ANTIPAF Angiotensin II Antagonist in Paroxysmal Atrial Fibrillation Trial

Transcription

1 European Society of Cardiology Hotline Stockholm - Zone K 31 st August 2010 Placebo ARB Kumagai K, et al. JACC 2003 Discussant ANTIPAF Angiotensin II Antagonist in Paroxysmal Atrial Fibrillation Trial John Camm St. George s University of London United Kingdom

2 European Society of Cardiology Hotline Stockholm - Zone K 31 st August 2010 Discussant ANTIPAF Angiotensin II Antagonist in Paroxysmal Atrial Fibrillation Trial John Camm Conflicts of Interest: Consultant/Advisor/Speaker Advisor / Speaker : Ambit, Servier, Novartis, sanofi aventis, Astra Zeneca, Cardiome, Prism, Astellas, Menarini, Xention, ARYx, Bristol Myers Squibb, Daiichi, Bayer, Merck, Medtronic, St. Jude, Biotronik, Boehringer Ingleheim, Takeda, GlaxoSmithKline, Boston Scientific, Pfizer, GlaxoSmithKline, Actelion, Johnson and Johnson, Solvay Pharma

3 Efficacy of ACE-Is/ARBs in 1 0 Prevention of AF All AF Madrid, 2004 Healey, 2005 Anand, 2006 Jibrini, 2008 Schneider, 2010 Primary prevention CHF Healey, 2005 Anand, 2006 Jibrini, 200 Schneider, 2010 Primary prevention HTN Healey, 2005 Anand, 2006 Jibrini, 2008 Schneider, 2010 Primary prevention MI Healey, 2005 Anand, 2006 Jibrini, 2008 Schneider, 2010 Point estimate (95%CI) 0.57 ( ) 0.72 ( ) 0.82 ( ) 0.81 ( ) 0.67 ( ) 0.56 ( ) 0.57 ( ) ( ) 0.52 ( ) 0.88 ( ) 0.94 ( ) ( ) 0.89 ( ) 0.74 ( ) 0.73 ( ) ( ) 0.72 ( ) Test for the overall effect, Z 2.98, p < , p < p < , p < , p= p < , p= , p=0.4 - p < , p= , p=0.3 p < , p= No ACEIs/ARBs better ACEIs/ARBs better Savelieva I, et al CHF = congestive heart failure; HTN = hypertension; MI = myocardial infarction.

4 The Natural Time Course of AF: Canadian Registry of Atrial Fibrillation N = 757 with baseline paroxysmal AF Follow-up 8 years Probability of progression to CAF by 1 year was 8.6% and thereafter steady progression to 24.7% by 5 years By 5 yrs, probability of documented recurrence of any AF (chronic or paroxysmal) was 63.2% 0 Kerr C, et al. Am Heart J 2005;149: Cumulative incidence of AF, % st documented AF recurrence Permanent AF Years

5 Free from atrial fibrilllation, % Prevention of AF with ACEIs/ARBs Prospective Studies No ACEI or ARB ARBs ACEIs 87 79, Freedom from persistent AF 49 * Madrid, 2002 n = 154, DCC Amio+Irbesartan 300 mg Follow-up 254 days Savelieva I, Europace, 2010 Ueng, 2003 n = 145, DCC Amio+Enalapril 20 mg Follow-up 270 days Madrid, 2004 (lone AF) n = 90, DCC Amio+Irbesartan 150 mg or Amio+Irbesartan 300 mg Follow-up 220 days CAPRAF, 2006 n = 171, DCC Candesartan 8-16 mg Follow-up 200 days Yin, 2006 (lone PAF) n = 177 Amio+Losartan 100 mg vs Amio+Perindopril 4 mg Follow-up 24 months Fogari, 2006 n = 250 PAF or DCC Amio+Losartan 100 mg Fogari, 2008 n = 329 PAF or DCC Amlodipine mg vs Ramipril 5-10 mg vs Valsartan mg Belluzzi, 2009 (lone AF) n = 62, DCC Ramipril 5 mg Follow-up 3 years GISSI AF, 2009 n = 1442 PAF or DCC (88%) Valsartan 320 mg J-RHYTHM II, 2010 n = 318 PAF Amlodipine mg vs Candesartan 8-12 mg

6 ANTIPAF Trial Endpoints AF Burden Days when AF was documented AF Burden All show no difference between Olmesartan and placebo Time to first Recurrence Time to first Recurrence Time to development of persistent AF Time to development of persistent AF

