ESC Congress 2012, Munich Anticoagulation in Atrial Fibrillation 2012: Which Anticoagulant for Which Patient? Stefan H. Hohnloser J.W. Goethe University Frankfurt am Main S.H.H. has served as a consultant, member of the steering committee, or speaker for: Bayer Healthcare, BMS, Boehringer Ingelheim, Boston Scientific, Cardiome, Forest RI, J&J, Medtronic, Pfizer, Portola, Sanofi aventis, St. Jude Medical
New versus Old Anticoagulants Vitamin K antagonists (phenprocoumon, warfarin, others) lowering of functional levels of vitamin K- dependent clotting factors Factor II or Xa inhibitors targeted inhibition of coagulation
Pharmacological Characteristics of Warfarin & the New Oral Anticoagulants for AF Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Administration Once a day Twice a day Once a day Twice a day Once a day Target Vitamin K- dependent factors Factor II Factor Xa Factor Xa Factor Xa Time to peak effect 3-5 d 1 h 2.5-4 h 3 h 1-2 h Dose Variable 150 mg BID 110 mg BID 20 mg OD (15 mg OD for renal impairment) 5 mg BID (2.5 mg BID for high risk) 30 mg OD and 60 mg OD (with adjustment for high exposure) Half-life 40 h 12-14 h 7-11 h 12 h 9-11 h Renal clearance, % 0 80 35 25 40 Anticoagulation monitoring egfr exclusion criteria (ml/min) Required Not required Not required Not required Not required u.a. < 30 < 30 < 25 < 30
Contemporary trials with NOAC in AF Study Anticoagulant Inclusion criteria Comparator Primary endpoint RELY ROCKET AF ARISTOTLE AVERROES Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg OD (15 mg OD in pts with CrCL 30-49 ml/min) Apixaban 5 (2.5) mg BID Apixaban 5 (2.5) mg BID AF & 1 vascular risk factor N = 18,113 pts AF & 2 vascular risk factors N = 14,264 pts AF & 1 vascular risk factor N = 18,201 pts AF, unsuitable for warfarin N = 5,599 pts Warfarin Warfarin Warfarin Aspirin Stroke SEE Stroke SEE Stroke SEE Stroke SEE Primary safety endpoint Exclusion criterion based on renal function Major bleed CrCl < 30 ml/min Major bleed CrCl < 30 ml/min Major bleed CrCl < 25 ml/min Major bleed CrCl < 25 ml/min
NOAC: Ischemic stroke NOAC Warfarin No. of events (%/yr) HR 95% CI Dabi 110 (ITT) Dabi 150 (ITT) Riva* (safety AT) Apixaban** (ITT) 159 (1.34) 143 (1.21) 111 (0.92) 143 (1.21) 149 (1.34) 161 (1.42) 162 (0.97) 175 (1.05) 0.0 0.5 1.0 Favors NOAC 1.5 1.11 0.76 0.94 0.92 Favors warfarin 0.88-1.39 0.59-0.97 0.75-1.17 0.74-1.13 *Only ischemic strokes are counted here. The no. of strokes with unknown type were 7 and 11 in the rivaroxaban and warfarin groups, respectively. ** Unknown type of stroke occurred in 14 patients in the apixaban group and 21 patients in the warfarin group. Among the patients with ischemic strokes, hemorrhagic transformation occurred in 12 patients with apixaban and 20 patients with warfarin. ITT: Intention to Treat AT: as treated. 2.0
1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92. NOAC: Hemorrhagic stroke NOAC Warfarin No. of events (%/yr) HR 95% CI Dabi 110 (ITT) Dabi 150 (ITT) Riva (safety AT) Apixaban (ITT) 14 (0.12) 45 (0.38) 12 (0.10) 45 (0.38) 29 (0.26) 50 (0.44) 40 (0.24) 78 (0.47) 0.31 0.26 0.59 0.51 0.17-0.56 0.14-0.49 0.37-0.93 0.35-0.75 0.0 0.5 1.0 1.5 2.0 Favors NOAC Favors warfarin
1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92. NOAC: Major bleeds NOAC Warfarin No. of events (%/yr) HR 95% CI Dabi 110 342 (2.87) 421 (3.57) 0.80 0.70-0.93 Dabi 150 399 (3.32) 421 (3.57) 0.93 0.81-1.07 Riva 395 (3.6) 386 (3.4) 1.04 0.90-1.20 Apixaban 327 (2.13) 462 (3.09) 0.69 0.60-0.80 0.0 0.5 1.0 1.5 2.0 Favors NOAC Favors warfarin
1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92. NOAC: Intracerebral bleeds NOAC Warfarin No. of events (%/yr) HR 95% CI Dabi 110 27 (0.23) 90 (0.76) 0.30 0.19-0.45 Dabi 150 38 (0.32) 90 (0.76) 0.41 0.28-0.60 Riva 55 (0.5) 84 (0.7) 0.67 0.47-0.93 Apixaban 52 (0.33) 122 (0.80) 0.42 0.30-0.58 0.0 0.5 1.0 1.5 2.0 Favors NOAC Favors warfarin
Anticoagulation - General Recommendations for prevention of thromboembolism in nonvalvular AF - general Recommendations Class Level 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. 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. The CHA 2 DS 2 -VASc score is recommended as a means of assessing stroke risk in non-valvular AF. I A Valvular AF = rheumatic valve disease or prosthetic valves I I A A www.escardio.org/guidelines European Heart Journal 2012 - doi:10.1093/eurheartj/ehs253
