Atrial fibrillation and mortality: where is the missing link? Isabelle C Van Gelder University Medical Center Groningen

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1 Atrial fibrillation and mortality: where is the missing link? Isabelle C Van Gelder The Netherlands Madrid Europace June 2011

2 Conflict of interests Research grants from Medtronic, SJM, Biotronik, Boston, Sanofi-Aventis, Boehringer Ingelheim and Astra Zeneca Speakers bureau Medtronic, Sanofi-Aventis, Boehringer Ingelheim

3 Atrial fibrillation AF affects 1-2% of the population Silent AF not accounted for Most studies included Caucasian subjects Men are more often affected than women Lifetime risk for AF is 25% in those who have reached the age of 40

4 Clinical events affected by atrial fibrillation Death rate doubled Stroke increased and more severe, even with VKA %/ yr Heart failure Hospitalizations frequent, may contribute to reduced quality of life Quality of life and wide variation, no effect to exercise capacity major reduction, also distress Left ventricular function wide variation, from no change to acute heart failure Camm, ESC AF Guidelines, Europace 2010

5 Mortality Framingham Heart Study OR for death age years FU Men: 1.5 (95% CI ) Women: 1.9 (95% CI ) Men AF Women AF Men no AF Women no AF Framingham Benjamin Circulation 1998

6 AF is independent predictor of MACCE in patients with type II diabetes (ADVANCE) patients with type II DM randomized to perindopril and indapimide or placebo 7.6%, n=847, had AF at baseline Median follow up 4.3 years AF patients were older (66 vs 68 yrs), higher blood pressure Du ADVANCE group, EHJ 2009

7 AF is independent predictor of MACCE in patients with type II diabetes (ADVANCE) All deaths HR 1.61, 95% CI P< AF Cardiovascular deaths HR 1.77, 95% CI P< AF No AF No AF Du ADVANCE group, EHJ 2009

8 AF is independent predictor of MACCE in patients with type II diabetes (ADVANCE) Major coronary events AF Major cerebrovascular events AF No AF No AF Heart failure AF No AF Du ADVANCE group, EHJ 2009

9 Mortality (%) AFFIRM: prim endpoint all cause mortality Rhythm Rate p = unadjusted p = adjusted Time (Years) Rhythm N: Rate N: Wyse et al New Engl J Med 2002

10 Determinants of mortality AFFIRM What determined survival? Epstein et al Circulation 2004

11 Determinants of mortality in AFFIRM Age at enrollment 1.06 ( ) < Coronary Artery Disease 1.56 ( ) < Heart failure 1.57 ( ) < Diabetes 1.56 ( ) < Stroke 1.70 ( ) < Smoking 1.78 ( ) < LV dysfunction 1.36 ( ) Mitral regurgitation 1.36 ( ) Epstein et al Circulation 2004

12 Determinants of mortality in AFFIRM Digoxin use 1.42 ( ) Antiarrhythmic drugs 1.49 ( ) Sinus rhythm 0.53 ( ) < Warfarin use 0.50 ( ) < Epstein et al Circulation 2004

13 Determinants of mortality in AFFIRM Digoxin use 1.42 ( ) Antiarrhythmic drugs 1.49 ( ) Sinus rhythm 0.53 ( ) < Warfarin use 0.50 ( ) < Epstein et al Circulation 2004

14 Determinants of mortality in AFFIRM Severity of underlying heart disease, and use of (old) antiarrhythmic drugs and digoxin whereas oral anticoagulation and, possibly, restoration of sinus rhythm may improve prognosis Epstein et al Circulation 2004

15 Electrical benefits of current AADs may be offset by adverse effects Serious adverse events associated with AADs include: Pro-arrhythmias (e.g. torsades de pointes) Heart failure Organ toxicity Neurotoxicity Pulmonary toxicity Hepatic toxicity Optic neuropathy Thyroid abnormalities may increase mortality Camm AJ Int J Cardiol 2008

16 Percent Survival Ion channel blocking AAD in AF (SPAF trials) No CHF on AAD No CHF off AAD CHF off AAD CHF on AAD Pts on AAD Days of SPAF observation G.C. Flaker et al., J Am Coll Cardiol 1992

17 Dronedarone reduces CV hospitalizations or all cause mortality On top of standard CV therapy HR 0.76 (95% CI , p<0.001) Hohnloser et al New Engl J Med 2009

18 MACCE and hospitalization in 5333 AF patients Euro Heart AF Survey Euro Heart AF Survey, Nieuwlaat R et al, Eur Heart J 2008 Follow up 1 year

