Assessing the Principles of Practice: Stroke Prevention in the New Era of Anticoagulation Moderator Bruce D. Lindsay, MD Section Head, Cardiac Electrophysiology and Pacing Department of Cardiovascular Medicine Cleveland Clinic, Cleveland, Ohio Panelists Stuart J. Connolly, MD Kenneth W. Mahaffey, MD Professor of Medicine Associate Professor of Medicine McMaster University Duke University Medical Center Hamilton General Hospital Co-Director, Cardiovascular Research McMaster Clinic Director, Clinical Events Classification Group Hamilton, Ontario Duke Clinical Research Institute Durham, North Carolina 2 Anhythmia &EP hart... MedscapeUse of Stroke or Bleeding Risk Strategies 1 5 ney Rating Never Often Often Average* CHADS, 7% 15% 41% 4.31 CHAD,S,-VASc 12% 17% 31% 4.08 HAS-BLED 25% 11% 15% Seley HEMORR,HAGES 58% 5% 4% 2.01 ATRIA 62% 2% 5% 1.85 *Scale: 1 Never > 6 Very often 2 Anhythmia &EP Survey data, theheart.org, 2012. BlatterHAS-BLED Letter Clinical Characteristic Points Awarded H Hypertension 1 Abnormal renal and liver i. function (1 point each) hore Ss Stroke 1 B Bleeding a L Labile INRs 1 E Elderly (eg, age > 65 years) 1 D Drugs or alcohol (1 point 1or2 each) Maximum 9 points arrhythmia &EP Camm AJ, et al.21 bartonPerformance of Bleeding Risk Scores HEMORR,HAGES _HAS-BLED ATRIA Relevant/Major Relevant/Major Relevant/Major 10.5% 9.1% 10.8% Low 1.4% 1.3% 1.5% ' 12.2% 12.7% Intermediate 2.5% 2.9% . 23.1% 16.6% 14.1% High eve 3.1% 3.9% arrhythmia &EP Apostolakis S, et al.!#] bartonWhich Is True? Select All That Apply Risk for recurrent embolic stroke in the first ; 9% 6 months is low Risk for death and dependency at 6 months : 30% is the same as non-AF related stroke Largest component of direct costs is 77% hospitalization Anticoagulation with warfarin or dabigatran is of no proven benefit in 6% preventing a second stroke 2 anthythmia &EP Survey data, theheart.org, 2012. Batten MedscapeRisk of Intracerebral Hemorrhage Which Is True? In the setting of ICH, dabigatran, rivaroxaban, and 3% abixaban are easily reversed 7 New anticoagulants are associated with decreased ICH compared with warfarin whether or not patients 65% have prior stroke/TIA New anticoagulants are associated with decreased ICH compared with warfarin only in patients without prior 17% stroke/TIA New anticoagulants are associated with decreased ICH compared with warfarin only in patients with prior 15% stroke/TIA Q mia &EP Survey data, theheart.org, 2012. HBlartesLevel of Confidence in Managing Anticoagulants 1 6 Not 5 Very Rating Confident Confident Confident Average* Warfarin 2% 26% 42% 4.81 Dabigatran 12% 17% 27% 3.65 Rivaroxaban 26% 16% 20% 3.21 Aspirin 9% 12% 42% 4.55 *Scale: 1 Not confident > 6 Very confident Q Anythmia &EP Survey data, theheart.org, 2012 HarteESC Guidelines: 2012 Focused Update: Recommendations for Prevention of Thromboembolism in Non-valvular AF Level of Recommendation Class Evidence Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those patients (both male and female) who are at ! A low risk {aged < 65 years and lone AF) or with contraindications. In patients with a CHA,DS,-VASc score 22, OAC therapy with: sadjusted-dose VKA (INR 2-3); or va direct thrombin inhibitor (dabigatran); or 1 A +an oral factor Xa inhibitor (eg, rivaroxaban, apixaban) is recommended, unless contraindicated. In