocker

Adapted from NICE-BHS hypertension guidelines 2011

Fig. 1: Flowchart of drugs inhibiting RAAS

the still inactive decapeptide angiotensin I (Ang I), which is then further cleaved by the membrane-bound metalloproteinase angiotensin-converting enzyme (ACE) to give the main effector hormone of RAAS, Ang II. Ang II is a known vasoconstrictor, causes fluid retention & has direct tissue toxic effects on vasculature, heart, brain & kidney. Ang II leads to CV damage by cell growth, inflammation & fibrosis, leading to vascular remodelling & endothelial dysfunction. Ang II also causes breakdown of bradykinin, an important mediator of ischemic preconditioning, endothelial function & fibrinolysis, important for CV protection.

ACEIS & ARBS – DO THEY ACT DIFFERENTLY?

While ACEIs act by reducing the production of Ang II, ARBs block the action of Ang II on AT1 receptors, and hence act differently. ACEIs correct all the changes caused by Ang II and have thus demonstrated cardiovascular protection in addition to the BP control (Figure 2). In contrast, ARBs do not up-regulate bradykinin thus lacking the potential CV protective benefits associated with it. Also, since ARBs only block the AT1 receptors, it leads to inhibition of negative feedback loop resulting in increase in Ang II levels by 200% to 300% from baseline. This increased Ang II stimulates AT2 receptors, which in diseased coronary arteries, may lead to plaque rupture (Figure 3), myocardial infarction and adverse vascular remodelling. This could minimize or even negate the potential CV benefit of BP lowering via AT1 receptor blockade.

ACEIS VS ARBS IN HYPERTENSION MANAGEMENT

Despite being in clinical use for many years, there has been no head to head comparison between angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in a randomised controlled trial set up for assessing mortality outcome in hypertension. The ONTARGET study did compare the two, but it was not a hypertension drug trial. The population it studied was high risk CAD patients, rather than that of hypertension (large proportions were normotensive). Still, it is because of ONTARGET, that the ARBs have the perception of being equivalent to ACEIs in terms of CV events reduction. ONTARGET compared telmisartan 80 mg (long acting ARB) to ramipril 10 mg (short acting ACEI, given at night in HOPE study to take care of early morning blood pressure

HYPERTENSION

678

Fig. 2: ACE Inhibitors: A complete Mode of Action on RAAS and Kallikrein-Kinin System surges), both given once daily in the morning. There was no difference between groups in primary end point (composite of CV death, MI, stroke, hospitalization for HF, HR=1.01, 95% CI 0.94-1.09) or for all-cause mortality (HR=0.98, 95% CI 0.90-1.07). Patients on telmisartan had a lower BP (0.9/0.6 mmHg) & hence 9% lower risk of stroke, but the risk of MI was increased by 7% when compared to ramipril, consistent with the results of other studies and meta-analyses. Though ONTARGET was designed and powered to be a ‘superiority’ trial, at best it could show the ‘noninferiority’ of telmisartan, which statistically means, that telmisartan is not ‘substantially worse’ than ramipril. This led to USFDA approval to telmisartan as a 2nd line therapy for high risk patients who are ACEI intolerant.

CLINICAL UTILITY OF ACEIS & ARBS

ACEIs are the agents of choice in persons with type I diabetes with frank proteinuria or evidence of kidney dysfunction because they delay the progression to end-stage kidney disease. ACEIs may also delay the progression of nondiabetic kidney disease. The HOPE trial demonstrated that ramipril reduced the number of cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes. It also reduced the incidence of new-onset heart failure, kidney dysfunction, and newonset diabetes in a population of patients at high risk for vascular events. ACEIs are drug of choice (usually in conjunction with a diuretic and a beta-blocker) in patients with reduced ejection fraction. A meta-analysis of 20 trials involving ACEIs and ARBs, all done after the year 2000 in predominantly (two-thirds) hypertensive patients (7 ACEI trials, n=76615, 13 ARB trials, n=82383 patients) was published recently. Patients had similar co-morbidities and background treatments, etc. With a 4.3 years average follow up, there was a significant 5% (p-0.05) reduction in all-cause mortality with either an ACEI or an ARB. An independent analysis showed that ACEIs reduced all-cause mortality by 10% (p=0.004), while ARBs were neutral (HR=0.99, p=0.683). So the mortality reduction in the combined analysis

Fig. 3: ARBs migh cause Plaques Rupture was driven by the ACEI trials. Only 19% patients in the ACEI trials had placebo as a comparator, while in the ARB trials, 51% patients had a placebo as a comparator. As BP differential would be more in trials with a placebo comparator than with an active drug as a comparator, ARB trials should have shown better mortality reduction.

SAFETY PROFILE OF ACEIS AND ARBS

A chronic dry cough is common, seen in 10% of patients or more, and may require stopping of the drug. Skin rashes are observed with any ACEIs. Angioedema is an uncommon but potentially dangerous side effect because of their inhibition of kininase. Exposure of the fetus to ACEIs during second & third trimesters of pregnancy has been associated with defects due to hypotension and reduced renal blood flow. Severe hypotension can occur in patients with bilateral renal artery stenosis; sudden increase in Creatinine may ensue but are usually reversible with discontinuation of ACE inhibition. Hyperkalemia may develop in patients with kidney disease and type IV renal tubular acidosis (commonly seen in diabetics) and in the elderly. Unlike ACE inhibitors, the ARBs do not cause cough and are less likely to be associated with skin rashes or angioedema. However, as seen with ACEIs, hyperkalemia can be a problem, and patients with bilateral renal artery stenosis may exhibit hypotension and worsened kidney function. Olmesartan has been linked to a sprue-like syndrome, presenting with abdominal pain, weight loss, and nausea, which subsides upon drug discontinuation.

CONCLUSIONS

To conclude, as recommended by all international hypertension guidelines, the primary goal of treating hypertension must be aimed at maximum reduction in cardiovascular morbidity and total mortality and not just surrogates of evidence, such as blood pressure and proteinuria. Special attention should be given to the choice of agent in high-risk hypertensive patients. Presently, the evidence from hypertension trials clearly & consistently suggests that there is less risk of death &

MI with ACEIs than the ARBs in hypertensive patients, which is over & above and “independent” of BP lowering.

Even Among the ACEIs, the maximum evidence for reducing hard end points in hypertensive population seems to be in favor of Perindopril with ASCOT, ADVANCE and HYVET studies. What is interesting to note is that the most commonly used ACEI (Ramipril) in India does not have a study in hypertensive population.

679

REFERENCES

Mancia G, et al. J Hypertension 2013; 31:1281-1357.

NICE clinical guideline 127, August 2011, published online.

Strauss MH, et al. Progress in CV Diseases 2016; 58:473-482

Turnbull F, et al. BPLTTC. J Hypertension 2007; 25:951-958.

Bangalore S, et al. BMJ 2011; 342:d2234.

The ONTARGET Investigators. N Eng J Med 2008; 358:154759.

Van Vark LC, et al. Eur Heart J 2012; 33 :2088-2097

The ASCOT Investigators. Lancet 2005; 366:895-906.

The HYVET Investigators. N Engl J Med 2008; 358:1887-98.

10. ACCOMPLISH study. N Engl J Med 2008; 359:2417-2428.

CHAPTER 146

Now if one looks at studies independently, five outcome trials in hypertension have compared ACEI with other agents. In ALLHAT (lisinopril vs. diuretic or calcium antagonist [CCB]); ANBP (enalapril vs. diuretic); ASCOT (perindopril and CCB vs. beta-blocker and diuretic); HYVET (perindopril and indapamide vs. placebo); and ACCOMPLISH (benazepril + diuretic vs. benazepril + CCB). ARBs have been compared with other agents in LIFE (losartan vs. atenolol); and VALUE (valsartan vs. amlodipine). This distribution of trial evidence suggests a greater quantum of evidence backing ACEI than ARB in the treatment of hypertension.

In addition to these clear outcome studies, the logical mechanisms which favorably differentiate an ACEI from an ARB have to be considered. The trials or statistical non-inferiority should not be interpreted as equivalence trials. ACEIs should therefore be preferred to ARBs in the treatment of hypertension as a first line treatment. As pointed out by the guidelines ARBs should be reserved for individuals who do not tolerate an ACEI.

Newer Beta Blocker in Hypertension

C H A P T E R

147

Anita Jaiswal

First generation (older, nonselective)-propranolol, sotalol, timolol, pindolol

Propranolol introduced in 1963 was the first betablocker.

Since then drugs of this class have proliferated and diversified.

Second generation (β1 selective)-metaprolol, atenolol, acebutolol, bisoprolol, esmolol

Third generation(additional α blocking property and vasodilator property)- labetolol, carvidilol, celiprolol, nebivolol

BETA BLOCKERS INHIBIT ADRENERGIC RESPONSES MEDIATED THROUGH THE BETA RECEPTORS

Mechanism of action 1.

Reduction of adrenergic response mediated via β receptors.

Inhibition of renin release.

Adverse effects of older agents

Inhibition of central nervous sympathetic outflow,thereby inducing presynaptic blockade which in turn reduces the release of cathecholamines.

Bronchoconstriction.

Deliterious effects on lipid profile and insulin sensitivity.

Reduction of venous return and plasma volume

Newer agents - generation of nitric oxide reducing PVR, attenuation of pressor response to cathecholamines with exercise and stress.

No cardiovascular and cerebrovascular morbidity and mortality benefits (Messerli et al, The life study, The carlberg et al, The ASCOT BPLA trial).

No significant blood pressure control.

Need for improved beta blockers

Classification of beta blockers 1.

Solubility based

Third generation beta blockers (Carvedilol, Labetolol, Nebivolol) –

Hydrophilic (atenolol,carvidilol,nebivolol)

Lipophilic— highly soluble(prapranolol), moderately soluble(metaprolol and labetalol)

Labetolol

Selectivity based

Nonselective (β1 and β2)

Without intrinsic sympathomimetic activity propranolol, sotalol, timolol

With intrinsic sympathomimetic activity- pindolol

With additional α blocking property- labetolol, carvedilol, nebivolol.

Cardioselective (β1) metaprolol, acebutolol, bisoprolol, esmolol, celiprolol, nebivolol

atenolol, betaxolol,

Time research based classification

Table 1: Comparison of Conventional and Newer Beta Blockers

Nonselective beta blocker.

But has additional α blocking activity.

No significant effect on heart rate and cardiac output.

Specific use in pheochromocytoma and PIH.

Available in injectable form so widely used in management of hypertensive emergencies.

But increase incidence of respiratory distress syndrome, sepsis and seizures in infants of labetolol treated PIH.

Carvedilol 1.

Non selective beta blocker.

Additional α blocking activity.

Limited effects on heart rate and cardiac contractility.

Used in LV dysfunction following MI.

Effects

Conventional

Newer

Chronic primary HTN.

Bronchoconstriction

Dyspidemia, diabetes

Useful in portal hypertension due to reduction in hepatic venous pressure gradient.

Primary prevention of CV risk

Vascular insulin sensitivity is preserved.

Core BP/ MAP reduction

Increased coronary flow reserve and improved endothelial function.

14.

Significantly increases urinary nitrite and nitrite excretion(indication of increased NO production).

10. Better glycemic effect/metabolic effect in diabetics as compared to metolor, best in both white and female sub group.(metolor increased HbA1c levels in all groups except non white and no black)

15.

PROBE trial showed better decrease in LV mass and mass index by nebivolol group as compared to Ramipril group

16.

Nebivolol equally effective in reducing peripheral BP and augmentation index like quinapril and aliskerin.

17.

equally effective as valsartan in hypertensive patients with obstructive sleep apnea with advantage of reducing heart rate.

11. Added therapy with carvedilol in diabetic patients has shown reduced TG, total cholesterol and microalbuminuria.

Nebivolol 1.

Highly selective β1 blockers.

Also acts as a NO donor from endothelium (due to stimulation of endothelial NO synthase) produces vasodilatation.

Newer β blockers nebivolol,carvidilol have comparable efficacy with CCB and ACEI/ARB with regards to control of hypertension and reduction of cardiovascular risk.

Improve endothelial function.

Anti oxidant property (directly reacts with free radicals scavenging reactive oxygen species).

Still more clinical trials are required to have better understanding regarding these agents.

Effective lowering of central aortic pressure and MAP than atenolol(both equally effective in lowering brachial pulse pressure and aortic stiffness).

REFERENCES

Bhadada SV, Patel BM, Mehta AA, Goyal RK. β(3) receptors: role in cardiometabolic disorders. Ther Adv Endocrinol Metab 2011; 2:65–79.

Belge C, Hammond J, Dubois-Deruy E, Manoury B, Hamelet J, Beauloye C, et al. Enhanced expression of b3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase. Circulation 2014; 129:451–462.

Elliott WJ, Childers WK. Shouldb blockers no longer be considered first-line therapy for the treatment of essential hypertension without comorbidities? Curr Cardiol Rep 2011; 13:507–516.

Provides relief in intermittent claudication.

Significantly lowers sitting BP (SBP and DBP in mild to moderate HTN).

Single dose(5-20mg) therapy so compliance is better.

Specifically used in older patients(> 62yrs) as this age group tends to have more systolic blood pressure

10.

Besides monotherapy, very effective in combination with diuretic,CCB and other antihypertensives.

Courand PY, Lantelme P. Significance, prognostic value and management of heart rate in hypertension. Arch Cardiovasc Dis 2014; 107:48–57.

11.

Favourable adverse effect profile.

12.

Evening dosing significantly lowers day time, night time and 24 hr BP and prewaking SBP called morning surge.

Salles GF, Cardoso CR, Fonseca LL, Fiszman R, Muxfeldt ES. Prognostic significance of baseline heart rate and its interaction with beta-blocker use in resistant hypertension: a cohort study. Am J Hypertens 2013; 26:218–226.

13.

In prehypertensives also significantly reduces central aortic systolic,diastolic BP and MAP

Fretheim A, Odgaard-Jensen J, Brørs O, Madsen S, Njølstad I, Norheim OF, et al. Comparative effectiveness of antihypertensive medication for primary prevention of cardiovascular disease: systematic review and multiple treatments meta-analysis. BMC Medicine 2012; 10:33.

681

CHAPTER 147

Lowering LV mass index and LVH (as compared to metolor).

C H A P T E R

148

Hypertension Guidelines for 2017 – The Evidence So Far

BACKGROUND

The three guidelines that have been instrumental in recent time to have implications in clinical practice in management of hypertension include: 1.

ESH guidelines

ASH / ISH guidelines

JNC VIII Panel Recommendation

Although these guidelines and recommendations have been quite comprehensive there still remain some unanswered questions. There is a possibility of new guidelines or addendum to the existing ones in the year of 2017 with contributions from North America.

EXPECTATIONS FROM THE NEW GUIDELINES

The new recommendations will have to address the following issues for further meaningful insights into what is already known in the previous ones 1.

