Heart Failure, AF and Anticoagulation : Navigating the new options

Transcription

1 Michael D. Ezekowitz, MBChB, DPhil, FACC, FAHA, FRCP, MA Professor, Thomas Jefferson Medical, Cardiovascular Research Foundation NY Lankenau Hospital Wynnewood, Pennsylvania Heart Failure, AF and Anticoagulation : Navigating the new options 1

2 Disclosure Michael D. Ezekowitz, MBChB, DPhil, FACC, FAHA, FRCP, MA Consultant: ARYx Therapeutics, AstraZeneca, Boehringer Ingelheim, BMS, Daiichi Sankyo, Medtronic, Portola, sanofi-aventis, Merck, Pfizer, J&J, Coherex Gilead, St Jude Medical Grants: ARYx Therapeutics, Boehringer Ingelheim, Daiichi Sankyo, Portola, sanofi-aventis CO-PI Petro and RELY : Executive committee Engage AF : Co PI Explore Xa, Co PI E-VERT 2

3 Introduction Atrial fibrillation (AF) and symptomatic heart failure (HF) commonly coexist; Atrial fibrillation begets heart failure and heart failure begets Atrial fibrillation, share a similar risk factor profile and when coexist possess a poorer prognosis. 3

4 Projected Number of Patients with AF by 2050 Patients with AF (millions) MarketScan and Thomson Reuters Medicare Databases, 2009 Olmsted County Data, 2006 (assuming a continued increase in AF incidence) Olmsted County Data, 2006 (assuming no further increase in AF incidence) ATRIA Study Data, Year ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation. Go AS, et al. JAMA. 2001;285(18): Miyasaka Y, et al. Circulation. 2006;114: Naccarelli GV, et al. Am J Cardiol. 2009;104(11):

5 Prevalence of AF Increases with Severity of HF SOLVD = Studies Of Left Ventricular Dysfunction; DIG = Digitalis Investigation Group; v-heft = Veterans Administration Heart Failure Trial; CHF STAT = Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy; CIBIS II = Second Cardiac Insufficiency Bisoprolol Study; MERIT HF = Metoprolol controlled release Randomised Intervention Trial in Heart Failure; DIAMOND CHF = Danish Investigation of Arrhythmia and Mortality ON Dofetilide in Congestive Heart Failure; GESICA = Grupo de Estudio de la Sobravida en la Insuficiencia Cardiaca en Argentina; OPTIME CHF = Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure; CONSENSUS = Cooperative North Scandinavian ENalapril Survival Study. Savelieva I, et al. Europace. 2004;5:(Suppl1):S5-S NYHA IV 50 NYHA III-IV 50 Patients with AF (%) NYHA I NYHA II-III

6 The Consequences of AF Thromboembolism Stroke: 4.5x increased risk Microemboli: reduced cognitive function Prothrombotic state Hospitalizations Most common arrhythmia requiring hospitalization 2x to 3x increased risk for hospitalization Reduced QoL Palpitations, dyspnea, fatigue, reduced exercise tolerance Mortality 2 increased risk independent of comorbid CV disease Sudden death in HF and hypertrophic cardiomyopathy Impaired hemodynamics Loss of atrial kick Irregular ventricular contractions HF Tachycardia-induced cardiomyopathy Reduced ventricular filling time AF is an enormous contributor to the growing cost of medical care QoL = quality of life; HF = heart failure. Van Gelder IC, et al. Europace. 2006;8: Narayan SM, et al. Lancet. 1997;350: Wattigney WA, et al. Circulation. 2003;108: Wyse DG, et al. Circulation. 2004;109:

7 Cost Increases with Each AF Recurrence, Mainly Driven by Hospital Costs FRACTAL Registry Mean Annual Costs of AF-Related Medical Care 12,000 10,000 P<.05 $10,312 P<.05 Cost ($) $2372 Permanent AF (n = 34) $ (n = 620) $ (n = 286) 3 (n = 33) Hospital Costs Outpatient Costs Drug Costs Documented Recurrences FRACTAL = Fibrillation Registry Assessing Costs, Therapies, Adverse Events, and Lifestyle. Reynolds MR, et al. J Cardiovasc Electrophysiol. 2007;18(6):

