Stroke Prevention in Atrial Fibrillation and the New Anticoagulant Drugs

Stroke Prevention in Atrial Fibrillation and the New Anticoagulant Drugs David J. Gladstone, MD, PhD, FRCPC Director, Sunnybrook Regional Stroke Prevention Clinic Assistant Professor of Medicine (Neurology) Co-leader, U of T Stroke Program University of Toronto

Research funding: Disclosures CIHR; Canadian Stroke Network; HSFO; Ontario Stroke Network; Heart and Stroke Foundation Centre for Stroke Recovery; Ontario Ministry of Research and Innovation; Dept. of Medicine, Sunnybrook &UofT Speaker s honoraria for CME events and advisory boards: BoehringerIngelheim, Sanofi Aventis, Bristol-Myers Squibb, Pfizer, Bayer This presentation may discuss unapproved uses of dabigatran, rivaroxaban, apixaban

Outline The state of the gap in the warfarin era The state of the art in new anticoagulant therapies Dabigatran etexilate Rivaroxaban Apixaban

Objectives At the end of this session, participants will: Understand the burden of AF-related strokes Appreciate the problem of under-diagnosis and under-treatment of AF Be familiar with AF risk stratification tools and new treatment guidelines Become more familiar with the promise (and perils) of the new anticoagulants and their key trial results Be more comfortable with anticoagulant decision-making, initiation and monitoring

Case 84 year old woman with TIA New diagnosis of atrial fibrillation Hypertension

What Do You Recommend? a) ASA b) ASA and clopidogrel c) warfarin d) warfarin and ASA e) dabigatran low dose f) dabigatran high dose g) rivaroxaban h) apixaban

The Burden of Atrial Fibrillation-Related Strokes Common 1 in 6 overall; 1 in 4 in the elderly Severe Strokes caused by atrial fibrillation are generally more severe than non-af strokes High mortality 24% at 30 days; 50% at 1 year

Prevalence of AF in Consecutive Hospitalized Ischemic Stroke Patients n=12,849 Registry of the Canadian Stroke Network, 2003-2007 17% had a past history of AF An additional 6% had AF newly detected in hospital At least another 6% had new AF documented on a subsequent hospital admission within 1 year Gladstone, Blakely, Silver, Kapral, et al. Stroke 2009

Prevalence of Diagnosed Atrial Fibrillation Stratified by Age and Sex Go, A. S. et al. JAMA 2001;285:2370-2375.

Projected Number of Adults With Atrial Fibrillation in the United States Between 1995 and 2050 Copyright restrictions may apply. Go, A. S. et al. JAMA 2001;285:2370-2375.

The Challenges with Warfarin Warfarin is underused Patient factors Physician factors Fear of bleeding side effects Drug and food interactions Need for regular INR monitoring Perioperative discontinuation Patients taking warfarin are outside the therapeutic INR range half of the time - van Walraven. Chest 2006

The Practice Gap

Warfarin Discontinuation Glader et al. Stroke 2010

Warfarin Discontinuation Gallagher et al. J Thromb Haemost 2008

Optimal Intensity of Anticoagulation Target 2.5 (range 2.0 3.0) Efficacy declines significantly below 2.0 Risk of hemorrhage increases most dramatically when INR >5.0 absolute risk 30% per year vs. to 1.4% per year with INR 2-3 CMAJ 2008;179(3):235-244

Missed Opportunities for Stroke Prevention Preadmission Meds in AF Patients Admitted With Ischemic Stroke (Primary Prevention Cohort) no antithrombotics, 29% dual antiplatelet therapy, 2% warfarin - therapeutic, 10% warfarin - subtherapeutic, 29% single antiplatelet agent, 29% Gladstone et al. Stroke 2009

Missed Opportunities for Stroke Prevention Preadmission Meds in AF Patients Admitted With Ischemic Stroke (Secondary Prevention Cohort) no antithrombotics, 15% dual antiplatelet therapy, 3% warfarin - therapeutic, 18% single antiplatelet agent, 25% warfarin - subtherapeutic, 39% Gladstone et al. Stroke 2009

CHADS2 Risk Stratification

Assess Thromboembolic Risk (CHADS 2 ) and Bleeding Risk (HAS-BLED) CHADS 2 = 0 CHADS 2 = 1 CHADS 2 2 aspirin OAC* OAC No antithrombotic may be appropriate in selected young patients with no stroke risk factors *Aspirin is a reasonable alternative in some as indicated by risk/benefit Dabigatran is preferred OAC over warfarin in most patients.