Appropriate targets for systolic BP to reduce cardiovascular mortality in subjects without diabetes

Appropriate targets for systolic BP to reduce cardiovascular mortality in subjects with diabetes

Safety of aggressive BP lowering in elderly patients

Existence of J Curve

Method of BP measurement – HBP/OBP/ABPM/ AOBP

Clinical Utility of Central Aortic Pressure

Recommendations for different ethnicity

Clarity on the evidence – RCT based or otherwise and the Strength of the evidence

NEWER EVIDENCE THAT CAN INFLUENCE OR MODIFY GUIDELINES

Systolic Blood Pressure Intervention Trial (SPRINT) was a large National Institutes of Health–sponsored multicenter randomized controlled trial that enrolled 9361 patients with a systolic blood pressure(SBP) of at least 130 mm Hg. The primary goal of SPRINT was to test whether reducing SBP to a lower goal (<120 mm Hg) than currently recommended (<140 mm Hg) would reduce the occurrence of cardiovascular disease (CVD) and chronic kidney disease(CKD) events. Enrolled patients were 50 years or

Uday M Jadhav, Amit Saraf

older with an SBP ≥130 mm Hg and at least one of the following: a history of CVD, stage 3 CKD (estimated glomerular filtration rate 20–59 mL/min/1.73 m2), an intermediate to high risk for CVD other than stroke, orage 75 years or older. A patient was defined as having CVD if they had a prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, carotid endarterectomy or carotid stenting, peripheral arterial disease with revascularization, acute coronary syndrome, abdominal aortic aneurysm ≥5 cmwith or without repair, a coronary calcium score >400, or left ventricular hypertrophy. At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group Trial participants assigned to the lower systolic bloodpressure target (intensive-treatment group), as compared with those assigned to the higher target (standardtreatment group), had a 25% lower relative risk of the primary outcome; in addition, the intensive-treatment group had lower rates of several other important outcomes, including heart failure (38% lower relative risk), death from cardiovascular causes (43% lower relative risk), and death from any cause (27% lower relative risk). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group.

LIMITATIONS OF SPRINT TRIAL TO INFLUENCE GUIDELINES

There was no evidence of substantial permanent kidney injury associated with the lower systolic blood pressure goal the number of renal events was small and the possibility of a long term adverse renal outcome cannot be excluded.

SPRINT excluded participants with diabetes

SPRINT excluded persons with prevalent stroke or transient ischemic attack at baseline

SPRINT enrolled an older cohort with a mean age of 68 years and may not be applicable to a younger population

Intensive treatment group in SPRINT had a nonsignificant 11% lower incidence of stroke

Syncope was more common among participants in the intensive-treatment group than among those in the standard-treatment group (3.5% vs. 2.4%, P = 0.003), as was hypotension (3.4% vs. 2.0%, P<0.001).

Higher rate of acute kidney injury or acute renal failure in the intensive-treatment group Electrolyte abnormalities also occurred more often in the intensive (3.1%) than in the standard (2.3%) arm

The manner in which BP was measured in the SPRINT trial using an automated manometer (AOBP), an average of 3 office BP readings taken with proper cuff size, participants seated with their back supported, 5 minutes of rest before measurement, and no conversation during the rest period or BP determinations. This is not the standard of clinical practice in most office practice and hypertension clinics globally

10.

Significant number of participants were lost to follow up in either arms which can have a impact on the event rates

ACCORD AND ACCORDION STUDY

In the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD BP) trial a median of 4.9 years of intensive (systolic BP [SBP] <120 mm Hg) versus standard (SBP <140 mm Hg) BP lowering reduced stroke but not mortality or the primary cardiovascular (CV) outcome (nonfatal MI, nonfatal stroke, or CV death) in 4733 people with type 2 diabetes (T2DM) and high CV risk. The ACCORD Follow-On (ACCORDION) study assessed the long-term effect of this intervention on the incidence of CV events or death. During a median follow-up period of 8.8 years from randomization, the annual rate of the primary outcome (composite of nonfatal MI or stroke or CV death) was 2.03% in the intensive group and 2.22% in the standard group and hazard ratios (CI, p value) for incident outcomes in participants allocated to intensive versus standard BP lowering were 0.91 (0.79, 1.05, p=0.19) for the primary outcome; 1.04 (0.91, 1.19,p=0.59) for death; 0.87 (0.72, 1.06, p=0.16) for nonfatal MI; 0.85 (0.66, 1.10, p=0.22) for stroke; and 0.96 (0.75, 1.23, p=0.74) for CV death. In conclusion, in patients with T2DM at increased CV risk, 4.9 years of intensive BP lowering did not reduce the rate of a composite of fatal and non-fatal major CV events or mortality over a median follow-up of 8.8 years. The stroke benefit observed during the active intervention did not persist after BP differences waned.

683

confidence interval that included the possibility of a 27% lower risk, which is consistent with the cardiovascular benefit observed in SPRINT.

Secondary Prevention of Small Subcortical Strokes (SPS3) Trial

SPS3 compared an SBP treatment target of <130 mm Hg with a target of 130 mm Hg to 149 mm Hg in participants with a recent lacunar stroke, showed a non-significant reduction in recurrent stroke in the group randomized to the lower target

Perspective

Given the totality of the evidence produced by recent clinical trials, although well conducted and with substantial rationale, it looks unlikely that these evidence will unequivocally find its way through the 2017 guidelines. Important studies like ESH-CHL-SHOT trial are underway and likely to address some of these gaps. The year of 2017 will see a more robust effort to lower BP effectively and reduce the patient and physician inertia. To this extent the new data generated has achieved its goal even when the guidelines will persist with the already established blood pressure targets.

REFERENCES

Ambrosius WT, Sink KM, Foy CG, et al. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT). Clin Trials 2014; 11:532–546.

The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373:2103– 2116.

Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362:1575–1585.

SPS3 Study Group Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, Pearce LA, et al. . Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; 382:507–515.

Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension. 1. Overview, metaanalyses and meta-regression analyses of randomized trials. J Hypertens 2014; 32:2285–2295.

Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering treatment on Prevention of heart failure and new-onset heart failure – meta-analyses of randomized trials. J Hypertens 2016; 34:373–386.

Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension Effects at different baseline and achieved blood pressure levels. Overview and metaanalyses of randomized trials. J Hypertens 2014; 32:2296–2299.

CHAPTER 148

ACCORD trial showed a non-significant 12% lower risk of its primary composite cardiovascular outcome, with a 95%

C H A P T E R

149

Combination Drug Therapy in Hypertension AU Mahajan, Zohaib Shaikh

Hypertension affects 1 billion people worldwide and remains the most common readily identifiable and reversible risk factor for myocardial infarction, stroke, heart failure, atrial fibrillation, aortic dissection and peripheral arterial disease. With increasing longevity and epidemic of obesity will add fuel to this fire and it is projected that one third of the world population will be consumed by hypertension by 2025. High blood pressure accounts for two thirds of all the strokes and half of ischemic heart disease case worldwide1, making it the leading cause of death worldwide.

Monotherapy will act on a single physiological systems involved in blood pressure regulation and can lead to counter regulatory mechanism in other system which results in uncontrolled BP. eg. Calcium channel blockers (CCB) and diuretics cause vasodilatation and natriuresis respectively can activate the renin angiotensin aldosterone system (RAAS). This counter regulatory mechanism can be limited by combining CCB/ diuretics with RAAS Blockade caused by ACE Inhibitors or angiotensin receptor blockers (ARB’s).

Despite being easy to diagnose and plethora of guidelines available; achievement of blood pressure targets remain dismal across all societies and countries. Even in developed countries like the United States blood pressure remains elevated—140/90 mm Hg or higher—in more than half of affected persons2. Physicians under treatment, pill burden, prescription drug costs, medication side effects, and insufficient time for patient education contribute to medication nonadherence and failure to achieve blood pressure targets3. It is this elevated blood pressure which contributes to 14% of deaths and 6% of DALYs lost globally4.

Persistently elevated blood pressure escalates cardiovascular risk; every 20 mmHg increase in systolic blood pressure, there is an approximate doubling of cardiovascular (CV) risk10 by use of combination therapy there is better achievement of target BP goals thereby reduction in CV risk.

Monotherapy especially with beta blockers results in variability in visit to visit BP recordings which is a strong predictor of both stroke and myocardial infarction11; this effect is reduced with combination drug therapy.

In hypertensive patients with high cardiovascular risk early control of blood pressure is essential to reduce CV risk, as documented in the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial, patients who achieved BP target at 6 months had fewer subsequent CV events. Furthermore, an earlier BP response within 1 month was predictive of better outcomes16. Both the said goals are achieved with combination therapy. Moreover, in a recent matched cohort study in patients with HTN, initial combination therapy was associated with a 34% risk reduction in CV events compared with monotherapy, and a more rapid achievement of BP target was the main contributor to this risk reduction17.

Fixed Dose Combination (FDC) therapy in a single pill reduces pill burden and improves compliance. In a meta-analysis of nine studies comparing the administration of FDC’s with their separate components, the adherence rate was improved by 26% in patients receiving FDC’s.12

Combination therapy reduces dose of individual agent thereby reducing side effects; besides two drugs may even reduce each other’s side effects.

Monotherapy achieves optimal guideline recommended blood pressure targets only in 20%–30% of patients with most hypertensive patients requiring a combination of two or more BP-lowering drugs5. Although Joint National Committee (JNC) 7 reserved combination drug therapy for mainly stage 2 hypertension (BP ≥ 160/110 mm Hg), European guidelines on hypertension6 and the more recent JNC 8 recognize low dose combination therapy as an excellent way to initiate drug therapy even for those with mild hypertension7. In this article, we review approach to the management of HTN in light of recent advances in combination therapy (Table 1). Rationale for combination therapy 1.

Hypertension results from the complex interplay of environmental and genetic factors leading to the activation or suppression of one or more of a host of physiological systems involved in blood pressure regulation8.It is these host physiological responses which determine drug response; most patients diagnosed with hypertension do not manifest a single disease causing mechanism9. Treatment therefore remains empirical, often requiring three or more pharmacologic agents with complementary mechanisms of action.

685

Table 1: Comparison between different Hypertension Management Strategies44 Low-dose monotherapy

High-dose monotherapy

Free combination therapy

Single-pill combination therapy

Efficacy

Time to reach BP target

BP variability

Simplicity

Tolerabihty

Abbreviations: HTN, hypertension; BP, blood pressure

E.g. pedal edema associated with dihydropyridine CCBs is partially relieved by co-administration of RAAS blockers13,14 and RAAS blockers may reduce the incidence of hypokalemia induced by thiazides15.

and CCBs will activate RAAS; therefore, the addition of a RAAS inhibitor to any of these agents will lead to potentiation of their BP-lowering effect21,22. 2.

COMBINATION THERAPY VS. UPTITRATION OF SINGLE AGENT

Monotherapy achieves Target BP Goals in a small proportion of patients (about 20%–30%), here increasing dose of single agent may not necessary result in incremental BP reduction; as seen with RAAS inhibitors doubling the dose has minimal incremental effect on blood pressure. In contrast, with CCBs, additional antihypertensive efficacy can be gained when dose of amlodipine is doubled at the cost of increased pedal edema. Additional blood pressure fall from combining drugs from two different classes is approximately 5 times greater than doubling the dose of a single drug18.

COMBINATION THERAPY VS SUBSTITUTION OF SINGLE AGENT

NOT ALL COMBINATIONS ARE BENEFICIAL!

Combining a beta-blocker with a centrally acting agent (clonidine, alpha-methyldopa) can lead to bradycardia and heart block, and their abrupt withdrawal can result in a hypertensive crisis.24

Dual RAAS Blockade as demonstrated in the ONTARGET25 and ALTITUDE26 trial is harmful. In the ONTARGET Study, combination of an ACEI and an ARB lead to increased incidence of adverse effects with no improvement in outcomes, similarly the ALTITUDE trial in Type 2 Diabetes, the addition of the DRI to an ARB resulted in increased incidence of hypotension, renal impairment, and hyperkalemia, which might have accounted for the significantly higher incidence of cardiac arrest in the combination therapy group.

Combination of beta-blockers with a nondihydropyridine CCB (such as verapamil) can lead to potentiation of the negative inotropic and chronotropic effect of these drugs27.

When a single agent is ineffective or produces severe adverse effects such as angioedema in RAAS inhibitors substitution is indicated. It may also be effective in blacks were RAAS inhibitors are unlikely to be effective even here combination therapy is superior. E.g. patients not responding to RAAS inhibitors addition of diuretics will activate RAAS and improve response of RAAS inhibitors as well as diuretics19. Anti-Hypertensive options currently available are diuretics, beta-adrenoceptor antagonists, CCBs, angiotensin converting enzyme inhibitors (ACEIs), ARBs, direct renin inhibitors (DRIs), alpha-blockers, and centrally acting agents(clonidine, alpha-methyldopa). Therefore, many combinations are possible.

PREREQUISITES OF COMBINING ANTIHYPERTENSIVE AGENTS:

The agents to combine should have an additive BP-lowering effect by acting on complementary mechanisms involved in the pathogenesis of HTN and blocking the counter-regulatory pathways triggered by one another20. For example, diuretics

Each agent of the combination therapy should neutralize the adverse effects of the other, thus improving the overall tolerability. A CCBinduced peripheral edema secondary to arteriolar vasodilation can be attenuated by the postcapillary venodilation exerted by the RAAS inhibitor.23 Similarly, thiazide diuretic-induced hypokalemia can be counterbalanced by addition of a RAAS inhibitor or a potassium-sparing diuretic such as amiloride, triamterene or spironolactone.21

International guidelines classify various combinations as preferred, acceptable, or not acceptable on the basis of large, outcome-driven clinical trials on safety and on the efficacy of the combination (Table 2).28

CHAPTER 149

Flexibility Compliance

HYPERTENSION

686

Table 2: Classification of Combination Therapy Preferred Combination

Acceptable Combination

Not Acceptable Combination

ACEI or ARB/ DHP CCB

Beta-blocker/ diuretic

Dual RAAS inhibition

ACEI or ARB / DIURETIC

DHP CCB/ diuretic

RAAS inhibitor/ beta-blocker

DHP CCB/betablocker

Non-DHP CCB/ beta-blocker

Thiazide diuretic/ potassiumsparing diuretic

Centrally acting agent/ betablocker

DHP CCB/nonDHP CCB DRI/DHP CCB DRI/diuretic RAAS inhibitor/ non-DHP CCB Abbreviations: HTN, hypertension; ACEI, angiotensinconverting enzyme inhibitor; ARB, angiotensin receptor blocker; DHP, dihydropyridine; CCB, calcium channel blocker; RAAS, Renin angiotensin aldosterone system; DRI, direct renin inhibitor.

PREFERRED COMBINATIONS

Renin–angiotensin–aldosterone system inhibitors and calcium channel blockers (ACEI or ARB/ DHP CCB)

The ACCOMPLISH trial showed that fixed combination of an ACE-Inhibitor (benazepril) with a CCB (amlodipine) was more beneficial with regard to morbidity and mortality reduction than the fixed combination of the same ACEInhibitor with hydrochlorthiazide.29 Generally, similar endpoint reductions have been demonstrated with ACEInhibitors and ARBs, although there is a suggestion that ACE-Inhibitors may be slightly more cardio protective and that ARBs may confer some advantages in stroke prevention.30 The addition of a RAAS blocker has been shown to mitigate this adverse effect. A recent meta-analysis has shown that ACE-Inhibitors are somewhat more efficacious than ARBs in decreasing peripheral edema associated with CCB therapy23. In the ACCOMPLISH trial, 31 hypertensive patients were randomized to a combination of the ACE-Inhibitor, benazepril, with either hydrochlorothiazide, or the CCB, amlodipine. After 3 years follow up, blood pressure levels were reduced similarly in the two arms of the trial, but cardiovascular events were significantly reduced by 20% in benazepril/amlodipine arm compared with the benazepril/hydrochlorothiazide arm. This included significant reduction in Myocardial infarction and nonsignificantly (16%) reduction in stroke. The beneficial effects were seen in both diabetic and non-diabetic patients Thus combining ACE Inhibitor/ ARB with a CCB apart

from achieving BP reduction provides CV risk reduction. Beside cost-effective analysis from the NICE Guidelines also demonstrates that CCBs and ACE-Is or ARBs are more cost-effective treatment choices than beta-blockers or thiazide diuretics.32

Renin–angiotensin–aldosterone system inhibitors and diuretics

As discussed earlier combination of RAAS blockade with diuretic enhances efficacy of both drugs and reduces adverse effect of both. Furthermore, the addition of a RAAS inhibitor will reduce the incidence of thiazideinduced hypokalemia as well as new-onset diabetes33. In elderly hypertensive patients the addition thiazidelike diuretic, indapamide, ACE-Inhibitor, perindopril, reduced the incidence of stroke and heart failure as documented in the HYVET trial.34The ADVANCE trial a randomized, double-blind, placebo-controlled trial that aimed to assess the effects of an single pill combination of an ACEI (perindopril) and indapamide in a large population of patients with type 2 diabetes achieved a 9% relative risk reduction in major macrovascular and microvascular events. The relative risk for death from CV causes was reduced by 18% and that for death from any cause by 14%.35 Among the diuretics chlorthalidone has been shown to be more effective than HCTZ in maintaining 24 hour BP control, including better nighttime BP control36 and may be preferred diuretic for combination with RAAS inhibitors.