8 Guideline-Based AF Treatment Options Rate control Maintenance of SR Stroke prevention Pharmacologic CCBs β-blockers Digitalis Amiodarone Dronedarone Nonpharmacologic Ablate and pace Pharmacologic Class IA Class IC Class III β-blockers Nonpharmacologic Catheter ablation Pacing Surgery Implantable devices Pharmacologic Warfarin Aspirin +/- clopidogrel Dabigatran Factor Xa inhibitors Nonpharmacologic Removal/isolation LA appendage Prevent remodeling CCBs ACE-Is, ARBs Statins Fish oil CCBs = calcium channel blockers; SR = sinus rhythm; ACE-Is = angiotensin-converting enzyme inhibitors; ARBs = angiotensin II receptor blockers; LA = left atrial. Wann LS, et al. Circulation. 2011;123:

9 2011 ACCF/AHA/HRS Guidelines: Antiarrhythmic Approaches to Maintain SR in Patients with Recurrent PAF or Persistent AF Maintenance of SR* No (or minimal) heart disease HTN CAD HF Dronedarone Flecainide Propafenone Sotalol No Substantial LVH Yes Dofetilide Dronedarone Sotalol Amiodarone Dofetilide Amiodarone Dofetilide Catheter ablation Dronedarone Flecainide Propafenone Sotalol Amiodarone Amiodarone Catheter ablation Catheter ablation Amiodarone Dofetilide Catheter ablation Catheter ablation A Safety-Driven Approach 2010 ESC Guidelines dronedarone recommended for patients with LVH and stable NYHA I/II CHF *Within each box, drugs are listed alphabetically and not in order of suggested use. ACCF/AHA/HRS = American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society; CAD = coronary artery disease; ESC = European Society of Cardiology; LVH = left ventricular hypertrophy; NYHA = New York Heart Association; PAF = paroxysmal atrial fibrillation. Wann LS, et al. Circulation. 2011;123: Camm AJ, et al. Eur Heart J. 2010;31:

10 AF-CHF Trial Study Design AF-CHF Screening CHF: NYHA Class II-IV and ejection fraction 35% NYHA I and prior hospitalization for CHF or ejection fraction 25% Qualifying AF: 1 episode 6 hours within last 6 months 1 episode 10 minutes within last 6 months and prior DC shock Randomization (open-label) Eligible patients consent Rhythm control AAD and/or nonpharmacologic therapy in resistant patients Cardioversion if needed Rate control Pharmacologic dosing adjustment AVN ablation for patients with inadequate rate control Follow-up 2 years, clinic visits every 4 months Optimal CHF management with ACE-I and β-blocker Atrial Fibrillation and Congestive Heart Failure (AF-CHF) Trial Investigators. Am Heart J. 2002;144(4):

11 AF/CHF Trial: Results Rhythm Control (%) Rate Control (%) P- Value CV Mortality (1º) Total Mortality NS Stroke NS Hospitalization* Worsening CHF NS *Mainly due to hospitalization for AF and bradyarrhythmias (8.5% vs 4.9%; P =.0074). CHF = congestive heart failure; NS = not significant. Roy D, et al. N Engl J Med. 2008;358(25):

12 AFFIRM Primary Endpoint: All-Cause Mortality 30 Cumulative Mortality (%) Rhythm Control Rate Control P =.08 Number of Deaths Number (%) Time (years) Rhythm Control 0 80 (4) 175 (9) 257 (13) 314 (18) 352 (24) Rate Control 0 78 (4) 148 (7) 210 (11) 275 (16) 306 (21) AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management. The AFFIRM Investigators. N Engl J Med. 2002;347(23):

13 AFFIRM Results: Additional Analysis Covariate Time dependent SR HR 99% CI P Value <.0001 Warfarin use <.0001 Digoxin use.0007 AAD use* Decrease Mortality Increase Mortality The toxicity of AADs (mainly amiodarone) counterbalanced the benefits of SR *Almost 70% of the AAD use was amiodarone. HR = hazard ratio; CI = confidence interval; AAD = antiarrhythmic drug. Corley SD, et al. Circulation. 2004;109:

14 Trials of Rhythm and Rate Control in AF Major overall findings Rate control can be an acceptable alternative to, but not necessarily better than, rhythm therapy Rhythm control was not superior to rate control in terms of morbidity/mortality Chronic anticoagulation is required in high-risk patients The clinician should adapt the therapeutic strategy to each individual patient Hohnloser SH, et al. Lancet. 2000;356: Wyse DG, et al. N Engl J Med. 2002;347(23): Van Gelder IC, et al. N Engl J Med. 2002;347(23): Opolski G, et al. Chest. 2004;126: Vora A, et al. J Cardiovasc Pharmacol Ther. 2004;9(2): Ogawa S, et al. Circ J. 2009; 73(2): Carlsson J, et al. J Am Coll Cardiol. 2003;41(10): Roy D, et al. N Engl J Med. 2008;358(25):

15 Stroke Risk Stratification in AF CHADS 2 Risk Factor Score Cardiac failure 1 HTN 1 Age 75 years 1 Diabetes 1 Stroke 2 CHA 2 DS 2 -VASc Risk Factor Score Cardiac failure 1 HTN 1 Age 75 years 2 Diabetes 1 Stroke 2 Vascular disease (MI, peripheral arterial disease, aortic atherosclerosis) 1 Age years 1 Sex category (female) Annual Risk of Stroke (%) CHADS 2 CHA 2 DS 2 -VASc Total Score HTN = hypertension; MI = myocardial infarction. Lip GY, et al. Am J Med. 2010;123(6): Camm AJ, et al. Eur Heart J. 2010:31;

16 HAS-BLED Bleeding Risk Score* Letter H A S B L E D Clinical Characteristic HTN Abnormal renal and liver function (1 point each) Stroke Bleeding Labile INRs Elderly (age >65 years) Drugs or alcohol (1 point each) Score 1 1 or or 2 Maximum 9 points Risk Factors/ Score Number of Bleeds Bleeds per 100 Patient- Years Any Score P-Value for Trend.007 *HAS-BLED study has not yet been validated in other data sets; Score of 3 indicates high risk, and some caution and regular patient review is needed following initiation of antithrombotic therapy. INRs = international normalized ratios. Camm AJ, et al. Eur Heart J. 2010;31(19): Pisters R. Chest. 2010;138: Lip GY, et al. Am J Med. 2010;123(6): N

17 Antiplatelet Therapy in AF ACTIVE-W: 6706 randomized patients; trial stopped ACTIVE-A: 7554 randomized patients; median follow-up of 3.6 years 8 P =.01 Outcome/Year (%) P =.0003 Clopidogrel + ASA Warfarin P =.001 P =.53 Outcome/Year (%) P<.001 Clopidogrel + ASA ASA P< Vascular Event Stroke Major Bleeding 0 Vascular Event Stroke Major Bleeding ACTIVE = AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events; ASA = acetylsalicylic acid. ACTIVE Investigators. Lancet. 2006;367: ACTIVE Investigators. N Engl J Med. 2009;360(20):

18 Efficacy of Warfarin Compared with Control in 5 Studies 62% to 67% RR reduction with warfarin vs placebo Number of Events Patient- Years Risk Reduction (%) AFASAK BAATAF CAFA SPAF SPINAF Combined Warfarin Better Warfarin Worse AFASAK = Atrial Fibrillation Aspirin and Anticoagulation; BAATAF = Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA = Canadian Atrial Fibrillation Anticoagulation; SPAF = Stroke Prevention in Atrial Fibrillation; SPINAF = Stroke Prevention in Non-Rheumatic Atrial Fibrillation. Atrial Fibrillation Investigators. Arch Intern Med. 1994;154(13):