7 Free from atrial fibrilllation, % Prevention of AF with ACEIs/ARBs Prospective Studies No ACEI or ARB ARBs ACEIs 87 79, * * Madrid, 2002 n = 154, DCC Amio+Irbesartan 300 mg Follow-up 254 days Madrid, 2004 (lone AF) n = 90, DCC Amio+Irbesartan 150 mg or Amio+Irbesartan 300 mg Follow-up 220 days Yin, 2006 (lone PAF) n = 177 Amio+Losartan 100 mg vs Amio+Perindopril 4 mg Follow-up 24 months Fogari, 2008 n = 329 PAF or DCC Amlodipine mg vs Ramipril 5-10 mg vs Valsartan mg GISSI AF, 2009 n = 1442 PAF or DCC (88%) Valsartan 320 mg ANTIPAF, 2010 n = 225 PAF Olmesartan 40 mg Ueng, 2003 n = 145, DCC Amio+Enalapril 20 mg Follow-up 270 days CAPRAF, 2006 n = 171, DCC Candesartan 8-16 mg Follow-up 200 days Fogari, 2006 n = 250 PAF or DCC Amio+Losartan 100 mg Belluzzi, 2009 (lone AF) n = 62, DCC Ramipril 5 mg Follow-up 3 years J-RHYTHM II, 2010 n = 318 PAF Amlodipine mg vs Candesartan 8-12 mg * freedom from persistent AF

8 Criticisms of ANTIPAF ANTIPAF is a well designed and well executed double blind controlled clinical trial, but: Use of rescue antiarrhythmic medication Intermittent, non-continuous rhythm monitoring Definition of AF burden is arbitrary Intermediate length of follow-up Mixed aetiologies

9 Conclusions Good cellular and animal data that suggest that ARBs should be effective in preventing AF, but less evidence for reversal of atrial remodelling Clinical trial data, often derived retrospectively and not 1 0 outcome data, confirm potential value of ARBs for primary prevention of AF Most data suggest that persistent and permanent AF is not helped by treatment using ARBs Early data suggest that paroxysmal AF can be effectively suppressed, particularly when combined with antiarrhythmic drug therapy However, recent data and the results of ANTIPAF, fail to confirm any benefit from ARB treatment of PAF

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11 Atrial Remodelling from AF Itself and from Underlying Structural Heart Disease Triggers modulators Hypertension, CAD, VHD Structural remodelling (fibrosis) During SR Pulmonary vein foci AF During AF Autonomic nervous system Electrical remodelling After Crijns H

12 Candesartan and Atrial Fibrosis RA pacing at 400 bpm for five weeks RA free wall (masson trichrome stain) Sham Placebo Percentage of fibrosis Sham Placebo Candesartan 0 ARB RAA RAFW LAA LAFW Kumagai K, et al. JACC 2003;41:

13 Free from atrial fibrilllation, % 2 0 Prevention of AF with ACEIs/ARBs No ACEI or ARB Prospective Studies 100 ARBs ACEIs 79, Madrid, 2002 n = 154, DCC Amio+Irbesartan 300 mg Follow-up 254 days Madrid, 2004 (lone AF) n = 90, DCC Amio+Irbesartan 150 mg or Amio+Irbesartan 300 mg Follow-up 220 days Yin, 2006 (lone PAF) n = 177 Amio+Losartan 100 mg vs Amio+Perindopril 4 mg Follow-up 24 months Fogari, 2008 n = 329 PAF or DCC Amlodipine mg vs Ramipril 5-10 mg vs Valsartan mg Ueng, 2003 n = 145, DCC Amio+Enalapril 20 mg Follow-up 270 days CAPRAF, 2006 n = 171, DCC Candesartan 8-16 mg Follow-up 200 days Fogari, 2006 n = 250 PAF or DCC Amio+Losartan 100 mg Belluzzi, 2009 (lone AF) n = 62, DCC Ramipril 5 mg Follow-up 3 years

14 On-going Studies of RAAS Inhibitors in AF Study No. of patients Drug 2 o prevention UHD and monitoring Current status CTAF Perindopril Yes HTN Recruiting DRAFT 200 Valsartan Yes Post cardioversion Suspended PREFACE 390 Ramipril No Post AFL ablation Expected 2012 Taiwan study 220 Losartan No SSS+pacemaker Expected 2009 RACE Aldo-antagonist, statin Yes New onset AF and CHF Expected 2012 EPLERAF 220 Eplerenone Yes Post cardioversion Expected 2011 Taichung Study 30 Spironolactone Yes PAF Expected 2011