patients with a CHA,DS,-VASc score of 1, OAC therapy with radjusted-dose VKA (INR 2-3); or ca direct thrombin inhibitor (dabigatran); or +an oral factor Xa inhibitor (eg, rivaroxaban, apixaban) na LS should be considered, based upon an assessment of the risk of bleeding complications and patient preferences. When patients refuse the use of any OAC antiplatelet therapy should be considered, using combination therapy with aspirin 75-100 mg plus clopidogrel lla B 75 mg daily (where there is a low risk of bleeding) or, less effectively, aspirin 75- 325 mg daily. Q anvhytimia EP een Harte, MedscapeATLAS: Aspirin Increases Bleeding Risk When Combined With Rivaroxaban Ciricallysignfcant beng (X) [Number at risk Placebo Bivaroxaban's mg Rivaroxaban 10 mg Rivaroxaban 25 mg Rivarexaban 20 mg 2 Anhythmia &EP — Rwvarexaban 20mg — Rivarexaban 15 m9 FM rates (ON) 353% (90/603) 327% (44/353) 30.9% (110/1046) 63% (18/307) 3.3% (7/2153) 2090 107s 205s 2082 2028 292 283 274 269 265 o” 920 ass, 363 850 28 320 299 292 288, 530 521 506 492 76Concern Regarding Efficacy and Safety of New Oral Anticoagulants AV 1 2 3 4 5 6 Rating 6.5% 12.9% 17.2% 18.8% 26/9% 17.7% 4.00 *Scale: 1 Not concerned > 6 Very concerned 2 Anhythmia &EP Survey data, theheart.org, 2012.Concerns Related to Dabigatran 1 6 Not 5 Very Rating Concerned Concerned Concerned Average* Int ial Cree 7% 20% 18% 4.11 hemorrhage Gl bleeding 4% 25% 24% 4.07 Efficacy MR and left atrial 12% 16% 11% 3.45 enlargement Renal dysfunction 6% 16% 24% 4.04 Recurrent stroke 11% 22% 18% 3.85 “Scale: 1 Not concerned > 6 Very concerned 2 Antiytiimia REP Survey data, theheart.org, 2012 HarteRE-LY ICH Subgroup Analysis: Sites/Rates of ICH Significantly lower rates of ICH and intracerebral hemorrhage with dabigatran 150 mg twice daily vs warfarin N/rate (%/y) Dabigatran 150 mg Warfarin AILICH 37/0.31 90/0.76 (n= 154) Intracerebral 11/0.09 46/0.39 (n=71) ‘Subdural 24/0.20 36/0.31 ae) Subarachnoid 2/0.02 8/0.06 {n= 13) 2 Anhythmia &EP Hart RG, et al.!®! Dabigatran 150 mg twice daily vs warfarin RR (95% Cl); P value 0.40 (0.27, 0.59); P< 001 0.23 (0.12, 0.45); P< .001 0.65 (0.39, 1.1); P=.10 0.24 (0.05, 1.2); P= .07 o 05 0 100 «15 (0 Dabigatran better Warfarin better harto. MedscapeACCP Guidelines: Patients With AF and Mitral Stenosis ¢ For patients with AF and mitral stenosis, we recommend adjusted-dose vitamin K antagonist therapy (target INR range, 2.0-3.0) rather than no therapy, aspirin (75 mg to 325 mg once daily), or combination therapy with aspirin and clopidogrel (all Grade 1B) ¢ For patients with AF and mitral stenosis who are unsuitable for or choose not to take adjusted-dose vitamin K antagonist therapy (for reasons other than concerns about major bleeding), we recommend combination therapy with aspirin and clopidogrel rather than aspirin (75 mg to 325 mg once daily) alone (Grade 1B). Ql ininytomia ae? porterConcerns Related to Rivaroxaban 1 6 Not 5 Very Rating Concerned Concerned Concerned Average* Intracranial 9% 20% 25% 4.08 hemorrhage Gl bleeding 9% 21% 14% 3.79 Efficacy MR and left atrial 12% 18% 9% 3.40 enlargement Liver dysfunction 9% 14% 8% 3.38 Recurrent stroke 11% 22% 15% 3.76 *Scale: 1 Not concerned > 6 Very concerned i ne 2 Antiytiimia REP Survey data, theheart.org, 2012 HartonConcerns Related to Warfarin 1 6 Not 5 Very Rating