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New Frontiers and Treatment Paradigms for

Stroke Prevention in Atrial Fibrillation


Evidence- and Guideline-Based Strategies for Optimizing Clinical Outcomes and Anticoagulation-Based Management for SPAF
Program Chairman

Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School

Samuel Z. Goldhaber, MD

Welcome and Program Overview


CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC
Commercial Support: This National Initiative is Sponsored by an Independent Educational Grant from the Bristol-Myers Squibb/Pfizer Cardiovascular Partnership.

Program Faculty
PROGRAM CHAIRMAN SAMUEL Z. GOLDHABER, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School CHRISTIAN T. RUFF, MD, MPH TIMI Study Group Brigham and Womens Hospital Harvard Medical School Boston, MA ELAINE M. HYLEK, MD, MPH Professor of Medicine Department of Medicine Boston University Medical Center Boston, Massachusetts

Conflict of Interest Disclosures


Program Chairman SAMUEL Z. GOLDHABER, MD Research Support: Eisai, EKOS, Johnson & Johnson, sanofi-aventis Consultant: Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventis CHRISTIAN T. RUFF, MD, MPH Research Support: Daiichi Sankyo, AstraZeneca, Bristol-Meyers Squibb, sanofi-aventis Consultant: Alere and Beckman Coulter ELAINE M. HYLEK, MD, MPH Research Support: Bristol-Myers Squibb, Ortho-McNeil Consultant: Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer

New Paradigms in the Science and Medicine of Stroke Prevention for Atrial Fibrillation

Risk, Disease Burden, and Deciphering the Maze of Risk-Specific Interventions for AF
Focus on Non-Monitored Oral Anticoagulation and the Unmet Need for Safer and More Effective Stroke Prevention in NVAF Samuel Z. Goldhaber, MD Program Chairman
Director, VTE Research Group Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School

Epidemiology and Overview

Faculty COI Disclosures


Research Support Eisai, EKOS, Johnson & Johnson, sanofiaventis Consultant Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventis

Formal Definition: Atrial Fibrillation

AF is an arrhythmia characterized by uncoordinated atrial activation, with consequent deterioration of atrial mechanical function

Circulation 2011; 121: e269-e367

The ECG of Atrial Fibrillation


Normal sinus rhythm Atrial fibrillation

The 3 Ps and Natural History of Atrial Fibrillation

Paroxysmal
Self-Terminating

Persistent
Lasts > 7 Days

Permanent
Cardioversion Failed or Not Attempted

Normal Sinus Rhythm Atrial Fibrillation

Paroxysmal AF is as likely to cause stroke as persistent or permanent AF

Atrial Fibrillation: Epidemiology


The No. 1 preventable cause of stroke In the United States, up to 16 million individuals will be affected by the year 2050 Increasing survival from heart attack and increasing age (the graying of America) help explain rise in incidence of AF

Atrial Fibrillation Risk Factors

Magnani JW et al. Circulation 2011; 124: 1982-1993

Atrial Fibrillation: An Epidemic


Projected Number of People with AF (millions)
18 16 14

US Prevalence

16 million

12

1 in 4 lifetime risk in men and women 40 years old 10


8 6 4

2 0

Miyakasa Y, et al. Circulation. 2006; 114:119-125.

Year

Relationship Between Atrial Fibrillation and Age

Prevalence, percent

Age, years
Go AS, et al. JAMA. 2001; 285:2370-2375.

Atrial Fibrillation Causes Stroke


Left Atrial Appendage Thrombus

Chimowitz. Stroke 1993; 24: 1015 Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622

Stroke and Atrial Fibrillation Burden


Approximately 5-fold increased risk of stroke
Quantify stroke risk: CHADS2/ CHA2DS2-VASc AF strokes have worse outcomes
30

Costly health care ~ $16 billion/year

Framingham
20

AF prevalence
Strokes attributable to AF

%
10

5059

Age Range (years)

6069

7079

8089

Wolf PA, et al. Stroke 1991; 22: 983-988

Ischemic Strokes in Atrial Fibrillation More Likely to be Severely Disabling


Framingham Heart Study

73 58

33 16

36 16

30 11

Lin HJ, et al. Stroke. 1996;27:1760-1764.

AF PIE: FUTURE

AF PIE: PAST

Fuster V. Circulation 2012; epubl April 18

ESC 2012 AF Update Guidelines

Assess stroke risk exclusively with CHA2DS2VASc and no longer use CHADS2 ESC Guidelines recommend anticoagulation for stroke prevention with CHA2DS2-VASc score of 1 or greater Preference given to novel, non-monitored anticoagulants: apixaban, rivaroxaban, and dabigatran

Anticoagulation in Atrial Fibrillation


Effects on Stroke Risk Reduction
Warfarin better Control better RRR of stroke: 62%

AFASAK SPAF
BAATAF CAFA SPINAF EAFT Aggregate 100%
RRR, relative risk reduction. Hart RG, et al. Ann Intern Med. 1999;131:492-501.

RRR All-cause mortality: 26%

50%

-50%

-100%

ESC 2012 Update Guidelines


HAS-BLED for Evaluation of Bleeding Risk
Clinical Characteristic Hypertension (systolic BP > 160 mm Hg) Abnormal renal or liver function Points
1 1+1 1 1 1 1 1+1 9

Stroke
Bleeding Labile INRs Elderly (age > 65 years) Drugs or alcohol
Maximum score
Pisters R, et al. Chest. 2010;138:1093-1100.

Swedish AF Cohort; Circulation 2011; 125: 2298-2307

Known Problems With Warfarin


1) Delayed onset/offset

2) Unpredictable dose response


3) Narrow therapeutic index

4) Drug-drug, drug-food interactions


5) Problematic monitoring

6) High bleeding rate


7) Slow reversibility

Warfarin Will Likely Survive: Why?


1) 2) Established efficacy Low cost ($4/month; $10/3 mos)

3)
4) 5) 6)

Long track record (1954)


Centralized anticoagulation clinics that maintain TTRs > 60% Rapid, turnaround genetic testing Point-of-care self-testing

7)

INR testing q 12 weeks if stable


CoumaGen-II. Circ 2012; March 19 ACCP Chest Guidelines 2012

COUMAGEN-II
Pharmacogenetic Dosing Achieves TTR of 71%

Circulation 2012; epub March 19

Comparison Overview of New Anticoagulants with Warfarin


Features
Onset
Dosing

Warfarin
Slow
Variable

New Agents
Rapid
Fixed

Food effect
Drug interactions

Yes
Many

No
Few

Monitoring
Half-life Antidote

Yes
Long Yes

No
Short No

Sites of Action in Coagulation System Novel Factor Xa and DT Inhibitors


Steps in Coagulation Pathway
TF/VIIa X VIIIa Va IXa IX

Drugs

Initiation

Propagation

Xa

II

Rivaroxaban Apixaban Edoxaban Betrixaban Dabigatran


Fibrin

Fibrin formation
Fibrinogen

IIa

Hankey GJ and Eikelboom JW. Circulation 2011;123:1436-1450

Novel Oral Anticoagulants


Important Comparative Features
Oral direct thrombin inhibitor Twice daily dosing Renal clearance

Dabigatran Rivaroxaban Apixaban

Direct factor Xa inhibitor Once daily (maintenance), twice daily (loading) Renal clearance
Direct factor Xa inhibitor Twice daily dosing Hepatic clearance Direct factor Xa inhibitor Once daily dosing Hepatic clearance

Edoxaban
Circulation 2010;121:1523

Comparison of Phase 3 SPAF Trials for NOACs: A Robust Trial Base


Novel Anticoagulants FIIa Inhibitor Dabigatran
Open Label Two Doses Twice Daily

Fxa Inhibitor
Rivaroxaban
Double Blind Two Doses Once Daily

Apixaban
Double Blind Two Doses Twice Daily

Edoxaban
Double Blind Two Doses Once Daily

RE-LY

ROCKET-AF

ARISTOTLE

ENGAGE

Best Options for Anticoagulation


The Consensus is Shifting Despite continued use of warfarin, NOACs are considered by many professional medical organizations to be the best option for anticoagulation of SPAF patients:

ESC 2012 AF Update Guidelines


ACCP 2012 Guidelines Canadian AF Guidelines

ESC 2012 UPDATE GUIDELINES For ATRIAL FIBRILLATION

The Rationale for AF Registries


Registries provide a real life perspective on patient populations, management in the field, and outcomes in settings that do not have the special resources and monitoring capabilities of pivotal randomized clinical trials. Information from registries complements clinical trial data. Registries can highlight the disconnect between evidence/guidelines and clinical practice.