CHA 2 DS 2 VASC C CHF (or LVsystolic dysfunction) 1 H Hypertension: blood pressure consistently above 140/90 (or treated hypertension on medication) 1 A 2 Age 75 years 2 D Diabetes Mellitus 1 S 2 Prior Stroke or TIA or thromboembolism 2 V Vascular disease (eg. PVD, MI, aortic plaque)1 A Age 65-74 years 1 Sc Sex category (female) 1

Age >75; or Anticoagulation is Recommended for: Prior ischemic stroke or TIA; or Female plus 1 other risk factor / Male plus 2 other risk factors; or Age 65-74, Hypertension, CHF, decreased LVEF, DM, vascular disease CHADS 2 score 1; or CHA 2 DS 2 VASC score 2 Lip et al. Chest 2010

Underdiagnosis of Atrial Fibrillation After TIA and Stroke 1 in 3 ischemic strokes are of undetermined cause Some of these may be due to undiagnosed paroxysmal atrial fibrillation, esp. in elderly and with embolic imaging pattern

Improved Methods for Detecting AF After TIA/Stroke Are Needed AF is difficult to diagnose because it is frequently paroxysmal and asymptomatic Current diagnostic methods are suboptimal: Holter monitoring has a low sensitivity for detecting AF Current monitors require adhesive skin contact electrodes that cause skin irritation, making prolonged monitoring difficult Loop recorders rely on patients to recognize palpitations, missing asymptomatic AF

Diagnostic Yield of Tests for Paroxysmal Atrial Fibrillation Holter monitor: 5% 4-day loop recorder: additional 6% 7-day loop recorder: additional 8% serial 7-day loop recorder at 0, 3, and 6 months: additional 14% 21-day telemetry: additional 5% daily EKG for 1 month additional 9% Liao et al. Stroke 2007;38:2935 Wallmann et al. Stroke 2007;38:2292 Tayal et al. Neurology 2008; Sept. 24 Gaillard et al. Neurology 2010

EMBRACE Trial Design Multicentre RCT, n = 564, 18 sites Target population Cryptogenic embolic ischemic stroke or TIA within 6 mo. No known history of atrial fibrillation Negative post-stroke EKG and Holter Randomly assigned (1:1) to 30-day study monitor (intervention group) or repeat 24-hour Holter monitor (control group) Primary outcome detection of atrial fibrillation at 90 days

The New Oral Anticoagulants Initiation Phase Amplification Propagation Phase Thrombin Activity Contact XII XI Warfarin VIII IX Common Pathway TF Xa VIIa Platelet Surface Thrombin X Rivaroxaban Apixaban Dabigatran etexilate Fibrinogen Fibrin

Advantages of New Agents Rapid onset/offset of action No bridging required More stable anticoagulant effect (avoids fluctuations) No routine coagulation monitoring or dosage adjustment needed (no INR monitoring) No food interactions, fewer drug interactions Easier to use/prescribe for patients/physicians Likely that more eligible patients will be treated

Dabigatran etexilate (Pradax) Oral direct thrombin inhibitor Half life 14-17 hours (depends on renal function) Bioavailability 6% (better in acidic ph) 80% renal elimination Onset of full anticoagulation 2h post-dose BID dosing

RE-LY Trial

RE-LY Trial Summary RCT, n=18,133 AF plus 1 RF Mean age 71.5 mean CHADS2 score 2.1 20% prior stroke/tia Median f/u 2 years Warfarin open label TTR 64% (mean); 67.3% (median) Drug discontinuation rates 21% vs. 17% at 2 years

Main Results High dose superior to warfarin for stroke prevention with similar rates of major bleeding efficacy equivalent to warfarin with TTR 79% 5-6 fewer strokes per 1000 patients treated, with no increase in major bleeding Low dose as good as warfarin (noninferior) and safer (signif. reduction in major bleeding)

