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Antithrombotic drugs

Fibrinolytics

Antithrombotic drugs

Fibrinolytics

Antithrombotic drugs

Fibrinolytics

Vitamin K-dependent clotting factors

ď&#x201A;ˇ Varying half-life (6-72 hours) ď&#x201A;ˇ Anticoagulant effect of vitamin K antagonists starts after several days

Vitamin K antagonists â&#x20AC;&#x201C; major use ď&#x201A;ˇ Prevention and treatment of thromboembolic diseases

Acute MI and LV Thrombus • In the absence of acute reperfusion therapy, intracardiac thrombi occurs in about 1/3 of patients in the first 2 weeks after anterior MI and in higher rates in those with large infarcts involving the LV apex. •

Cerebral infarcts occur in about 10% of patients with LV thrombus in the absence of anticoagulation therapy.

•

Ventricular mural thrombi occur in patients with chronic ventricular dysfunction resulting from CAD, hypertension, or other dilated cardiomyopathy.

•

These are at persistent risk of stroke and systemic embolism whether or not AF is documented.

Acute MI and LV Thrombus • On the basis of available clinical trial results, Class I recommendations have advised oral anticoagulation of patients with echocardiographically detected LV thrombi after AMI.

• No consensus regarding duration of anticoagulant treatment. • Stroke risk persists several months after MI.

• The risk of thromboembolism seems to decrease after the first 3 months. • In patients with chronic ventricular aneurysm, the risk of embolism is fairly low, even through intracardiac thrombi occur frequently in this condition. ©2010 American Heart Association, Inc. All rights reserved.

Recommendations for Patients With Cardioembolic Stroke Types Risk Factor â&#x20AC;&#x201C; Prosthetic Heart Valves

Class/Level of Evidence

For patients with ischemic stroke or TIA who have mechanical prosthetic heart valves, warfarin is recommended with an INR target of 3.0 (range, 2.5 to 3.5).

Class I; LOE B

For patients with mechanical prosthetic heart valves who have an ischemic stroke or systemic embolism despite adequate therapy with oral anticoagulants, aspirin 75 mg/d to 100 mg/d in addition to oral anticoagulants and maintenance of the INR at a target of 3.0 (range, 2.5 to 3.5) is reasonable if the patient is not at high bleeding risk (e.g., history of hemorrhage, varices, or other known vascular anomalies conveying increased risk of hemorrhage, coagulopathy).

Class IIa; LOE B

For patients with ischemic stroke or TIA who have bioprosthetic heart valves with no other source of thromboembolism, anticoagulation with warfarin (INR 2.0 to 3.0) may be considered.

Class IIb; LOE C

AF indicates atrial fibrillation; INR, international normalized ratio; LMWH, low-molecular-weight heparin; LV, left ventricular; LVEF, left ventricular ejection fraction; MVP, mitral valve prolapse; and TIA, transient ischemic attack. *See Tables 1 and 2 for explanation of class and level of evidence ÂŠ2010 American Heart Association, Inc. All rights reserved.

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Recommendation

Class

Level

First event, transient risk factor: Vitamin K Antagonists (VKA) for 3 months

„Idiopathic“/“unprovoked“ event: VKA for at least 3 months

Idiopathic event, low bleeding risk, stable anticoagulation: consider long-term treatment

IIb

In PE with cancer, LMWH for 3-6 months;

IIa

then long-term therapy with VKA or LMWH

Why only 3 months?

Electrocardiogram (2) Regular rhythm P

Irregularly irregular rhythm

Normal sinus rhythm – – – –

Normal heart rate Regular rhythm P waves Steady baseline

AF – Heart rate increased (tachyarrhythmia)* – Irregularly irregular rhythm – No P wave

*Reduced heart rate (bradyarrhythmia) may also be observed Ashley EA & Niebauer J. Cardiology Explained. Remedica: London 2004; ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429 12 Apr 2012

Types of Atrial Fibrillation

www.escardio.org/guidelines

European Heart Journal (2010) 31, 2369-2429

Current Treatment Strategies for AF Prevention of thrombo-embolism

Rate control Rhythm control

ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906

AF is an Independent Risk Factor for Stroke AF patients have a near 5fold increased risk of stroke1

 1 in every 6 strokes occurs in a patient with AF  Ischemic stroke associated with AF is typically more severe than stroke due to other etiologies3  Stroke risk persists even in asymptomatic AF4

1. Wolf et al. Stroke 1991;22:983-9882. Fuster V et al. Circulation 2006;114:e257-e354 3. Dulli DA et al. Neuroepidemiology 2003;22:118-1234. Page RL et al. Circulation 2003;107:1141-1145

Transthoracic echocardiography Non-invasive Used to identify: – Atrial thrombi – Atrial and ventricular size and functioning – Ventricular hypertrophy – Pericardial disease – Valvular heart disease

Thrombus in left atrium

Asinger RW. Echocardiography 2000;17:35764; ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114: e257–354 & Eur Heart J 2006;27:1979–2030; lower image from Lazraq M et al. Arch Cardiovasc Dis 2008;101:67980 19 Apr 2012

Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention Warfarin Better

Control Better Unblinded

AFASAK SPAF

Unblinded

BAATAF

Unblinded Terminated early

CAFA SPINAF

Double-blind; Men only 2o prevention; Unblinded

EAFT Aggregate 100%

50%

Hart R, et al. Ann Intern Med 2007;146:857.

-50%

-100%

Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reduction Treatment Better

Treatment Worse

Warfarin vs. Placebo/Control

6 Trials n = 2,900

Antiplatelet drugs vs. Placebo

8 Trials n = 4,876

100% Hart R, et al. Ann Intern Med 2007;146:857.

