Spaf Boston Slidecast 181

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:


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.
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
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
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
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
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
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)
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

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

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.
Assess bleeding risk (HAS-BLED score) Consider patient values and preferences
NOAC
VKA
LINE SOLID = BEST OPTION DASHED = ALTERNATIVE OPTION

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.
Stroke Prevention in Atrial Fibrillation

Megatrends, Challenges, and Clinical Dilemmas
Samuel Z. Goldhaber, MD, Program Chairman
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
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

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.

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.

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.

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?

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

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

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

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

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.

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

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

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

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.

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

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

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

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

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

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

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

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

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.

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

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.

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

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.

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

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
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New Frontiers and Treatment Paradigms for

Stroke Prevention in Atrial Fibrillation

Welcome and Program Overview

Conflict of Interest Disclosures

Epidemiology and Overview

Faculty COI Disclosures

Formal Definition: Atrial Fibrillation

Circulation 2011; 121: e269-e367

The ECG of Atrial Fibrillation

The 3 Ps and Natural History of Atrial Fibrillation

Normal Sinus Rhythm Atrial Fibrillation

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

Atrial Fibrillation: Epidemiology

Atrial Fibrillation Risk Factors

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

Atrial Fibrillation: An Epidemic

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

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

Relationship Between Atrial Fibrillation and Age

Atrial Fibrillation Causes Stroke

Stroke and Atrial Fibrillation Burden

Costly health care ~ $16 billion/year

Age Range (years)

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

Ischemic Strokes in Atrial Fibrillation More Likely to be Severely Disabling

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

Fuster V. Circulation 2012; epubl April 18

ESC 2012 AF Update Guidelines

Anticoagulation in Atrial Fibrillation

RRR All-cause mortality: 26%

ESC 2012 Update Guidelines

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

Known Problems With Warfarin

2) Unpredictable dose response

4) Drug-drug, drug-food interactions

6) High bleeding rate

Warfarin Will Likely Survive: Why?

Long track record (1954)

INR testing q 12 weeks if stable

Circulation 2012; epub March 19

Comparison Overview of New Anticoagulants with Warfarin

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

Rivaroxaban Apixaban Edoxaban Betrixaban Dabigatran

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

Novel Oral Anticoagulants

Dabigatran Rivaroxaban Apixaban

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

Best Options for Anticoagulation

ESC 2012 AF Update Guidelines

ESC 2012 UPDATE GUIDELINES For ATRIAL FIBRILLATION

The Rationale for AF Registries

The GARFIELD Registry

Novel approach to outcomes research

Summary of Garfield Data Cohort One: ESC 2012

VKAs not prescribed in:

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

5333 AF patients in 35 countries: 20032004 64

OAC therapy (%)

A Failure to Prophylax Syndrome

The SPAF Landscape 2012: Conclusions

New Paradigms in the Science and Medicine of Heart Disease

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

Independent Predictors of Stroke in AF