Beta blockers with diuretics

Diuretics enhance the antihypertensive efficacy of betablockers in low renin hypertension e.g. African-American patients. The combination results in reduction in morbidity and mortality. But both the drug classes increase the risk of glucose intolerance, new-onset diabetes, fatigue, and sexual dysfunction.32

Calcium channel blockers and diuretics

Addition of hydrochlorthiazide to Amlodipine resulted in reduction in morbidity and mortality similar to valsartan with hydrochlorthiazide combination in the VALUE study at a cost of higher risk of new onset diabetes and hyperkaliemia when compared with the valsartan with hydrochlorthiazide combination.37

Dual calcium channel blockade

The combination of a dihydropyridine CCB with either verapamil or diltiazem has been documented by a metaanalysis to have an additive effect on blood pressure lowering without significantly increasing adverse events. Dual CCB blockade may be useful in patients with documented angioedema on RAAS inhibitors or in patients with advanced renal failure at risk for hyperkaliemia. However, no outcome data are available with dual CCB therapy and long-term safety remains undocumented.

Table 3: Before selecting a Combination therapy for a given patient recommended drug classes for specific compelling indications must be borne in mind Recommended Drugs* Compelling Indication*

Diuretic

ACEI

ARB

CCB

Heart failure

•

High coronary disease Risk

•

Diabetes

•

Chronic kidney disease Recurrent stroke prevention

•

ALDOANT Clinical Trial Basis‡ •

ACC/AHA Heart Failure Guideline,40 MERIT-HF41 COPERNICUS,42 CIBIS,43 SOLVD.44 AIRE,45 TRACE.46 ValHEFT,47 RALES48

•

ACC/AHA Post-MI Guideline,49 BHAT,50 SAVE,51 Capricorn,52 EPHESUS53

•

ALLHAT,33 HOPE,34 ANBP2,36 LIFE.32 CONVINCE33

•

NKF-ADA Guideline,21,22 UKPDS,54 ALLHAT33 NKF Guideline,22 Captopril Trial,55 RENAAL56 IDNT,57 REIN58 AASK59

•

Calcium channel blocker with beta blocker

The addition of a dihydropyridine CCB to a betablocker will result in a complementary and additive BPlowering effect.39 but combining a non dihydropyridine CCB (verapamil or diltiazem) with a beta blocker is not acceptable in lieu of bradycardia and heart block.

Dual RAAS Blockade

As demonstrated in the ONTARGET25 and ALTITUDE26 trial is harmful. In the ONTARGET Study, combination of an ACEI and an ARB lead to increased incidence of adverse effects with no improvement in outcomes, similarly the ALTITUDE trial in Type 2 Diabetes, the addition of the DRI to an ARB resulted in cardiovascular mortality, attributable to hyperkalemia.

Renin–angiotensin–aldosterone system blockers and betablockers

The said combination is preferred in patients with myocardial infarction and heart failure but it is not preferred combination for management of hypertension, as combination produces little additional blood pressure reduction compared with either monotherapy.

Triple drug combination

About 24% to 32% of patients with HTN will require more than two drugs to achieve their BP target29, 40. A rational combination in this setting would be an RAAS inhibitor, a CCB, and a diuretic6. A prospective, randomized, double-blind trial aimed to assess the efficacy and safety of an SPC containing VAL/ AML/HCTZ compared with a dual-combination SPC of the same components (VAL/AML, V AL/HCTZ, and AML/HCTZ) in 2271 patients with stage 2 HTN. At the end of this 12-week study, significantly more patients achieved BP target in the triple-therapy group (about 70% of patients) compared with in the dual-combination

PROGRESS35

groups (around 50%of patients). In addition, the triplecombination therapy was well-tolerated, with reportedly less peripheral edema. In the TRINITY (triple therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in hypertensive patients study) trial, the efficacy and tolerability of a triple SPC containing OM/AML/HCTZ was compared with the components’ dual combinations (OM/AML, OM/HCTZ, and AML/HCTZ) in patients with moderate to severe HTN. At 12 weeks, the triplecombination therapy resulted in significantly more BP reduction when compared with dual therapy, with no significant difference in adverse events.42

RESISTANT HYPERTENSION

In Resistant hypertension in addition to maximum doses or maximum tolerated doses of three antihypertensive drugs including a RAAS blocker, a CCB, and a thiazide diuretic, quadruple therapy is frequently required. Spironolactone added to triple therapy is associated with substantial further reductions in blood pressure of on average, 22/9.5 mm Hg.43Spironolactone is therefore recommended as a component of combination therapy in patients with resistant hypertension.

CONCLUSIONS

A large number of patients remain uncontrolled with monotherapy, combination of antihypertensive agents with complementary mechanisms of action helps to achieve BP targets in such patients. The JNC 8 recommends low dose combination therapy as an excellent way to initiate drug therapy even for those with mild hypertension7. At times not just two but triple or even quadruple therapy may be required as in cases with resistant hypertension. While choosing a combination therapy for a given patient the underlying compelling

CHAPTER 149

Postrnyocardial infarction

687

HYPERTENSION

688

indications for selecting specific drug class based on comorbidity such as heart failure, myocardial infarction, renal disease or stroke should be borne in mind (Table 3). Combination therapy should always be combined with LIFE STYLE MODIFICATION which is the key element in management of hypertension. Fixed Dose Combination (FDC) therapy in a single pill, reduces pill burden and improves compliance. In a metaanalysis of nine studies comparing the administration of FDC’s with their separate components, the adherence rate was improved by 26% in patients receiving FDCs12Whenever convenience and cost outweigh other considerations fixed-dose combinations rather than individual drugs should be used.

13. Lv Y, Zou Z, Chen GM, Jia HX, Zhong J, Fang WW. Amlodipine and angiotensin converting enzyme inhibitor combination versus amlodipine monotherapy in hypertension: a meta-analysis of randomised control trials. Blood Press Monit 2010; 15:195–204. 14. Messerli FH, Grossman E. Pedal edema-not all dihydropyridine calcium antagonists are created equal. Am J Hypertens 2002; 15:1019–1020. 15. Kaplan N. Clinical Hypertension. In Kaplan NM, ed. 8th ed. Lippincott Williams and Wilkins, 2002, p247. 16. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet 2004; 363:2049–2051.

REFERENCES

17. Gradman AH, Parisé H, Lefebvre P, Falvey H, Lafeuille MH, Duh MS.Initial combination therapy reduces the risk of cardiovascular events in hypertensive patients: a matched cohort study. Hypertension 2013; 61:309–318.

18. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versusmonotherapy in reducing blood pressure: meta-analysis on 11,000 participantsfrom 42 trials. Am J Med 2009; 122:290–300.

Lawes CM, Vander HS, and Rodgers A: Global burden of blood pressure related disease, 2001. Lancet 2008; 371: pp. 1513. Gu Q, Burt VL, Dillon CF, and Yoon S: Trends in antihypertensive medication use and blood pressure control among United States adults with hypertension: The National Health And Nutrition Examination Survey, 2001 to 2010. Circulation 2012; 126: 2105

Khanna RR, Victor RG, Bibbins Domingo K, et al: Missed opportunities for treatment of uncontrolled hypertension at physician office visits in the United States, 2005 through 2009. Arch Intern Med 2012; 172: 1344.

Lawes CM, Vander Hoorn S, and Rodgers A: Global burden of blood pressure related disease, MacMahon S. Blood pressure and the risks of cardiovascular disease. In Swales JD, Textbook of Hypertension. Blackwell Scientific Publication, 1994, p46–57.2001. Lancet 2008; 371:1513.

Morgan TO, Anderson AI, MacInnis RJ. ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic hypertension. Am J Hypertens 2001; 14:241–247.

Mancia G, Laurent S, Agabiti-Rosei E, et al; for European Society of Hypertension. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27:2121–2158.

James PA, Oparil S, Carter BL, et al 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507.

Page IH. The MOSAIC theory. In Page IH, ed. Hypertension Mechanisms. New York: Grune and Stratton, 1987; 910–923.

Sever PS. The heterogeneity of hypertension: why doesn’t every patient respond to every antihypertensive drug? J Hum Hypertens 1995; 9:S33–S36.

10. MacMahon S. Blood pressure and the risks of cardiovascular disease. In Swales JD, Textbook of Hypertension. Blackwell Scientific Publication, 1994, p46–57. 11. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlo¨ f B, Sever PS, Poulter NR. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010; 375:895–905. 12. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 2007; 120:713–719.

19. Jamerson KA. Rationale for angiotensin II receptor blockers in patients with low renin hypertension. Am J Kidney Dis 2000; 36(Suppl. 1):S24–S30. 20. Sever PS, Messerli FH. Hypertension management 2011: optimal combination therapy. Eur Heart J 2011; 32:2499– 2506. 21. Ambrosioni E, Borghi C, Costa FV. Captopril and hydrochlorothiazide: rationale for their combination. Br J ClinPharmacol 1987; 23 Suppl 1:43S–50S. 22. Frishman WH, Ram CV, McMahon FG, et al. Comparison of amlodipine and benazepril monotherapy to amlodipine plus benazepril in patients with systemic hypertension: a randomized,double-blind, placebo-controlled, parallelgroup study. The Benazepril/Amlodipine Study Group. J ClinPharmacol 1995; 35:1060–1066. 23. Makani H, Bangalore S, Romero J, Wever-Pinzon O, Messerli FH. Effect of renin-angiotensin system blockade on calcium channel blocker associated peripheral edema. Am J Med 2011; 124:128–135. 24. Mehta JL, Lopez LM. Rebound hypertension following abrupt cessation of clonidine and metoprolol. Treatment with labetalol. Arch Intern Med 1987; 147:389–390. 25. Yusuf S, Teo KK, Pogue J, et al; for ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–1559. 26. Parving HH, Brenner BM, McMurray JJ, et al; for ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2diabetes. N Engl J Med 2012; 367:2204–2213. 27. Taddei S. Fixed-dose combination therapy in hypertension: pros. High Blood Press Cardiovasc Prev 2012; 19:55–57. 28. Gradman AH, Basile JN, Carter BL, Bakris GL; for American Society of Hypertension Writing Group. Combination therapy in hypertension. J Am Soc Hypertens 2010; 4:42–50. 29. Jamerson K, Weber MA, Bakris GL, Dahlo¨ f B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. NEJM 2008; 359:2417–2428. 30. Sever PS, Poulter NR. Management of hypertension: is it the

pressure or the drug? Blood pressure reduction is not the only determinant of outcome. Circulation 2006; 113:2754– 2774. 31. Jamerson K, Weber MA, Bakris GL, Dahlo¨ f B, Pitt B, Shi V, Hester A, Gupte J,Gatlin M, Velazquez EJ; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. NEJM 2008; 359:2417–2428. 32. Nice guidelines. Management of hypertension in adults in primary care. 2004. www.nice.org.uk. 33. Alderman MH. New onset diabetes during antihypertensive therapy. Am J Hypertens 2008; 21:493–499.

35. Patel A, MacMahon S, Chalmers J, et al; for ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370:829–840. 36. Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006; 47:352–358. 37. Julius S, Kjeldsen SE, Brunner H, Hansson L, Platt F, Ekman S, Laragh JH,McInnes G, Schork AM, Smith B, Weber M, Zanchetti A; VALUE Trial. VALUE trial: Long-term blood pressure trends in 13,449 patients with hypertension and high cardiovascular risk. Am J Hypertens 2003; 7:544–548.

689

39. Frishman WH, Hainer JW, Sugg J; for M-FACT Study Group. A factorial study of combination hypertension treatment with metoprolol succinate extended release and felodipine extended release results of the Metoprolol Succinate-Felodipine Antihypertension Combination Trial (M-FACT). Am J Hypertens 2006; 19:388–395. 40. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351:1755–1762. 41. Calhoun DA, Lacourcière Y, Chiang YT, Glazer RD. Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide: a randomized clinical trial. Hypertension 2009; 54:32–39. 42. Oparil S, Melino M, Lee J, Fernandez V, Heyrman R. Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: The TRINITY multicenter, randomized, double-blind, 12-week, parallel-group study. Clin Ther 2010; 32:1252–1269. 43. Chapman N, Dobson J, Wilson S, Dahlof B, Sever PS, Wedel H, Poulter NR, on behalf of the ASCOT Trial Investigators. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007; 49:839–845. 44. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combinatory therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med 2009; 122:290–300.

CHAPTER 149

34. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D,Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F,Rajkumar C, Thijs L, BanyaW, Bulpitt CJ, for the HYVET Study Group. Treatment of hypertension in patients 80 years of age and older. NEJM 2008; 358:1887–1898.

38. Alviar CL, Devarapally S, Romero J, Benjo AM, Nadkarni G, Javed F,Suryadevara R, Kang H, Messerli FH. Efficacy and Safety of Dual Calcium Channel Blocker Therapy for the Treatment of Hypertension: A Meta-analysis. ASH, 2010.

C H A P T E R

150

Recent Advances in Ambulatory Blood Pressure

The understanding of Hypertension has evolved over the last century. A single mercury manometer reading in the office as a target of normalization was considered the goal for the clinician attempting to prevent target organ damage. Oscillometric digital recording of BP has now made it possible to dispense with mercury which is toxic to the workers who manufacture manometers. New digital instruments and self measuring devices have made it possible to do home and out of office BP measurements.1 24 hrs Ambulatory BP monitoring is now considered the Gold Standard in BP measurement and its usage has demonstrated that a single office reading is not enough. BP variability: The patients of 24 hrs BP readings in ABPM are classified as

Ashok L Kirpalani, Dilip A Kirpalani

•

The machine then takes blood pressure readings at regular intervals throughout the day.

•

At the end of the 24 hours, the patient can remove the machine and cuff and give it back to the hospital. The machine will have stored all the readings and these will then be analyzed for.

24 hour Average BP

Daytime and nighttime BP pattern

Nocturnal dipping status and excessive dipping if any

Early morning surge

BP load i.e. percentage of reading higher than normal

BP variability derived from 95% confidence units (i.e.± 2 SD) of readings

Normotensive

Sustained hypertension

When should doctor order ABPM ?