50%

-50%

Efficacy of Warfarin in Trials vs. Practice Stroke Risk Reductions Treatment Better

Treatment Worse

Warfarin vs. Placebo/Control

6 Trials n = 2,900

Warfarin vs. No anticoagulation

Medicare cohort n = 23,657

100%

Hart R, et al. Ann Intern Med 2007;146:857 Birman-Deych E. Stroke 2006; 37: 1070â&#x20AC;&#x201C;1074

50%

-50%

Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions Warfarin Better

Antiplatelet Rx Better

ACTIVE-W Anticoagulation vs. Aspirin + Clopidogrel

n = 6,706

Anticoagulation vs. Antiplatelet drugs

7 Trials n = 4,232

100% Connolly S, et al. Lancet 2006; 367:1903. Hart R, et al. Ann Intern Med 2007;146:857.

50%

-50%

ACTIVE W: dual antiplatelet therapy inferior to oral anticoagulation for stroke prevention in AF Stroke

Cumulative hazard rates

0.05 0.04 0.03

Dual antiplatelet therapy Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d)

RR 1.72 (95% CI: 1.242.37)

Oral anticoagulation

P=0.001

VKA (target INR = 2.0–3.0)

0.02 0.01 0.00 0

0.5

1.0

1.5

2419 2466

941 930

Years n= n=

3335 3371

3168 3232

INR = international normalized ratio; RR = relative risk; VKA = vitamin K antagonist ACTIVE Investigators. Lancet 2006;151:1903–12

Warfarin better

Aspirin better

AFASAK I AFASAK II Chinese ATAFS EAFT PATAF SPAF II

Age 75 yrs Age >75 yrs

RRR 38%

All trials 100

(95% CI: 18–52%)

–50

RRR (%)*

–100

Warfarin compared with Aspirin for stroke prevention in AF

Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) Hart RG et al. Ann Intern Med 2007;146:857–67

Anticoagulant Control & Outcomes in AF Among patients with atrial fibrillation taking warfarin, good INR control resulted in REDUCED:

 stroke or systemic embolism  MI  death  bleeding White – Arch Intern Med 2007;167:239

Antithrombotic Trials in AF: Core Findings Anticoag. at INR 2.0-3.0 very effective - Generally safe - Moderately burdensome

Aspirin is much less effective

Safety of Anticoagulation for AF Absolute Rates of Intracranial Hemorrhage: Anticoagulation Pooled 1째 RCTs

0.3% per yr

Control 0.1% per yr

ASA and Warfarin Use • Generally AVOID

• No additional benefit for most patients • Definite increase in bleeding risk

• There must be a good reason for the ASA e.g. coronary artery stent; high-risk mechanical heart valve; TIA despite INR >2

• Therefore, the combination of an antiplatelet agent and warfarin must be an ACTIVE decision

Diet and Warfarin Use  Do NOT advise restriction of vitamin K-containing food = associated with less stable INR values

 Encourage foods high in vitamin K (broccoli, spinach, brussels sprouts)  “Let me know if you plan a major change in your usual diet.”

Anticoagulation Rule If the INR value is not what you expected, ask the question, “Why did this happen?”

INR Higher than Expected • Miscommunication about dosing or change in dosing (doctor or patient) “Tell me what doses you’ve taken since the last INR”

• New medication – antibiotics, high dose acetaminophen, amiodarone, NSAIDs, statins, omeprazole, OTC, herbals • Substantial alcohol excess

• Stopped medication – phenytoin • Intercurrent illness • Nutrition change – decrease vitamin K intake

Drug and food interactions associated with increased VKA potency Drug/food

Examples

Analgesics

Acetaminophen, propoxyphene, salicylates

Anti-arrhythmics

Amiodarone, propafenone, quinidine

Antibiotics

Ciprofloxacin, erythromycin, metronidazole

Antifungals

Fluconazole, itraconazole, miconazole

Beta-blockers

Propranolol

H2-receptor antagonists/PPIs

Cimetidine, omeprazole

Lipid-lowering agents

Lovastatin, atorvastatin

Herbal products/dietary supplements

Vitamin E, garlic, devil’s claw

Miscellaneous

Alcohol (if concomitant liver disease)

PPIs = proton pump inhibitors; VKA = vitamin K antagonist Holbrook AM et al. Arch Intern Med 2005;165:1095–106; du Breuil AL & Umland EM. Am Fam Physician 2007;75:1031–42 36 Apr 2012

Drug and food interactions associated with reduced VKA potency Drug/food

Examples

Antibiotics

Dicloxacillin, nafcillin, rifampicin

Antifungals

Griseofulvin

Immunosupressants

Azathioprine, cyclosporine

Lipid-lowering agents

Cholestyramine

Herbal products/dietary supplements

Coenzyme Q10, ginseng, St John’s wort

Foods

Green tea, avocados (large amounts), food with high vitamin K content (e.g. broccoli and spinach)

Miscellaneous

Carbamazepine, sucralfate, trazodone

VKA = vitamin K antagonist Holbrook AM et al. Arch Intern Med 2005;165:1095–106; du Breuil AL & Umland EM. Am Fam Physician 2007;75:1031–42 37 Apr 2012

INR Lower than Expected • Compliance

• Compliance • Compliance

• Miscommunication about dosing or change in dosing (doctor or patient) “Tell me what doses you’ve taken since the last INR”

• Nutrition change – increase vitamin K • New medication – ginseng, green tea

Anticoagulation Rule Donâ&#x20AC;&#x2122;t over-react to small changes in INR value and Generally make small changes in dose (unless dangerous to do so) - e.g. 5-10% of weekly dose

Warfarin Discontinuation Rates

within 5 years

did not fill second prescription

8.9%

61.3%

within 1 year

31.8%

43.2%

within 2 years

Men discontinued warfarin therapy earlier than women, and patients aged 66 to 75 years more likely than olders Gomes T et al. Arch Intern Med 2012 on line

INR Equation

(

)

Patientâ&#x20AC;&#x2122;s PT in Seconds ISI INR = Mean Normal PT in Seconds INR = International Normalized Ratio ISI = International Sensitivity Index

How Different Thromboplastins Influence the PT Ratio and INR Blood from a single patient

Thromboplastin Reagent

Patientâ&#x20AC;&#x2122;s Mean PT Normal

PTR

(Seconds)

1.3

1.5

1.6

2.2

14.5

2.6

ISI

INR

How Different Thromboplastins Influence the PT Ratio and INR Blood from a single patient