The GARFIELD Registry

Novel approach to outcomes research


Planned to be conducted in 50 countries 50,000 prospective and 5000 retrospective patients Patients newly diagnosed with non-valvular AF Five sequential cohorts Random site selection Sites representative of national AF care settings

Consecutive patients
Minimum follow-up period of 2 years

Summary of Garfield Data Cohort One: ESC 2012

10,537 were available for this analysis 5075 retrospective and 5462 prospective Newly diagnosed patients carry high risk for stroke

57% with CHADS2 score >2 83% with CHA2DS2-VASc score >2

VKAs not prescribed in:

38% of patients with CHADS2 score >2 40% of patients with CHA2DS2-VASc score >2

Modest Use of Vitamin K Antagonists Even in High-Risk Patients


European Heart Survey

100

5333 AF patients in 35 countries: 20032004 64

OAC therapy (%)

80 60 40 20 0 1 2
58 59

61

CHADS2 score
OAC, oral anticoagulant Nieuwlaat et al. Eur Heart J 2006; Gage et al. JAMA 2001

A Failure to Prophylax Syndrome

Over the past decade, about 40% of patients with atrial fibrillation are unprotected from stroke because of failure to prescribe anticoagulation. Because criteria for anticoagulation have expanded in 2012, the problem has intensified. Heightened awareness of the disconnect between guidelines/evidence and suboptimal intervention for SPAF. Anticoagulation is necessary as a first step.

The SPAF Landscape 2012: Conclusions

The frequency of atrial fibrillation is increasing, so risk of devastating stroke is increasing as well. Anticoagulants can effectively reduce stroke risk, but they are underutilized.
NOACs have less ICH bleeding risk than warfarin and are superioror at least noninferiorfor stroke prevention. We must overcome the failure-to-prophylax syndrome.

New Paradigms in the Science and Medicine of Heart Disease

State-of-the-Art Risk Stratification of Patients with Atrial Fibrillation


Anticoagulation Strategies Based on Established and Evolving Atrial Fibrillation Scoring Systems for Thrombosis and Hemorrhagic Risk
Elaine M. Hylek, MD, MPH Professor of Medicine Department of Medicine Boston University Medical Center Boston, Massachusetts

Independent Predictors of Stroke in AF


Systematic Review
Significant by Multivariate Analysis
Prior stroke or TIA Increasing age History of hypertension or systolic BP > 160 mm Hg Diabetes Female gender Heart failure Coronary artery disease 5 of 5 studies 6 of 6 studies 5 of 5 studies 4 of 4 studies 3 of 6 studies 0 of 4 studies* 0 of 4 studies

Adjusted Relative Risk (95% CI)


2.5 (1.83.5) 1.5/decade (1.31.7) 2.0 (1.62.5) 1.8 (1.522) 1.6 (1.41.9) Not significant Not significant

* Significant in a subgroup of participants undergoing echocardiography in trials included AFI pooled analysis
Hart RG et al. Neurology 2007; 69: 546.

Nonvalvular Atrial Fibrillation


Stroke Rates Without Anticoagulation According to Isolated Risk Factors

Prior Hypertension Age Stroke/TIA > 75 years


Hart RG et al. Neurology 2007; 69: 546.

Female

Diabetes Heart Failure LVEF

Risk Stratification in Atrial Fibrillation


Established Stroke Risk Factors

High-Risk Factors
Mitral stenosis Prosthetic heart valve History of stroke or TIA

Moderate-Risk Factors
Age > 75 years Hypertension Diabetes mellitus Heart failure or LV function

Less Validated Risk Factors


Age 6575 years Coronary artery disease Female gender Thyrotoxicosis

Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

The CHADS2 Score


Stroke Risk Threshold Favoring Anticoagulation

Score (points) 0
Approximate Risk Threshold for Anticoagulation

Risk of Stroke (%/year) 1.9

1
2 3 4 5 6

2.8
3%/year

4.0 5.9 8.5 12.5 18.2

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.

The CHADS2 Score


Stroke Risk Score for Atrial Fibrillation

Score (points)

Prevalence (%)*
32 65 28 18 10 50-60 40-50

Congestive Heart failure Hypertension Age > 75 years Diabetes mellitus Stroke or TIA
Moderate-High risk Low risk

1 1 1 1 2 >2 0-1

VanWalraven C, et al. Arch Intern Med 2003; 163:936. * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).

CV Event Rates in Patients with Atrial Fibrillation Related to CHADS2 Score


REACH Registry

Goto S, et al. Am Heart J 2008; 156: 855.

The CHA2DS2-VASc Score


Stroke Risk Score for Atrial Fibrillation
Weight (points)

Congestive heart failure or LVEF < 35% Hypertension Age > 75 years Diabetes mellitus Stroke/TIA/systemic embolism Vascular Disease (MI/PAD/Aortic plaque) Age 65-74 years Sex category (female)
Moderate-High risk Low risk
Lip GYH, Halperin JL. Am J Med 2010; 123: 484.

1 1 2 1 2 1 1 1
>2 0-1

Patient Selection for Anticoagulation


Additional Considerations

Risk of bleeding Newly anticoagulated vs established therapy Availability of high-quality anticoagulation management program Patient preferences

Published Bleeding Risk Scores


Patients on Oral Vitamin K Antagonist Anticoagulant Therapy
Low Kuijer et al. Arch Intern Med 1999;159:457. Beyth et al. Am J Med 1998;105:91. Gage et al. Am Heart J 2006;151:713. 0 Moderate High 1-3 >3 1.6 x age + 1.3 x sex +2.2 x cancer; 1 point for 60 years old, female or malignancy; 0 if none 65 years old; GI bleed within 2 weeks; prior stroke; comorbidities (recent MI, Hct < 30%, diabetes, Cr > 1.5 mg/dL) ;1 point for each condition; 0 if absent HEMORR2HAGES score: liver/renal disease, EtOH abuse, malignancy, > 75 years old, low platelet count or function, rebleeding risk, uncontrolled Htn, anemia, genetic factors (CYP2C9) risk of fall or stroke; 1 point for each factor; 2 points for previous bleeding (0.49 x age > 70) + (0.32 x female) + (0.58 x remote bleed) + 0.62 x recent bleed) + 0.71 x EtOH/drug abuse) + (0.27 x diabetes) + (0.86 x anemia) + (0.32 x antiplatelet drug use); 1 point for each; 0 if none

1-2

<1

2-3

Shireman et al. Chest 2006;130:1390.

1.07

1.07 - 2.19

> 2.19

Tay, Lane & Lip. Thromb Haemost 2008; 100: 955.

Advances in the Science and Medicine of SPAF

Importance of the HAS-BLED Score


Risk Score for Predicting Bleeding in Anticoagulated Patients with Atrial Fibrillation

Weight (points)

Hypertension (> 160 mm Hg systolic) Abnormal renal or hepatic function Stroke Bleeding history or anemia Labile INR (TTR < 60%) Elderly (age > 75 years) Drugs (antiplatelet, NSAID) or alcohol
High risk Moderate risk Low risk (> 4%/year) (2-4%/year) (< 2%.year)

1 1-2 1 1 1 1 1-2 >4 2-3 0-1

Pisters R, et al. Chest 2010; 138: 1093. Lip GYH, et al. J Am Coll Cardiol 2010; 57: 173.

Canadian Cardiovascular Society AF Guidelines 2012 Update


Assess Thromboembolic Risk (CHADS2)

CHADS2 = 0
Increasing stroke risk No antithrombotic No additional risk factors of stroke

CHADS2 = 1

CHADS2 > 2

ASA

OAC*

OAC*

OAC

Either female sex or vascular disease

Age > 65 y or combination of female sex and vascular disease

*Aspirin is a reasonable alternative in some as indicated by risk/benefit

Canadian Cardiovascular Society AF Guidelines 2012 Update

All patients with atrial fibrillation or atrial flutter (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke (eg, CHADS2) and for the risk of bleeding (eg, HAS-BLED), and that most patients should receive either an oral anticoagulant or aspirin. (Strong recommendation, high quality

evidence)

When oral anticoagulation therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban* in preference to warfarin.

(Conditional recommendation. high-quality evidence).


*Once approved by Health Canada.