White coat hypertension

Masked hypertension

•

Non Dippers

Use of ABPM to confirm diagnosis of Hypertension and initiate antihypertensive treatment following patients benefit most.

Night Risers Nocturnal hypertension

•

Early morning “spiker”

Poorly controlled blood pressure (resistant or labile hypertension)

Hypotensive

•

Frequent hypotensive symptoms

9. Extreme dipper (standard deviation >20 mm seen in diseases like pheochromocytoma).

•

White coat hypertension (i.e. high BP in doctor`s clinic, normal at home )

•

Masked hypertension (i.e. normal BP in doctor`s clinic, high at home)

•

Nocturnal hypertension and early morning spike

•

Fine adjustment of timing ,dose and type of antihypertensive medicine

•

In “well controlled” or “prehypertensive” patients if there is a relentless progression of Target Organ Damage.

BP is recorded over 24 hrs during the “Awake” and “Sleep” period. Generally the Awake period is 6 a.m. to 10 p.m. (16 hours). The frequency of recording is generally set at every 20 minutes i.e. 3/hour. In the sleep period i.e., 10 p.m. to 6 a.m. The machine takes readings at 1-hourly intervals. These machine settings can be re-adjusted; for e.g., in a patient who works as a night watchman, the sleep setting may be reversed. ABPM (ABPM) is a non-invasive method of obtaining blood pressure readings over a 24-hour period, whilst the patient is in his own environment, representing a true reflection of his blood pressure. •

It uses a small digital blood pressure recording machine that is attached to a belt around the body and which is connected to a cuff around the upper arm. It is small enough, so that patient can go about his normal daily life and even sleep wearing it.

A FEW CLASSICAL CHARTS OF ABPM (FIGURE 1 - FIGURE 7)

Please note: •

Light blue shaded area is white coat (1-1/2 hours after starting).

•

Purple area, sleep time 10 p.m. to 6 a.m. (normal value 120/70)

•

White area is wake period (normal value 135/85).

•

Green denotes normalcy.

691

Office Reading : 134/91 (start) 126/74 (end) 24 hr average reading at home : 147 / 86 Night average reading : 146 /77 Early Morning Surge

24 hr Avg BP : 160 /100 ; Night Dip : 9.4 % sys,16 % diast Fig. 2: Sustained Hypertension

Average Night reading: 130/81 Early morning reading: 190/110 6.43 am and 190/141 at 8 am Fig. 5: Masked Hypertension

Night Avg : 131 /80 ; Day Avg : 131/82; % Dip : 0.1 % Fig. 3: Classical White Coat hypertension with non dipping Well controlled but patient experienced hypotensive symptoms on more than 3 occasions Fig. 6: Over-controlled hypertension

Office reading : 148/87 (start); 130 /93 (end); 24 hour average reading : 123 / 77; Daytime avg : 126/79 Night avg: 106/68 Fig. 4: Classical White Coat •

Bright red denotes abnormalcy (high).

WHITE COAT HYPERTENSION

This phenomenon is often detected while investigating a patient who apparently has resistant hypertension. Many patients are already aware that they have white coat

Office BP and daytime BP well controlled, No nocturnal dip, Night average BP greater that awake BP Fig. 7: Classical Night Riser hypertension. The incidence reported varies significantly between 2 to 5% of the normal population. This type of hypertension is first detected while doing ABPM. It is attributed to high-strung and emotionally labile people

CHAPTER 150

Patient slept after midnight Fig. 1: Normal BP

HYPERTENSION

692

who become nervous in the presence of their doctors or medical attendants. It is a benign phenomenon. This type of hypertension can mislead the physician into treating the patient over-aggressively and thereby causing significant symptoms attributable to the antihypertensive over-medication such as repeated fall, syncopal attacks, “micturition syncope” occurring particularly in old people at night, and even very rarely, fatality due to severe overtreatment of the patient. The incidence of subsequent development of hypertension is probably 15% more than the average normotensive population who do not have white coat hypertension. There are devices such as the Bp-TRU, (which I use in my department at BHIMS) and this instrument obviates in some patients, the use of ABPM for the detection of white coat hypertension. The Bp-TRU monitor is fixed on a wall in a quiet isolated room 4 feet x 4 feet with a chair on which the patient sits down. The attendant then takes a BP reading after 5 minutes with a standard manometer or an electronic oscillometric monitor. Thereafter, the correct size of BP cuff is put on the patient and the first reading of the Bp-TRU is taken in the presence of the attendant. The machine then is set to taking readings for another 5 times at any interval that it is adjustable. Usually, a 2-minute interval for each reading is kept so that the whole process takes about 10-12 minutes. During the last 5 readings, the patient is isolated and left alone in the quiet chamber which is well lit but has no extraneous sounds to disturb the patient and the average of the last 5 readings is taken. The average reading of the last 5 readings over 10 minutes interval is the Bp-TRU Avg reading. A large number of patients will have 5-10 mm drop between the first reading and the average of the last 5 readings. A similar protocol was adopted while doing

Well controlled on 3 drugs, but got up 2 times to pass urine at night. Fig. 8: Well controlled hypertension

the blood pressure monitoring in the SPRINT trial. This is a very appropriate method of checking blood pressure but time-consuming and space-consuming. The device is made in Canada and costs about US$1200 without custom duty if imported personally. The limitations of Bp-TRU are that it should not be used if the attendant detects an arrhythmia during his initial reading.

MASKED HYPERTENSION

Masked Hypertension is the exact opposite of white coat hypertension, i.e., that is the blood pressure in the office is normal and the blood pressure at home is abnormal. There are 3 types of Masked Hypertension. 1.

Daytime Hypertension, which is usually stressinduced.

Morning Hypertension or early morning spike of blood pressure.

Nocturnal hypertension.

Of these three, it is only possible to detect the one type of masked hypertension accurately, by the conventional home blood pressure monitoring and that is the stressinduced daytime hypertension. In the past, good control of blood pressure was synonymous with good control of clinic blood pressure. Today, the triad of perfect BP control, which is aimed at reducing the incidence of target organ damage in patients with high blood pressure includes three major criteria. 1.

Strict 24-hour average blood pressure below 130/80, and daytime average less than 135/85 using the ABPM data. (Note that this is equivalent to 140/90 using the mercury manometer). The average of night or sleep , i. e. readings between going to bed and waking up in the morning should be less than 120/70. The circadian rhythm should establish the presence of between 10 and 20 mm of nocturnal blood pressure dip during sleep and the BP variability should be less than that of the top 10 percentile of the BP. All 3 criteria must be met so as to avoid cardiovascular, cerebrovascular, and renal target organ damage.

Not all patients can undergo ABPM. Home blood

Modern Concept of Hypertension (Pickering has redefined hypertension) Office BP (mmHg)

24-Hour ABPM Average (mmHg)

ABPM Daytime Average (mmHg)

ABPB Nighttime Average (mmHg)*

True Normotensive

Below 140/90

Below 130/80

Below 135/85

Below 120/70

White Coat Hypertension

Above 135/85

Below 130/80

Below 135/85

Below 120/70

True Hypertensive

Above 140/90

Above 130/80

Above 135/85

Above 120/70

Masked Hypertension

Below 135/85

Above 130/80

Above 135/85

Above 120/70

*Night readings should be interpreted carefully since many patients may have fallacious readings due to ABPM machine interrupting the patient`s sleep.

pressure monitoring is an important supplement. On a regular basis, home blood pressure is a good but limited substitute for those who cannot undergo ABPM and those who have already undergone ABPM and require further follow-up with home BP monitoring on a regular basis.

MORNING BLOOD PRESSURE SURGE (MBPS)

MBPS is associated with left ventricular hypertrophy, left ventricular diastolic dysfunction, myocardial ischaemia and increased QTC and QTC dispersion. In diabetics, it is associated with albuminuria. In the presence of MBPS, it is found that there is higher CRP, higher IL-6, and higher IL-18. Increase in inflammatory markers results in pathology of large arteries causing increase of carotid intima media thickness, development of vulnerable plaques, and increase in pulse wave velocity. In the smaller arteries, the media-to-lumen ratio of the resistant arteries increases and there is a high incidence of silent cerebral infarction. Additionally, there is increase of BP variability with high incidence of orthostatic hypertension and hypotension, and increase in the standard deviation of BP in the daytime to more than 15 mm. All the ambulatory machines record and exhibit the degree of standard deviation. The patients with exaggerated MBPS exhibit increase of cardiac-afterload due to increase of arterial stiffness which leads to progressive left ventricular hypertrophy. The left ventricular hypertrophy is also manifested on echocardiography by left ventricular mass index and

As far as strokes are concerned, not only large infarcts occurring in the brain and producing clinically-obvious neurological damage are high in those who have MBPS, but also Silent Cerebral Infarcts (SCI) are a very strong surrogate marker of small strokes in patients who have early morning surge or exaggerated MBPS. The exaggeration of MBPS is related to increased alphaadrenergic activity which can be blocked by the alphaadrenergic agents like doxazosin.

CHRONIC KIDNEY DISEASE

Chronic kidney disease, particularly in diabetics, has been shown to be very commonly presented with the absence of a dip or a non-dipping pattern of nocturnal hypertension. This non-dipping pattern usually precedes the onset of microalbuminuria, particularly in new-onset type II diabetic normotensive patients. The early morning surge under these circumstances is generally attributed to disrupted autoregulation of the afferent arterioles of the glomerulus. The Resistant Index using Doppler USG is an indicator of the degree of vascular resistance in the kidney and in disease states like diabetic kidney disease, an increased RI correlates with MBPS.

WHAT CAUSES MBPS?

MBPS is closely associated with multiple factors which are age, essential hypertension, high-normal normotension i.e. pre-hypertensive state, diabetes, inflammation, excess alcohol intake, smoking, physical stress, psychoemotional stress, and poor sleep quality. The positive factors are activation of neurohumoral systems such as the Renin Angiotensin System and the SNS. This may be related to the central and peripheral clock genes. Another interesting finding is extreme dipping, i.e. when people dip more than 20 mm during sleep, they experience subsequently orthostatic hypotension, i.e. orthostatic increase in blood pressure and this steep increase in blood pressure can contribute to MBPS. Surge is also noted to be more on the first day of the week and in cold weather, particularly in old subjects. This may explain the higher incidence of cardiovascular events in winter in the cold countries and on the first morning of the week, i.e. Monday morning week.

PATHOGENESIS OF EARLY MORNING SURGE OR MBPS

The neurohumoral factors in the body exhibit a circadian rhythm. The levels of plasma norepinephrine rise between 4 a.m. and 10 a.m. Similarly, the Renin Angiotensin System has a surge during the same period. An exaggeration of

693

CHAPTER 150

It is well known that a large percentage of cardiovascular and cerebrovascular events of acute nature occur during the first five hours of the day, i.e. between 5 a.m. and 11 a.m. Muller et al in2 have shown that ischaemic strokes, sudden cardiac death and acute myocardial infarctions coincide with a rise of blood pressure between 5 and 11 a.m., and the incidence of these events is highest at that time. The rise of pressure during this time is known as the “morning surge of blood pressure” (MBPS). Part of this surge may occur before the waking period, followed by increase on waking up and further increase on standing up (also called orthostatic hypertension). There are various definitions and no one standard definition appears perfect. But, the conundrum of definitions culminates in the understanding that this is the most vulnerable period of blood pressure and any significant hemodynamic variation at this point in time affecting blood pressure and heart rate can be catastrophic. In particular, the difference between the sleep dip and the first 2 hours of the awake period contributes to this very vulnerable morning surge. Since the sleep blood pressure is most important in defining the surge, the home BP monitor is somewhat inadequate as it is currently developed. Therefore, one must presently depend on the ABPM for the sleep blood pressure. The Japanese are involved in developing new home nocturnal sleep time BP monitors with timers which unfortunately have not yet appeared in the Indian market. When they become available, they will be a useful boon for those who cannot undergo ABPM for various reasons.

the AE ratio, which represents diastolic dysfunction. Kaneda et al,3 have reported that some well-controlled hypertensives with average BP full day less than 130/80 have significant LVMI, which is associated with sleep trough surge (MBPS). Even in normotensives who are not on treatment, the sleep trough surge of MBPS was significantly correlated with left ventricular mass index. Therefore, in untreated and in treated patients who are within the range of normal clinic BP, there is a population who will have a rise of MBPS leading to unexpected target organ damage.

HYPERTENSION

694

this surge related to sympathetic nervous system overactivity is the cause of MBPS. An increase for hemostatic abnormalities with thrombotic over-activity during the early morning surge is also noted. These are manifested as hypercoagulability, low fibrinolytic activity, i.e., increase in the PAI-1 (Plasminogen Activator Inhibitor 1) and increase in platelet aggregation. The JMS ABPM study ( ) showed an increase of stroke risk in patients with MBPS was associated with increased plasma levels of Prothrombin Factor 1 + 2 (F1+2). The F1+2 is a biomarker of activated coagulation factor X-A and PAI-1 is known to inhibit fibrinolysis. There are vascular factors which lead to big-vessel stiffness and remodeling of small blood vessels with increase in media thickness and narrowing of the lumen diameter resulting in increase of Media/ Lumen (M/L) ratio, which is a measure of remodeling of the subcutaneous arteries in patients with essential hypertension such as radial, femoral, etc. Morning blood pressure rise and Sustained nocturnal hypertension are very similar in causing increased target organ damage. Nocturnal blood pressure is of two types; non-dipping and rising. In considering the definition of nocturnal hypertension, we are considering the period between falling asleep and waking up totally. The risks involved in nocturnal hypertension are increased cardiovascular and stroke risks. A study by Komori in 20084 has shown a significantly poorer stroke-free survival in patients whose mean sleep systolic BP is above 120 mmHg. It is impossible to enumerate all the variables of ambulatory blood pressure; however, in conclusion, one may say that the order of today is to subject every difficult-to-treat hypertension with one round of ABPM.

BLOOD PRESSURE VARIABILITY

The understanding of blood pressure variability and the presence of this enigmatic phenomenon, which has been discovered only due to the availability of ABPM has led to definition of a new syndrome called SHATS (Systemic Hemodynamic Atherothrombotic Syndrome).1

THE PATHOGENIC MECHANISMS INVOLVED IN DEVELOPMENT OF SHATS

The following risk factors contribute to target organ damage in the brain, heart, kidneys, and the arteries including the aorta, i.e., •

Diabetes.

•

Dyslipidemia.

•

Inflammation.

•

Thrombogenesis.

•

CKD.

The target organ damage produces neurohumoral activation thereby involving both; the SNS in the brain, and increasing the central aortic blood pressure. In the brain, sympathetic activation produces baroreceptor

insensitivity. Due to increased central aortic pressure, the large arteries become stiff. The smaller arteries are remodeled due to endothelial damage and become narrowed. Together, these two events produce reduced attenuation of pulse wave, increased blood pressure variability, and reduced autoregulation. These cause overall pulsatile hemodynamic stress which further accentuates target organ damage.

CLINICAL MANIFESTATIONS OF PRESSURE VARIABILITY

High peak pressures due to:

•

Orthostatic hypertension (Blood pressure rises immediately on standing up).

•

MBPS (morning blood pressure surge).

•

Daytime blood pressure surge.

•

Absence of nocturnal dip.

•

Nocturnal rise in pressure (nocturnal hypertension).