Thromboplastin reagent

Patientâ&#x20AC;&#x2122;s Mean PT Normal

PTR

ISI

INR

(Seconds)

1.3

3.2

2.6

1.5

2.4

2.6

1.6

2.0

2.6

2.2

1.2

2.6

14.5

2.6

1.0

2.6

Adjusted odds ratios for ischaemic stroke and intracranial bleeding Randomised trials of antithrombotic therapy for patients with AF Odds ratio 20 Ischaemic stroke

Intracranial bleeding 10 5

1 1.0

2.0 3.0 4.0 5.0 6.0 7.0 International Normalised Ratio

8.0

ACC/AHA/ESC Guidelines. Circulation 2001;104:2118-30

Advantages and Diasadvantages of Current Antithrombotics Advantages

Disadvantages

Used for many years Well studied/experience Effective if INR kept in therapeutic range Well known drug and food interactions Low cost Antidote/easy to recover

Erratic INR control / frequent monitoring Narrow therapeutic index Medications adjustments often required Drug and food interactions Risk of bleeding Patients reluctance Underuse in high risk patients

Targets For Novel Antithrombotic Agents In The Coagulation Cascade1

Vitamin K antagonist: Tecarfarin (Ph II completed)2

Tissue factor/VIIa

Indirect Factor Xa inhibitors: Idraparinux (Ph III terminated)3 SSR 126517 (withdrawn 2009)4

VIIIa

IXa

Direct Factor Xa inhibitors: Apixaban Rivaroxaban Edoxaban Betrixaban (Ph II

Va Xa

Direct thrombin inhibitors: II

Thrombin

ongoing)9

Fibrinogen AT= antithrombin; Ph = Phase

Fibrin

Dabigatran etexilate (Ph III completed)10 Ximelagatran (withdrawn 2006)11,12 AZD0837 (Ph II completed)13

Trials With New Oral Anticoagulants Trial

RELY

ROCKET-AF

ARISTOTLE

Drug used

Dabigatran Vs Warfarin

Rivaroxaban vs Warfarin

Apixaban vs Warfarin

Dose

150 or 110 mg BID

20 or 15mg QD

vs Warfarin (INR 2-3)

5mg BID vs Warfarin

(INR 2-3) No. of Patients

18.113

14.000

18.201

Mean age (yrs)

71.5

Percentage of Hypertension

80%

90%

85%

Mean CHADS2 Score

2.1

Conclusions:

Dabigatran 110mg non-inferior to warfarin, with 20% less major bleedings Dabigatran 150 mg superior to warfarin with similar rate of major bleedings

Rivaroxaban non-inferior to warfarin on intention to treat analysis but superior in on treatment analysis Similar rate of major bleedings

Apixaban was superior to warfarin in the risk of stroke or systemic embolism, bleeding and all cause mortality

Approval

FDA

FDA approved 9/11

Doses of 150 mg and 75mg

EMA: under consideration

(if CI Cr 15-30 mL/min

Manolis AJ et al. Curr Hypertens Rep 2012;350

Meta-analysis of Efficacy and Safety of New Oral Anticoagulants Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients Major bleeding

Intracranial bleeding

GI Bleeding

Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354.51

Systematic Review and Adjusted Indirect Comparison Meta-analysis of Oral Anticoagulants in AF

Conclusions:

Apixaban lowers the risk of major and gastrointestinal bleeding versus dabigatran and rivaroxaban. Dabigatran lowers the composite of stroke or systemic emboli, and ischemic stroke versus rivaroxaban. Head-to-head clinical trials are required to confirm these findings

William L et al. Circ Cardiovasc Qual Outcomes 2012;5:711

Which Anticoagulant ?

New anticoagulants

Warfarin

Reversal of NOACs Types of Studies Evaluating Reversal of New Oral Anticoagulants Apixaban

Dabigatran

Rivaroxaban

Oral activated charcoal

No data

In vitro

No data

Hemodialysis

No data

Human volunteers

No data

Hemoperfusion with activated charcoal

No data

In vitro

No data

Fresh frozen plasma

No data

Mouse model

No data

Activated factor VIIa

No data

Rat model

Rat and baboon model

3-factor PCC

No data

4-factor PCC

No data

Human volunteers and rat model

Human volunteers

Kaatz S, et al. Am J Hematol. 2012 May;87 Suppl 1:S141-5. Pub Med PMID: 22473649.

Reversal of NOACs Suggestions for Reversal of New Oral Anticoagulants Apixaban

Dabigatran

Rivaroxaban

Oral activated charcoal

Yes

Hemodialysis

Yes

Hemoperfusion with activated charcoal

Possible

Yes

Possible

Fresh frozen plasma

Activated factor VIIa

Unclear

3-factor PCC

Unclear

4-factor PCC

Possible

Kaatz S, et al. Am J Hematol. 2012 May;87 Suppl 1:S141-5. Pub Med PMID: 22473649.

Limitations of New Agents • No monitoring – Unable to titrate dose – Failure of therapy vs. poor compliance

• Short t1/2 – Poor compliance may affect efficacy more than VKA

• No antidote • Renal/hepatic dose adjustments likely required • Cost

Trials of Antithrombotic Therapy in AF Lessons learned:  Warfarin, INR 2-3, is extremely effective and can be safe 

ASA has little efficacy in AF



Warfarin is tough to beat or even tie in RCTs

Optimizing Benefit and Reducing Risk

Hemorrhage

Thrombosis

Risk of UGIB with Different Combinations of Antithrombotic Agents

Mean age=72 years Hallas J, et al. BMJ doi:10.1136/bmj.38947.697558.AE

CHA2DS2 VaSc Score and Annual Risk of Stroke Risk Factors

Score

Recent congestive heart failure

Hypertension

Age â&#x2030;Ľ 75 y

Diabetes mellitus

History of stroke or transient ischemic attack

Vascular disease (prior MI, PAD, or aortic plaque)

Age 65-74

Sex category (female sex)

Stroke Rate %

20 15.2

15 9.8 10

9.6

1.3

2.2

3.2

4.0

1.9 0

Relationship between CHADS2 score and annual risk of stroke

6.7

CHADS2 Score

Manolis AJ et al. Curr Hypertens Rep 2012; in press

The CHADS2 Index

Stroke Risk Score for Atrial Fibrillation

Approximate Risk threshold for Anticoagulation

Score (points)

Risk of Stroke (%/year)

0 1

1.9 2.8 3%/year

2 3 4 5 6

Van Walraven C, et al. Arch Intern Med 2003; 163:936. Go A, et al. JAMA 2003; 290: 2685. Gage BF, et al. Circulation 2004; 110: 2287.