Bleeding Both doses had a significant reductions in intracranial hemorrhage 0.23% vs. 0.30% vs. 0.74% life-threatening hemorrhage 1.22% vs. 1.45% vs. 1.80% total bleeding

Major Bleeding and Age Intracranial hemorrhage Significantly reduced with both doses, irrespective of age Extracranial hemorrhage Low dose dabi had less extracranial bleeding in patients aged <75 years and similar rates in patients aged >75 years High dose dabi had more extracranial bleeding - Eikelboom et al. Circulation 2011

Adverse Events Dyspepsia 11%-12% (main side effect) Myocardial infarction 0.82% vs. 0.81% vs. 0.64% More GI bleeds with high dose 1.51% vs. 1.02% (p<0.001)

Rivaroxaban (Xarelto) Factor Xa inhibitor Half life 5-13 hours 20mg once daily dosing 1/3 renal clearance; 2/3 CYP450

ROCKET AF Trial

ROCKET AF Trial Summary Double blind RCT, n=14,264 AF plus 3 RF or prior stroke/tia mean age 73 mean CHADS 3.5 (87% CHADS 3 or more) 55% prior TIA/stroke/embolism 17% prior MI Rivaroxaban 20mg OD vs. warfarin (INR 2-3) Median f/u 1.9 years Discontinuation rates: 23.9% vs. 22.4% Warfarin TTR 58% (median); 55% (mean)

Main Results

Main Results Rivaroxaban non-inferior to warfarin for stroke prevention (ITT analysis) superior to warfarin in on-treatment analysis 1.71% vs. 2.16%, p<0.001 (21% RRR) Similar rates of major bleeding vs. warfarin (approx. 3.5%) Significant reductions in intracranial hemorrhage (0.49% vs. 0.74%), critical organ bleeding, and fatal bleeding vs. warfarin

Apixaban (Eliquis) Factor Xa inhibitor Half-life 12 hours 27% renal elimination BID dosing

AVERROES Trial

AVERROES Trial Summary DB RCT, n=5599 AF plus 1 RF and unsuitable for warfarin Mean age 70 Mean CHADS2 score 2.1 Previous stroke/tia 13.5% Apixaban 5mg bid vs.asa Median f/u 1.1 years

Primary Outcome

Main Results Primary Outcome: Stroke or Systemic Embolism 1.6% VS. 3.7% (p<0.001), 55% RRR Ischemic stroke: 1.1% vs. 3.0% (p<0.001) Major Bleeding 1.4% vs. 1.2% (p<0.57) Fewer drug discontinuations with apixaban vs. ASA 2-year d/c rate: 17.9% vs. 20.5% (p=0.03)

ARISTOTLE Trial

ARISTOTLE Trial Design Double blind RCT, n=18,201 AF and at least 1 RF Median age 70 (1/3 aged 75) CHADS mean 2.1CHADS score 1 (1/3); 2 (1/3); 3 (1/3) 19% prior stroke/tia/se Apixaban 5mg bid (2.5mg in selected pts*) vs. warfarin (INR 2-3) *2 of: age 80, Cr >150, weight <60 kg Median f/u 1.8 years Drug discontinuation 25.3% apixaban vs. 27.5% warfarin (p=0.001) TTR: median 66%; mean 62%

Efficacy Results Primary Outcome: Stroke or Systemic Embolism 1.27% vs. 1.60% (p=0.011) 21% RRR stat signif for non-inferiority and superiority Mortality 11% RRR (p=0.047)

Primary Safety Outcome Major Bleeding Major bleeds 2.13% vs. 3.09% (p<0.001) 31% RRR Intracranial bleed 0.33% vs. 0.80% (p<0.001) 58% RRR GI bleed 0.76% vs 0.86% (n.s.) Any bleeding 18.1% vs. 25.8% (p<0.001)

Common Themes Across the Trials All trials met non-inferiority vs. warfarin All agents reduced intracranial hemorrhage vs. warfarin Major bleeds 2%-4% All trials had short duration follow-up A major challenge with all agents is adherence (1/5 to 1/4 discontinuation rates over 2 years)