19 First detected AF and survival Euro Heart AF Survey Euro Heart AF Survey, Nieuwlaat R et al, Eur Heart J 2008 Follow up 1 year

20 All cause mortality- Euro Heart AF Survey Euro Heart AF Survey, Nieuwlaat R et al, Eur Heart J 2008 Follow up 1 year

21 All cause mortality- Euro Heart AF Survey Euro Heart AF Survey, Nieuwlaat R et al, Eur Heart J 2008 Follow up 1 year

22 Improvement of prognosis of AF Optimal therapy of the underlying disease No potentially dangerous AADs Use of oral anticoagulation if indicated Epstein et al Circulation 2004

23 Yearly CV event rate RACE I and RACE II 15 % RACE I RACE II 10 more ACE-I/ ARBs more VKA Pacemaker Adverse drug effects Major bleeding 5 Thrombo-embolism Heart failure CV mortality 0 Rate C Rhythm C Lenient Strict Van Gelder, N Engl J Med 2002; N Engl J Med 2010

24 Total Mortality Mortality AFFIRM data of AFFIRM Steinbeck Circulation 2004

25 Determinants of mortality in AFFIRM Note that 30-40% of mortality is not of cardiovascular Epstein et al Circulation 2004

26 Depression related to CV mortality in HF Adjusted HR 1.57 (95% CI ,p<0.001) Frasure-Smith for the AF-CHF Investigators Circulation 2009

27 Prognostic significance of AF in heart failure Is AF important in heart failure? Is AF a marker of increased mortality? or Is AF an (innocent) bystander in heart failure?

28 AF-CHF: primary endpoint CV mortality 27% in rhythm control 25% in rate control HR rhythm control 1.06 (95% CI , p=0.59, log rank test Roy et al. AF-CHF New Engl J Med 2008

29 SOLVD (Studies of Left Ventricular Dysfunction Prevention and Treatment Trials) LVEF <35%, 79% ischemic CHF 419 AF 6098 SR Follow-up: 33.4±14.3 months Dries et al. J Am Coll Cardiol 1998

30 SOLVD Dries et al. J Am Coll Cardiol 1998

31 PRIME II (Prospective Randomized study of Ibopamine on Mortality and Efficacy) NYHA III-IV, 77% ischemic CHF 84 AF 325 SR Follow-up: 3.4 years ( years) Crijns et al. Eur Heart J 2000

32 PRIME II P=ns (multivariate) SR AF Crijns et al. Eur Heart J 2000

33 CHARM Candesartan versus placebo 7599 patients with symptomatic CHF randomized to candesartan or placebo LVEF 40% LVEF > 40% 670 AF pts (17%) 478 pts (19%) median follow up 37 months Olsson for CHARM Invest JACC 2006

34 CHARM all cause mortality AF associated with increased risk of mortality irrespective of LVEF Olsson for CHARM Invest JACC 2006

35 AF: independent predictor of mortality in HF V-HeFT-II, NYHA II-III, 53% ICM, LVEF<45% AF Mahoney, NYHA II-IV, 52% ICM, LVEF<40% PRIME II, NYHA III-IV, 77% ICM, LVEF<35% V-HeFT-I, NYHA II-III, 44% ICM, LVEF<45% Ahmed, NYHA I-IV, 26% ICM, LVEF -- COMET, NYHA II-IV, 53% ICM, LVEF<35% AVID, NYHA I-III, 71% ICM, LVEF<40% Stevenson, NYHA III-IV, 49% ICM, LVEF<30% SOLVD-Prevention and Treatment, NYHA I-III, 79% ICM, LVEF<35% CHARM Alternative / Added, NYHA II-IV, 58% ICM, LVEF<40% MADIT-II, NYHA I-III, 100% ICM, LVEF<30% Middlekauff, NYHA III-IV, 45% ICM, LVEF<30% Better prognosis Worse prognosis Independent impact of AF on all cause mortality (Hazard ratio [95% confidence interval]) Rienstra Thesis 2007

36 AF: independent predictor of mortality in HF New onset AF CARE-HF, NYHA III-IV, 38% ICM, LVEF<35% TRACE, acute MI, LVEF<35% CHARM Alternative / Added, NYHA II-IV, 58% ICM, LVEF<40% Ahmed, NYHA I-IV, 26% ICM, LVEF -- Val-HeFT, NYHA II-IV, 59% ICM, LVEF<40% COMET, NYHA II-IV, 53%, LVEF<35% Framingham Heart Study, males Framingham Heart Study, females MADIT-II, NYHA I-III, 100% ICM, LVEF<30% Better prognosis Worse prognosis Independent impact of new-onset AF on all cause mortality (Hazard ratio [95%confidence inter Rienstra Thesis 2007