Low pressure dips

•

Orthostatic hypotension

•

Extreme dipper (more than 20 mm at night)

Such patients have worsening of target organ damage in a vicious cycle manner because the initial pathogenesis is due to already existing target organ damage. In conclusion, not all hypertensives are easily identifiable by office BP, masked hypertensive, early morning “spikers”, Nocturnal “Risers”, pre hypertensives with other risk factors, are invisible hypertensives at high risk of TOD. Also, white coat hypertensives are at risk of suffering from over-aggressive reduction of blood pressure. The following individuals should be subjected to ABPM: •

Every new case of elevated office blood pressure.

•

Prehypertensive patients with predictors of masked hypertension such as CKD, DM, PCOS, OSA.

•

Those patients who have apparent good control of office BP, but persistent progression of target organ damage.

•

Resistant hypertension not on goal on 3 medications or controlled using 4 medications.

REFERENCES

Essential manual of 24 Hour Blood Pressure Management, First Edition. By Kazuomi Kario. 2015 John Wiley & Sons, Ltd.

Muller et al. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989; 79:733-743.

Kaneda et al. Morning blood pressure hyperactivity is an independent predictor for hypertensive cardiac hypertrophy in a community-dwelling population. Am J Hypertens 2005; 18;1528-1533.

Komori et al. Factors associated with incident ischemic stroke in hospitalized heart failure patients; a pilot study. Hypertens Res 2008; 31:289-294.

C H A P T E R

151

A Review of Nutritional Factors in Hypertension Management Ashok K Taneja, Tejinder Singh, Ashok Chandna

ABSTRACT

Worldwide hypertension is a major health problem posing a great risk to Neuro-Renal-Cardiovascular axis. Increased blood pressure put a lot of impact on patient’s quality of life and survival due to enhanced morbidity and mortality. Normalizing blood pressure is known to improve overall health outcomes, which can be achieved through Pharmacological and Non-pharmacological measures. In Non-pharmacological measures changing Life-style is of paramount importance. In life-style alteration dietary modification plays an important role. Many dietary components such as proteins/fats/ carbohydrates, minerals like sodium, potassium, calcium, magnesium and vitamins have been studied substantially in the past decades. While some of these nutrients have clear evidence for their recommendation, some remain controversial. Hence, dietary modification remains the main focus in non-pharmaceutical measures. Of the 27 dietary factors widely studied, 17 have been proposed to have protective effects against hypertension, six were proposed to be risk factors for hypertension and rest were neutral. Excessive sodium intake is an important risk factor for hypertension, whereas a diet rich in fruit, vegetables, and low-fat dairy products play a beneficial role.

INTRODUCTION

As per JNC-7 guidelines. adults aged 18 years and older, hypertension is defined as a systolic blood pressure (SBP) equal or more than 140 mmHg and/or diastolic blood pressure (DBP) equal or more than 90 mmHg based on the mean of 2 or more sated blood pressure readings on each of 2 or more visits1. JNC-8 recommends the target BP in >60 yr old as 160/90mm whereas in <60 yrs of age as 140/90 mm of HG.2 As per World Health Organization (WHO), hypertension affects approximately 24.8% of the global population with the range from 19.7% to 35.5% in different regions. It is one of the most common diseases that lead to outdoor visit or hospitalizations and a major risk factor for stroke, congestive heart failure (CHF), myocardial infarction (MI), peripheral vascular disease, and overall mortality. As many of hypertensives remain undiagnosed, and of those who are diagnosed about two-thirds are sub optimally controlled.Now it is conclusively proved that early diagnosis and treatment of hypertension reduces the complications significantly.4 Therapeutic options include diet and lifestyle changes (including weight loss, smoking cessation, and increased physical activity), antihypertensive drugs, and surgery

in special situations. Many studies have conclusively proved that some dietary factors like sodium, potassium, calcium, dietary fibres, fat intake affect blood pressure levels. Modification of these esp.in pre-hypertensive stage (SBP 120-139 & DBP 80-89 mmHg) help in preventing complications.3 Let us review the role of each individual dietary factors.

SODIUM

Guyton’s physiologic concept that the role of the kidney in handling sodium is key to the long-term regulation of blood pressure is now generally accepted.5 However, the exact role that dietary sodium plays in this relationship remains controversial. The relationship between renal handling of sodium and blood pressure is apparently influenced by a complex combination of factors including nutritional, environmental, genetic, neuro-hormonal, and metabolic factors. Various studies have proved that hypertension is predominantly observed in persons with average sodium chloride intake >100 mmol/day and very rare in populations consuming <50 mmol/day.4 As a review of physiology, sodium homeostasis is maintained by glomerular filtration and tubular reabsorption. About 3/4th of sodium reabsorption is mediated by neuro-humoral hormone in the proximal (angiotensin II and norepinephrine) and collecting tubules (aldosterone, atrial natriuretic peptide), whereas 1/3rd occurs in the loop of Henle and distal tubules. However, the link between salt and hypertension is still an on going debate. Heterogenous blood pressure response, both in hypertensive & normotensive individuals, to salt intake has led to the concept of salt sensitivity vs salt resistance. Salt sensitivity is a measure of how your blood pressure responds to salt intake. People are either salt-sensitive or salt-resistant. Those who are sensitive to salt are more likely to have high blood pressure than those who are resistant to salt. Salt sensitivity is defined as decrease in mean arterial pressure ≥10 mmHg and salt resistance as decrease in ≤ 5 mmHg after giving 2 Litres of normal saline intravenous with 3 doses of oral 40 mg furosemide. Salt sensitivity has a higher prevalence in certain populations older age, black, insulin resistance, micro-albuminuria, chronic kidney disease (CKD), and low renin level. Salt sensitivity has been proved to be an independent prognostic factor for increased risk of left ventricular hypertrophy, cardiovascular events, and cumulative mortality, regardless of blood pressure. The

HYPERTENSION

696

physiological mechanism of salt sensitivity hypertension is by affecting renal tubular Na+K+ ATPase activity, decreasing dopamine receptor function in renal proximal tubule, or altering endothelium receptor activity4,5. Dietary sodium restriction is strongly advocated as a lifestyle change for prevention and treatment of hypertension and consequently cardiovascular morbidity and mortality. Evidence from several clinical studies like INTERSALT 5,DASH-Sodium Trial6 shows that a reduction in sodium intake leads to moderate to large reduction in blood pressure in normotensive and hypertensive participants, blunting of age related increase in BP and decreased risk of cardiovascular events as well. Galletti et al. found that in salt sensitive patients, there was a strong correlation between 24-hr urinary sodium excretion and blood pressure changes7. On the contrary, some studies have shown the harmful effects of lower salt intake on important clinical outcomes like in diabetics including MI, stroke, ESRD patients. There is increased cardiovascular mortality and higher CHF readmissions due to increased levels of sympathetic hormones, fasting plasma glucose, insulin, brain natriuretic peptide and cholesterol. In addition, there is enhanced development of end stage renal disease (ESRD). Hence, restriction of salt intake is recommended with caution to the climate conditions (high temperate zones), diabetic status, ESRD (End stage Renal Disease), strokes7 etc. Currently, based on available evidence, the WHO strongly recommends the restriction of daily sodium intake to less than 2000 mg, while the AHA advises lower than 1500 mg sodium per day8.

POTASSIUM

Potassium intake is inversely related to both SBP and DBP. This is well proven in many population-based studies.Patients with potassium intake of 1000 mg/day had a 0.9 mm Hg lower SBP and a 0.8 mm Hg lower DBP. Potassium depletion has been shown to be associated with decrease in sodium excretion, plasma renin activity, and plasma aldosterone concentrations with an increase of 7 mmHg of SBP and 6 mmHg of DBP. A meta-analysis of 27 trials in adults demonstrated the same relationship between BP & potassium intake9. The magnitude of BP reduction may be smaller but taking into the consideration of complications associated with hypertension, the benefit calculates to be a large one. The benefit effect of potassium intake on blood pressure reduction appears to be greater in patients with hypertension, longer duration of supplementation, and concurrent high intake of sodium. And moreover, this protective effect of potassium did not differ by other dietary variables and known cardiovascular risk factors (age, sex, blood pressure, blood cholesterol level, obesity, fasting blood glucose level, and cigarette smoking. The antihypertensive effect of potassium supplementation seems to be from following: 1.

Natriuresis by inhibiting sodium reabsorption in

the proximal renal tubules and suppressing renin secretion. 2.

Normalization of the plasma level of digitalis like substance.

Increased urinary volume excretion.

Smooth muscle relaxation by increasing nitric oxide production.

Suppression of free radical formation.

Protection against vascular injury in salt sensitive hypertension.

Hyperpolarization induced vasodilatation.

Which one of these mechanisms plays a predominant role in the reduction of blood pressure and/or cardiovascular mortality is not quite clear10. The 2003 WHO/International Society of Hypertension statement on management of hypertension supported an increased dietary potassium intake11. The daily intake recommended is 4700mg/day11. Foods rich in potassium are vegetables, fruit, dairy products, nuts, and so forth. Natural source of potassium is preferable. Currently, pharmacological potassium supplementation is not recommended as a method of increasing daily intake of potassium12.

CALCIUM

The relationship between calcium intake and hypertension is a complex and difficult. The evidence on benefits is inconclusive. This is largely because of the interaction with other nutrients in the diets and difficulty in reliably collecting calcium intake data. Many studies have proved an inverse relationship between dietary calcium intake and blood pressure. Supplementation with 1000 mg calcium/day has shown to decrease blood pressure, though the results were inconsistent and mainly among hypertensives. In contrast, other studies report minimal or no effect of dietary calcium or supplementation on blood pressure13. Whereas, contradictory results have been exemplified by the Nurses’ Health Study and the NHANES13. Proposed mechanisms by which calcium intake regulates blood pressure include i.

Alteration in intracellular calcium which in turn affects vascular smooth muscle contraction.

ii.

Increased natriuresis.

iii.

Modulation of the function of the sympathetic nervous system14.

Currently, the evidence on the benefit of calcium supplementation in prevention or treatment of hypertension is weak; therefore, there is no justification to increase the intake of calcium above the recommended dietary allowance of 1000–1300 mg/day based on age and gender. Foods rich in calcium are mainly dairy products (preferably low fat) such as milk, cheese, and yogurt.

MAGNESIUM

Relationship between magnesium & BP control is still ill defined. Some studies have shown that its deficiency results in increased blood pressure. Whereas, a meta-analysis of 29 observational studies points to a negative correlation between dietary magnesium intake and blood pressure. On the basis of these data, the relationship between magnesium and hypertension seems inconsistent and not convincing. Currently magnesium supplementation is not recommended as a means of hypertensive treatment15.

OMEGA-3 POLYUNSATURATED FATTY ACID (FISH OIL)

Omega-3 Fatty acids aka Polyunsaturated fatty acids (PUFA) contains both Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA). Omega-3 fatty acids are essential nutrients that are important in preventing and managing heart diseases. It helps to lower blood pressure, reduce triglycerides, slow the development of plaque in the arteries, reduce the chance of abnormal heart rhythm, reduce the likelihood of heart attack and stroke, lessen the chance of sudden cardiac death in people with heart disease17. In many studies daily dietary fish consumption has shown benefits in reducing blood pressure. An analysis of 17 clinical studies using fish oil supplements found that taking 3 or more grams of fish oil daily may reduce blood pressure in people with untreated hypertension. Care should be taken for eating contaminated fish as contains very high levels of mercury. Mercury tend to raise the blood pressure due to high levels of methylmercury, which has a direct bearing on SBP & DBP.

7. GARLIC

Garlic is one of the most commonly used natural herbs. Its role in hypertension has also been explored by researchers. In patients with baseline elevated blood pressure, compared with placebo, garlic significantly reduced SBP by a mean of 16.3 mmHg and DBP by 9.3 mmHg The effect was repeatedly illustrated in another meta-analysis18.

8. NUTS-DRY FRUITS

Hazelnut (per 30 gms) contains high fats but low saturated fats & high potassium (193 mg); magnesium (46 mg) and fibres (3 gms).

Resins :Very high in Potassium, low in sodium, very low saturated fats.

Cashews: High in fat content but mostly MUFA, high in sodium (3.5 mg); high potassium (185 mg).

Peanuts: are not actually nuts but are legumes, but because of their similarties to nuts. Contains high levels of niacin & anti-oxidants.

Walnut (per 30 gms) contain higher level of PUFA (1980 mg); low in sodium (1 mg); high in fibres (4 mg), Potassium.20

FLAX SEEDS

Extraordinary results reported in a rare example of a double-blinded, placebo-controlled, randomized trial of a dietary intervention (flaxseeds) to combat high blood pressure, flax seeds intake every day reduce systolic blood pressure about 10 mm, and their diastolic, by about 7 mm21.

10. GREEN TEA

Green tea contains polyphenol, an antioxidants recognized for disease prevention and anti-aging effects. Polyphenols are flavonoids, which contain catechins.Epigallocatechin3-gallate (EGCG) is the most powerful catechin. After 12 weeks of drinking tea, blood pressure was lower by 2.6 mmHg systolic and 2.2 mmHg diastolic22. Matcha green tea and Tulsi—provide the maximum benefits. Besides being an excellent source of antioxidants, green tea is also packed with vitamins A, D, E, C, B, B5, H, and K, manganese, and other beneficial minerals such as zinc, chromium, and selenium. To boost the benefits of green tea, add a squirt of lemon juice to your cup. Previous research has demonstrated that vitamin C significantly increases the amount of catechins available for your body to absorb. In fact, citrus juice increased available catechin levels by more than five times, causing 80 percent of tea’s catechins to remain bioavailable. EGCG acts by vasodilatation22.

FRUITS & VEGETABLES

Starchy vegetables, such as potatoes and sweet potatoes, are high in potassium and low in sodium, hence tend to lower blood pressure. Citrus fruits, such as oranges, tangerines and grapefruits, and berries, such as strawberries, raspberries, blueberries and blackberries, are high in potassium, vitamin C and dietary fibre, hence lower BP.

The pistachio (per 30gm) is low in sodium (3mg); high in potassium (295mg); high fibres (3gms); high magnesium (34 mg) with high levels of MUFA19.

Beans, peas and lentils are legumes are good for high blood pressure because they are high in dietary fibre and potassium.

Almonds (per 30 gm) contains high magnesium (76 mg);Potassium (200mg);fibres (4 gm);high levels of vit.E (24.2mg) with low saturated fats.

Dark green leafy vegetables are high in dietary fibre, potassium, vitamin C and magnesium. Romaine lettuce,

They are also good sources of magnesium.

697

CHAPTER 151

FIBRE

Fibre is the indigestible portion from plant-based food. Increased fibre intake has inverse relationship with blood pressure. The exact mechanism of action is not clear. In a study of 30,681 male health professionals, 40–75 years old,it was found that those with a fibre intake of less than 12 g/day were at higher risk of developing hypertension. Whereas, persons taking more than 24 g/day had lower blood pressure. This relationship was independent of other nutrients including sodium, potassium, calcium, and magnesium16.

698

spring greens and fresh spinach, broccoli, mustard greens are good examples. Opt for fresh greens because canned vegetables have added sodium. Frozen vegetables can also be used as nutrients are same as fresh vegetables and they are easy to store22.

HYPERTENSION

Berries, especially blueberries-strawberries are rich in flavonoids. Study found that flavonoids prevent hypertension and help to reduce cholesterol levels. Blueberries, raspberries, and strawberries should be added to your diet. BEET: Beetroot juice has shown to lower BP in hypertensives & lower serum cholesterol & blood sugar levels.The study found that the nitrates in the juice brought down the participants’ blood pressure within just 24 hours. Skim milk: The DASH Diet26 recommends increasing the amount of calcium-rich foods. Skim milk is an excellent source of calcium and is also low in fat. High-fiber, low-fat, and low-sodium foods are ideal foods for lowering blood pressure, and oatmeal fits the scheme. Bananas are a great way to add potassium to your diet. Eating foods that are rich in this mineral is better than taking supplements26.