4.0 5.9 8.5 12.5 18.2

Bleeding Risk Assessment in AF: HAS-BLED Bleeding Risk Score Letter

Clinical Characteristic*

Points Awarded

Hypertension

Abnormal renal and liver function (1 point each )

Stroke

Bleeding

Labile INRS

Elderly

Drugs or alcohol

1 1 or 2

1 or 2 Risk of bleeding >3

ESC AF Guidelines 2012: Recommendations for Anticoagulation in Patients with Non-valvular AF Class

Recommendation

Level

In patient with CHA2DS2-VASc score ≥ 2, OAC therapy with: A dose-adjusted VKA (INR 2-3); or A direct thrombin inhibitor ( dabigatran ) ; or An oral factor Xa inhibitor (eg, rivaroxaban, apixaban*) …is recommended unless contraindicated In patient with CHA2DS2-VASc score of 1, OAC therapy with: A dose-adjusted VKA (INR 2-3); or A direct thrombin inhibitor ( dabigatran ); or An oral factor Xa inhibitor (eg, rivaroxaban, apixaban*) …should be considered, based upon an assessment of the risk for bleeding complications and patient preferences INR= international normalized ratio; OAC= oral antigulation; VKA = vitamin antagonist

*Pending approval Camm AJ, et al. Eur HeartJ. 2012 Aug 24.

AHA/ASA 2012 Scientific Advisory Statement for Oral Antithrombotics for Stroke Prevention in Nonvalvular AF ď&#x192;&#x2DC;Warfarin (class I; level of evidence A), dabigatran (class I;

level of evidence B), apixaban (class I; level of evidence B), and rivaroxaban (class IIa; level of evidence B) are all indicated for the prevention of first and recurrent stroke in

patients with nonvalvular AF ď&#x192;&#x2DC;The selection of an antithrombotic agent should be individualized on the basis of risk factors, cost, tolerability, patients preference, potential for drug interactions, and other clinical characteristics, including time in INR therapeutic range if the patient has been taking warfarin AHA = American Heart Association; ASA = American stroke Association

Furie KL, et al. Stroke. 2012 Aug 2.

Pharmacokinetic and Pharmacodynamic Changes with Aging

►

Metabolism  Generally, lower drug doses are required to achieve

   

the same effect Receptor numbers, affinity, or post-receptor cellular effects may change Overall decline in metabolic capacity Decreased liver mass Decreased oxidative metabolism through P450 system  decreased clearance of drugs

Ideas Based upon Life Expectancy • “Average Life Expectancy” can be misleading – Overall average 77 years in 2002 – But, a 70-year-old woman on average can expect to live another 18 years! – 10% of 90 year olds will live to 100

Standard Creatine Clearance ml/min/1.73

Kidney Function and Age

140 130

120 110

100

Age (years) Andres and Tobin, 1976

Polypharmacy in the Elderly ►

Elderly = 12% of population;

32% of prescriptions ►

Average of 6 prescription medications; 1 to 3.5 over-the-counter drugs

►

Average nursing home patient takes 7 medications

►

Average American senior spends $670/year for pharmaceuticals

Adverse Drug Reactions

â&#x2013;ş

About 15% of hospitalizations in the elderly are related to adverse drug reactions

â&#x2013;ş

The risk of adverse drug reactions increases with the number of prescription medications

Prevalence of Dementia

North America: 6.9% prevalence; 63% increase 20102030; 151% increase 2010-2050

Polypharmacy and Non-adherence

►

Strongest predictor of non-adherence is the number of medications

►

Non-adherence rates estimated 25-50%

►

Intentional about 75% of the time

Changes in regimen made by patients to: - Increase convenience - Reduce adverse effects or - Decrease refill expense

Comorbidity and Frailty With Age Among MI Patients Older adults also have more comorbidity, end-organ dysfunction, frailty and cognitive impairment. Accordingly, older patients may also have competing risks for poor outcomes and survival following MI. 50 45 40

% of population

35 CHF Renal Insuff Stroke Frailty* Cognitive Impairment

30 25 20 15 10

* Frailty: Fatigue, Slow Gait, Weak Grip, Wt loss >10 lbs, Low Activity

5 0 <65

65-74

75-84

85+

Patient Age (Yrs) REFS: Evolution of Care for Older Adults with AMI, J Am Coll Cardiol 2005;46:1479-87; Fried Frailty Phenotype from Cardiovascular Health Study, J Geront Biol Sci 2001;56:M158-66 ; Cognitive Impairment from Canadian Study of Health and Aging CMAJ. 1994 March 15; 150(6): 899â&#x20AC;&#x201C;913.

Older Adults in MI Randomized Trials vs. US MI Population Individuals over the age of 75 years account for 6% of the U.S. population, but over 60% of deaths from myocardial infarction and are often excluded or underrepresented in clinical trials.

% Age > 75

40 35

% MI Pts >75yrs

30 25

% RCT Pts >75yrs

20 15 10 5 0 1966-70

1971-80

1981-90

1991-00

Time Period MI population based on Worcester Heart Study Data REF: Lee PY, Alexander KP, Hammill BG, et al. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA 2001;286(6):708-13.

Use of Early Invasive Strategy by Age Older adults may gain greater absolute benefits with an early invasive strategy compared with younger adults because of their higher risk for adverse outcomes with conservative management (often despite increased procedural risks).

Event Rate (%)

Age Group

(n)

â&#x2030;¤55 y

(716)

4.8

5.0

1.07

56-65 y

(614)

9.1

7.6

0.82

66-75 y

(612)

10.3

7.8

0.73

â&#x2030;Ľ75 y

(278)

21.6

10.8

0.44* P <0.016

Cons.