37 AF: independent predictor mortality in IHD + HF? Pts with IHD and AF vs others HR =1.25 (95% CI , p<0.0001) Post Hoc analysis Diamond CHF Pedersen Eur Heart J 2006

38 Survival in lone AF Jahangir Circulation 2007

39 Survival in lone AF Olmstad County patients with first episode of AF between No hypertension or heart disease 34 pts with PAF, 37 with pers AF and 5 with perm AF Mean age 44 years, 77% male Mean follow up 25 ±10 years Jahangir Circulation 2007

40 Survival in lone AF 92% Lone AF 86% 68% Age, sex matched 57% Jahangir Circulation 2007

41 Survival in lone AF Age at initial diagnosis of AF Jahangir Circulation 2007

42 Lone AF does not always remain lone AF Patients without events Patients with events Median follow up 26 years Osranek Eur Heart J 2005

43 AF and mortality where is the missing link? Mortality in AF patients is increased due to associated disease use of (old) antiarrhythmic drugs and associated with older age May differ depending on severity and type of associated disease Non cardiac causes also contribute to mortality, cancer but also depression Outcome in lone AF is favorable, but these patients may develop associated diseases deteriorating prognosis

44 AF and mortality where is the missing link? Rate versus rhythm control trials showed no beneficial effect of rhythm control but sinus rhythm maintenance rate was relatively low Possible more curative therapies like atrial ablation may increase sinus rhythm maintenance and prognosis, which is insinuated by the AFFIRM and ATHENA trials that showed that AF may be one of the modifiable factors associated with death and CV morbidity This will be investigated in the EAST (Early treatment of AF for Stroke prevention Trial) and CABANA trials

45 Thank you for your attention

46 Free of heart failure Lone AF Age, sex matched Age at initial diagnosis of AF Jahangir Circulation 2007

47 Total Mortality Cardiac mortality AFFIRM data of AFFIRM Steinbeck Circulation 2004

48 Yearly CV event rate RACE I and RACE II % RACE I RACE II Van Gelder, N Engl J Med 2002; N Engl J Med 2010

49 Yearly CV mortality RACE I and RACE II 4 % RACE I RACE II non cardiac vascular death non arrh cardiac death arrhythmic death 0 Rate C Rhythm C Lenient Strict Van Gelder, N Engl J Med 2002; N Engl J Med 2010

50 Therapeutic goals in AF Comprehensive management of AF should address its multiple impacts Prevention of thromboembolism Reduction of AF burden Reduction in morbidity Reduction in mortality Long-term: CV outcome-driven Short-term: Symptom-driven

51 Depression related to CV mortality in HF Frasure-Smith for the AF CHF Investigators Circulation 2009

52 AF is independent predictor of MACCE in patients with type II diabetes (ADVANCE) Du ADVANCE group, EHJ 2009

53 AF and long term prognosis in HF hospitalized pts Shotan Eur Heart J 2009

54 AF and long term prognosis in HF hospitalized pts Shotan Eur Heart J 2009

55 Independent predictors of in-hospital mortality Rivero-Ayerza Eur Heart J 2008 UMCG Dept. of Cardiology Thoraxcenter

56 Risk factors for mortality Framingham Heart Study Framingham Heart Study wang JAMA 2003

57 Risk factors for mortality Framingham Heart Study Framingham Heart Study wang JAMA 2003

58 Precursor diseases in AF The Framingham Heart Study Odds Ratio (95% confidence interval [CI]) Men (n=2,090) Women (n=2,641) Heart failure Valvular heart disease Hypertension Diabetes Myocardial infarction ; not significant Because of its high prevalence, hypertension is responsible for more AF in the population (14%) than any other risk factor Benjamin EJ JAMA 1994; Kannel WB Am J Cardiol 1998

59 AF-related events Yearly cardiovascular event rate in RACE I and II studies % endpoint 5 Pacemaker Adverse drug effects Major bleeding Thrombo-embolism Heart failure CV mortality 0 rate control RACE I rhythm control lenient rate control RACE II strict rate control Van Gelder, N Engl J Med 2002; Van Gelder, N Engl J Med 2010 UMCG Dept. of Cardiology Thoraxcenter