19 Characteristics of New Oral Anticoagulants Drug Dabigatran Rivaroxaban Apixaban Betrixaban Edoxaban Mechanism of action Thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor T 1/ hours 5-9 hours 12 hours hours 6-12 hours Regimen BID QD, BID BID QD QD Peak to trough ~2 12 (QD) 3-5 ~3 ~3 Renal excretion of absorbed drug ~80% 36%-45% 25%-30% ~15% 35% Potential for drug interactions P-glycoprotein inhibitor CYP3A4 substrate and P-glycoprotein inhibitor CYP3A4 substrate and P-glycoprotein inhibitor Not substrate for major CYPs CYP3A4 substrate and P-glycoprotein inhibitor CYP3A4 = cytochrome P450 3A4. Usman MH, Ezekowitz MD Curr Treat Cardiovasc Med. 2008;10(5): Piccini JP, et al. Curr Opin Cardiol. 2010;25(4):

20 Stroke Prevention in AF Dabigatran Etexilate vs Warfarin (RE-LY) 18,113 patients with nonvalvular AF+ 1: CVA/TIA Hx, LVEF <40, NYHA II, age 75 years, and age years and DM, HTN or CAD Percent/Year *P<.001 P<.001 P =.003 P<.001 P<.001 Dabigatran 110 mg Dabigatran 150 mg Warfarin INR P=.09 Avg TTR: 67% Stroke/Systemic Embolism Major Bleed Intracranial Hemorrhage *Noninferiority; Superiority. Dabigatran 110 mg is not FDA for this indication. FDA = US Food and Drug Administration; TTR = time in therapeutic range. Connolly SJ,EzekowitzMD et al. N Engl J Med. 2009;361(12): Connolly SJ,Ezekowitz MD et al. N Engl J Med. 2011;363: MI

21 ROCKET AF: Primary Efficacy & Safety Outcomes 14,262 patients with Nonvalvular AF + CVA/TIA/embolism or 2: CHF, HTN, 75 years, and DM Event Rate per 100 Patient-Years Hazard ratio 0.79 (95% CI 0.65, 0.95) Superiority P =.01 P=.015 Hazard ratio 0.88 (95% CI 0.74, 1.03) Non inferiority P<.001 P=.117 Hazard ratio 1.04 (95% CI 0.90, 1.20) P=.576 Hazard ratio 0.41 (95% CI 0.28, 0.60) P<.001 On Treatment ITT Major Bleeding IC Hemorrhage* Stroke and Non-CNS Embolism Safety Rivaroxaban Warfarin *Hemorrhagic stroke, intracranial hemorrhage including subarachnoid, subdural bleed ITT = intention-to-treat; IC = intracranial; CNS = central nervous system. Patel MR, et al, N Engl J Med Published online August 30, 2011.

22 ARISTOTLE: ITT Analysis 8,201 patients with AF+ 1: TIA/CVA/embolism, 75 years, History CHF or LVEF 40, HTN, DM Apixaban n = 9120 Warfarin n = 9081 Hazard ratio 0.89 (95% CI 0.80, 0.99) P=.047 Hazard ratio 0.69 (95% CI 0.60, 0.80) 3.9% P< % Percent/Year Hazard ratio 0.79 (95% CI 0.66, 0.95) Non inferiority P<.001 Superiority P< % 1.6% 2.1% 3.1% Hazard ratio 0.51 (95% CI 0.35, 0.75) P< Stroke/Systemic Embolism Major Bleeding 0.5% 0.2% Hemorrhagic Stroke Mortality Granger CB, et al. N Engl J Med. 2011;365(11):

23 Novel Anticoagulants Apixaban, dabigatran, rivaroxaban... As effective (rivaroxaban) or more so (dabigatran and apixaban) than warfarin for AF stroke prophylaxis (at TTR 55%-64%) Similar or lower risk of major bleeding than warfarin Lower risk of hemorrhagic stroke Directional trends toward/improved survival Reversal agents ( antidotes ) not yet available Compliance Cost-effectiveness Rivaroxaban is not FDA-approved for stroke prevention. Apixaban is not FDA-approved. Patel MR, et al. N Engl J Med. 2011; /NEJMoa Connolly SJ, et al. N Engl J Med. 2009;361(12): Granger CB, et al. N Engl J Med. 2011; /NEJMoa