ALCOHOL

A standard drink in the USA is equal to 14 g of alcohol,which is present in 12 oz (355 ml) of regular beer (6% alcohol), 5 oz (150 ml)of wine (12% alcohol), and 3 oz (90 ml) of 42% proof whiskey or distilled spirits. This serving size can be varied in different countries. However we refer “a drink” to the US serving size.23 **Moderate alcohol intake, defined as a maximum of 2 alcoholic drinks/day in men and 1 alcoholic drink/ day in women and lighter-weight persons (AHA 2006 scientific statement of hypertension management.28 After adjustment for measurement error, BMI and dietary variables, the dose calculating variable is 0.68 (large BMI i.e.>28 and 0.46 in smaller BMI (>28). In a prospective cohort study involving 11,711 men with pre-existing hypertension, individuals who consumed a moderate amount of alcohol tended to have a lesser BP & decreased risk of MI. ** On the other hand, heavy drinking, generally referred to as any amount of alcohol use above the moderate level, is associated with a higher risk of hypertension in a dosedependent manner. The risk seems more pronounced in individuals with a smaller BMI. In the INTERSALT study, compared to non-drinkers, men who drank 300– 500 mL alcohol/week had higher SBP/DBP, on average 2.7/1.6 mmHg. Women who drank at least 300 mL/week had blood pressures higher by 3.9/3.1 mmHg than nondrinkers. Alcohol reduction was associated with a fall in blood pressure. Available data supports that moderate alcohol consumption should be recommended as one of the components of hypertensive therapy23.

PRODUCTS WITH POTENTIAL HARMS

Caffeine

Caffeine, found in coffee, tea, sodas and many energy drinks, is used as a stimulant. Caffeine can elevate blood pressure in non habitual caffeine users whereas, little or no effect was seen in habitual coffee drinkers. It has been conclusively proved that chronic coffee drinkers who have hypertension need not to stop it on basis of available data, as it can potentially be harmful for irregular coffee drinkers24.

Licorice

Licorice is used as a flavoring agent in chewing tobacco, candies, spices, and as a medical product in some gastrointestinal and upper respiratory disorders. It contains glycyrrhetinic acid which inhibits 11-betahydroxysteroid dehydrogenase enzyme type 2 isoform, allowing cortisol to bind to the mineralocorticoid receptors creating a status of mineralocorticoid excess and subsequently blood pressure elevation. The excessive use of licorice can be potentially dangerous in hypertensive individuals25.

SPECIAL DIETARY SYSTEMS

DASH Diet

The DASH diet is a diet rich in fruits and vegetables (4-5 servings/day) and low-fat dairy products (2-3 servings/ day) and includes whole grains, poultry, fish, and nuts. This diet is rich in potassium, magnesium, calcium, dietary fibres, and protein and has reduced fat (total and saturated) and cholesterol (<25%), red meat, sweets, and sugar-containing beverages26. The initial DASH trial with participants with prehypertension and stage I hypertension showed blood pressure reduction by 5.5/3.0 mmHg and 2.8/1.1 mmHg This reduction was higher among the subset of hypertensives (GR II & above) at 11.4/5.5 mmHg compared with 3.5/2.1 mmHg. In addition, the reduction in blood pressure began within two weeks and was sustained for the next six weeks. In this study salt intake was kept at constant measure. The DASH-sodium trial35 was a crossover trial with participants on DASH Diet but with 3 levels of sodium intake (low: 1.2 gm/day, intermediate: 2.3 gm/day, and high: 3.5 gm/day). Participants had SBP between 120 to 159 mmHg and DBP between 80 to 95 mmHg. Similar to the earlier study, the DASH diet significantly lowered blood pressure and reducing the sodium intake significantly decreased blood pressure. These effects persisted in those with and without hypertension, as well as across the different races and sex. The combination of the DASH diet and low sodium intake had the greatest impact, reducing SBP by 11.5/5.7 mmHg and 7.1/3.1 mmHg among hypertensives and –non-hypertensives.The effect was so much so that the level of BP reduction in hypertensive was comparable to that obtained with drug monotherapy.26 Other potential benefits of the DASH diet include reduction in cardiovascular morbidity, mortality,

CHF events, and cardiovascular risks factors as well as prevention of type 2 diabetes. AHA, JNC-7 & now 8, AACE & almost all Hypertension Education Programmes recommend DASH diet with Low sodium Intake27.

Vegetarian Diet

JNC-8 RECOMMENDATIONS29

Grade A Recommendation: Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; includes low‐fat dairy products, poultry, fish, legumes, non‐tropical vegetable oils and nuts; and limits intake of sweets, sugar‐ sweetened beverages and red meats.29 *Adapt this dietary pattern to appropriate calories requirement, cultural food preferences and nutrition therapy for other medical conditions like Diabetes. **Achieve this pattern by following plans such as Dash Diet, Vegetarian Diet, USFDA Food pattern or American Heart Association Diet.

Lower sodium intake. Consume no more than 2,400 mg of sodium per day and that a further reduction of sodium intake to 1,500 mg can result in even greater reduction in blood pressure. Combine the DASH dietary pattern with lower sodium intake.

CONCLUSION

Dietary modification plays a very important therapeutic role in blood pressure control. Strong evidence supports the recommendation of a diet containing high potassium, moderate alcohol, and high fibre intake. As a whole, a DASH / Vegetarian diet rich in fruits, vegetables, lowfat dairy products, whole grains, nuts, and fish with reduced amount of red meat, fat, sugar-sweetened food and beverages is recommended. The BP lowering effect can further be compounded by Sodium restriction & high potassium intake. The recommendation is not quite definite in terms of increased intake of calcium, magnesium, fish oil, and garlic. Irregular coffee drinkers and licorice consumers face a possibility of inducing hypertension; thus, these habits need to be avoided in patients at risk. These recommendations are proven to be helpful in reducing blood pressure and hypertensionrelated complications and overall mortality. However, in view of the heterogeneity in risk factors, patient features,

699

REFERENCES

A. V. Chobanian, G.L.Bakris, H. R. Black et al., “Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure,” Hypertension 2003; 42:1206–1252.

World Health Statistics, 2012, www.who.int/gho/ publications: world_health_statistics/EN_WHS201.

H. J. Adrogue and N. E. Madias, “Sodium and potassium in the pathogenesis of hypertension,” The New England Journal of Medicine 2007; 356:1966–1978.

Guyton AC, Coleman TG, Cowley AW Jr., Scheel KW,Norman RA. Arterial Pressure Regulation: Overriding dominance of the kidneys in long- term regulation and in hypertension. Am J Med 1972; 52:584–594.

G. Rose, J. Stamler, R. Stamler et al., “Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion,” British Medical Journal 1988; 297:319–328.

F. M. Sacks, L. P. Svetkey, W. M. Vollmer et al., “Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (dash) diet,” The New England Journal of Medicine 2001; 344:3–10.

M. C. Thomas, J. Moran, C. Forsblom et al., “The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes,” Diabetes Care 2011; 34:861–866.

WHO, “Guideline: sodium intake for adults and children,” World Health Organization (WHO), 2012.

9. J. M. Geleijnse, F. J. Kok, and D. E. Grobbee, “Blood pressure response to changes in sodium and potassium intake: a metaregression analysis of randomised trials,” Journal of Human Hypertension 2003; 17:471–480. 10. A. J. Vander, “Direct effects of potassium on renin secretion and renal function,” The American Journal of Physiology 1970; 219:455–459. 11. J. A. Whitworth, “2003 World Health Organization (WHO)/ International Society of Hypertension (ISH) statement on management of hypertension,” Journal of Hypertension 2003; 21:1983–1992. 12. S. Männistö, M. L. Ovaskainen, and L. Valsta, The National Findiet 2002 Study, Publications of the National Public Health Institute, 2003. 13. D. A. McCarron and C. D. Morris, “Blood pressure response to oral calcium in persons with mild to moderate hypertension: a randomized, double-blind, placebocontrolled, crossover trial,” Annals of Internal Medicine, 1985; 103:825–831. 14. D. C. Hatton and D. A. McCarron, “Dietary calcium and blood pressure in experimental models of hypertension: a review,” Hypertension 1994; 23:513–530. 15. S. Mizushima, F. P. Cappuccio, R. Nichols, and P. Elliott, “Dietary magnesium intake and blood pressure: a qualitative overview of the observational studies,” Journal of Human Hypertension, 1998; 12:447–453. 16. L. J. Appel, M. W. Brands, S. R. Daniels, N. Karanja, P. J. Elmer, and F. M. Sacks, “Dietary approaches to prevent and treat hypertension: a scientific statement from the

CHAPTER 151

Many cohort population based studies have proved the lower levels of blood pressure in vegetarians compared to persons consuming Non-vegetarian diets. It is probably low sodium intake in vegetarian diet. Vegetarian diet with increased intake of fruit and vegetables, polyunsaturated vegetable margarines, and oils, fibre, calcium, and magnesium and decreased intake of protein in mild untreated hypertensive patients resulted in a fall of 5 mmHg in SBP. This diet improved blood pressure without a change in urinary sodium or potassium excretion or body weight28.

and pathogenesis of hypertension, the approach should be individualized.

700

American Heart Association,” Hypertension 2006; 47:296– 308. 17. H. R. Knapp and G. A. Fitzgerald, “The antihypertensive effects of fish oil. A controlled study of polyunsaturated fatty acid supplements in essential hypertension,” The New England Journal of Medicine vol. 1989; 320:1037–1043.

HYPERTENSION

18. K. M. Reinhart, C. I. Coleman, C. Teevan, P. Vachhani, and C. M. White, “Effects of garlic on blood pressure in patients with and without systolic hypertension: a meta-analysis,” Annals of Pharmacotherapy vol. 2008; 42:1766–1771. 19. Angerer P, von Schacky C. n-3 polyunsaturated fatty acids and the cardiovascular system. Curr Opin Lipidol. 2000; 11:57-63. 20. S. Azadmard-Damirchi, Sh. Emami, J. Hesari, S.H. Peighambardoust, and M. Nemati : Nuts Composition and their Health Benefits; World Academy of Science, Engineering and Technology International Journal of Biological, Biomolecular, Agricultural, Food and Biotechnological Engineering Vol:5, No:9, 2011. 21. Michael Gregor: 22,Jan.2015.

Flax

Seeds

for

Hypertension;Vol

22. Gang Liua1, Xue-Nan Mia2, Xin-Xin Zhenga1, Yan-Lu Xua1, Jie Lua1 and Xiao-Hong Huanga1: Effects of tea intake on blood pressure: a meta-analysis of randomised controlled trials; British Journal of Nutrition 2014;112:10431054.

23. J. W. J. Beulens, E. B. Rimm, A. Ascherio, D. Spiegelman, H. F. J. Hendriks, and K. J. Mukamal, “Alcohol consumption and risk for coronary heart disease among men with hypertension,” Annals of Internal Medicine, 2007; 146:10–19. 24. D. S. Sharp and N. L. Benowitz, “Pharmacoepidemiology of the effect of caffeine on blood pressure,” Clinical Pharmacology and Therapeutics 1990; 47:57–60. 25. D. J. Morris, E. Davis, and S. A. Latif, “Licorice, tobacco chewing, and hypertension,” The New England Journal of Medicine, vol. 322, no. 12, pp. 849–850, 1990. 26. L. J. Appel, T. J. Moore, E. Obarzanek, W. M. Vollmer, L. P. Svetkey, F. M. Sacks, et al., “A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group,” The New England Journal of Medicine, vol. 336, no. 16, pp. 1117–1124, 1997. 27. A. Parikh, S. R. Lipsitz, and S. Natarajan, “Association between a DASH-like diet and mortality in adults with hypertension: findings from a population-based follow-up study,” American Journal of Hypertension, vol. 2009; 22:409– 416. 28. I. L. Rouse, B. K. Armstrong, L. J. Beilin, and R. Vandongen, “Blood-pressure-lowering effect of a vegetarian diet: controlled trial in normotensive subjects,” The Lancet vol. 1, no. 8314, pp. 5–10. 29. Paul A. James, MD1; Suzanne Oparil, MD2; Barry L. Carter, PharmD1; 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults; Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8); JAMA 2014; 311.

Life Style Modification in Non Communicable Diseases

C H A P T E R

152

BB Thakur, Smita Thakur

THE NCD EPIDEMIC IN INDIA

Our life style depends on Nature and Nurture, needless to say that both have been very adversely affected. We are born with an average life expectancy of 85 years minimum and around 122 years maximum, however because of drastic changes in life style we are dying earlier due to non-infectious diseases (Non-communicable diseases [NCDs]) then due to infectious diseases majority of which are under control. Among a thousand people, only one dies a natural death; the rest succumb to irrational modes of living.– Live sensibly – Maimonides “I am not a product of my circumstances. I am a product of my decisions” – Stephen Covey The changes in lifestyle (Achar, Bichar, Vyavhar and Ahar) and environment are the main causes of non-infectious chronic diseases. As these diseases progress slowly and gradually, their symptoms appear gradually and steadily, they are chronic in nature, hence they are put in the group of chronic diseases. Cardiovascular Diseases, Diabetes, Chronic Respiratory Diseases and the Cancers are the most important examples of NCDs. Non-communicable diseases (NCDs) are the biggest killers across the world. According to Global Status Report, in 2012, out of 56 million deaths, 38 million deaths (68%) occurred because of NCDs of which more than 40% were premature, before the age of 70. Approximately 80% of the burden of these WHOby Data causes of deathcountries. in 2005 andFor diseases is borne low- Main and middle income the South East Asia Region, WHOfor estimated that 50.6% projections 2025

of all mortality and 43.7% of all disability adjusted life years (DALYs) is due to NCDs. WHO indicates that India ranks very high among the nations affected by premature deaths caused by NCDs. It bears the burden of death of more than 5.8 million people because of Cancer, Diabetes, Stroke, Lung & Heart Diseases each year. The risk level has increased significantly due to the lack of prevention and awareness, absence of proper national health policy related to NCDs, poor healthcare financing and infrastructure and the risk factors: tobacco use, physical inactivity, unhealthy diet and the harmful use of alcohol which leads to metabolic/physiological changes like overweight/obesity, raised blood glucose, raised blood pressure and raised cholesterol. Contrary to the belief that people who maintain high levels of fitness are at low risk of being affected by Non-Communicable Diseases compared to those who are unfit and lead an unhealthy life style, we have many such well known examples of people at 20 and 30 years being diagnosed with cancer & heart attack who have been fit and maintaining normal life style. As people of all ages, nationalities and classes are affected an early detection and preventive health screening is required across the globe.

THE MOST IMPORTANT DISEASES AMONGST NCDS

Cardiovascular diseases, such as high blood pressure and coronary artery disease, Diabetes, Various types of cancers, Chronic respiratory diseases, such as Asthma, chronic obstructive pulmonary disease and emphysema,

Proportional mortality (% of total deaths, all ages, both sexes)

35.90%

12% Main causes of deaths, 2005

Injuries

28%

Cardiovascular 26%

Projected deaths in 16%

8% Cancer

Injuries

29%

2025

Other Chronic Diseases

Fig. 1: WHO Data - Main causes of death in 2005 and projections for 2025

12%

13%

diseases Cancers

Fig. 2: WHO – Non-communicable Diseases (NCDs) in India, 2014

702

Disease of Digestive System (Peptic Ulcers, GERD) Genitourinary Conditions (Nephritis, Chronic kidney disease) Abdominal obesity Cirrhosis Neuro-Psychiatric Disorders (Stroke, Depression, Dementia, Anxiety, Stress etc.