60 LA volume in lone AF median follow up 26 years median follow up 29 years Osranek Eur Heart J 2005

61 Atrial arrhythmias and outcome CRT Death or HF hospitaliation Santini JACC 2011

62 Atrial arrhythmias and outcome CRT HF hospitaliation Santini JACC 2011

63 Myocardial infarction, hospitalisation and death D 110mg Annual % D 150mg Annual % Warfarin D110 vs Warfarin D 150 vs Warfarin Annual % RR 95%CI P RR 95%CI P Myocardial Infarction Hospitalisation Death Connolly New Engl J Med 2009

64 Hypertensives and LVH: new AF New AF losartan atenolol 150 pts 220 pts Wachtell Life Study J Am Coll Cardiol 2005 UMCG Dept. of Cardiology Thoraxcenter

65 Hypertensives and LVH: new AF despite comparable blood pressure lowering atenolol losartan Wachtell Life Study J Am Coll Cardiol 2005 UMCG Dept. of Cardiology Thoraxcenter

66 CV mortality, stroke and myocardial infarction Wachtell LIFE study J Am Coll Cardiol 2005

67 ARB reduces new-onset AF and stroke in hypertensives Wachtell LIFE study J Am Coll Cardiol 2005

68 All cause mortality for patients in SR vs AF after CRT Upadhyay J Am Coll Cardiol 2009 UMCG Dept. of Cardiology Thoraxcenter

69 Sinus rhythm but not AADs associated with reduced risk of death Rhythm-control drug AFFIRM on-treatment analysis (n=2,796; on average 3.3 years follow-up): time-dependent variables after adjustment for other factors HR(99%CI) for mortality Sinus rhythm Less mortality Moremortality Corley SD Circulation 2004

70 Conclusions stroke prevention Stroke is an important problem in AF treatment CHADSVASC score identifies patients with moderate risk who preferably are treated with oral anticoagulation VKA has important disadvantages Newer anticoagulant drugs may reduce stroke and bleeding rate

71 Cummulative Incidence (%) Cummulative Incidence (%) Total and Cardiovascular Mortality All Cause Mortality (ACM) Not statistically significant Cardiovascular Mortality Analysis plan: not assessed if ACM not +ve HR=0.84 [ ] p=0.18 Placebo HR=0.71 [ ] p=0.03 Placebo 4 Dronedarone 2.5 Dronedarone 2 Patients at risk Placebo Dronedarone Months Months Mean follow-up 21±5 months Hohnloser SH et al. ATHENA Investigators. N Engl J Med Feb 12;360(7):

72 Mortality UMCG Dept. of Cardiology Thoraxcenter

73 Effect of CRT on SR conversion *p<0.01 *p<0.01 Kiès et al., Heart 2005 UMCG Dept. of Cardiology Thoraxcenter

74 Risk of baseline AF for CV events depending on LVEF ( ) ( ) CHARM Olsson for CHARM Invest JACC 2006 UMCG Dept. of Cardiology Thoraxcenter

75 Risk of baseline AF for CV events depending on LVEF CHARM Multivariate regression analysis: Risk for CV death or hospitalization: - Baseline AF and preserved LVEF HR1.32, , p= Baseline AF and low EF: no independent risk factor HR 1.12, , p=0.12 Risk for all cause mortality: - Baseline AF and preserved LVEF HR 1.37, Baseline AF and low LVEF HR 1.22, Olsson for CHARM Invest JACC 2006 UMCG Dept. of Cardiology Thoraxcenter

76 New onset AF in CHARM Preserved LVEF (>40%) 4.9% Low LVEF ( 40%) 7.8% Median follow up 37 months Any AF [(a)symptomatic, par/pers/perm] CHARM Olsson for CHARM Invest JACC 2006 UMCG Dept. of Cardiology Thoraxcenter

77 Risk for new onset AF on CV events depending on EF CHARM Olsson for CHARM Invest JACC 2006 UMCG Dept. of Cardiology Thoraxcenter

78 Treatment effects depending on baseline rhythm HR 0.83 ( ) HR 0.84 ( ) CHARM Olsson for CHARM Invest JACC 2006 UMCG Dept. of Cardiology Thoraxcenter

79 Roy et al. AF-CHF New Engl J Med 2008 UMCG Dept. of Cardiology Thoraxcenter

80 AF-CHF hospitalizations rhythm control rate control p hospitalizations 64% 59% 0.06 during 1 st yr 46% 39% hospital. for AF 14% 9% Roy et al. AF-CHF New Engl J Med 2008 UMCG Dept. of Cardiology Thoraxcenter