ESC 2012 AF Update Guidelines

2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace. 2012 Aug 24

ESC 2012 Guidelines: Identifying Truly Low-Risk Patients with AF


Thus, this guideline strongly recommends a practice shift toward greater focus on identification of truly low-risk patients with AF (ie,age <65 and lone FL who do not need any antithrombotic therapy), instead of trying to focus on identifying high-risk patients. To achieve this, it is necessary to be more inclusive (rather than exclusive) of common stroke risk factors as part of any comprehensive stroke risk assessment. Indeed, patients with AF who have stroke risk factor(s) > 1 are recommended to receive effective stroke prevention therapy, which is essentially OAC with either well-controlled VKA therapy [INR 2-3, with a high percentage of time in the therapeutic range (TTR), for example, at least 70%] or one of the NOACs
2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace. 2012 Aug 24

CHA2DS2-VASc vs. CHADS2


Is More Information Better?

The new scoring systems have been adopted in Europe but not in the United States, even in the latest practice guideline updates. The components of the CHA2DS2-VASc score are less well validated than those of the CHADS2 score. The C-statistic used to validate the CHA2DS2-VASc score is only marginally superior to those of other schema. There is no consensus about how to combine stroke risk and bleeding risk scores into a composite instrument.

Current AF Stroke Risk Stratification Schemes


Limitations, Challenges, and Opportunities

All have modest predictive value for thromboembolism

Patients classified as low risk must truly be at low risk to safely avoid anticoagulation Should classify small proportion into the intermediate risk category, for which optimum therapy is less clear

Incorporate risk factors as cumulative Should be comprehensive yet easy to apply


Scoring systems are the most popular method Acronym for easy recall

Should be validated in multiple populations, ideally clinical practice populations, rather than in the control arms of trial cohorts
Risk schemes must evolve to address the wider therapeutic margin offered by new oral anticoagulants
Lip GYH, Halperin JL. Am J Med 2010;123:484

Atrial Fibrillation and Thromboembolism


The Next Challenges

Better risk-stratification that balances stroke and bleeding and addresses new anticoagulants Noninvasive methods to better predict events and guide therapy Safer treatments for the highest risk patients Achieving and confirming successful rhythm control over time Targeted atrial fibrillation prevention

New Paradigms in the Science and Medicine of Heart Disease

Deciphering the Maze of Evidence from Landmark Trials Evaluating Non-Monitored, Oral Anticoagulants (NOACs) for SPAF

Christian T. Ruff, MD, MPH TIMI Study Group Brigham and Womens Hospital Harvard Medical School Boston, MA

Faculty COI Disclosures


Research Support Daiichi Sankyo, AstraZeneca, Bristol-Meyers Squibb, sanofi-aventis Consultant Alere and Beckman Coulter

Properties of an Ideal Anticoagulant


Properties Oral, once-daily dosing Rapid onset of action Benefit Ease of administration No need for overlapping parenteral anticoagulant

Minimal food or drug interactions


Predictable anticoagulant effect

Simplified dosing
No coagulation monitoring Safe in patients with renal disease Simplifies management in case of bleeding or intervention For emergencies

Extra renal clearance


Rapid offset in action Antidote

Major Advances In Oral Anticoagulation for SPAF

6 Trials of Warfarin vs Placebo 1989-1993

ROCKET AF (Rivaroxaban) 2010

ENGAGE AF (Edoxaban) 2013

(Dabigatran) 2009

RE-LY

ARISTOTLE (Apixaban) 2011

Comparative Pharmacokinetics/ Pharmacodynamics of Novel Agents


Dabigatran Apixaban Rivaroxaban Edoxaban

Target Hrs to Cmax CYP metabolism Bioavailability

IIa (thrombin)
2 None 7%

Xa 1-3 15% 66%

Xa 2-4 32% 80%

Xa 1-2 NR > 45%

Transporters
Protein binding Half-life Renal elimination Linear PK

P-gp
35% 12-14h 80% Yes

P-gp
87% 8-15h 25% Yes

P-gp/BCRP
>90% 9-13h 33% No

P-gp
55% 8-10h 35% Yes

BCRP = breast cancer resistance protein; CYP = cytochrome P450; NR = not reported; P-gp = P-glycoprotein Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14 Ericksson BI, et al. Clin Pharmacokinet 2009;48:1-22

The RE-LY Trial: Dabigatran

RE-LY
Atrial fibrillation 1 Risk Factor Absence of contra-indications

951 centers in 44 countries

PROBE=Prospective Randomized Open Trial with Blinded Adjudication of Events


open

R
Blinded
Dabigatran Etexilate 110 mg bid N = 6015 Dabigatran Etexilate 150 mg bid N = 6076

Warfarin (INR 2.0-3.0)


N = 6022

10 efficacy outcome = stroke or systemic embolism 10 safety outcome = major bleeding Non-inferiority margin 1.46

RE-LY Efficacy (Dabigatran)


Stroke/Systemic Embolic Event
Non-inferiority Superiority P-value P-value

Dabigatran 110 vs Warfarin

< 0.001

0.34

Dabigatran 150 vs Warfarin

< 0.001

< 0.001

Margin = 1.46

Connolly, et al. N Engl J Med 2009;361:1139-51

0.50

0.75
HR

(95% CI)

1.00

1.25

1.50

RE-LY Efficacy (Dabigatran)


Dabigatran 110 mg Dabigatran 150 mg

Stroke/SEE

0.91 (0.74-1.11) 0.66 (0.53-0.82)

Ischemic Stroke

1.11 (0.89-1.40) 0.76 (0.60-0.98)

Hemorrhagic Stroke

0.31 (0.17-0.56) 0.26 (0.14-0.49)


0.1 0.3 0.5 1.0 2.0
Warfarin Better

Connolly, et al. N Engl J Med 2009;361:1139-51

Dabigatran Better

RE-LY Safety Results (Dabigatran)


Dabigatran 110 mg Dabigatran 150 mg

Major Bleed

0.80 (0.69-0.93) 0.93 (0.81-1.07) 0.31 (0.20-0.47)

ICH

0.40 (0.27-0.60) 1.10 (0.86-1.41) 1.50 (1.19-1.89)


1.29 (0.96-1.75) 1.27 (0.94-1.71)
0.1 0.3 0.5 1.0 2.0
Warfarin Better

GI Bleed

MI

Connolly, et al. N Engl J Med 2009;361:1139-51

Dabigatran Better

RE-LY Efficacy Stratified by CHADS2


D110 mg D150 mg

Annualized Rate Stroke/SEE (%)


CHADS2 0-1 2 3-6 D110 1.06 1.43 2.12 D150 0.65 0.84 1.88 WARF 1.05 1.38 2.68

P=

0.44
0.50 1.00 Dabigatran better

P=

0.82

0.50 1.00 1.50 Dabigatran Warfarin better better

1.50 Warfarin better

Oldgren J, et al. ACC 2010

RE-LY Efficacy Stratified by Prior Vitamin K Anatagonist

Ezekowitz MD, et al. Circulation 2010;122:2246-2253

RE-LY Cardioversion (Dabigatran)


Stroke/SEE Major Bleeding

1.8 1.6
1.4

1.7

1.2 1
0.8 0.8

0.6 0.4
0.2

0.6 0.3

0.6

0.6

0 Dabi 110 mg
(N = 647)

Dabi 150 mg
(N = 672)

Warfarin
(N = 664)

Nagarakanti R, et al. Circulation 2011;123:131-136

Dabigatran Approval

Prevention of stroke in AF
Available in 75 mg and 150 mg (twice daily) Dose of 75 mg if CrCl 15-30 mL/min

Data in favor of 110 mg were suggestive, but not entirely convincing

ROCKET AF: Rivaroxaban

Atrial Fibrillation
Rivaroxaban
20 mg daily 15 mg for Cr Cl 30-49
Randomize Double blind / Double Dummy (n = 14,266)

Risk Factors CHF Hypertension At least 2 Age 75 required Diabetes OR Stroke, TIA or Systemic embolus

Warfarin
INR target - 2.5 (2.0-3.0 inclusive)

Monthly Monitoring and adherence to standard of care guidelines

Statistics: non-inferiority, > 95% power, 2.3% warfarin event rate

Primary End point: Stroke or non-CNS Systemic Embolism

ROCKET AF Efficacy
Stroke/Systemic Embolic Event
Rivaroxaban Warfarin

Event Rate
On Treatment
N = 14,143

Event Rate 2.15

HR (95% CI) 0.79 (0.65, 0.95)


0.88 (0.74, 1.03)

P-value

1.70

0.015

ITT
N = 14,171

2.12
2

2.42

0.117

0.5

Rivaroxaban better

Warfarin better

Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat through Site Notification populations