Anticoagulation - NOACs Recommendations for prevention of thromboembolism in nonvalvular AF - NOACs Recommendations Class Level When adjusted-dose VKA (INR 2 3) cannot be used in a patient with AF where an OAC is recommended, due to difficulties in keeping within therapeutic anticoagulation, experiencing side effects of VKAs, or inability to attend or undertake INR monitoring, one of the NOACs, either: a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d is recommended. Where OAC is recommended, one of the NOACs, either: a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d should be considered rather than adjusted-dose VKA (INR 2 3) for most patients with non-valvular AF, based on their net clinical benefit. I IIa B A www.escardio.org/guidelines European Heart Journal 2012 - doi:10.1093/eurheartj/ehs253
Recommendations Class Level 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. In patients with a CHA 2 DS 2 -VASc score 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. is recommended, unless contraindicated. In patients with a CHA 2 DS 2 -VASc score of 1, 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. I I IIa B A A www.escardio.org/guidelines European Heart Journal 2012 - doi:10.1093/eurheartj/ehs253
Anticoagulation General Antiplatelet Agents Recommendations for prevention of thromboembolism in nonvalvular AF - general Recommendations Class Level When patients refuse the use of any OAC (whether VKAs or NOACs), antiplatelet therapy should be considered, using combination therapy with aspirin 75 100 mg plus clopidogrel 75 mg daily (where there is a low risk of bleeding) or less effectively aspirin 75 325 mg daily. IIa B www.escardio.org/guidelines European Heart Journal 2012 - doi:10.1093/eurheartj/ehs253
Choice of Anti-coagulant * Includes rheumatic valvular AF, hypertrophic cardiomyopathy, etc. Yes Atrial fibrillation Valvular AF* No Yes Assess risk of stroke (CHA 2 DS 2 -VASc score) No (i.e. non-valvular AF) < 65 years and lone AF (including females) ** Antiplatelet therapy with aspirin plus clopidogrel, or less effectively aspirin only, may be considered in patients who refuse any OAC 0 1** 2 Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences No antithrombotic therapy NOAC VKA www.escardio.org/guidelines European Heart Journal 2012 - doi:10.1093/eurheartj/ehs253
LAA Closure/Occlusion/Excision Recommendations for LAA closure/occlusion/excision Recommendations Class Level Interventional, percutaneous LAA closure may be considered in patients with a high stroke risk and contraindications for long-term oral anticoagulation. IIb B Surgical excision of the LAA may be considered in patients undergoing open heart surgery. IIb C www.escardio.org/guidelines European Heart Journal 2012 - doi:10.1093/eurheartj/ehs253
New versus Old Anticoagulants Warfarin (Class I; Level of Evidence A), dabigatran (Class I; Level of Evidence B), apixaban (Class I; Level of Evidence B), and rivaroxaban (Class IIa; Level of Evidence B) are all indicated for the prevention of first and recurrent stroke in patients with nonvalvular AF. The selection of an antithrombotic agent should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including time in INR therapeutic range if the patient has been taking warfarin. Stroke. published online August 2, 2012
VKA versus NOAC? VKA: Remaining indications in AF Patient preference (INR self-monitoring?) Creatinine clearance < 15-30 ml/min Valvular heart disease (= rheumatic valve disease or prosthetic heart valves)
NOAC: Data gaps Cardioversion: data available for dabigatran 1 little data available for apixaban data missing for rivaroxaban (but propsective study ongoing) 1 Nagarakanti R et al, Circulation 2011:123:131 AF ablation: uncontrolled data available for dabigatran 2,3 data missing for apixaban data missing for rivaroxaban (but propsective study ongoing) 2 Winkle RA, et al. JCE 2012;23.264-8 3 Lakkireddi D, et al. JACC 2012;59:1168-74
Summary In AF patients with a CHA 2 DS 2 VASc 1, OAC should be applied. Targeted inhibition of coagulation by means of factor II or Xa antagonists should be the preferred mode of stroke prevention in most AF patients based on individual risk-benefit assessment. Dabigatran 150 mg bid has the most prominent effect on prevention of ischemic stroke (indirect comparison). Apixaban and dabigatran 110 mg bid have the greatest reduction in major bleeding relative to VKA (indirect comparison). More data, both from post-marketing registries and from prospective studies, are needed to further direct individual treatment choices.