HYPERTENSION

BEHAVIORAL RISK FACTORS

The major cause of NCD is behavioral risk factors like eating unhealthy foods like foods with too much of sweet, high salt, high-fat, unhealthy grilled and other junk foods, Fruits, Vegetables, Milk and other foods processed and preserved with chemical, fertilizers and insecticides, drinking excess amount of alcohol; are smokers; leading a couch life, doing no physical activity; have increased working hours and sleep too late and too little; have high stress levels; and taking out of counter drugs.

ALCOHOL

Annually 3.3 million people die due to alcohol misuse. There are 60 diseases where alcohol has a significant causal role.

BLOOD PRESSURE

In 2014, roughly 22% of adults > 18 had raised blood pressure, globally.

OVERWEIGHT/OBESITY

Globally in 2014, out of the Adults aged 18 > around 39% were overweight & around 13% were obese. “Sudden death is more common in those who are naturally fat than in the lean” – Hippocrates

HEART ATTACKS & STROKES

In 2012 C V D was the leading cause of death due to NCD. Out of total of 7.5 million deaths, heart attacks killed 46% or 7.4 million people and 6.7 million deaths were due to strokes.

CHOLESTEROL

In 2008 roughly 39% of adults aged 25 and over had raised cholesterol.

UNHEALTHY DIET

PHYSICAL INACTIVITY

Insufficient physical activity kills 3.2 million people globally and around 23% of adults aged >18 years are insufficiently active.

Low fruit and vegetable consumption was responsible for 1.7 million of deaths worldwide.

In view of the prevalence, global reach and health effect of physical inactivity, the issue should be appropriately described as pandemic, with far-reaching health, economic, environmental and social consequences.”

More than 20% of the population in India has at least one chronic disease and more than 10% of the people have more than one. As per 2011 estimates 61.3 million people aged 20-79 years are diabetics which is expected to rise to 101.2 million by 2030, leave aside the pre diabetics, Indians get diabetes 10 years earlier on average than their western counterparts, 118 million people were suffering from hypertension in 2000, and this number is likely to increase to 213 million by 2025 The death due to cardiovascular diseases in people aged 30-59 is double then that in the U.S. There are around 2,50,000 cancer cases in India and1/3rd Indians have high levels of Triglycerides and 30-70% have low levels of HDL. Lifestyle changes leads to decreased physical activity, increased consumption of sugar, fat and calories, and higher stress levels which affects insulin sensitivity and causes obesity. There are around 85 million obese persons in India and obesity in Children is rising fast with its consequential effects, which is grave sign for future of nation.

– Lancet July 2012

BLOOD GLUCOSE

As per the statics of 2014 around 8.5% of adults aged 18 and above have raised blood glucose.

TOBACCO

Tobacco use and exposure to tobacco smoke results in death of 6 million people annually. 22% of people aged 15 are smokers in the world.

INDIAN STATISTICS REGARDING NCDS

PREVENTION NCDS

The interventions that lower NCD risk factors can result in reducing pre-mature deaths by half to two-third. It can be prevented by controlling major risk factors like the harmful use of tobacco, alcohol consumption, obesity, unhealthy diet and physical inactivity and others.

MODIFICATIONS

For reducing the risk of NCDs we should focus on making healthy food choices from all five food groups, with special emphasis on fresh vegetables and fruits. avoid foods that are overly sweet, salty, high in fat, or even grilled.

If we give every individual the right amount (& Types) of nourishment and exercise, not too little and not too much, we have found the safest way to health.” – Hippocrates “Be the Change you wish to see in the World” – Mahatma Gandhi

HEALTHY DIET

“Eat what you Love and Love what you eat: but eat only healthy foods.”

Meditation). •

Adequate Sleep.

BENEFITS OF YOGA

Improves all round fitness

•

Relieves Stress & Anxiety

•

Boosts immunity, positive Energy and Mood

•

Helps normalize Blood Pressure and have been found to be beneficial in IHD also.

•

Helps in management of pulmonary diseases.

•

Speeds up a Sluggish Digestion by massaging surrounding muscles

Plant based diet with less sugar and refined carbohydrates.

•

Fruits, vegetables, legumes, and whole grains and nuts intake should be increased.

•

Increases Muscle Flexibility, Strength & Endurance

•

Dietary fiber intake should be increased, Men 4555g/day, Women 55-65g/day.

•

Increases feelings of Calmness & Wellbeing

•

Boost sexual life

•

Decreased intake of processed foods, refined sugars, saturated fats and cholesterol

EXERCISE

ABSTINENCE FROM ALCOHOL

Even 15-20 minutes of concentrated yoga is all that you need. Even at work, a few minutes of meditation will make you refreshed and recharged and you are back to your work tension-free and energetic

GET SUFFICIENT REST AND SLEEP

•

Adult needs 7-8 hours of sleep per night. However, more than 40% of adults sleep for less than 7 hours in 24 hours.

•

Adolescents need more than 9 hours per night. Almost 70% get less than that on average weeknight.

•

Insufficient sleep is associated with diabetes, HTN, CVD, depression and obesity.

•

In the year 2008 drowsy driving contributed to 100,000 MVA’s and 15,000 deaths.

•

Importance of Obstructive sleep Apnoea is well known and it should be appropriately managed

Stop smoking

Tobacco use cessation counseling is very important aspect of clinical management and medications ex. Chantix, bupropion are also available to be used if necessary.

AVOID STRESS

•

S – Smile. Keep smiling

•

T – Tolerance. Grow in tolerance.

•

R – Relax. Never be tensed

•

E – Easy. Take it easy but be not lazy.

•

S – service, Keep serving

•

S – Silence. Practice silence and there by turn to God

PRACTICE YOGA AND MEDITATION

Yoga has been practiced for more than 5000 years and Yoga is one of the most effective and proven way of staying healthy and fit and keeping diseases away. If we want a workable solution for health issues, want to lose weight, be stronger with good physique or want a peaceful mind, yoga is the way which offers a holistic benefit over any other physical activity. Yoga is not just a physical movement and postures of body but it helps in maintaining a harmony between body, mind and soul which benefits a lots.

YOGIC LIFE STYLE

•

Natural-Living according to laws of nature & body.

•

Discipline.

•

Balanced Diet.

•

Asana,

Pranayam,

Relaxation

(Yoga

Nidra,

MULTIDIMENSIONAL APPROACHES TO PREVENT AND REDUCE THE BURDEN OF NCDS

It is the lack of awareness, screening, diagnosis, training, financing and efficient referral that collectively denies access to healthcare. Primary health care system has to be revamped with training to healthcare workers especially regarding counseling for change in lifestyle. The Medicines for treating NCDs should be made easily available and affordable as they are needed lifelong. It is important that along with the government the other agencies should come forward with schemes like insurance policies for specific diseases, health awareness programmes and other technological advancements to address the growing burden of NCDs at the regional, state and national level. Promotion of traditional methods to reduce diseases and promote health like yoga and meditation, engaging religious leaders to raise awareness to modify lifestyle and follow a balanced diet, use of electronic media for IEC and NCDs prevention programmes for healthier behavior change at workplaces of the employees like having physical education training and gym can be of great help.

CHAPTER 152

•

30/45 minutes a day, at least 5 times a week/all seven days for Indians.

703

Private practitioners should be involved along with patients and their representative in the design and delivery of strategies to prevent and manage NCDs. Training in latest medical technologies to promote awareness through all perspectives may also be helpful.

704

HYPERTENSION

CONCLUSION

Fig. 3: Model for a comprehensive approach to healthy lifestyle promotion, education, and interventions

M-HEALTH

The mobile technology becoming so economical, Print and Media can be of great help in the management and prevention of for NCDs. To make people aware about the chronic diseases and its outcome, through WhatsApp or SMS can be another way to approach to the maximum people.

Surveillance & Policy Strengthening of Healthcare Systems and Healthcare Financing are needed. With a Concrete policy-with improvement in health systems, India can successfully address the serious issue of NCDs and can present a roadmap for others to follow. We need to have a competent public health system along with innovative strategies, technology-based initiatives and an efficient use of the existing resources. A multi pronged approach is the needed where different players have their specific roles. It is therefore important to develop NCDs prevention and control program involving multiple agencies and innovative approach. Success of any programme depends on provision of facilities and monitoring its progress. The Government is doing a lot in this direction but still a lot has to be done.

REFERENCES

http://dx.doi.org/10.1093/eurheartj/ehv207 2097-2109

Consultation paper addressing non-communicable diseases in India through innovation and multi-sectoral approach taken jointly published by the partnership to fight chronic disease (PFCD) and strategic partners group (SPAG ASIA) January 2015

http://siteresources.worldbank.org/SOUTHASIAEXT/ Resources/223546-1296680097256/7707437-1296680114157/ NCD_IN_Policy_Feb_2011.pdf

C H A P T E R

153

Approach to the Patients with Hypertension

Person who is detected as high blood pressure should have complete history and physical examination to confirm the diagnosis of hypertension & also screen for other cardiovascular disease risk factor, secondary causes of hypertension, consequences of hypertension, complications of hypertension and associated comorbidities and lastly determine the potentials for proper therapeutic or surgical intervention to control the hypertension. The patients with raised blood pressure are asymptomatic, but some patient complaints of headache which occur in the morning and localised to occipital region, other nonspecific symptoms like dizziness, palpitations early fatigability and impotence. These symptoms are usually related to causes of secondary hypertension. History taking should be excellent & include family history of hypertension and other CVS diseases, DM, dietary & psychosocial history weight gain, dyslipidaemia, smoking, physical inactivity. The renal disease, change in physical appearance, muscle weakness, excessive sweating, palpitation, tremors, erratic sleep and snoring, hypo or hyperthyroidism and drug consumption favour secondary hypertension. History taking will determine the type of hypertension primary or secondary hypertension. The physical examination includes measurement of BMI to exclude metabolic and endocrine causes. The pulse rate, rhythm, volume and equal pulses in upper and lower extremities gives idea of AF, coarctation, hyper dynamic circulation (anemia, hyperthyroid & aortic incompetence, hypokalemia, shock, CCF) etc. The technique of BP measurement should be accurate. Now days BP machine are replaced with aneroid oscillometric devices. These devices should be calibrated periodically and accuracy should be confirmed and maintained. Patient’s position is very important; patient should be seated in quiet room in a chair with feet on floor for five minutes. The temperature of room should be normal, patient should not exercise, consume tea, coffee any drug prior to measurement of blood pressure. Two BP reading should be taken. The centre of cuff should be at heart level. The width of bladder cuff should equal at least 40% of the arm circumference and length of the cuff bladder should encircle at least 80% of arm circumference. The bladder cuff and stethoscope placement should be proper. The bladder cuff should be inflated till patients pulse disappear and it should be raised 20 mm/Hg above then

BR Bansode

deflate the cuff 2mm of Hg/sec, the systolic BP is first two regular tapping sounds (Korotkoff) & diastolic BP is point at which regular Korotkoff sound is disappear. Now days 24 hours ambulatory BP monitoring is more reliably predict cardiovascular disease risk. In suspected white coat hypertension, resistant hypertension, symptomatic hypotension, autonomic failure or episodic hypertension it is more useful. The blood pressure should be measure in supine, sitting and standing position for evidence of postural hypotension. The neck should be examined for enlargement of thyroid gland for exclude hypothyroidism or hyperthyroidism. The examination of blood vessels may provide underlying vascular disease like atherosclerotic diseases. The second heart sound is due to closure of aortic valves and S3 gallop attributed to atrial contraction against non-complaint left ventricles. The LVH may be detected as sustained and laterally displaced apical impulse. The abdominal bruit throughout systole into diastole gives clue to renovascular hypertension. Palpable kidneys suspect polycystic or obstructed kidneys due to stone, stricture either unilateral or bilateral. The sign of CHF gives clue to heart enlargement and reduced pump (LVEF) action. Neurological examination shows evidence of TIA, embolic phenomenon and neurodeficit.

INVESTIGATION

(CBC, urine analysis, ECG, Funduscopy, X-ray chest and USG Abdomen pelvis). CBC-shows type of anaemia type, renal function, electrolytes, fasting and Post meal blood sugar & lipid to rule out secondary causes of hypertension. Special investigation like MR angiogram is to localise the site of lesion in hypertension.

MANAGEMENT OF HYPERTENSION

Implementation of lifestyle as a first step in hypertension management is for prevention and treatment of hypertension. The impact of lifestyle interventions i.e. weight reduction, salt restriction is more pronounced in persons with hypertension. It prevents development of hypertension, avoids hypertensive complication as well as drug therapy in early or prehypertensives. Dietary modification like weight reduction, salt reduction and increase potassium and morning brisk walk with 5 days a week, effectively lower blood pressure, reduced obesity and metabolic complications & increase insulin

706

Table 1 : Patient’s Relevant History • Duration of hypertension • Previous therapies: responses and side effects • Family history of hypertension and cardiovascular disease •

Dietary and psychosocial history

HYPERTENSION

• Other risk factors: weight change, dyslipidemia, smoking, diabetes, physical inactivity. • Evidence of secondary hypertension: history of renal disease; change in appearance; muscle weakness; spells of sweating, palpitations, tremor; erratic sleep, snoring, daytime somnolence; symptoms of hypo-or hyperthyroidism; use of agents that may increase blood pressure • Evidence of target organ damage: history of TIA, stroke, transient blindness; angina, myocardial infarction, congestive heart failure; sexual function • Other comorbidities Abbreviation: TIA, transient ischemic attack.

sensitivity. Average BP reduction 6.3/3.1mm of Hg with reduction in mean body weight 9.2kg. Many long terms prospective trials have reported that reduction in salt intake reduces cardiovascular events. Ideally BMI should be maintained at or below < 25Kg/m2 for reducing the risk related to hypertension. In patients with advance renal disease, dietary protein restriction may have modest effect in mitigating renal damages by reducing the intra renal transmission of systemic arterial pressure. DASH (Dietary approaches to stop hypertension) trial convincingly shown that over 8 weeks period diet high in fruits, vegetables, low fat dairy products lower BP in mild hypertensive and further salt reduction 4-6 gm/day augment this effect on blood pressure. Fruits & vegetables are rich sources of potassium, magnesium, fibre and diary product for calcium.

PHARMACOLOGICAL THERAPY

Drug therapy is recommended for persons who follow life style modification and having blood pressure more than 140/90mm of Hg. Systolic BP reduction by 10-12 mm of Hg & diastolic blood pressure by 5-6mm of Hg confer the risk reductions of 35-40% stroke, 12-16% for CHD & heart failure 50% within 5 yrs of treatment. The reduction of blood pressure is single most factors for slowing the rate of progression of hypertension related kidney disease. Most of available drug reduces SBP 7-13mm of Hg & DBP 4-8mm of Hg. Proper combination of these antihypertensive agents augment BP reduction and reach goal BP. Selection of drug should be based on age, severity of BP, risk factors, associated comorbid conditions, practically affordable cost for masses, less side effects and frequency of drug dosing.