Disadvantages of the New Anticoagulants Limited experience/familiarity No long-term data No antidote BID dosing (adherence issues?) Short half-life (greater risk of missed doses?) No INR to monitor (how to monitor therapy?) Contraindicated in renal failure; caution with renal impairment (need to monitor renal function) Treated patients ineligible for IV thrombolysis Expensive Potential for inappropriate off-label uses

Areas of Uncertainty Patients with recent ischemic stroke/tia (esp. within 2 weeks) Patients with prior intracranial hemorrhage CHADS 2 0 patients Cryptogenic embolic strokes with suspected (but unproven) atrial fibrillation Patients with multiple brain microbleeds on MRI Patients who require concomitant antiplatelet therapy Patients with renal dysfunction Drug interactions

Advantages of Warfarin Familiarity (>50 years of experience) In expert clinician hands, TTR can be high INR monitoring Ability to assess good/poor adherence Ability to assess treatment failures PO and IV antidotes available Non-renal clearance; can use in patients with renal failure Slow onset of action often desirable (post-stroke) Long half-life (40 hours) Inexpensive Known benefits in AMI, CAD, mechanical valves, etc.

Dabigatran and Rivaroxaban Patient Selection Approved for prevention of stroke/se in patients with AF in whom anticoagulation is appropriate VTE prophylaxis after hip/knee surgery Not studied in patients with mechanical heart valves Contraindicated in severe renal insufficiency (CrCL<30) Patients should be able to reliably take daily medication (o.d. for riva; b.i.d. for dabi)

Dabigatran and Rivaroxaban Prescribing Tips Before prescribing, ensure CrCL>30 2 doses Dabigatran: 150mg bid for patients aged <75, CrCL>50, average bleeding risk 110mg bid for patients aged 75, CrCL 30-50, increased bleeding risk Rivaroxaban: 20mg od for patients with CrCL 50 15mg od for patients with CrCL 30-49 Switching from warfarin start dabigatran when INR <2.0; start rivaroxaban when INR <2.5 Monitor renal function at least annually in patients >75 years or with CrCL<50 Concomitant use of antiplatelet agents discouraged; NSAIDs may increase GIB risk

Dabigatran and Rivaroxaban Patient Instructions Adherence Importance of taking every day (with or without food) at 12h intervals Patients missing 1-2 consecutive doses may be subtherapeutic Formulation Dabigatran: Capsules - must not be opened, chewed or broken (not for use in patients who cannot swallow intact capsule or those with feeding tubes) Rivaroxaban: Tablets Side effects bleeding dyspepsia with dabigatran Cost $120/month for dabi; $106/month for riva

Peri-Procedure Management For dabigatran For elective surgery/procedures, stop dabigatran 2 days before if CrCL 50 3 days before if CrCL 30-49 5 days before if CrCL<30 Van Ryn et al. ThrombHaemost2010 If aptt is normal (<35 seconds), it is reasonable to assume that there is unlikely to be a significant dabigatran bleeding risk

Dabigatran and Rivaroxaban Management of Bleeding No specific antidote to reverse the anticoagulant effect Mild bleeding: hold 1 or more doses Mod-severe bleeding: manage local bleeding site, fluids, RBC transfusion if needed, contact hematologist Oral charcoal PCC? Factor VIIa?

Contraindications Dabigatran (Pradax) Drug Interactions ketoconazole, rifampin Drug interactions: P-glycoprotein inhibitors (increase dabigatran blood levels): amiodarone, dronedarone, carvedilol, cyclosporine, diltiazem P-glycoprotein inducers (decrease dabigatran blood levels): Carbamazepine, phenytoin, St. John s wort

Warfarin-Associated Intracerebral Hemorrhage Accounts for 12% of all ICH in Ontario (RCSN data) Higher mortality vs. ICH in non-anticoagulated patients 52% vs. 33% in-hospital mortality Half of deaths occurred within 24 hours Only ¼ had INR>3.0 Gladstone, Rodan, Silver, Kapral, Hill et al. CJNS (in press)

ICH Rates in Trials of New RE-LY Anticoagulants dabigatran low dose 0.23% dabigatran low dose 0.30% warfarin 0.74% ROCKET rivaroxaban 0.49% warfarin 0.74% ARISTOTLE apixaban 0.33% warfarin 0.80%

