Managing Patients Who Cannot Take Anticoagulants Kenneth W. Mahaffey, MD, FACC Professor of Medicine, Cardiology Faculty Associate Director, DCRI Director, DCRI MegaTrials & CEC Duke Clinical Research Institute Durham, NC

Disclosures Consultant Fees/Honoraria Adolor; Amgen; AstraZeneca; Bayer HealthCare; Biotronik, Inc.; Boehringer Ingelheim; Bristol-Myers Squibb; Daiichi Sankyo, Inc.; Eli Lilly; Elsevier; Exeter Group; Forest; Genentech; Gilead; GlaxoSmithKline; Haemonetics; Johnson and Johnson; Medtronic; Merck and Co., Inc.; Novartis; Orexigen Therapeutics; Ortho-McNeil; Pfizer Inc; sanofi-aventis U.S. Inc.; Sun Pharma; Springer Publishing; WebMD Research/Research Grants Abbott Vascular; Amgen; Amylin; AstraZeneca; Baxter; Bayer HealthCare; Boehringer Ingelheim; Bristol-Myers Squibb; Cordis; Daiichi Sankyo, Inc.; Edwards Lifesciences; Eli Lilly; GlaxoSmithKline; Guidant; Ikaria; INC Research; Johnson and Johnson; Kai Pharmaceuticals; Luitpold; Merck and Co., Inc.; Portola Pharmaceuticals; Pozen; Regado Biosciences; Roche; sanofi-aventis U.S. Inc.; Schering Plough; The Medicines Company

Fibrin Platelet aggregate Hemostasis and Thrombosis Atherosclerotic Plaque Red Blood Cells Pathobiology is complex Understanding relationships is important Antiplatelet therapy Anticoagulant therapy

Antithrombotic Therapy for AF Overview: Antiplatelet Agents Compared with Placebo or Control Hart RG, et al. Ann Intern Med. 2007;146: Study, Year Favors AntiplateletFavors Placebo or Control RRR (95% CI) AFASAK I, 1989; 1990 SPAF I, 1991 EAFT, 1993 ESPS II, 1997 LASAF, 1997 Daily Alternate day UK-TIA, mg daily 1,200 mg daily JAST, 2006 Aspirin trials (n = 7) SAFT, 2003 ESPS II, 1997 Dipyridamole Combination All antiplatelet trials (n = 10) 100%50%0%-50%-100%

Contraindications to Oral Anticoagulation 1,409 / 10,124 (14%) with a contraindication

ACTIVE A: Primary Outcome (Stroke, MI, Non-CNS Systemic Embolism, Vascular Death) Connolly SJ, et al. N Engl J Med. 2009;361: HR = 0.89 ( ) p = Placebo + Aspirin Clopidogrel + Aspirin Years Cumulative Hazard Rates No. at Risk C + A ASA

Apixaban 5 mg twice daily ASA ( mg/d) AF and ≥ 1 risk factor and demonstrated or expected unsuitable for VKA Primary Outcome: Stroke or Systemic Embolic Event 5,599 patients 2.5 mg twice daily in select patients R 36 countries, 522 centres Double-Blind AVERROES Trial Design Connolly SJ, et al. N Engl J Med. 2011;364:

AVERROES: Primary Endpoint Stroke or Systemic Embolic Event Cumulative Risk ASA Apixaban Months HR = % CI = P < Connolly SJ, et al. N Engl J Med. 2011;364:

ESC Guidelines AF, EHJ 2012 RecommendationsClass a Level b Ref c Recommendations for prevention of thromboembolism in non-valvular AF─general Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those patients (both male and female) who are at low risk (aged < 65 years and lone AF), or with contraindications. IA 21, 63, 104, 105, 106 The choice of antithrombotic therapy should be based upon the absolute risks of stroke/thromboembolism and bleeding and the net clinical benefit for a given patient. IA21, 63, 105 The CHA 2 DS 2 -VASc score is recommended as a means of assessing stroke risk in non-valvular AF.IA25, 36, 39 In patients with a CHA 2 DS 2 -VASc score of 0 (i.e., aged < 65 years with lone AF) who are at low risk, with none of the risk factors, no antithrombotic therapy is recommended. IB21, 36, 82 In patients with a CHA 2 DS 2 -VASc score of ≥ 2, OAC therapy with: Adjusted-dose VKA (INR 2-3); or A direct thrombin inhibitor (dabigatran); or An oral factor Xa inhibitor (e.g., rivaroxaban, apixaban) d …is recommended, unless contraindicated. IA3, 4, 70, 82 In patients with a CHA 2 DS 2 -VASc score of I, OAC therapy with: Adjusted-dose VKA (INR 2-3); or A direct thrombin inhibitor (dabigatran); or An oral factor Xa inhibitor (e.g., rivaroxaban, apixaban) d …should be considered, based upon an assessment of the risk of bleeding complications and patient preferences. IIaA33, 44 Female patients who are aged < 65 and have lone AF (but still have a CHA 2 DS 2 -VASc score of I by virtue of their gender), are low risk and no antithrombotic therapy should be considered. IIaB33, 44 When patients refuse the use of any OAC (whether VKAs or NOACs), antiplatelet therapy should be considered, using combination therapy with aspirin mg plus clopidogrel 75 mg daily (where there is a low risk of bleeding or─less effectively─aspirin mg daily. IIaB 21, 26, 51, 109 Recommendations for prevention of thromboembolism in non-valvular AF

Summary Few patients have true contraindications to anticoagulant therapy ASA vs. placebo ─Modest reduction in thromboembolic events ─ Modest increase in bleeding ASA + clopidogrel vs. ASA ─Reduces thromboembolic events ─Increases bleeding Apixaban is a potentially attractive alternative in patients with VKA contraindications