Patel, et al. N Engl J Med 2011;365(10);883-891

ROCKET AF Key Secondary Efficacy


Rivaroxaban (%/yr) 1.34 0.26 0.91 1.87 1.53 Warfarin (%/yr) 1.42 0.44 1.12 2.21 1.71 Hazard Ratio (95% CI) 0.94 (0.75-1.17) 0.59 (0.37-0.93) 0.81 (0.63-1.06) 0.85 (0.70-1.02) 0.89 (0.73-1.10) Pvalue 0.581 0.024 0.121 0.073 0.289

Event
Ischemic Stroke Hemorrhagic Stroke MI Total Mortality Vascular Mortality

Patel, et al. N Engl J Med 2011; 365(10);883-891

ROCKET AF Safety (Rivaroxaban)

Event Major and Clinically Relevant Bleed Major Bleed

Rivaroxaban (%/yr) 14.9

Warfarin (%/yr) 14.5

Hazard Ratio (95% CI) 1.03 (0.96-1.11)

Pvalue 0.44

3.6

3.4

1.04 (0.90-1.20)

0.58

Fatal Bleed

0.2

0.5

0.50 (0.31-0.79)

0.003

ICH

0.5

0.7

0.67 (0.47-0.93)

0.02

Patel, et al. N Engl J Med 2011; 365(10);883-891

ROCKET AF Efficacy (Rivaroxaban)


Moderate Renal Impairment

Fox KA, et al. Eur Heart J 2011;32(19):2387-94.

ROCKET AF Safety
Moderate Renal Impairment

Fox KA, et al. Eur Heart J 2011;32(19):2387-94.

Rivaroxaban Approval

Prevention of stroke in AF Dose 20 mg if CrCl > 50 mL/min Dose of 15 mg if CrCl 15-50 mL/min

AVERROES

AVERROES Trial Design: Apixaban


36 countries, 522 centers

AF and >1 risk factor, and demonstrated or unexpected unsuitable of VKA

Apixaban 5 mg bid 2 mg bid in selected patients

R
Double-blind

5600 patients

ASA (81-324 mg/d) Primary Outcome: Stroke or Systemic Embolic Event (SEE)

AVERROES: Apixaban
Stroke or Systemic Embolic Event
0.05 0.04 0.03 0.020

Major Bleeding
Apixaban
P < 0.001

Aspirin
P < 0.001

0.015 0.010

0.02
0.01 0.00 0 3 6 9 12

Aspirin

Apixaban
18

0.005 0.000 0 3 6 9 12 18

HR 0.45 (0.32-0.62)

HR 1.13 (0.74-1.75)

Connolly SJ, et al. N Engl J Med 2011 (epub)

ARISTOTLE: Apixaban

ARISTOTLE Trial Design: Apixaban


Inclusion risk factors Age 75 years Prior stroke, TIA, or SE HF or LVEF 40% Diabetes mellitus Hypertension

Randomize double blind, double dummy (n = 18,201)

Exclusion Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine

Apixaban 5 mg oral twice daily


(2.5 mg bid in selected patients)

Warfarin
(target INR 2-3)

Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism
Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

ARISTOTLE Efficacy: Apixaban

HR 0.79 (0.660.95)

(1.60 %/yr)

21% RRR
(1.27 %/yr )

P (non-inferiority) < 0.001 P (superiority) = 0.011

Granger CB, et al. NEJM 2011; 365:981-992

ARISTOTLE Efficacy Outcomes


Warfarin (N = 9081) Event Event Rate Rate (%/yr) (%/yr) 1.27 1.19 0.97 0.24 0.09 3.52 4.49 0.53 1.60 1.51 1.05 0.47 0.10 3.94 5.04 0.61 Apixaban (N = 9120)

Outcome

HR (95% CI)

P Value

Stroke or systemic embolism* Stroke Ischemic or uncertain Hemorrhagic Systemic embolism (SE) All-cause death* Stroke, SE, or all-cause death Myocardial infarction

0.79 (0.66, 0.95) 0.79 (0.65, 0.95) 0.92 (0.74, 1.13) 0.51 (0.35, 0.75) 0.87 (0.44, 1.75) 0.89 (0.80, 0.998) 0.89 (0.81, 0.98) 0.88 (0.66, 1.17)

0.011 0.012 0.42 < 0.001 0.70 0.047 0.019 0.37

Granger CB, et al. NEJM 2011; 365:981-992

ARISTOTLE Safety End Points


Apixaban (%/yr) 2.13 Warfarin (%/yr) 3.09 Hazard Ratio (95% CI) 0.69 (0.60-0.80) Pvalue < 0.001 < 0.001 < 0.001 0.37

Event

ISTH Major Bleeding

ICH

0.33

0.80

0.42 (0.30-0.58)

GUSTO Severe

0.52

1.13

0.46 (0.35-0.60)

Gastrointestinal

0.76

0.86

0.89 (0.70-1.15)

Granger CB, et al. NEJM 2011; 365:981-992

ARISTOTLE: Apixaban
Renal Function
Stroke or SEE Annualized Event Rate Major Bleeding

Baseline Cockcroft-Gault eGFR mL/min


Hohnloser SH, et al. EHJ 2012 (epub August 29)

Phase III: Protocol Schema


N = 21,105
DOUBLE BLIND DOUBLE DUMMY

AF on Electrical Recording < 12 mo Intended oral A/C CHADS2 >2

R
High dose regimen Edoxaban 60 mg qd (n 7000)

Randomization Stratified By 1. CHADS2 2-3 vs 4-6 2. Drug Clearance

Low dose regimen Edoxaban 30 mg qd (n 7000)

Active Control Warfarin (n 7000)

Median Duration of Follow-up 24 Months

Primary Objective Edoxaban: Therapeutically as Good as Warfarin


1 EP = Stroke or SEE (Noninferiority Boundary HR 1.38) 2 EP = Stroke or SEE or CV mortality Safety EPs = Major Bleeding, Hepatic Function

EVENT DRIVEN

SEE = systemic embolic event

Ruff CR et al. Am Heart J 2010; 160:635-41

Pivotal Atrial Fibrillation Trials


Baseline Characteristics
RE-LY (Dabigatran) # Enrolled Age (yrs) Female CHADS2 score 3 VKA naive 18,113 72 9 36% 32% 50% ARISTOTLE (Apixaban) 18,201 70 [63-76] 35% 30% 43% ENGAGE AF-TIMI 48* (Edoxaban) 21,105 72 [64-77] 38% 52% 41% ROCKET-AF (Rivaroxaban) 14,264 73 [65-78] 40% 87% 38%

Paroxysmal AF
Prior stroke/TIA Diabetes Prior CHF Hypertension

33%
20% 23% 32% 79%

15%
19% 25% 35% 87%

25%
18% / 12% 36% 56% 90%

18%
55%** 40% 62% 91%

*Preliminary data **includes prior systemic embolism

Connolly SJ et al. N Engl J Med 2009; 361:1139-51 Patel MR et al. N Engl J Med 2011; 365:883-91 Granger CB et al. N Engl J Med 2011; 365:981-92 89 Ruff CR et al. Am Heart J 2010; 160:635-41

Pivotal Atrial Fibrillation Trials


Dose Comparison
RE-LY Drug N Dose (mg) Frequency Dabigatran 18,113 150, 110 bid ROCKET-AF Rivaroxaban 14,266 20 qd ARISTOTLE Apixaban 18,201 5 bid ENGAGE AF-TIMI 48 Edoxaban 21,105 60, 30 qd 60 30 mg 30 15 mg > 25 Yes 2 x blind

Initial Dose adj*


Dose adj (%) Dose adj* after randomization Design

No
0 No PROBE

20 15 mg
21 No 2 x blind

5 2.5 mg
4.7 No 2 x blind

*Dose adjusted in patients with drug clearance. PROBE = prospective, randomized, open-label, blinded end point evaluation

Connolly SJ et al. N Engl J Med 2009; 361:1139-51 Patel MR et al. N Engl J Med 2011; 365:883-91 Granger CB et al. N Engl J Med 2011; 365:981-92 90 Ruff CR et al. Am Heart J 2010; 160:635-41

Pivotal Atrial Fibrillation Trials


Results to Date
RE-LY
Drug Dose (mg)

ROCKET-AF
Rivaroxaban 20 mg qd
ITT cohort: non-infer. On Rx cohort: Superior Superior similar similar similar

ARISTOTLE
Apixaban 5 mg bid
Superior Superior Lower Superior: P = 0.047 similar

Dabigatran 110 bid 150 BID


non-infer Superior Lower similar similar Superior Superior similar P = 0.051 Lower

Stroke + SEE ICH Bleeding Mortality Ischemic stroke Mean TTR Stopped drug WD consent

64% 21% 2.3%

55% 23% 8.7%

62% 23% 1.1%

TTR = time in therapeutic range WD consent = withdrawal of consent, no further data available

Efficacy of New Oral Anticoagulants

Stroke & SEE

Ischemic & Unsp. Stroke

13%
55%
Favors NOACs Favors Warfarin 92

Hemorraghic Stroke

Miller CS, et al. Am J Cardiol 2012;110(3):453-460.