Concerned Concerned Concerned Average* Burden of INR nae 3% 31% 25% 4.36 monitoring piriculty 4% 29% 20% 4.22 maintaining INR Managing multiple <1% 31% 21% 413 medications *Scale: 1 Not concerned ~> 6 Very concerned 2 Anhythmia &EP Survey data, theheart.org, 2012. BlatterConcerns Related to Warfarin (cont) 1 Not 5 6 Very Rating Concerned Concerned Concerned Average* Side effects 3% 26% Quality of life 3% 22% Compliance 5% 20% *Scale: 1 Not concerned > 6 Very concerned 2 Anhythmia &EP Survey data, theheart.org, 2012 21% 4.13 16% 3.98 26% 4.10 bartonUnderutilization of Anticoagulants 1004 © Cardiologists ‘O Non Cardiologists 909 = QUrban oq MF Rural Percent of Pts Receiving Antithrombotic at D/C 6883 8 8 Propensity Score Quintile 2 Anthythmia &EP Flaker G, etal! Republished with permission HBartes MedsRate Your Agreement: Patients With Excellent INR Control Show Little Benefit From Change to New Oral Anticoagulants 1 6 Strongly Strongly Average Disagree 2 3 4 5 Agree _ Rating* 4.8% 11.1% 10.6% 15.9% 28.6% 29.1% 4.40 *Scale: 1 Strongly disagree > 6 Strongly agree 2 Anhythmia &EP Survey data, theheart.org, 2012 hart... MedscapeICH Reduction: A Case for Switching Warfarin Reduction in Experienced ICH ARISTOLE? 57% 0.42 P< .001 RE-LY® 50% 0.40 P< .001 ROCKET-AF° 62% 0.67 P=.02 2 Anhythmia &EP a. Granger C, et al#41b. Connolly Set alle. Patel MR, et al!!! ABSartRE-LY: Rate of Ischemic Stroke Dabigatran Dabigatran P Value P Value 150 mg 110 mg Warfarin D150vsW D110 vsW Ischemic or unspecified 0.92 1.34 1.21 0.03 (0:35) stroke 2 Anhythmia &EP Connolly s, et al)Level of Confidence in Managing Antiarrhythmic Medications 1 Not 5 ot Rating Confident Confident Confident Average* Amiodarone 7% 18% 29% 4.35 Dronedarone 36% 14% 9% 2.74 Sotalol 18% 18% 15% 3.29 Flecainide 30% 14% 12% 2.99 Propafenone 27% 17% 12% 3.10 Dofetilide 52% 3.3% 3.3% 2.05 *Scale: 1 Not confident > 6 Very confident 2 Anhythmia &EP Survey data, theheart.org, 2012 BlatterAbbreviations AF = atrial fibrillation aPTT = activated partial thromboplastin time ARISTOTLE = Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation ATLAS = Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With or Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome ATRIA = anticoagulation and risk factors in atrial fibrillation CHADS2 = congestive heart failure, hypertension, age, diabetes, stroke CHADS2-VASc= congestive heart failure, hypertension, age, diabetes, stroke, vascular disease Gl = gastrointestinal HAS-BLED = hypertension, abnormal renal or liver function, stroke, bleeding history or disposition, labile international normalized ratio, elderly, drug therapy or alcohol intake HEMORR2HAGES = hepatic or renal disease, ethanol abuse, malignancy, older age, reduced platelet count or function, re-bleeding, hypertension, anemia, genetic factors, excessive fall risk, and stroke 2 Anhythmia &EP Harte MedscapeAbbreviations ICH = intracranial hemorrhage INR = international normalized ratio MR = mitral regurgitation OAC = oral anticoagulant RE-LY = Randomized Evaluation of Long-term Anticoagulant Therapy ROCKET-AF = Rivaroxaban — Once-daily, oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation TIA = transient ischemic attack TTR = time in the therapeutic range Q Anhythmia &EP harto. 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