24 LAA Device for AF: PROTECT-AF Study 707 patients with nonvalvular AF randomized to LAA device + 45 days of warfarin vs warfarin alone Primary efficacy endpoint of stroke, CV death, or systemic embolism was 3.0% ( ) with device and 4.9% ( ) with warfarin [RR 0.62, 95% CI ( )] Primary safety endpoint of excessive bleeding, serious pericardial effusion, device embolization, or procedurerelated stroke was 7.4% with device and 4.4% with warfarin [RR 1.69, 95% CI ( )] PROTECT-AF = Embolic Protection in Patients with Atrial Fibrillation. Holmes DR, et al. Lancet. 2009;374:

25 McMurray, J.J.V, et al.. EHJ (2012) 33 (Abstract Supplement), 519 and ESC 2012 oral presentation available at For medical non-promotional reactive use only

26 McMurray, J.J.V, et al.. EHJ (2012) 33 (Abstract Supplement), 519 and ESC 2012 oral presentation available at For medical non-promotional reactive use only

27 McMurray, J.J.V, et al.. EHJ (2012) 33 (Abstract Supplement), 519 and ESC 2012 oral presentation available at For medical non-promotional reactive use only

28 Pharmacologic AF Management: AADs

29 Dronedarone Amiodarone-like compound lacking the iodine moiety Similar electrophysiologic properties to amiodarone Low propensity to cause TDP 13- to 30-hour T ½, but administered as BID regimen Food effect (2x-3x increase in levels) Extensive first-pass hepatic metabolism through CYP4503A4 system Only 15% bioavailability Elevates serum creatinine 10% to 15% without a change in glomerular filtration rate Drug interactions similar to amiodarone, except no significant interaction with warfarin No evidence of thyroid or pulmonary toxicity but rare cases of serious hepatotoxicity Hynes BJ, et al. Future Cardiol. 2005;1(2): US Food and Drug Administration. Accessed March 10, 2011.

30 Dronedarone: Indications and Considerations Approved by the FDA in July 2009 to Reduce the risk of CV hospitalization in patients with paroxysmal or persistent AF or atrial flutter, with a recent episode of AF/atrial flutter, and 1 or more associated CV risk factors: age >70 years, HTN, DM, prior CVA, LA diameter 50 mm, or LVEF <40% Treat patients who are in SR, or who will be cardioverted Special considerations and contraindications Two cases of liver toxicity requiring transplant has been reported, consider obtaining periodic hepatic enzymes during the first 6 months (it is not known whether monitoring will prevent injury) Exposure to dabigatran is higher when it is administered with dronedarone Contraindicated in Class IV HF or lesser HF with recent decompensation Should not be used in patients with permanent AF based upon the very recent PALLAS trial results LA = left atrial; PALLAS = Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy. Dronedarone. Medication Guide. Accessed July 28, 2011.

31 ATHENA: Primary Endpoint (CV Hospitalization or Death) 4628 patients with paroxysmal or persistent AF were randomized if they met the following criteria: 75 years of age with or without additional risk factors or 70 years of age and 1 risk factor (HTN, diabetes, prior stroke/tia, LA diameter 50 mm, LVEF 0.40) Cumulative Incidence (%) Placebo Dronedarone HR = 0.76 P< % reduction in relative risk Months ATHENA = A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation. Hohnloser SH, et al. N Engl J Med. 2009;360(7):

32 ANDROMEDA: Primary End Point and Results Inclusion Criteria Hospitalized 18 years old with symptomatic CHF (current NYHA class II-IV) with 1 episode of decompensation corresponding to NYHA class III-IV within the last month treated with a diuretic and with WMI 1.2 ~ LVEF 0.35 Primary End Point All-cause mortality or hospitalization for HF vs placebo Results Analysis Up to Study Discontinuation Placebo (n=317) Dronedarone 800 mg/day (n=310) Number of patients who died Relative risk (relative to placebo) % CI 1.07, 4.25 P value.03 ANDROMEDA = Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe CHF Evaluating Morbidity Decrease. Køber L, et al. N Engl J Med. 2008;358(25):