Safety of New Oral Anticoagulants


Bleeding
Major

ICH

51%

GI

Favors NOACs

Favors Warfarin

iller CS, et al. Am J Cardiol 2012;110(3):453-460.

Does INR Matter?


Treatment Group Warfarin P-value Event Rate / Year Event Rate / Year (interaction) 0.74 1.77 2.53 1.94 2.18 1.90 2.14 1.33 1.80 0.20 1.92 2.06 1.51 1.34 0.29 1.75 1.30 2.28 1.61 Hazard Ratio (95% CI)
Study Drug Favors Warfarin

ROCKET AF 0.00-50.62% 50.71-58.54% 58.63-65.71% 65.74-100.0%

RE-LY (Dabigatran 150 mg) < 57.1% 1.1 57.165.5% 1.04 65.572.6% 1.04 > 72.6% 1.27 ARISTOTLE < 58.0% 58.065.7%

65.772.2 % > 72.2 %

1.21 0.83

1.55 1.02

Wallentin L, et al. Lancet 2010;376:975-983 Patel, et al. NEJM 2011;365(10);883-891 Granger CB, et al. NEJM 2011; 365:981-992

0.2

1
www.fda.gov

Warfarin Treatment Interruption

Rauns J, et al. Eur Heart J 2012; 33:1886-1892

All-Cause Death & Thromboembolism

Novel Oral Anticoagulants


More Events Off-Drug

13% 25%

%/yr
P = 0.015 P = 0.117

ROCKET AF
Rivaroxaban Increased Events at End of Trial

81.3

Warfarin
# Primary Events

P = 0.008
48.8

Rivaroxaban

Rivaroxaban

Warfarin
Safety/Days 3 to 30 after the last dose

# Primary Events during first 30 days of transition

Patel MR, et al. NEJM 2011; 365:883-891 Piccini JP, AHA Emerging Science Series, April 25, 2012 webinar. Abstract 114

ARISTOTLE
Apixaban Increased Events at End of Trial

Days after last dose


130 12 37 814 1530

Apixaban to VKA group n/N


21/6791 1/6791 4/6787 5/6780 11/6771

Warfarin to VKA group n/N


5/6569 1/6569 0/6566 1/6559 3/6548

%/year
4.02 2.69 4.31 3.85 4.18

%/year
0.99 2.78 0 0.80 1.18

Stroke or systemic embolism

Pattern mirrored the first 30 days of the trial where warfarin-nave patients starting warfarin had a higher rate of stroke or systemic embolism (5.41%/year) than warfarin-experienced patients (1.41%/year).
Granger CB, et al. European Heart Journal 2012; 23 (Supplement):685-686

After the Deluge of SPAF Trials

Translating Trials into Practice and Guidelines: 2012 Update


Post-Trial, Real World Concerns, Guidelines, and ActionsWhere Have Landmark SPAF Trials Taken Us? How Have Recent Guidelines Made Sense of These Data?

NOACs Elevated to "Favored" Status by ESC 2012 Update Guidelines for Management of AF
The net clinical benefit of VKAs, balancing ischaemic stroke against ICH in patients with non-valvular AF, has been modeled on to stroke and bleeding rates from the Danish nationwide cohort study for dabigatran, rivaroxaban, and apixaban, on the basis of recent clinical trial outcome data for these NOACs. At a CHA2DS2-VASc score of 1, apixaban and both doses of dabigatran (110 mg bid and 150 mg bid) had a positive net clinical benefit while, in patients with CHA2DS2-VASc score 2, all three NOACs were superior to warfarin, with a positive net clinical benefit, irrespective of bleeding risk.

2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace. 2012 Aug 24

Assess bleeding risk (HAS-BLED score) Consider patient values and preferences

NOAC

VKA

LINE SOLID = BEST OPTION DASHED = ALTERNATIVE OPTION


2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace. 2012 Aug 24

Bleeding Risk with Dabigatran


Fact vs Fiction

Bleeding Risk with Dabigatran


Fact vs Fiction: What Do Regulators Conclude?
Disconnect Between Clinical Trials and Post-Marketing Surveillance Bias: A Case Study

EMA Report on Dabigatran: May 24, 2012


"What are the conclusions of the CHMP?

The CHMP concluded that the latest available data are consistent with the known risk of bleeding and that the risk profile of dabigatran was unchanged. The Committee found that frequency of reported fatal bleedings with dabigatran was significantly lower than what had been observed in clinical trials at the time of authorisation, but considered that the risks should nonetheless continue to be kept under close review."

EMA Report on Dabigatran May 24, 2012


What is the updated advice for prescribers?

Prescribers are reminded of the need to follow all the necessary precautions with regard to the risk of bleeding with dabigatran, including the assessment of kidney function before treatment in all patients and during treatment if a deterioration is suspected, as well as dose reductions in certain patients.
Dabigatran must not be used in patients with a lesion or condition putting them at significant risk of major bleeding (see the revised product information for details). Dabigatran must not be used in patients using any other anticoagulant, unless the patient is being switched to or from dabigatran (see the revised product information for details).

A European Commission decision on this opinion will be issued in due course.

Dabigatran vs. Warfarin: Surgical Bleeding

, even among patients having major or urgent surgery. Patients receiving dabigatran were 4 times more likely to have their procedure or surgery within 48 hours of withholding anticoagulation

Circulation, Healey et al., 2012

ESC 2012 Atrial Fibrillation Guidelines Update: Risk Assessment


Risk Profile Class / Level
No antithrombotic therapy IB VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban IIa A (Favored) VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban I A (Favored)

CHA2DS2-VASc = 0

CHA2DS2-VASc = 1

CHA2DS2-VASc 2

Conclusions: From Trials and Evidence to Strategy and Practice

New therapies provide the promise of providing safer, more effective, and more convenient anticoagulation. Trials are consistent in reduction of intracranial hemorrhage and bleeding mortality.

SPAF trials are consistent in demonstrating that NOACs are at least as good as, and in some cases, superior to warfarin in preventing stroke in patients with AF. There are important differences in the PK/PD of these agents (half-life, metabolism, renal elimination) that will alter the risk/benefit profile in specific populations; in particular, careful monitoring of renal function is a precondition for optimizing safety and efficacy of these agents.

Conclusions

No reversal agent is currently available but whether the lack of such agents lead to increased bleeding or mortality risk has not been substantiated. New ESC 2012 Update Guidelines for AF have refined and incorporated a new suite of risk prediction strategies (CHA2DS2-VASc, HAS-BLED) that will result in a greater proportion of patients being eligible for oral anticoagulation. New ESC 2012 Update Guidelines for AF have elevated NOACs to "favored" status over VKA for patients who meet risk stratification criteria for requiring oral anticoagulation for AF.

New Paradigms in the Science and Medicine of Heart Disease

Stroke Prevention in Atrial Fibrillation


Megatrends, Challenges, and Clinical Dilemmas
Samuel Z. Goldhaber, MD, Program Chairman
Director, VTE Research Group Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School

Faculty COI Disclosures Research Support


Eisai, EKOS, Johnson & Johnson, sanofi-aventis

Consultant
Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventis

Risk Assessment Megatrend

CHA2DS2-VASc has replaced CHADS2 as the predominant assessment tool to predict stroke risk (ESC 2012 AF Guidelines Update).

HAS-BLED has gained dominance as the most predictive bleeding index. It is best used as a cautionary yellow flag rather than as a reason to withhold anticoagulation (ESC 2012).

Clinical Dilemma and Challenge Stroke Risk Underestimated

Paroxysmal AF is difficult to detect.

24h Holter is often insufficient. Long-term noninvasive or invasive monitoring may be necessary.
Many strokes are misclassified as cryptogenic and are treated with aspirin or other antiplatelet agents, with questionable efficacy for AF. The misclassified strokes are really thromboembolic and warrant anticoagulants.