0.5

Invasive Better

1.5

2.0

Conservative Better

Odds of DEATH or MI Source: (TACTICS TIMI 18) Bach AIM 2004; 141:186-195; J Am Coll Cardiol 2007;50:658-752

Inv. (Inv v. Cons)

Prevalence of AF by Age

Prevalence (%)

20 18

Framingham Study

Cardiovascular Health Study

Mayo Clinic Study

Western Australia Study

10 8 6

4 2 0 40

60 Age (years)

Feinberg WM. Arch Intern Med. 1995;155(5):469â&#x20AC;&#x201C;473

Stroke Risk in Atrial Fibrillation

Stroke Rate (% per year)

Untreated Control Groups of Randomized Trials

Age (years)

Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449.

Atrial Fibrillation Morbidity and Mortality

►4- to 5-fold increased risk of stroke

►Doubling of the risk for dementia ►Tripling of risk for heart failure ►40 to 90% increased risk for overall mortality ►Risk of stroke in AF patients by age group – 1.5% in 50 to 59 year age group

– 23.5% in 80 to 89 year age group

Benjamin EJ, et al. Circulation 2009;119:606-618

Warfarin Use in Patients With 100 <80 y N=5888 community AF 90 residents with AF ď&#x201A;ł80 y

Percentage Use

80 70

60 50 40 30

20 10 0

n=110 n=34 n=79 n=32 n=80 n=34 n=83 n=36 n=78 n=38 n=73 n=57 n=72 n=63 1989-1990 1990-1991 1991-1992 1992-1993 1993-1994 1994-1995 1995-1996

Smith et al. Arch Intern Med. 1999;159:1574-1578.

Examination Year

Cumulative Incidence of Major Bleeding

0.04 0.06 0.08 0.10 0.02 0.00

Cumulative Proportion with Major Hemorrhage

First Year Among Patients Newly Starting Warfarin by Age

100

200 Days of Warfarin

Age < 80 Hylek EM et al, Circulation 2007;115(21):2689-2696.

300

Age >=80

400

Bleeding and Risk of Falls ď&#x201A;§ decision analysis in elderly with atrial fibrillation

ď&#x201A;§ Risk of falling is not an important factor in decision re antithrombotic therapy

ď&#x201A;§ With an average risk of stroke from AF (5%/yr), benefit:risk favors anticoagulation unless the person falls > 300 times/yr!

Man-Son-Hing - Arch Intern Med 1999;159:677

Συμπεράσματα ►

Oι υπερήλικες με κολπική μαρμαρυγή έχουν τον υψηλότερο κίνδυνο για ΑΕΕ και αιμμοραγίες και , επομένως, χρειάζονται ειδική ματαχείρηση

►

Ο κίνδυνος για ΑΕΕ υπερβαίνει κατά πολύ τον κίνδυνο των μειζόνων αιμαρραγιών από τα αντιπηκτικά

►

Τα νεώτερα αντιπηκτικά ίσως αποδειχθούν ασφαλέστερα στους υπερήλικες

Ποιός ασθενής είναι υποψήφιος για NOAC

1.Άρνηση για λήψη sintrom

2.Ασταθής χρόνος INR 3.Νεοδιαγνωσθείς ασθενής

Σε ασθενή με βαλβιδική νόσο επιτρέπεται να δώσουμε NOAC Σε ασθενή πού παίρνει NOAC και ανακαλύψουμε ότι έχει βαλβιδική νόσο τί κάνουμε; Αν η βαλβιδική νόσος είναι αιμοδυναμικά σημαντική διακόπτουμε το NOAC Δεν έχει αποδειχτεί ότι δεν είναι αποτελεσματικό σε βαλβιδική νόσο, απλώς δεν έχει δοκιμαστεί (επί του παρόντος τρέχει μελέτη σε προσθετικές βαλβίδες- RE-ALIGN http://clinicaltrials.gov/ct2/show/NCT01505881?term=re-align&rank=1 )

Πώς γίνεται η μετάβαση (switching) από βαρφαρίνη σε NOAC

1. Διακοπή της βαρφαρίνης 2. Προοδευτική ελάττωση INR

3. Όταν INR < 2.0, έναρξη NOAC

Πώς γίνεται η μετάβαση (switching) από NOAC σε βαρφαρίνη; Switching NOAC → βαρφαρίνη (Cr Cl > 50 ml/min)

(Cr Cl 30-50 ml/min)

• Έναρξη βαρφαρίνης 1.

• 3 ημέρες αργότερα, διακοπή NOAC

• Αποδρομή δράσης NOACεντός 24 ωρών

• 2 ημέρες αργότερα, διακοπή NOAC

• Αποδρομή δράσης NOACεντός 3 ημερών

Τί γίνεται αν χάσουμε μια δόση;

Χαμένη δόση dabigatran -“Ο κανόνας των 6 ωρών” Χρόνος παρέλευσης από την προγραμματισμένη ώρα λήψης της δόσης

Λαμβάνει τη δόση

Παραλείπει τη δόση SPC: “Δε θα πρέπει να λαμβάνεται διπλή δόση για την αναπλήρωση των μεμονωμένων δόσεων που παρελήφθησαν”

Σε πόσο χρόνο από τη λήψη του NOAC μπορούμε να περάσουμε σε άλλο παρεντερικό αντιπηκτικό;

Συνιστάται να αναμένουμε 12 ώρες μετά την τελευταία δόση προτού αλλάξουμε από dabigatran σε κάποιο παρεντερικό αντιπηκτικό.

Σε ασθενή που θα κάνει στεφανιογραφία πότε κόβουμε τη νταμπιγκατράνη;

Διακοπή θεραπείας με dabigatran επί προγραμματισμένης επέμβασης

Δοκιμασίες πήξης και ερμηνεία τους Η θεραπεία με dabigatran δεν απαιτεί τακτικές εξετάσεις παρακολούθησης της πήξης, είτε πρόκειται για βραχυχρόνια, είτε για μακροχρόνια θεραπεία. Ωστόσο, σε περίπτωση υποψίας υπερδοσολογίας ή σε ασθενείς υπό αγωγή με dabigatran που παρουσιάζονται στα τμήματα επειγόντων περιστατικών, μπορεί να είναι χρήσιμη η αξιολόγηση της πηκτικότητας αίματος σε ασθενή υπό αγωγή με dabigatran.