THIAZIDE DIURETICS

Inhibit Na+/Cl in distal convoluted tubules so it increases

sodium execretion. In long term use they act as vasodilators. It is safe, effective and low cost. They provide additive BP reduction when combine with B blocker, ACE, ARB, while with CCB it is less effective. Dose 6.25-50mg/day. Higher doses it increases potassium loss (hypokalaemia), insulin resistance and increase cholesterol but it is short acting (half life 9-15hrs). Chlorthalidone is a diuretic structurally; similar to hydrochloride blocks sodium-chloride in the early distal tubule. Chlorthalidone has a longer half-life (40-60 h vs.915h) an antihypertensive potency ~1.5-2.0 times that of hydrochlorothiazide. Potassium loss is also greater with chlorthalidone. These agents are weak antihypertensive agents but may be used in combination with a thiazide to protect against hypokalemia. The main pharmacologic target for loop diuretics is the Na+, - K+ - 2Cl- cotransporter in the thick ascending limb of the loop of Henle. Loop diuretics generally are reserved for hypertensive patients with reduced glomerular filtration rates. Serum Creatinine (>2.5mg/dL)CHF or sodium retention and edema for some other reason, potent vasodilator, e.g., minoxidil. Blockers of the Renin-Angiotensin system: ACEIs decrease the production of angiotensin II, increase bradykinin levels, and reduce sympathetic nervous system activity. ARBs provide selective blockade of AT1 effect of angiotensin II on unblocked AT2 receptors may augments their hypotensive effect& reduce the risk of developing diabetes in high-risk hypertensive patients. ACE1/ARB combinations are less effective in lowering blood pressure. In patients with high risk of diabetes, combination ACE1/ARB therapy has been associated with more adverse events (e.g cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure) without increase in benefit. Side effects of ACEs and ARBs include efferent renal arteriolar dilation in a kidney with stenotic lesion of the renal artery. Additional predisposing conditions to renal insufficiency induced by these agents are dehydration, CHF, and non-steroidal anti-inflammatory drugs. Dry cough and angioedema occurs in <1%. Angioedema occurs most commonly Asian origin and more commonly in African Americans. Hyperkalemia due to hypoaldosteronism is an occasional side effect of both ACE and ARBs. Blockade of the rennin-angiotensin system is more complete with renin inhibitors than with ACEIs or ARBs. Monotherapy with aliskiren seems to be as effective as an ACEI or ARB lowering blood pressure.

Aldosterone antagonists

Spironolactone particularly effective agent in patients with low-renin primary hypertension, resistant hypertension and primary aldosteronism. In patients with CHF, low-dose spironolactone reduces mortality and hospitalizations for heart failure when given in addition to conventional therapy with ACEIs, digoxin, and loop diuretics. Spironolactone side effects may include gynecomastia, impotence, and menstrual abnormalities. Eplerenone selective.

707

Table 2 : Examples of Oral Drugs Used in Treatment of Hypertension Drug class

Examples

Usual Total Daily Dose (Dosing Frequency/Day)

Hydrochlorothiazide

6.25-50mg (1-2)

Chlorthalidone

25-50 mg (1)

Furosemide

40-80 mg (2-3)

Ethacrynic acid

50-100mg (2-3)

Aldosterone antagonists

Spironolactone

25-100mg (1-2)

Eplerenone

50-100mg (1-2)

K+ retaining

Amiloride

5-10 mg (1-2)

Triamterene

50-100mg (1-2)

Atenolol

25-100mg (1)

Metoprolol

25-100mg (1-2)

Propranolol

40-160mg (2)

Propranolol LA

60-180 (1)

Labetalol

200-800mg (2)

Carvedilol

125-50mg (2)

Prozosin

2-20 ,g (2-3)

Doxazosin

1-16 mg (1)

Terazosin

1-10mg (1-2)

Phenoxybenzamine

20-120mg (2-3)

Clonidine

0.1-0.6mg (2)

Clonidine patch

0.1-0.3mg (1/week)

Methyldopa

250-1000mg (2)

Reserpine

0.05-0.25mg (1)

Guanfacine

0.5-2mg (1)

Captopril

25-200mg (2)

Lisinopril

10-40mg (1)

Ramipril

2.5-20mg (1-2)

Losartan

25-100mg (1-2)

Valsartan

80-320 mg (1)

Candesartan

2-32mg (1-2)

Other Indications

Contraindications/ Cautions

Diuretics Thiazides

Loop diuretics

Diabetes, dyslipidaemia, hyper-uricemia, gout, hypokalemia Diabetes, dyslipidaemia, hyper-uricemia, gout, hypokalemia

Renal failure, CHF due to systolic dysfunction, primary Hyperkalemia aldosteronism Renal failure, Hyperkalemia

Beta Blockers Cardioselective

Nonselective Combined alpha/beta

Angina, CHF due to systolic dysfunction, post-MI, sinus tachycardia, ventricular tachyarrhythmias

Asthma, COPD, 2nd-or 3rd-degree heart block, sicksinus syndrome.

?Post MI, CHF

Alpha antagonists Selective

Nonselective

Prostatism

Pheochromocytoma

Sympatholytics Central

ACE inhibitors

Angiotension II antagonists

Post-MI, coronary syndromes, CHF with low ejection fraction, nephropathy

Acute renal failure, bilateral renal artery stenosis, pregnancy, Hyperkalemia

CHF with low ejection fraction, nephropathy, ACE Inhibitor cough

Renal failure, bilateral renal artery stenosis, pregnancy Hyperkalemia Contd...

CHAPTER 153

CHF due to systolic dysfunction, renal failure

708

Table 2 : Examples of Oral Drugs Used in Treatment of Hypertension Drug class

Examples

Usual Total Daily Dose (Dosing Frequency/Day)

Other Indications

Contraindications/ Cautions

Renin inhibitors

Aliskiren

150-300mg (1)

Diabetic nephropathy

Pregnancy

Nifedipine (longacting)

30-60mg (1)

2nd- or 3rd-degree heart block

Verapamil (longacting)

120-360mg (1-2)

Post-MI, supraventricular tachycardias, angina

Diltiazem (longacting)

180-420mg (1)

Hydralazine

25-100 mg (2)

Minoxidil

2.5-80 mg (1-2)

Calcium antagonists Dihydropyridines

HYPERTENSION

Nondihydropyridines

Direct vasodilators

Severe coronary artery disease

*At the initiation of therapy, lower doses may be preferable for elderly patients and for select combinations of antihypertensive agents. Abbreviations: ACE, angiotensionconverting enzyme; CHF, congestive heart failure, COPD, chronic obstructive pulmonary disease, MI, myocardial infarction.

Betablockers

β-Adrenergic receptor blockers lower blood pressure by decreasing cardiac output, reduction of heart rate and contractility. Central nervous system effect and inhibition of rennin release, beta blockers are particularly effective in hypertensive patients by co administration with a diuretic. Beta blockers without intrinsic sympathomimetic activity decrease the rate of sudden death, overall mortality and recurrent myocardial infarction. In patients with CHF, beta blockers reduce the risk of hospitalization and mortality. Beta blockers remain appropriate therapy for hypertensive patients with concomitant heart disease. Carvedilol and labetalol block both B receptors and peripheral a-adrenergic receptors. Nebivolol represents another class of cardioselective beta blockers that has additional vasodilator actions related to enhancement of nitric oxide activity. Alpha blockers are also effective in treating lower urinary tract symptoms in men with prostatic hypertrophy. Sympatholytic agents centrally acting alpha 1625 2 sympathetic agonists decrease peripheral resistance by inhibiting sympathetic outflow. They may be particularly useful in patients with autonomic neuropathy. Drawbacks include somnolence, dry mouth and rebound hypertension on withdrawal. Although they are potentially effective antihypertensive agents, their usefulness is limited by orthostatic hypotension, sexual dysfunction. Rebound hypertension is another concern with abrupt cessation of drugs with a short half-life.

CALCIUM CHANNEL BLOCKERS

Reduce vascular resistance through L-channel blockade, which reduces intracellular calcium and blunts vasoconstriction. Three classes of calcium channel blocker are Phenylalkylamines (Verapamil), benzothiazepines (diltiazem) and 1,4-dihydropyridines (Nifedipine-like)

effectively lowers Blood pressure. There are used in combination with ACEI and ARBs. The side effects are flushing; headache and edema with dihydropyridine use are related to their potencies as arterioliar dilator. Edema is due to an increase in transcapillary pressure gradient, and not due to net salt and water retention.

Direct Vasodilators

They decrease peripheral resistance via sympathetic nervous system. Minoxidil is a particularly potent agent and is used most frequently in patients with renal insufficiencies that are refractory to all other drugs. Side effects of minoxidil include hypertrichosis, pericardial effusion. Intravenous nitroprusside can be used to treat malignant hypertension and life-threatening left ventricular heart failure associated with elevated arterial pressure.

COMPARISON OF ANTIHYPERTENSIVES

On average, standard doses of most antihypertensive agents reduce blood pressure by 8-10/4-7 mmHg; however, there may be subgroup differences in responsiveness. Younger patients may be more responsive to beta blockers and ACEIs, over age 50 may be more responsive to diuretics and calcium antagonists. Patients with highrenin hypertension may be more responsive to ACEIs and ARBs patients with low-renin hypertension are more responsive to diuretics and calcium antagonists. ACEIs and ARBs A meta-analysis of more than 30 randomized trials of blood pressure-lowering therapy indicates that reduction in blood pressure, the major drug classes seem to produce similar overall net effects on total cardiovascular events. ALLHAT trial demonstrated that the occurrence of CHD and nonfatal myocardial infarction, overall mortality, was virtually identical in hypertensive patients treated with either an ACEI (lisinopril) a diuretic (Chlorthalidone) & Calcium antagonist. ACEI and ARBs decrease intraglomerular pressure and paroteninuria and may retard the rate of progression of renal insufficiency.

After a stroke, combination therapy ACEI and a diuretic, but not with ARB reduce the rate of recurrent stroke. There is a recent resurgence of interest in two nonpharmacologic, antihypertensive therapies which interrupt sympathic outflow (1) device-based cartotid baroreflex activation by electrical stimulation of the carotid sinus; (2) endovascular radiofrequency ablation of the renal sympathetic nerves. Whereas renal denervation is a minimally invasive procedure, both interventions inhibit sympathetic drive and decrease blood pressure by increasing the capacity of the kidney to excrete sodium and by decreasing renin release. Experience with these interventions is limited. In the short term, blood pressure is lowered in 75-80% of patients, and the magnitude of the blood pressure reduction is similar for both procedures. Most impressive results have been observed in patients with “resistant” hypertension and with obesity-related hypertension.

BP that are either too high or too low. Too low BP may exceed auto regulatory capacity of cerebral, coronary and renal blood flows. Caution should be exercised in lowering blood pressure <130/80 mmHg in patients with diabetes, CHD, and other high risk patients. Patient with renal insufficiency may show Serum creatinine concentration. In older patient isolated systolic hypertension, further lowering of diastolic blood pressure does not result in harm. However, gradual blood pressure reduction to a less aggressive target level of control may be appropriate. Three or more drugs frequently required in patients with diabetes and renal insufficiency to control the blood pressure. For most agent reduction of blood pressure at half-standard dose is only ~20% less than at standard doses. Appropriate combinations of agents at these lower have additive or almost additive effects on blood pressure with a lower incidence of side effects. The term resistant hypertension refers to patients with blood pressures persistently >140/90 mm/Hg despite taking three or more antihypertensive agents, including a diuretic. Resistant or difficult to-control hypertension is more common in patients >60 years than younger patients. Resistant hypertension may be related to “pseudo resistance” (high office BP and low home BP), nonadherence therapy, identifiable causes of hypertension (Including obesity excessive alcohol intake) and use of any non-prescription drugs. Rarely older patient pseudo hypertension may be related to the inability to measure blood pressure accurately in severely sclerotic arteries. This condition is suggested if the Radial pulse remains palpable despite occlusion of the bronchial artery by the cuff. The actual blood pressure can be determined direct intra-arterial measurement. The resistance hypertension may be evaluated by measuring of home and office blood pressure or ambulatory blood pressure monitoring.

REFERENCES

Kalil GZ, Haynes WG Sympathetic nervous system in obesity-related hypertension: mechanisms and clinical implication. Hypertens Res 2012; 35:4-16.

Matsui Y, Ishikawa J, Eguchi K, et al. Maximum value of home blood pressure: a novel indicator of target organ damage in hypertension. Hypertension 2011; 57:1087-93.

World Health Organisation. (2015). Raised blood pressure. (On line) Avaiable from http://www.whoint/gho/ncd/risk_ factors/blood_pressure_prevalence_text/en/#. (Accessed November, 2015)

Parato G, Stergiou G, O’Brien E, et al. European society of hypertension practice guidelines for ambulatory blood pressure monitoring. J Hypertens 2014; 32:1359-66.

Akbar S, Alorainy MS. The current status of beta-blockers use in the management of hypertension. Saudi Med J 2014; 35:1307-17.

DiNicolantonio JJ, Fares H, Niazi AK, et al. Β-blockers in hypertension, diabetes, heart failure and acute myocardial infarction: a review of the literature. Open Heart 2015; 2:e000230.

Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of

BLOOD PRESSURE GOALS OF ANTIHYPERTENSIVE THERAPY

Maximum protection against combined cardiovascular endpoints is achieved with pressures <135-140mmHg for systolic blood pressure and <80-85 mmHg for diastolic blood pressure. In diabetic patients, effective blood pressure control reduces the risk of cardiovascular events and death as well as the risk for micro vascular disease (nephropathy, retinopathy). Hypertension control have recommended more aggressive blood pressure targets <130/80 in patients with diabetes, CHD, chronic kidney disease patients with diabetes and coronary heart disease, “tight control” of systolic blood pressure is not associated with improved cardiovascular outcomes. The concept “J-curve” suggest that the risk of CVS events increases at

709

CHAPTER 153

In patients with type 2 diabetes, treatment with an ACEI, and ARB, or aliskiren decreases proteinuria and delays the progression of renal disease. Among African Americans with hypertensionrelated renal disease, ACEIs appear to be more effective than beta blockers or dihydropyridine calcium channel blockers in slowing, although not preventing, the decline of glomerular filtration rate. In most patients with hypertension and heart failure due to systolic, diastolic dysfunction, the use of diuretics, ACEIs or ARBs, and beta blockers is recommended to improve survival. Independent of blood pressure, in both hypertensive and normotensive individuals, ACEIs attenuate the development of left ventricular hypertrophy, improve symptomatology and risk of sudden death from CHF, & reduce morbidity and mortality in post-myocardial infarction patients. The use of ACEIs provide better coronary protection than do calcium channel blockers, whereas calcium channel blockers provide more stroke protection than do either ACE1 of beta blockers. Combination treatment with an ACEI (benazepril) plus a calcium antagonist was superior to treatment with ACEI plus a diuretic in reducing the risk of cardiovascular events and death among high-risk patient with hypertension. Combination of an ACEI, diuretic recently been shown to produce major reductions in morbidity and mortality in the very elderly.

the European Society of Cardiology (ESC). Eur Heart J 2013; 34:2159-219.

HYPERTENSION

710 8.

Goff DC, Lloyd-Jones DM, Bennet G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Fprce on Practice Guidelines. J Am Coll Cardiol 2014; 63(25 Pt B): 2935-59.

Kasper DL, Fauci AS, Hause SL, et al. Principles of Internal Medicine by Harrison, 19th edition 2015.

10. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in highrisk hypertensive patients randomized to angiotensionconverting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAWA 2002; 288:2981-97. 11. Smith SM, Gong Y, Handberg E, et al. Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens 2014; 32:635-43.