Rapid Reversal of Warfarin in Patients with Severe Bleeding Vitamin K 10 mg IV and Prothrombin Complex Concentrate (Octaplex) or FFP Canadian National Advisory Committee on Blood and Blood Products recommends PCC over FFP

Minimizing Risk of Intracerebral Hemorrhage on Anticoagulant Therapy Careful warfarin dosing and close INR monitoring Tight blood pressure control Avoid unnecessary concomitant antiplatelet therapy Stroke 2005;36(7):1588-93 Caution re: renal dysfunction with the new oral anticoagulants

Warfarin Failures For patients with AF who suffer an ischemic stroke or TIA despite therapeutic anticoagulation, no data indicate that either increasing the intensity of anticoagulation or adding an antiplatelet agent provides additional protection against future ischemic events. In addition, both strategies are associated with an increase in bleeding risk. AHA/ASA Guidelines (Stroke 2006;37:577-617)

Warfarin Plus ASA Associated with increased risk of major bleeding, without additional benefit for prevention of stroke or MI SPORTIF trial post-hoc analysis: the addition of aspirin to warfarin provided no significant reduction in rates of stroke, systemic embolism or MI the combination was associated with significantly increased annual risk of major bleeding (3.9% vs. 2.3% per year, p=0.01) and major/minor bleeds (62.8% vs. 36.8%, p<0.01) (Am Heart J. 2006;152: 967 973; Stroke 2007;38:1652).

Annual Bleeding Risks with Single, Dual, Triple Therapy Warfarin 3.9% ASA 3.7% Clopidogrel 5.6% ASA + clopidogrel 7.4% Warfarin + ASA 6.9% Warfarin + clopidogrel 13.9% Warfarin + ASA + clopidogrel 15.7% Hansen et al. Arch Intern Med 2010;170(16):1433-41

Conclusions AF is a major preventable cause of stroke Search for occult AF in patients with unexplained embolic strokes Optimize warfarin use and monitoring Aim for safe/appropriate use of new anticoagulants Careful patient selection Patient and physician education Encourage and assess medication adherence Regular patient follow-up Good BP control Avoid unnecessary concomitant antiplatelet therapy Caution re: renal dysfunction

Resources www.strokebestpractices.ca 2010 Canadian Best Practice Recommendations for Stroke Care www.ccsguidelineprograms.ca 2010 Canadian Cardiovascular Society AF guidelines www.canadianstrokenetwork.ca Making Choices University of Ottawa AF decision aid www.heartandstroke.ca/af Heart and Stroke Foundation patient information www.tigc.org Thrombosis Interest Group of Canada warfarin handout for patients www.ccpn.ca Canadian Cardiovascular Pharmacists Network SPAF Tool

New Oral Anticoagulants Drug Interactions DABIGATRAN RIVAROXABAN APIXABAN* P-gp inhibitors (e.g., verapamil, quinidine, amiodarone) P-gp inducers (e.g., carbamazepine, St. John s Wort) Potent CYP3A4 and P-gp inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, and HIV protease inhibitors [ritonavir]) Potent CYP3A4 and P-gp inducers (e.g., rifampicin, and the anticonvulsants phenytoin, carbamazapine, phenobarbitone) Potent CYP3A4 and P-gp inhibitors (e.g., ketoconazole, HIV protease inhibitors) Potent CYP3A4 and P-gp inducers (e.g., rifampicin) Note: Concomitant administration of NSAIDs, aspirin or clopidogrel may increase bleeding time for rivaroxaban, dabigatran and apixaban. * Not approved in Canada for stroke prevention in patients with atrial fibrilliation Pradax (dabigatran etexilate) Product Monograph. Boehringer Ingelheim Canada Ltd. June 13, 2011; Xarelto (rivaroxaban) Product Monograph. Bayer Canada Inc. January 11, 2012; Eliquis (apixaban) Summary of Product Characteristics. Bristol-Myers Squibb/Pfizer EEIG, United Kingdom. May 18, 2011; Camm AJ, Bounameaux H. Drugs. 2011;71(12):1503-26. 79

The low dose of dabigatran (110 mg bid) is recommended for patients with: a) CrCL <30 b) CrCL 30-50 c) CrCL >50