Υπάρχει στενή συσχέτιση μεταξύ της συγκέντρωσης πλάσματος του dabigatran και του βαθμού της αντιπηκτικής δράσης.

How do I Determine if my Patient is Anticoagulated? 3.6

 A 2.5-fold prolongation in aPTT correlates with an excessive anticoagulant effect1,2

3.3 3.0

aPTT

2.7 2.4 2.1 1.8 Multiple dose y = 0.86 + 0.06873* • x1/2 r2 = 0.8514

1.5

 No single test (aPTT, INR, TT, ECT) is adequate to reliably assess the anticoagulant activity of dabigatran following administration3

1.2 0.9 0

100

200

300

400

500

600

700

800

900

1000

Dabigatran plasma concentration (ng/mL) aPPT = activated partial thromboplasmin time; ECT = ecarin clotting time; INR = international normalized ratio; TT = thrombin clotting time 1. Stangier J et al. Br J Clin Pharmacol 2007;64:292–303; 2. Stangier J. Clin Pharmacokinet 2008;47:285–95; 3. Pradaxa® Product Monograph

Δοκιμασίες πήξης και ερμηνεία τους Ο χρόνος προθρομβίνης (INR) δεν είναι αρκετά ευαίσθητος και δε συνιστάται Η δοκιμασία ενεργοποιημένης μερικής θρομβοπλαστίνης (aPTT) μπορεί να χρησιμεύσει στην ανίχνευση υπερβολικής αντιπηκτικής δράσης, παρόλο που ο aPTT έχει μικρότερη ευαισθησία ως προς τη δράση του dabigatran σε επίπεδα που υπερβαίνουν τα θεραπευτικά. Να σημειωθεί: κατά τις πρώτες 2-3 ημέρες μετά από εγχείρηση, μπορεί να ανιχνευτούν ψευδώς παρατεταμένες τιμές. Μία τιμή aPTT >80 δευτερόλεπτα στο χαμηλότερο σημείο (όταν πρέπει να χορηγηθεί η επόμενη δόση) σχετίζεται με υψηλότερο κίνδυνο αιμορραγίας.

Δοκιμασίες πήξης και ερμηνεία τους

Ο μετρούμενος χρόνος θρομβίνης (TT) είναι μία τιμή η οποία εξαρτάται από το μετρητή πήξης και από την παρτίδα της θρομβίνης που χρησιμοποιείται στη μέτρηση. Για το λόγο αυτό συνιστάται η χρήση της βαθμονομημένης δοκιμασίας αναστολέα θρομβίνης Hemoclot® (μία δοκιμασία χρόνου αραιωμένης θρομβίνης, dTT) με πρότυπα dabigatran για τον υπολογισμό της συγκέντρωσης του dabigatran αντί του προσδιορισμού του TT

Δοκιμασίες πήξης και ερμηνεία τους

Ο χρόνος πήξης Ecarin (ECT) προσδιορίζει άμεσα τη δραστικότητα των άμεσων αναστολέων της θρομβίνης. ECT αυξημένος περίπου 3-4 φορές σε σχέση με τα φυσιολογικά επίπεδα πριν από τη λήψη της επόμενης δόσης του dabigatran (μετρούμενος στο χαμηλότερο σημείο) σχετίζεται με υψηλότερο κίνδυνο αιμορραγίας.

Χρονική στιγμή: Οι παράμετροι πήξης εξαρτώνται από το χρόνο που λήφθηκε το δείγμα αίματος σε σχέση με το χρόνο που χορηγήθηκε η προηγούμενη δόση.

Τα αποτελέσματα που θα προκύψουν από ένα δείγμα αίματος που λήφθηκε 2 ώρες μετά τη χορήγηση του PRADAXA (~μέγιστο επίπεδο) θα είναι διαφορετικά (υψηλότερα) σε όλες τις δοκιμασίες πήξης συγκριτικά με ένα δείγμα αίματος που λήφθηκε 10-16 ώρες (χαμηλότερο επίπεδο) μετά από τη χορήγηση της ίδιας δόσης

Σε ασθενή που παίρνει νταμπιγκατράνη και παθαίνει μεγάλη αιμορραγία τί κάνουμε;

Αντιμετώπιση μεγάλης αιμορραγίας σε ασθενή

υπό αγωγή με dabigatarn (1)  Διακοπή νταμπιγκατράνης  Γενική αίματος, Hb, PLT, Cr, CrCl, aPTT  Διερεύνηση εστίας αιμορραγίας – μηχανική πίεση ή χειρουργική αντιμετώπιση εάν κριθεί απαραίτητο  Διατήρηση επαρκούς διούρησης  Χορήγηση πρόσφατα κατεψυγμένου πλάσματος FFP ή φρέσκου πλήρους αίματος

Αντιμετώπιση μεγάλης αιμορραγίας σε ασθενή

υπό αγωγή με dabigatarn (2) Επί αποτυχίας ελέγχου: A. αιμοδιάλυση ( ↓ σύνδεση με πρωτεΐνες) B. χορήγηση ειδικών αιμοστατικών παραγώγων 

συμπυκνωμένα σκευάσματα προθρομβινικού συμπλέγματος - PPC (4 παράγοντες πήξης: II, VII, IX, X) Δοσολογία 50IU/kg - «Beriplex» (250 & 500 IU)



ενεργοποιημένος παράγοντας VII rFVII (Novoseven 40-80μg/kg)]

Αντιμετώπιση μεγάλης αιμορραγίας σε ασθενή

υπό αγωγή με dabigatarn (3)

Συγχορήγηση dabigatran σε ασθενείς που λαμβάνουν ασπιρίνη ή/και κλοπιδογρέλη;

• Υπάρχει αυξημένος κίνδυνος αιμορραγιών με τη συγχορήγηση (όπως επίσης με τα κουμαρινικά) σε ασθενείς που ήδη λαμβάνουν ασπιρίνη ή/και κλοπιδογρέλη •Σε αυτούς τους ασθενείς, δοσολογία 220mg dabigatran (110 x 2), πρέπει να ληφθεί υπ’ όψιν.

