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 Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School 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 Women’s Hospital Professor of Medicine Harvard Medical School CHRISTIAN T. RUFF, MD, MPH TIMI Study Group Brigham and Women’s 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 Epidemiology and Overview 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 Women’s Hospital Professor of Medicine Harvard Medical School 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 Persistent Permanent Self-Terminating Lasts > 7 Days 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 Projected Number of People with AF (millions) Atrial Fibrillation: An Epidemic 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 Prevalence, percent Relationship Between Atrial Fibrillation and Age 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 Costly health care ~ $16 billion/year 30 Framingham 20 AF prevalence 10 Strokes attributable to AF % 0 50–59 60–69 70–79 Age Range (years) Wolf PA, et al. Stroke 1991; 22: 983-988 80–89 Ischemic Strokes in Atrial Fibrillation More Likely to be Severely Disabling Framingham Heart Study 73 58 36 33 16 Lin HJ, et al. Stroke. 1996;27:1760-1764. 30 16 11 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 AFASAK RRR of stroke: 62% SPAF BAATAF CAFA SPINAF RRR All-cause mortality: 26% EAFT Aggregate 100% 50% RRR, relative risk reduction. Hart RG, et al. Ann Intern Med. 1999;131:492-501. 0 -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 Stroke 1 Bleeding 1 Labile INRs 1 Elderly (age > 65 years) 1 Drugs or alcohol 1+1 Maximum score 9 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) Established efficacy 2) Low cost ($4/month; $10/3 mos) 3) Long track record (1954) 4) Centralized anticoagulation clinics that maintain TTRs > 60% 5) Rapid, turnaround genetic testing 6) 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 Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed Yes No Many Few Yes No Half-life Long Short Antidote Yes No Food effect Drug interactions Monitoring Sites of Action in Coagulation System Novel Factor Xa and DT Inhibitors Steps in Coagulation Pathway Drugs TF/VIIa Initiation X IX VIIIa IXa Va Propagation II Rivaroxaban Apixaban Edoxaban Betrixaban IIa Dabigatran Xa Fibrin formation Fibrinogen Hankey GJ and Eikelboom JW. Circulation 2011;123:1436-1450 Fibrin Novel Oral Anticoagulants Important Comparative Features Dabigatran Rivaroxaban • Oral direct thrombin inhibitor • Twice daily dosing • Renal clearance • Direct factor Xa inhibitor • Once daily (maintenance), twice daily (loading) • Renal clearance Apixaban • Direct factor Xa inhibitor • Twice daily dosing • Hepatic clearance Edoxaban • Direct factor Xa inhibitor • Once daily dosing • Hepatic clearance Circulation 2010;121:1523 Comparison of Phase 3 SPAF Trials for NOACs: A Robust Trial Base Novel Anticoagulants Fxa Inhibitor FIIa Inhibitor Dabigatran Rivaroxaban Apixaban Edoxaban Open Label Double Blind Double Blind Double Blind Two Doses Two Doses Two Doses Two Doses Twice Daily Once Daily Twice Daily 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 OAC therapy (%) 100 5333 AF patients in 35 countries: 2003–2004 80 60 58 59 1 2 64 61 3 4 40 20 0 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 superior—or at least noninferior—for 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 Adjusted Relative Risk (95% CI) Prior stroke or TIA 5 of 5 studies 2.5 (1.8–3.5) Increasing age 6 of 6 studies 1.5/decade (1.3–1.7) History of hypertension or systolic BP > 160 mm Hg 5 of 5 studies 2.0 (1.6–2.5) Diabetes 4 of 4 studies 1.8 (1.5–22) Female gender 3 of 6 studies 1.6 (1.4–1.9) Heart failure 0 of 4 studies* Not significant Coronary artery disease 0 of 4 studies 