Subclinical AF and Risk of Stroke


Atrial tachyarrhythmia > 6 min 3 months after pacemaker or defibrillator implantation
Stroke or Systemic Embolism

Healey JS, et al. NEJM 2012; 366:120-129

Years

Redefining Risk vs Benefit for OAC


HAS-BLED
Letter Clinical Characteristic Points

H
A S B L E D

Hypertension
Abnormal Liver or Renal Function Stroke Bleeding Labile INR Elderly (age > 65) Drugs or Alcohol Maximum Score

1
1 or 2 1 1 1 1 1 or 2 9

HAS-BLED Score
0 1 2

Stroke (% / yr)
1.1 % 1.0 % 1.9 %

3
4 >5

3.7 %
8.7 % ?? %

Lip GYH. Am J Med. 2011;124:111-114.

ESC Guidelines: Eur Heart J . 2010;31:2369-2429.

Clinical Dilemma: Bleeding Risk Correlates With Stroke Risk

The higher the bleeding risk, as assessed by the HAS-BLED Index, the higher the stroke riskA Catch 22 when considering and/or deploying oral anticoagulation.

Based on observational and trial evidence, we must be especially vigilant to prescribe anticoagulation to AF patients at high risk of bleeding, when the thrombosis risk assessment justifies this course of action.

Action Plan When OAC is Indicated and Patient Has High HAS-BLED Index

Modify bleeding risk factors. Intensify surveillance for bleeding and for triggers that cause bleeding.

Consider renal dose for NOAC, especially in the presence of some renal dysfunction or frailty or age 80 years.
Monitor renal function with vigilance. Prescribe PPI when indicated.

Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease


Danish Registry 146,251 patients were discharged with nonvalvular atrial fibrillation (1997-2008)
13,879 were excluded

127,884 (96.6%) did not have renal disease

3587 (2.7%) received a diagnosis of non-end-stage chronic kidney disease

901 (0.7%) underwent renal-replacement therapy

4538 (3.5%) received a diagnosis of non-end-stage chronic kidney disease


Olesen JB. NEJM 2012; 367: 625-635

228 (6.4%) underwent renal-replacement therapy during follow-up

Stroke Risk and Renal Disease


Aspirin does not prevent stroke
Total Population (n = 132,372) No Renal Disease (n = 127,884)

Characteristic

Hazard Ratio (95% CI)

P Value

Hazard Ratio (95% CI)


1.00

P Value

All participants
Antithrombotic Therapy None 1.00

1.00

Warfarin
Aspirin Warfarin and aspirin

0.59 (0.57-0.62)
1.11 (1.07-1.15) 0.70(0.65-0.75)

< 0.001
< 0.001 < 0.001

1.10 (1.06-1.14)
1.10(1.06-1.14) 0.69(0.64-0.74)

< 0.001
< 0.001 < 0.001

Olesen JB. NEJM 2012; 367:625-635

Bleeding Risk and Renal Disease


Aspirin and warfarin/aspirin increase bleeding
Total Population (n = 132,372) Hazard Ratio (95% CI) No Renal Disease (n = 127,884) Hazard Ratio (95% CI)
1.00

Characteristic

P Value

P Value

All participants Antithrombotic Therapy None Warfarin 1.00 1.28(1.23-1.33) < 0.001

1.00 1.28(1.23-1.33) < 0.001

Aspirin
Warfarin and aspirin

1.21(1.16-1.26)
2.15(2.04-2.26)

< 0.001
< 0.001

1.21(1.16-1.26)
2.18(2.07-2.30)

< 0.001
< 0.001

Olesen JB. NEJM 2012; 367:625-635

Megatrend: Recognizing Overuse of Aspirin

Role of aspirin in the setting of SPAF is called into question.

Aspirin is often prescribed for CAD prevention, without a clear evidence-based rationale, thus increasing bleeding risk when combined with OACs used for SPAF. Evaluate necessity for ASA.

Dosing Options for Renal Dysfunction


Consider also for age 80, weight 60 KG (frailty)

Dabigatran 75 mg bid (USA)

50%

Dabigatran 110 mg bid (non-USA)


Rivaroxaban 15 mg daily 25%

Apixaban 2.5 mg bid

50%

ESC 2012

Dilemmas in Under-Anticoagulation

Anticoagulants clearly prevent stroke in AF patients but are markedly underutilized

Failure to prophylax in the setting of nonvalvular AF is characterized by fear of:

Bleeding Older age Renal dysfunction Lack of medication adherence

Dilemmas: NOACs vs Warfarin

By most metrics, NOACs are the best option for SPAF (ESC 2012 Update for AF) Failure to prescribe NOACs is characterized by:

Lack of familiarity Lack of reversal agent Inability to measure NOAC level Inertia, fear of change, preapprovals

NOACs vs Warfarin A View From 30,000 Feet

NOACs generally more effective than warfarin for stroke prevention NOACs are generally safer (less bleeding, with some exceptions, but NOACs uniformly cause less intracranial hemorrhage, most devastating and mortality-inducing bleeding complication of OAC) NOACs, overall, reduce mortality NOACs are more convenient for patient/clinician

New Anticoagulant Therapies Compared to Warfarin: All-cause Mortality

Dabigatran 150 mg b.i.d. Dabigatran 110 mg b.i.d. Rivaroxaban 20 mg o.d. Abixaban 5 mg b.i.d. 0.5 1 2

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011

Limitations of Novel Agents are Exaggerated


Best treatment is prevention Warfarin has no great antidote Time is a great antidote RELY analysis 2012 shows no increase in bleeding in this setting Do not need one Time since last dose is helpful Rivaroxaban, apixaban modest renal effect Highly cost effective in analyses

No antidote when bleeding

No antidote for urgent procedures

Lack standard measurement

Dependence on renal function

Cost

Deciphering the Pharmaco-economic Maze


Cost-effectiveness

Cost: Must take into account the costs of caring long-term for debilitated thromboembolic stroke patients and the costs of caring for intracranial hemorrhage when doing a cost-effectiveness analysis of NOACs vs warfarin. However, we continue to have mostly silo budgeting.

Cost of Dabigatran vs Warfarin


Dabigatran retail: $240/month Warfarin discount retail: $4/month Will the high price of dabigatran cause poor medication adherence? The cost of medical care looms as the single largest threat to the US economy.

Avorn J. Circulation 2011: 123: 2519-2521

Prevent > 50% AF Cases by Modifying Cardiovascular Risk Factors


N = 14,598 middle-aged subjects Over 17 years, 1520 incident cases of AF in the Atherosclerosis Risk in Communities (ARIC) Study 56% of cases explained by elevated CV risk factors, especially hypertension, obesity, diabetes, and smoking

Circulation 2011; 123: 1501-1508

Guidelines for Bridgingwith Dabigatran (RE-LY)


Renal Function Impairment (CrCL mL/min) Stopping Dabigatran Before Surgery/Procedure High Risk for Bleeding Standard Risk for Bleeding

Estimated Halflife, h (Range)

Mild: > 50 to 80

15 (12-18) 18 (18-24) 27 (> 24)

2-3d* 4d > 5d

24 h (2 doses)

Moderate: > 30 to < 50


Severe: < 30

At least 2 d (48 h)
2-4 d

Healey JS. Circulation 2012; 126: 343-348

Interrupting Dabigatran and Warfarin


RE-LY

1 of 4 patients underwent peri-procedural anticoagulant interruption Stroke rate: 0.5%; major bleeding rate: 4%, 7 days pre- to 30 days post Dabigatran was withheld an average of 2 days, whereas warfarin was withheld an average of 5 days preop

Healey JS. Circulation 2012; 126: 343-348

Medication Adherence Failure


Failing to fill or refill a prescription Omitting doses Overdosing

Prematurely discontinuing medication


Taking someone elses medication

Taking a medication with prohibited foods


Taking outdated medications

Questions Regarding the New Non-Monitored, Oral Anticoagulants

Do they represent a significant improvement for patients who have been taking warfarin with consistently therapeutic INR values for months or years? They may. Will the elimination of regular INR measurement reduce or improve compliance? How will their cost compare to current costs (including INR monitoring, dose adjustment, etc)?

Selecting Patients for Non-Monitored Oral Anticoagulation (NOAC)

Clinical Dilemma #1

Which patients are the best candidates for nonmonitored oral anticoagulation? Treatment-naive and de novo patients? And/or patients on warfarin? Established patients on warfarin doing "well?" Established on warfarin, doing well, but at high risk for bleeding? High HAS-BLED? Previous stroke?

On warfarin, and doing "reasonably" well, but requiring multiple interventions to keep INR/TTR controlled?
Patients on warfarin who are doing well, but only with intensive monitoring?