Dabigatran και γαστροπροστασία

Ο κίνδυνος γαστρεντερικής αιμορραγίας αυξάνεται από τη χρήση ΑΣΑ, κλοπιδογρέλης ή ΜΣΑΦ, καθώς και από την παρουσία οισοφαγίτιδας, γαστρίτιδας ή ΓΟΠ που απαιτούν αγωγή με PPI ή ανταγωνιστές Η2 Σε αυτούς τους ασθενείς: • δοσολογία 220mg dabigatran (110x2), πρέπει να ληφθεί υπόψη. • Η χορήγηση ενός PPI μπορεί να ληφθεί υπόψη για την πρόληψη της γαστρεντερικής αιμορραγίας

Ερώτηση 1

Ηλικίας 82 ετών άνδρας προσέρχεται για ετήσια εξέταση. Τι πιθανότητα έχετε να διαγνώσετε κολπική μαρμαρυγή;

1. 2. 3. 4.

1% 5% 10% 25%

Prevalence of Diagnosed AF Stratified by Age and Sex

12.0 10.0

Women Men

11.1 10.3 9.1

8.0

7.3

6.0

5.0

4.0 3.0

1.7

2.0 0.0

0.1 0.2 0.4 <55

0.9

7.2

5.0

x-axis = % y-axis = # of men/women

3.4

1.7

1.0

55-59

60-64

65-69

70-74

75-79

80-84

> 85

# Women

530

310

566

896

1498

1572

1291

1132

# Men

1529

634

934

1426

1907

1886

1374

759

Go AS, JAMA. 2001 May 9;285(18):2370-5. Pub Med PMID: 11343485

108

Ερώτηση 2

Ανδρας ηλικίας 46 ετών προσερχεται για ετήσιο έλεγχο. Ποιός είναι ο διά βίου κίνδυνος για ανάπτυξη κολπικής μαρμαρυγής

1. 2. 3. 4.

1% 5% 10% 25%

Incidence of AF Lifetime Risk for AF at Selected Index Ages by Sex Index Age, yrs

Men

Women

26.0% (24.0 – 27.0)

23.0% (21.0 – 24.0)

25.9% (23.9 – 27.0)

23.2% (21.3 – 24.3)

25.8% (23.7 – 26.9)

23.4% (21.4 – 24.4)

24.3% (22.1 – 25.5)

23.0% (20.9 – 24.1)

22.7% (20.1 – 24.1)

21.6% (19.3 – 22.7)

1 in 4 Men & women >40 Years will develop AF

Lifetime risk if currently free of AF

Lloyd-Jones DM, et al. Circulation. 2004 Aug 31;110(9):1042-6. Pub Med PMID: 15313941.

110

Ερώτηση 3

Γυναίκα ηλικίας 68 ετών με κολπική μαρμαρυγή χωρίς άλλες παθήσεις. Πως θα εκτιμούσατε τον κίνδυνο για ΑΕΕ;

1. Χαμηλό 2. Μέτριο 3. Υψηλό

Atrial Fibrillation Risk Stratification 12 Schemes applied to 1000 patients from SPAF III study High

Moderate

Stroke Risk in Atrial Fibrillation Working Group. Stroke. 2008 Jun;39(6):1901-10. Pub Med PMID: 18420954.

Low

112

CHA2DS2-VASc

Stroke or Other TE at One Year CHA2DS2VASc Score

#TE Events

TE Rate During 1 yr (95% CI)

TE Rate During 1 yr, Adjusted for Aspirin RX

103

0% (0-0)

162

0.6% (0.0-3.4)

0.7%

184

1.6% (0.3-4.7)

1.9%

203

3.9% (1.7-7.6)

4.7%

208

1.9% (0.5-4.9)

2.3%

3.2% (0.7-9.0)

3.9%

3.6% (0.4-12.3)

4.5%

8.0% (1.0-26.0)

10.1%

11.1% (0.3-48.3)

14.2%

100% (2.5-100)

100%

Total

1,084

P Value for trend 0.003

Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest. 2010 Feb;137(2):263-72. Pub Med PMID: 19762550.

113

CHA2DS2 VaSc Score and Annual Risk of Stroke Risk Factors

Score

Recent congestive heart failure

Hypertension

Age â&#x2030;Ľ 75 y

Diabetes mellitus

History of stroke or transient ischemic attack

Vascular disease (prior MI, PAD, or aortic plaque)

Age 65-74

Sex category (female sex)

Stroke Rate %

20 15.2

15 9.8 10

9.6

1.3

2.2

3.2

4.0

1.9 0

Relationship between CHADS2 score and annual risk of stroke

6.7

CHADS2 Score

Manolis AJ et al. Curr Hypertens Rep 2012

Ερώτηση 4

Άνδρας 78 ετών με κολπική μαρμαρυγή και αρτηριακή υπέρταση (CHA2DS2-VASc = 3 {4% ΑΕΕ ανά έτος} ). Ποιά είναι η ετήσια συχνότητα μειζόνων αιμορραγιών;

1. 1% 2. 2% 3. 3% 4. 5% 5. 10%

Bleeding Risk Scores Widely Used in AF • HAEMORRHAGES1 • HASBLED2 • ATRIA Score3

1. Gage BF, et al. Am Heart J. 2006 Mar;151(3):713-9. PMID: 16504638. Pub Med PMID:16504638. 2. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. Chest. 2010 Nov;138(5):1093-100. PMID:20299623. 3. Fang MC, et al. J Am Coll Cardiol. 2011 Jul 19;58(4):395-401. Pub Med PMID:21757117.