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 Moderate-Risk Factors ► Mitral stenosis ►Age > 75 years ►Hypertension ►Diabetes mellitus ►Heart failure or ↓ LV function ► Prosthetic heart valve ► History of stroke or TIA Less Validated Risk Factors ► ► ► ► Age 65–75 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 Approximate Risk Threshold for Anticoagulation Score (points) Risk of Stroke (%/year) 0 1.9 1 2.8 3%/year 2 3 4 5 6 Van Walraven C, et al. Arch Intern Med 2003; 163:936. Go A, et al. JAMA 2003; 290: 2685. Gage BF, et al. Circulation 2004; 110: 2287. 4.0 5.9 8.5 12.5 18.2 The CHADS2 Score Stroke Risk Score for Atrial Fibrillation Score (points) Prevalence (%)* Congestive Heart failure Hypertension Age > 75 years Diabetes mellitus Stroke or TIA 1 1 1 1 2 32 65 28 18 10 Moderate-High risk Low risk >2 0-1 50-60 40-50 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) 1 1 2 1 2 1 1 1 Moderate-High risk Low risk >2 0-1 Lip GYH, Halperin JL. Am J Med 2010; 123: 484. 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. 0 Moderate High 1-3 >3 Beyth et al. Am J Med 1998;105:91. 0 1-2 ≥3 Gage et al. Am Heart J 2006;151:713. <1 2-3 ≥4 Shireman et al. Chest 2006;130:1390. ≤ 1.07 1.07 - 2.19 > 2.19 Tay, Lane & Lip. Thromb Haemost 2008; 100: 955. 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 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 1 1-2 1 1 1 1 1-2 High risk Moderate risk Low risk >4 2-3 0-1 (> 4%/year) (2-4%/year) (< 2%.year) 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 = 1 CHADS2 = 0 CHADS2 > 2 Increasing stroke risk No antithrombotic No additional risk factors of stroke ASA Either female sex or vascular disease OAC* Age > 65 y or combination of female sex and vascular disease OAC* *Aspirin is a reasonable alternative in some as indicated by risk/benefit OAC 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 Women’s 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 Benefit Oral, once-daily dosing Ease of administration Rapid onset of action No need for overlapping parenteral anticoagulant Minimal food or drug interactions Simplified dosing Predictable anticoagulant effect No coagulation monitoring Extra renal clearance Safe in patients with renal disease Rapid offset in action Simplifies management in case of bleeding or intervention Antidote For emergencies Major Advances In Oral Anticoagulation for SPAF ROCKET AF (Rivaroxaban) 2010 6 Trials of Warfarin vs Placebo 1989-1993 RE-LY (Dabigatran) 2009 ENGAGE AF (Edoxaban) 2013 ARISTOTLE (Apixaban) 2011 Comparative Pharmacokinetics/ Pharmacodynamics of Novel Agents Dabigatran Apixaban Rivaroxaban Edoxaban IIa (thrombin) Xa Xa Xa 2 1-3 2-4 1-2 None 15% 32% NR Bioavailability 7% 66% 80% > 45% Transporters P-gp P-gp P-gp/BCRP P-gp Protein binding 35% 87% >90% 55% 12-14h 8-15h 9-13h 8-10h Renal elimination 80% 25% 33% 35% Linear PK Yes Yes No Yes Target Hrs to Cmax CYP metabolism Half-life 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 R open Warfarin (INR 2.0-3.0) N = 6022 Blinded Dabigatran Etexilate 110 mg bid N = 6015 Dabigatran Etexilate 150 mg bid N = 6076 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 Dabigatran 150 vs Warfarin < 0.001 0.34 < 0.001 Margin = 1.46 Connolly, et al. N Engl J Med 2009;361:1139-51 0.50 0.75 HR 1.00 1.25 (95% CI) 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) Connolly, et al. N Engl J Med 2009;361:1139-51 0.1 0.3 0.5 Dabigatran Better 1.0 2.0 Warfarin Better RE-LY Safety Results (Dabigatran) Dabigatran 110 mg Dabigatran 150 mg Major Bleed ICH GI Bleed MI 0.80 (0.69-0.93) 0.93 (0.81-1.07) 0.31 (0.20-0.47) 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) Connolly, et al. N Engl J Med 2009;361:1139-51 0.1 0.3 0.5 Dabigatran Better 1.0 2.0 Warfarin Better RE-LY Efficacy Stratified by