Transitioning Patients from Warfarin to a Non-Monitored Oral Anticoagulant

Clinical Dilemma #2

How do we actually transition patients from warfarin to dabigatran, rivaroxaban, apixaban, or other agents? What INR do we wait for? What are the renal issues that need to be considered for each agent?

How do I Convert a Patient from Warfarin to Dabigatran and Vice Versa?


Warfarin to dabigatran: Discontinue warfarin and start dabigatran when the international normalized ratio (INR) is below 2.0. Dabigatran to warfarin:
CrCl > 50 mL/min, start warfarin 3 days before discontinuing dabigatran. CrCl 31-50 mL/min, start warfarin 2 days before discontinuing dabigatran. CrCl 15-30 mL/min, start warfarin 1 day before discontinuing dabigatran. CrCl < 15 mL/min, no recommendations can be made.

Because dabigatran can contribute to an elevated INR, the INR will better reflect warfarins effect after dabigatran has been stopped for at least 2 days.
Dabigatran prescribing information 2010

Managing Patients Who Are on Non-Monitored Oral Anticoagulation and Have Had a Stroke

Clinical Dilemma #3

How do we approach a patient who has had an embolic stroke while on a non-monitored oral anticoagulant? Should we switch? Why? Why not? To what agent would we switch? From one nonmonitored oral anticoagulant to another? To warfarin? If we switch to warfarin, at what INR? What if the patient is at risk for hemorrhage?

What Should I Do if my Patient Has an Ischemic Stroke on Dabigatran?

Consider:

Is the patient compliant with dabigatran? Check aPTT or thrombin time if dose taken within past 12 hours, these levels should be prolonged. If the stroke is cryptogenic, consider adding antiplatelet therapy. Convert dabigatran to warfarin (target INR 2-3 or higher?). Switch to another NOAC?

Aligning Specific Patient and Risk Profiles with Specific NOACS: Apixaban, Dabigatran, Rivaroxaban

Clinical Dilemma #4

Based on AVERROES, RE-LY, ARISTOTLE, and ROCKETAF, should we be aligning specific, non-monitored oral anticoagulants with specific risk groups? Should the warfarin-intolerant/ineligible patient be "steered" toward apixaban? The "high-risk" patient be steered toward rivaroxaban? The intermediate-risk patient be "steered" toward apixaban or dabigatran? How do we know whether this kind of alignment is evidence-based, or if it is an artifact of the trial designs?

What Should We Use For Hemorrhage on a NonMonitored Oral Anticoagulant?

Clinical Dilemma #5

What should be our clinical approach to a patient who has had a hemorrhage on a non-monitored oral anticoagulant? Does it depend on the type of hemorrhage? Other factors? Should we ever consider warfarin in these patients?

Guide to the Management of Bleeding in Patients Taking NOAC


Patients with bleeding on NOAC therapy Moderate-Severe bleeding
Mechanical compression Surgical intervention Fluid replacement and hemodynamic support Blood product transfusion Oral charcoal Hemodialysis ? Prothrombin Complex Concentrate?

Mild bleeding

Life-threatening bleeding

Delay next dose or discontinue treatment as appropriate

Consideration of rFVIIa or PCC Charcoal filtration ? Prothrombin Complex Concentrate


(Circulation 2011; 2011: 124: 1573-9)

(Circulation 2011; 2011: 124: 1573-9)

Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450

Antithrombotic Agents
A New Era of Alignment and Flexibility?
Dabigatran: Superior SPAF compared with warfarin Rivaroxaban: Once-daily administration and less dependence on kidneys for metabolism; non-inferior in ITT analysis in very high-risk patient population Apixaban: Safety equivalent to aspirin in AVERROES, and superior stroke prevention in warfarin intolerant or ineligible Apixaban: Superior SPAF, less major bleeding, lower all-cause mortality.

SPAF Clinical Trial Programs


Translational Dilemmas and Cautionary Notes
Do clinical trial results apply to real world medicine in busy clinical practices with brief office visits and minimal telephone follow-up? Are patients who participate in clinical trials healthier/more motivated than most? Does this make favorable results more likely in both the new drug and the comparison groups? Do the costs of a copay affect patient decisions to fill a prescription for a potentially more effective, safer drug vs a less expensive but less effective alternative?

Unresolved Issues with NOACs


No established methods of monitoring No known therapeutic ranges

Lack of a proven antidote


Uncertain management of bleeding

Long term safety: to be determined


No head-to-head comparisons of new agents

Properties of Ideal Anticoagulant Do NOACS Fit the Bill?

Proven efficacy

Low bleeding risk


Fixed dosing Good oral bioavailability No routine monitoring needed Reversibility: ?PCC, FEIBA, rVIIa Rapid onset of action Few drug or food interactions

NOACs: Advancing Opportunities to Connect Guidelines with Practice


Lower stroke rates Fewer major and fatal bleeds, especially ICH

Lower dose options for chronic kidney disease, elderly, and the frail or underweight patient
Use in conjunction with RF reduction: treat congestive heart failure, diabetes, hypertension, obesity Facilitate periprocedural treatment

Should improve medication adherenceno injections/ no routine lab blood testing

Advances in the Science and Medicine of Stroke Prevention in AF

So What Now? Trials in Translation


Applying Evidence-Driven Strategies to AF Patients at the Front Lines of Clinical Practice
Audience Response System-Based Interactions
Samuel Z. Goldhaber, MD Program Chairman
Director, VTE Research Group Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School

Atrial Fibrillation Case Study #1


A 71-year-old white female with a history of chronic, non-valvular AF, controlled hypertension, and a history of mild congestive heart failure has been evaluated by a cardiologist and found to be a suitable candidate for warfarin therapy. Due to logistical barriers that make monitoring difficult and dietary variations, the patient has had difficulty controlling her INR. Wide fluctuation in her INR has made her question continued warfarin therapy.

Audience Response System (ARS) Question


Because of her high risk for embolic stroke, her cardiologist is considering alternative forms of thromboprophylaxis for SPAF. She has a HAS-BLED SCORE of 2. Which of the following should we consider? Are any of these strategies optimal in this patient type?
1) Keep patient on warfarin

2) Replace warfarin with aspirin


3) Replace warfarin with aspirin + clopidogrel 4) Replace warfarin with a non-monitored oral anticoagulant

Atrial Fibrillation Case Study #2


An 81-year-old white female with a history of chronic, non-valvular AF, a history of a previous ischemic stroke, and a history of mild congestive heart failure has been on a combination of clopidogrel and aspirin therapy because she was found to be intolerant of warfarin. She is on a proton pump blocker, an ACE inhibitor, a diuretic, and digoxin. She is admitted to the hospital for a GI bleed, and is found to have a hematocrit of 29 and a hemoglobin of 9.8. The aspirin and clopidogrel are discontinued.

Atrial Fibrillation Case Study #2


The patient stabilizes, and the cardiologist is consulted to determine the subsequent course of her antithrombotic treatment. She has a HAS-BLED score of 3. It is your opinion that:
1) Because of the documented GI bleed, the patient should not be treated with antithrombotic agents, because the risk of bleeding outweighs the risk of stroke and its complications. 2) Because of the patient's risk profile, there should be an attempt to provide thromboprophylaxis against embolic stroke.

Atrial Fibrillation Case Study #2


The cardiologist has determined that this patient requires antithrombotic management for stroke prevention. At this point you would most likely:
1) Try the patient on warfarin again
2) Try to re-introduce clopidogrel and aspirin 3) Treat the patient with aspirin alone

4) Introduce a non-monitored oral anticoagulant to the patient's regimen.

Atrial Fibrillation Case Study #3


An 82-year-old man with hypertension and diabetes has permanent atrial fibrillation. He has a history of spinal stenosis and walks with a walker and has a history of falls.

He has a CHADS-VASc score of 3, and a HAS BLED score of 2. Which regimen would you prescribe for prophylaxis against thromboembolism?