116

Bleeding Risk Scores in AF ATRIA

HAS-BLED

HEMORR2HAGES

Anemia1

Hypertension4

Hepatic10 or disease2

1 1

Severe renal disease2

Abnormal Renal5 or

1 1

Ethanol abuse

Age ≥75 yrs

Stroke

Malignancy

Any prior hemorrhage

Bleeding

Older Age (>75 yrs)

Hypertension3

Labile INR8

Reduced platelet number

Elderly (>65 yrs)

Rebleeding12

Drugs9 or

1 1

Hypertension4

Anemia13

Genetic factors14

Excessive fall risk15

Stroke

1. 2. 3. 4. 5. 6. 8. 9. 10. 11. 12. 13. 14. 15.

Liver

function6

Alcohol

Hemoglobin <13 g/dl men; <12 g/dl women Estimated glomerular filtration rate <30 ml/min or dialysis-dependent Diagnosed hypertension Systolic blood pressure >160 mmHg Presence of chronic dialysis or renal transplantation or serum creatinine ≥200 mmol/L Chronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.) Unstable/high INRs or poor time in therapeutic range (eg <60%) Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc. Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia Prior hospitalization for bleeding Most recent hematocrit <30 or hemoglobin <10 g/dl CYP2C9*2 and/or CYP2C9*3 Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls

Renal

or function11

Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000–000. 2012 Jul 24. [Epub ahead of print] Online Appendix. PMID: 22858389.

117

AMADEUS Cohort Stratified by the HEMORR2HAGES, HAS-BLED, and ATRIA Schemes

All Patients

Clinically Relevant Bleeding

Major Bleeding

1,738 (76.6)

182 (10.5)

25 (1.4)

517 (22.8)

63 (12.2)

13 (2.5)

13 (0.5)

3 (23.1)

1 (7.7)

2,268

248 (10.9)

39 (1.7)

Low Risk (<3)

1,739 (75.9)

159 (9.1)

22 (1.3)

High Risk (≥3)

553 (24.1)

92 (16.6)

17 (3.1)

2,292

251 (11.0)

39 (1.7)

Scheme HEMORR2HAGES Low (≤1) Risk Intermediate Risk (2–3) High Risk (>3)

TOTAL HAS-BLED

TOTAL ATRIA Low Risk (<4)

2,038 (90)

220 (10.8)

31 (1.5)

Intermediate Risk (4)

102 (4.4)

13 (12.7)

3 (2.9)

High Risk (>4)

128 (5.6)

18 (14.1)

5 (3.9)

2,268

248 (10.9)

39 (1.7)

TOTAL

Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000–000. 2012 Jul 24. [Epub ahead of print] Online Appendix. PMID: 22858389.

118

Question #5 78 year old female with atrial fibrillation, hypertension and CHF. CHADS2 = 3 CHA2DS2-VASc = 5 HAS-BLED = 2 What would you use for stroke prevention? 1. No anti-thrombotics 2. Aspirin 3. Aspirin + clopidogrel 4. VKA antagonist 5. Dabigatran or Rivaroxaban 119

Ερώτηση 5

Γυναίκα 78 ετών με κολπική μαρμαρυγή, αρτηριακή υπέρταση και καρδιακή ανεπάρκεια.

Τι συστήνετε για πρόληψη ΑΕΕ 1. 2. 3. 4. 5.

Καμία αγωγή Aspirin Aspirin + clopidogrel Κουμαρινικά Dabigatran

European Society of Cardiology Guidelines CHA2DS2-VASc and Stroke Rate Risk Factors For Stroke and Thrombo-embolism in Non-valvular AF

Risk Factor

Score

Congestive heart failure/LV dysfunction*

Hypertension*

Age >75**

Diabetes Mellitus*

Stroke / TIA / Thrombo-embolism**

Vascular Disease*

Age 65-74*

Sex category (i.e. female sex)*

Maximum Score

Note: maximum score is 9 since age may contribute 0,1, or 2 points

* ‘Clinically relevant non-major’ risk factor ** “Major” risk factor

Camm AJ. Europace. 2010 Oct;12(10):1360-420. Pub Med PMID: 20876603.

121

Bleeding Risk Scores in AF Low Risk (<3) High Risk (≥3)

ATRIA

HAS-BLED

HEMORR2HAGES

Anemia1

Hypertension4

Hepatic10 or disease2

1 1

Severe renal disease2

Abnormal Renal5 or

1 1

Ethanol abuse

Age ≥75 yrs

Stroke

Malignancy

Any prior hemorrhage

Bleeding

Older Age (>75 yrs)

Hypertension3

Labile INR8

Reduced platelet number

Elderly (>65 yrs)

Rebleeding12

Drugs9 or

1 1

Hypertension4

Anemia13

Genetic factors14

Excessive fall risk15

Stroke

1. 2. 3. 4. 5. 6. 8. 9. 10. 11. 12. 13. 14. 15.

Liver

function6

Alcohol

Renal

or function11

Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000–000. 2012 Jul 24. [Epub ahead of print] Online Appendix. PMID: 22858389.

122

Ερώτηση 5

Γυναίκα 78 ετών με κολπική μαρμαρυγή, αρτηριακή υπέρταση και καρδιακή ανεπάρκεια. CHA2DS2-VASc = 5 HAS-BLED = 2

Τι συστήνετε για πρόληψη ΑΕΕ 1. 2. 3. 4. 5.

Καμία αγωγή Aspirin Aspirin + clopidogrel Κουμαρινικά Dabigatran

ESC AF Guidelines 2012: Recommendations for Anticoagulation in Patients with Non-valvular AF Class

Recommendation

Level

*Pending approval Camm AJ, et al. Eur HeartJ. 2012 Aug 24.

Warfarin Use in Patients With AF 100 N=5888 community residents with AF

Percentage Use

<80 y ď&#x201A;ł80 y

60 50 40 30

20 10 0

n=110 n=34 n=79 n=32 n=80 n=34 n=83 n=36 n=78 n=38 n=73 n=57 n=72 n=63 1989-1990 1990-1991 1991-1992 1992-1993 1993-1994 1994-1995 1995-1996

Smith et al. Arch Intern Med. 1999;159:1574-1578.

www.HRSonline.org

Examination Year