CHADS2 Annualized Rate Stroke/SEE (%) CHADS2 D110 D150 WARF 0-1 1.06 0.65 1.05 2 1.43 0.84 1.38 3-6 2.12 1.88 2.68 D150 mg D110 mg P= 0.44 0.50 1.00 1.50 Dabigatran Warfarin better better Oldgren J, et al. ACC 2010 P= 0.50 1.00 Dabigatran better 0.82 1.50 Warfarin better RE-LY Efficacy Stratified by Prior Vitamin K Anatagonist Ezekowitz MD, et al. Circulation 2010;122:2246-2253 RE-LY Cardioversion (Dabigatran) Stroke/SEE 1.8 Major Bleeding 1.7 1.6 1.4 1.2 1 0.8 0.8 0.6 0.6 0.4 0.6 0.6 0.3 0.2 0 Dabi 110 mg Dabi 150 mg (N = 647) (N = 672) Nagarakanti R, et al. Circulation 2011;123:131-136 Warfarin (N = 664) 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 Risk Factors • CHF • Hypertension At least 2 • Age 75 required • Diabetes OR • Stroke, TIA or Systemic embolus Atrial Fibrillation Rivaroxaban 20 mg daily 15 mg for Cr Cl 30-49 Randomize Double blind / Double Dummy (n = 14,266) Warfarin INR target - 2.5 (2.0-3.0 inclusive) Monthly Monitoring and adherence to standard of care guidelines Primary End point: Stroke or non-CNS Systemic Embolism Statistics: non-inferiority, > 95% power, 2.3% warfarin event rate ROCKET AF Efficacy Stroke/Systemic Embolic Event Rivaroxaban Warfarin On Treatment Event Rate Event Rate HR (95% CI) P-value 1.70 2.15 0.79 (0.65, 0.95) 0.015 2.12 2.42 0.88 (0.74, 1.03) 0.117 N = 14,143 ITT N = 14,171 0.5 1 Rivaroxaban better 2 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) Warfarin (%/yr) Hazard Ratio (95% CI) Pvalue Ischemic Stroke 1.34 1.42 0.94 (0.75-1.17) 0.581 Hemorrhagic Stroke 0.26 0.44 0.59 (0.37-0.93) 0.024 MI 0.91 1.12 0.81 (0.63-1.06) 0.121 Total Mortality 1.87 2.21 0.85 (0.70-1.02) 0.073 Vascular Mortality 1.53 1.71 0.89 (0.73-1.10) 0.289 Event Patel, et al. N Engl J Med 2011; 365(10);883-891 ROCKET AF Safety (Rivaroxaban) Rivaroxaban (%/yr) Warfarin (%/yr) Hazard Ratio (95% CI) Pvalue Major and Clinically Relevant Bleed 14.9 14.5 1.03 (0.96-1.11) 0.44 Major Bleed 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 Event 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 R Apixaban 5 mg bid 2 mg bid in selected patients 5600 patients Double-blind ASA (81-324 mg/d) Primary Outcome: Stroke or Systemic Embolic Event (SEE) AVERROES: Apixaban Stroke or Systemic Embolic Event Major Bleeding 0.020 0.05 0.04 Aspirin 0.03 P < 0.001 Apixaban 0.01 0.00 3 6 P < 0.001 0.010 0.02 0 Apixaban 0.015 9 12 18 HR 0.45 (0.32-0.62) Connolly SJ, et al. N Engl J Med 2011 (epub) Aspirin 0.005 0.000 0 3 6 9 12 HR 1.13 (0.74-1.75) 18 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 Warfarin (2.5 mg bid in selected patients) (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 (0.66–0.95) (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 Apixaban (N = 9120) Outcome Stroke or systemic embolism* Warfarin (N = 9081) Event Event Rate Rate (%/yr) (%/yr) HR (95% CI) P Value 1.27 1.60 0.79 (0.66, 0.95) 0.011 1.19 1.51 0.79 (0.65, 0.95) 0.012 Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42 Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) < 0.001 0.09 0.10 0.87 (0.44, 1.75) 0.70 All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047 Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019 Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37 Stroke Systemic embolism (SE) Granger CB, et al. NEJM 2011; 365:981-992 ARISTOTLE Safety End Points Apixaban (%/yr) Warfarin (%/yr) Hazard Ratio (95% CI) Pvalue ISTH Major Bleeding 2.13 3.09 0.69 (0.60-0.80) < 0.001 ICH 0.33 0.80 0.42 (0.30-0.58) < 0.001 GUSTO Severe 0.52 1.13 0.46 (0.35-0.60) < 0.001 Gastrointestinal 0.76 0.86 0.89 (0.70-1.15) 0.37 Event Granger CB, et al. NEJM 2011; 365:981-992 ARISTOTLE: Apixaban Renal Function Major Bleeding Annualized Event Rate Stroke or SEE 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 Low dose regimen