33 PALLAS Trial: Dronedarone in Permanent AF Rate per 100 Patient-Years PALLAS enrolled 3236 patients 65 years with >6 month history of permanent AF and risk factors for major vascular events. The study was stopped for safety reasons P = Stroke, MI, Systemic Embolism, or CVD P< Death or Unplanned CV Hospitalization P =.049 Dronedarone Placebo P = P =.02 Connolly, SJ et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011; DOI: /NEJMoa Published Nov 14, Accessed Nov 15, Death Stroke Hospitalization for HF P< HF Episode or Hospitalization

34 Common Lesions Performed in AF Ablation A. Circumferential ablation around left and right PV antra B. and C. Additional linear lesion sets for the roof, mitral isthmus, carinae, SVC, and cavotricuspid isthmus D. Targeting fractionated electrograms and/or ganglionic plexi LSPV LIPV LSPV LIPV A. B. RSPV RIPV IVC LSPV LIPV C. D. PV = pulmonary vein; SVC = superior vena cava; LSPV = left superior pulmonary vein; RSPV = right superior pulmonary artery; LIPV = left inferior pulmonary vein; RIPV = right inferior pulmonary vein; IVC = inferior vena cava. Calkins H, et al. Heart Rhythm. 2007;4(6): SVC SVC RSPV RIPV IVC LSPV LIPV SVC RSPV RIPV IVC SVC RSPV RIPV IVC

35 Indications for Catheter AF Ablation Symptomatic AF refractory or intolerant to at least 1 Class I or III AAD Selected symptomatic patients with HF and/or reduced ejection fraction As an alternative to device implantation to support AAD therapy in bradycardic patients Presence of an LA thrombus is a contraindication to catheter ablation of AF Discontinuation of anticoagulation is not an indication for ablation Calkins H, et al. Heart Rhythm. 2007;4(6):

36 Ongoing Ablation Trials CABANA: Catheter Ablation vs AAD for AF NIH/industry-cooperative, 5-year study to investigate whether mortality is improved with ablation compared with drug therapy (rate or rhythm control) CASTLE-AF: Catheter Ablation vs Standard Conventional Treatment in Patients with LV Dysfunction and AF Time to first event of death or hospitalization for HF NIH = National Institutes of Health. Calkins H, et al. Heart Rhythm. 2007;4(6): Marrouche NF, et al. Pacing Clin Electrophysiol. 2009;32(8):

37 Conclusion When AF and Heart Failure Co Exist worse prognosis Anticoagulation provides relative benefit Antiarrythmic agents of choice Amiordarone and Dofedilide Role of Ablation for AF cure unproven Evolving picture.la occlusion devices

38 Dabigatran: DC Cardioversion N (Patients/CV) CVA/SEE Dabigatran 110 mg 409/647 5 (0.8%) Dabigatran 150 mg 415/672 2 (0.3%) Warfarin 431/664 4 (0.6%) Nagarakanti R, et al. Circulation. 2011;123:

39 Apixaban with Antiplatelet Therapy After Acute Coronary Syndrome: Results of the APPRAISE-2 Trial John H. Alexander, MD, MHS on behalf of the APPRAISE-2 Investigators Sponsored by Bristol-Myers Squibb and Pfizer

40 Primary Outcome CV Death, MI, Ischemic Stroke Apixaban 279 (7.5%) Placebo 293 (7.9%) HR 0.95; 95% CI ; p=0.509

41 TIMI Major Bleeding Apixaban 48 (1.3%) Placebo 18 (0.5%) HR 2.59; 95% CI ; p=0.001

42 PRIMARY EFFICACY ENDPOINT: CV Death / MI / Stroke* (Ischemic + Hemg.) Estimated Cumulative Rate (%) Placebo Rivaroxaban (both doses) 2 Yr KM Estimate 10.7% 8.9% HR 0.84 ( ) ARR 1.7% mitt p = ITT p = NNT = 59 Months After Randomization Placebo No. at Risk Rivaroxaban *: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mitt approach; Stratified log-rank p-values are provided for both mitt and ITT approaches; ARR=Absolute Relative Reduction; NNT=Number needed to treat; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.