Atrial Fibrillation Case Study #3


Which regimen would you prescribe for prophylaxis against thromboembolism?
1. Warfarin (INR 2.0-3.0) 2. Warfarin (INR 1.5-2.0) 3. Aspirin 81 mg daily 4. Aspirin 81 mg + clopidogrel 75 mg daily

5. An oral Factor Xa or direct thrombin inhibitor

Atrial Fibrillation Case Study


Anticoagulation in Patients at Risk of Falls

persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin not to be the optimal therapy

Atrial Fibrillation Case Study #4


A 71-year-old man with AF, heart failure, and a prior history of stroke presents with unstable angina and proceeds to cardiac catheterization where a culprit lesion is identified. Optimal management includes:
1) Placement of a drug-eluting stent with plan to continue anticoagulation in addition to 1 year of dual antiplatelet therapy 2) Placement of a drug-eluting stent with 1 year of dual antiplatelet therapy alone 3) Placement of a bare metal stent with plan to continue anticoagulation in addition to 1 month of dual antiplatelet therapy 4) Placement of a bare metal stent with 1 month of dual antiplatelet therapy alone

Atrial Fibrillation Case Study #5


A 67-year-old female with a history of mitral stenosis with subsequent mechanical mitral valve replacement has AF. Which of the following anticoagulants can be used for stroke prevention in this patient?
1) Warfarin

2) Dabigatran
3) Apixaban 4) Rivaroxaban 5) All of the above

Atrial Fibrillation Knowledge Assessment Question


The major potential benefits of the new nonmonitored oral anticoagulants include:
1) Rapid therapeutic anticoagulant effect

2) Greater safety with regards to intracranial hemorrhage


3) Proven reversal agent 4) All of the above 5) Both 1 and 2

Atrial Fibrillation Case Study #6


An 82-year-old man with AF has had several admissions over the past 6 months for heart failure complicated by worsening renal function. His creatinine clearance is currently 20 mL/min but frequently fluctuates to 10-15 mL/min. He has a HAS-BLED score of 3. The best anticoagulant regimen for stroke prevention is:
1) Dabigatran 150 mg twice daily 2) Dabigatran 75 mg twice daily 3) Warfarin titrated to goal INR 2-3 4) Rivaroxaban 20 mg once daily 5) Rivaroxaban 15 mg once daily

Atrial Fibrillation Case Study #7


A 79-year-old woman with a CHADS-VASc score of 2 who has been on warfarin for the past 2 years returns to clinic for routine follow-up. Her INR control has been excellent and she has never experienced a stroke or had significant bleeding. Her HAS-BLED score is 2.

Her complaints today are thinning hair, cold intolerance, and fatigue.
Her laboratory work is normal including a TSH.

Atrial Fibrillation Case Study #7


Which of her symptoms could be due to warfarin?
1) Thinning hair 2) Cold intolerance

3) Fatigue
4) Both 1 and 2 5) All of the above

Atrial Fibrillation Case Study #8


A 69-year-old woman with AF and CHADS2 score of 4 has a creatinine clearance that is stable at 40 mL/min. Which of the following anticoagulation regimens are suitable for her?
1) Dabigatran 150 mg twice daily 2) Dabigatran 75 mg twice daily 3) Rivaroxaban 20 mg once daily 4) Rivaroxaban 15 mg once daily 5) Both 1 and 4

Atrial Fibrillation Case Study #8


What would her options be if her creatinine clearance was stable at 25 mL/min?
1) Dabigatran 75 mg twice daily

2) Rivaroxaban 15 mg once daily


3) Only warfarin can be used in patients with creatinine clearance < 30 mL/min

4) Both 1 and 2

Atrial Fibrillation Case Study #9


A 74-year-old man with AF on dabigatran is involved in a motor vehicle accident and needs emergency surgery. It is unclear if he is taking this medication but the surgeon is concerned about operating on him if he is fully anticoagulated.

Atrial Fibrillation Case Study #9


Which of the following lab tests, if normal, would reassure the team that the patient is not anticoagulated?
1) INR (international normalized ratio) 2) aPTT (activated partial thromboplastin time) 3) PT (prothrombin time)

4) Bleeding time

Atrial Fibrillation Case Study #10


A 60-year-old man with AF has been on warfarin but it has been very difficult to control his INR. You have decided to switch to dabigatran. Which of the following is true regarding transitioning a patient from warfarin to dagibatran?
1) Start dabigatran when his INR < 3 2) Start dabigatran when his INR < 2 3) Start dabigatran 24 hours after his last dose of warfarin

Atrial Fibrillation Case Study #10


What if you decided to switch the patient to rivaroxaban?
1) Start rivaroxaban when his INR < 3

2) Start rivaroxaban when his INR < 2


3) Start rivaroxaban 24 hours after his last dose of warfarin

Atrial Fibrillation Case Study #11


A 78-year-old female with AF, systolic heart failure, hypertension, diabetes, and a history of significant GI bleeding has been on warfarin for many years but has had a difficult time controlling her INR with frequent supertherapeutic values despite intensive monitoring and titration of her warfarin dose. Her HAS-BLED score is 3. The best treatment option for her is:
1) No antithrombotic therapy
2) Discontinue warfarin and start aspirin 3) Discontinue warfarin and start dabigatran 4) Discontinue warfarin and start rivaroxaban 5) Discontinue warfarin and start apixaban

Atrial Fibrillation Case Study #12


A 76-year-old woman with heart failure, hypertension, diabetes, and declining renal function (creatinine clearance 35 mL/min) has an embolic stroke due to newly diagnosed AF. She refuses to take warfarin.

What is the best validated antithrombotic regimen in this particular patient?


1) Aspirin 2) Aspirin and clopidogrel 3) Dabigatran

4) Apixaban
5) Rivaroxaban

Atrial Fibrillation Case Study #13


A 68-year-old man with a mechanical mitral valve develops AF. The best anticoagulant option for him is:
1) Warfarin 2) Dabigatran

3) Apixaban
4) Rivaroxaban 5) Aspirin

Atrial Fibrillation Case Study #14


A 76-year-old man with heart failure and hypertension undergoes successful catheter ablation for symptomatic AF. Which of the following is true regarding his anticoagulation management?
1) He no longer requires anticoagulation now that he is in sinus rhythm 2) Patient should be on both aspirin and an anticoagulant 3) Patient should be on an anticoagulant alone 4) Aspirin and clopidogrel together is as effective as anticoagulation in these patients

Atrial Fibrillation Case Study #14


The cardiologist has determined that this patient requires antithrombotic management for stroke prevention. At this point you would most likely:
1) Try the patient on warfarin again

2) Treat the patient with aspirin alone


3) Introduce the non-monitored oral anticoagulant, apixaban, into the patient's regimen

4) Introduce dabigatran into the patients regimen


5) Introduce rivaroxaban into the patients regimen

Atrial Fibrillation Case Study #15


A 75-year-old male with a history of chronic, non-valvular AF, diabetic renal disease, previous history of ischemic stroke, history of mild HF, and controlled hypertension has been on warfarin therapy. The HAS-BLED score is 4.

For the past 6 months, despite repeated visits for monitoring and warfarin dose adjustment, his INR has varied between 1.5 and 4.3.
His estimated GFR is 30 mL/min.

Atrial Fibrillation Case Study #15


At this point you would:
1) Continue to try to stabilize his INR on warfarin

2) Change to aspirin alone


3) Introduce the non-monitored oral anticoagulant rivaroxaban into the patient's regimen

4) Introduce the non-monitored oral anticoagulant apixaban into the patient's regimen
5) Introduce the non-monitored oral anticoagulant dabigatran into the patient's regimen

Atrial Fibrillation Case Study #17


An 82-year-old man with hypertension, diabetes, mild congestive heart failure, and previous ischemic stroke, is diagnosed with atrial fibrillation. He has not been taking any anticoagulants.

Atrial Fibrillation Case Study #17


Which regimen would you initiate for prophylaxis against stroke?
1) Warfarin (INR 2.0-3.0) 2) Aspirin 81 mg + clopidogrel 75 mg daily 3) Rivaroxaban 4) Apixaban

5) Dabigatran

Atrial Fibrillation Case Study #18


An 82-year-old man with hypertension, diabetes, mild CHF, and a previous ischemic stroke has permanent atrial fibrillation. He has been on warfarin for about 5 years and his INR has remained constant between 2.3 and 2.7. He has a HAS-BLED score of 3.

Atrial Fibrillation Case Study #18


Which regimen would you continue or switch to for prophylaxis against stroke?
1) Continue current therapy with warfarin 2) Aspirin 81 mg + clopidogrel 75 mg daily 3) Rivaroxaban 4) Apixaban

5) Dabigatran

Atrial Fibrillation Case Study #19


A 75-year-old man with a CHADS2 of 3 has been taking dabigatran 150 mg for SPAF. His estimated GFR was 55 mL/min 6 months ago and is now 40 mL/min.

I would now:
1) Continue to monitor patient 2) Switch patient to 75 mg dabigatran twice per day 3) Switch patient to warfarin 4) Switch patient to rivaroxaban 5) Start ASA and clopidogrel

New Paradigms in the Science and Medicine of Heart Disease

Interactive Question and Answer Session