Edoxaban 30 mg qd (n ≈ 7000) AF on Electrical Recording < 12 mo Intended oral A/C CHADS2 >2 R Randomization Stratified By 1. CHADS2 2-3 vs 4-6 2. Drug Clearance High dose regimen Edoxaban 60 mg qd (n ≈ 7000) Active Control Warfarin (n ≈ 7000) Median Duration of Follow-up 24 Months Primary Objective Edoxaban: Therapeutically as Good as Warfarin 1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38) 2º EP = Stroke or SEE or CV mortality Safety EP’s = Major Bleeding, Hepatic Function SEE = systemic embolic event EVENT DRIVEN Ruff CR et al. Am Heart J 2010; 160:635-41 Pivotal Atrial Fibrillation Trials Baseline Characteristics RE-LY (Dabigatran) ARISTOTLE (Apixaban) ENGAGE AF-TIMI 48* (Edoxaban) ROCKET-AF (Rivaroxaban) # Enrolled 18,113 18,201 21,105 14,264 Age (yrs) 72 ± 9 70 [63-76] 72 [64-77] 73 [65-78] Female 36% 35% 38% 40% CHADS2 score ≥3 32% 30% 52% 87% VKA naive 50% 43% 41% 38% Paroxysmal AF 33% 15% 25% 18% Prior stroke/TIA 20% 19% 18% / 12% 55%** Diabetes 23% 25% 36% 40% Prior CHF 32% 35% 56% 62% Hypertension 79% 87% 90% 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 J89 Med 2011; 365:981-92 Ruff CR et al. Am Heart J 2010; 160:635-41 Pivotal Atrial Fibrillation Trials Dose Comparison Drug N Dose (mg) Frequency Initial Dose adj* Dose adj (%) Dose adj* after randomization Design RE-LY ROCKET-AF ARISTOTLE ENGAGE AF-TIMI 48 Dabigatran Rivaroxaban Apixaban Edoxaban 18,113 14,266 18,201 21,105 150, 110 bid 20 qd 5 bid 60, 30 qd No 20 → 15 mg 5 → 2.5 mg 60 → 30 mg 30 → 15 mg 0 21 4.7 > 25 No No No Yes PROBE 2 x blind 2 x blind 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 Engl90 J Med 2011; 365:981-92 Ruff CR et al. Am Heart J 2010; 160:635-41 Pivotal Atrial Fibrillation Trials Results to Date Drug Dose (mg) RE-LY ROCKET-AF ARISTOTLE Dabigatran 110 bid 150 BID Rivaroxaban 20 mg qd Apixaban 5 mg bid Stroke + SEE non-infer Superior ITT cohort: non-infer. On Rx cohort: Superior Superior ICH Superior Superior Superior Superior Bleeding Lower similar similar Lower Mortality similar P = 0.051 similar Superior: P = 0.047 Ischemic stroke similar Lower similar similar Mean TTR 64% 55% 62% Stopped drug 21% 23% 23% WD consent 2.3% 8.7% 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% Hemorraghic Stroke 55% Favors NOACs Miller CS, et al. Am J Cardiol 2012;110(3):453-460. Favors Warfarin 92 Safety of New Oral Anticoagulants Bleeding Major 51% ICH GI Favors NOACs iller CS, et al. Am J Cardiol 2012;110(3):453-460. Favors Warfarin Does INR Matter? ROCKET AF 0.00-50.62% 50.71-58.54% 58.63-65.71% 65.74-100.0% 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 RE-LY (Dabigatran 150 mg) < 57.1% 1.1 57.1–65.5% 1.04 65.5–72.6% 1.04 > 72.6% 1.27 Hazard Ratio (95% CI) Study Drug Favors Warfarin 0.20 1.92 2.06 1.51 1.34 ARISTOTLE < 58.0% 58.0–65.7% 0.29 1.75 1.30 2.28 1.61 65.7–72.2 % > 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 2 5 All-Cause Death & Thromboembolism Warfarin Treatment Interruption Raunsø J, et al. Eur Heart J 2012; 33:1886-1892 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 # Primary Events Warfarin P = 0.008 48.8 Rivaroxaban Rivaroxaban Warfarin # Primary Events during first 30 days of transition Safety/Days 3 to 30 after the last dose 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 Apixaban to VKA group n/N Warfarin to VKA group %/year n/N %/year Stroke or systemic embolism 1–30 21/6791 4.02 5/6569 0.99 1–2 1/6791 2.69 1/6569 2.78 3–7 4/6787 4.31 0/6566 0 8–14 5/6780 3.85 1/6559 0.80 15–30 11/6771 4.18 3/6548 1.18 Pattern mirrored the first 30 days of the trial where warfarin-naïve 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 Actions—Where 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 CHA2DS2-VASc = 0 No antithrombotic therapy IB CHA2DS2-VASc = 1 VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban IIa A (Favored) CHA2DS2-VASc ≥ 2 VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban I A (Favored) 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 Women’s 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 Stroke or Systemic Embolism Atrial tachyarrhythmia > 6 min ≤ 3 months after pacemaker or defibrillator implantation Healey JS, et al. NEJM 2012; 366:120-129 Years Redefining Risk vs Benefit for OAC HAS-BLED Letter Clinical Characteristic Points H Hypertension 1 Stroke (% / yr) A Abnormal Liver or Renal Function HAS-BLED Score 1 or 2 0 1.1 % 1 1.0 % S Stroke 1 2 1.9 % B Bleeding 1 3 3.7 % L Labile INR 1 4 8.7 % E Elderly (age > 65) 1 >5 ?? % Lip GYH. Am J Med. 2011;124:111-114. D Drugs or Alcohol Maximum Score 1 or 2 9 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 risk—A “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 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 901 (0.7%) underwent renal-replacement therapy Stroke Risk and Renal Disease Aspirin does not prevent stroke Characteristic Total Population (n = 132,372) Hazard Ratio (95% CI) P Value All participants No Renal Disease (n = 127,884) Hazard Ratio (95% CI) P Value 1.00 Antithrombotic Therapy None 1.00 1.00 Warfarin 0.59 (0.57-0.62) < 0.001 1.10 (1.06-1.14) < 0.001 Aspirin 1.11 (1.07-1.15) < 0.001 1.10(1.06-1.14) < 0.001 Warfarin and aspirin 0.70(0.65-0.75) < 0.001 0.69(0.64-0.74) < 0.001 Olesen JB. NEJM 2012; 367:625-635 Bleeding Risk and Renal Disease Aspirin and warfarin/aspirin increase bleeding Characteristic Total Population (n = 132,372) Hazard Ratio (95% CI) P Value All participants No Renal Disease (n = 127,884) Hazard Ratio (95% CI) P Value 1.00 Antithrombotic Therapy None 1.00 1.00 Warfarin 1.28(1.23-1.33) < 0.001 1.28(1.23-1.33) < 0.001 Aspirin 1.21(1.16-1.26) < 0.001 1.21(1.16-1.26) < 0.001 Warfarin and aspirin 2.15(2.04-2.26) < 0.001 2.18(2.07-2.30) < 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) ► Dabigatran 110 mg bid (non-USA) ► Rivaroxaban 15 mg daily 25% ► Apixaban 2.5 mg bid 50% ESC 2012 50% 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 Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011 1 2 Limitations of Novel Agents are Exaggerated No antidote when bleeding • Best treatment is prevention • Warfarin has no great antidote • Time is a great antidote No antidote for urgent procedures • RELY analysis 2012 shows no increase in bleeding in this setting Lack standard measurement • Do not need one • Time since last dose is helpful Dependence on renal function • Rivaroxaban, apixaban modest renal effect Cost • Highly cost effective in analyses 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 “Bridging”with Dabigatran (RE-LY) Renal Function Impairment (CrCL mL/min) Estimated Halflife, h (Range) Stopping Dabigatran Before Surgery/Procedure High Risk for Bleeding Standard Risk for Bleeding Mild: > 50 to 80 15 (12-18) 2-3d* 24 h (2 doses) Moderate: > 30 to < 50 18 (18-24) 4d At least 2 d (48 h) Severe: < 30 27 (> 24) > 5d 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 else’s 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 warfarin’s 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 Mild bleeding • Delay next dose or discontinue treatment as appropriate • • • • • • • Mechanical compression Surgical intervention Fluid replacement and hemodynamic support Blood product transfusion Oral charcoal Hemodialysis ? Prothrombin Complex Concentrate? Life-threatening bleeding • 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 adherence—no 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 Women’s 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 patient’s regimen 5) Introduce rivaroxaban into the patient’s 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