81 DIAMOND Pedersen Circulation 2001 UMCG Dept. of Cardiology Thoraxcenter

82 AVID (Registry of the Antiarrhythmics Versus Implantable Defibrillators Trial) VF or sustained VT, NYHA I-III, 76% ischemic CHF 917 AF 2845 SR Follow-up: 773±420 days Wyse et al. J Interv Card Electrophysiol UMCG Dept. of Cardiology Thoraxcenter

83 AVID Wyse et al. J Interv Card Electrophysiol UMCG Dept. of Cardiology Thoraxcenter

84 Time to CV death or hospitalization for HF AF associated with increased risk of CV morbidity irrespective of LVEF CHARM Olsson for CHARM Invest JACC 2006 UMCG Dept. of Cardiology Thoraxcenter

85 Outcomes affected by AF 2 times increased mortality Stroke even with O.A.C %/ year Heart failure Bleeding due to OAC Impaired quality of life Economic burden Camm, ESC AF Guidelines, Europace 2010

86 % mortality RACE I and RACE II 4 RACE I RACE II non cardiac death non cardiac vascular death non arrh cardiac death arrhythmic death 0 Rate C Rhythm C Lenient Strict

87 Cardiac mortality data of AFFIRM Steinbeck Circulation 2004

88 AF-CHF primary endpoint CV mortality 27% in rhythm control 25% in rate control HR rhythm control 1.06 (95% CI , p=0.59 Roy et al. AF-CHF New Engl J Med 2008 UMCG Dept. of Cardiology Thoraxcenter

89 Incidence of AF in CHF CRT-UMCG n=100 Incidence of AF / year MADIT-II COMET MERIT-HF Val-HeFT CHARM- Alternative/Added CARE-HF PRIME II prehtx-umcg n=70 0 CHARM-Preserved mean NYHA functional class UMCG Dept. of Cardiology Thoraxcenter

90 Prevalence of AF in CHF SENIORS Prevalence of AF MADIT-II ELITE II Mahoney DIAMOND-CHF ELITE CRT-UMCG PEP-CHF COMET PRIME II CHARM-Preserved MERIT-HF CIBIS II SCD-HeFT prehtx-umcg CAT CHARM- VAL-HeFT Alternative/Added US Carvedilol BEST mean NYHA functional class UMCG Dept. of Cardiology Thoraxcenter

91 AF in CHF 344 CHF patients in sinus rhythm (48% NYHA III/IV, LVEF 0.23±0.07) follow up 19±12 months 28 pts developed AF (8%) NYHA class, peak VO2, MI and TI worsening Pozzoli et al. J Am Coll Cardiol 1998 UMCG Dept. of Cardiology Thoraxcenter

92 CRT in AF versus SR patients versus CRT Gasparini J Am Coll Cardiol 2008 UMCG Dept. of Cardiology Thoraxcenter

93 CRT in AF versus SR patients AV node ablation only in case of inadequate rate control (< 85% biventricular pacing) Median University follow Medical Center up 34 Groningen months Gasparini J Am Coll Cardiol 2008 UMCG Dept. of Cardiology Thoraxcenter

94 CRT in AF versus SR patients N=118 N=125 Median University follow Medical Center up 34 Groningen months AV node ablation improved survival in CRT patients? Gasparini J Am Coll Cardiol 2008 UMCG Dept. of Cardiology Thoraxcenter

95 CHF-STAT (Veterans Affairs Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy) At least NYHA II and LVEF <40%, 60% ischemic CHF 564 SR 103 AF: Amiodarone 51 Placebo 52 Deedwania Circulation 1998 UMCG Dept. of Cardiology Thoraxcenter

96 CHF-STAT Conversion on amiodarone (n=51) Deedwania Circulation 1998 UMCG Dept. of Cardiology Thoraxcenter

97 DIAMOND (Danisch Investigations of Arrhythmia and Mortality ON Dofetilide) DIAMOND: NYHA III/ IV, LVEF <35%, DIAMOND-MI: LVEF<35% after recent MI 506 AF-AFL Dofetilide 249 Placebo 257 Pedersen Circulation 2001 UMCG Dept. of Cardiology Thoraxcenter

98 DIAMOND RR = 0.43 ( , p<0.001) Restoration of sinus rhythm is associated with lower mortality rate both in the placebo and dofetilide group RR = 0.38 ( , p<0.004) Pedersen Circulation 2001 UMCG Dept. of Cardiology Thoraxcenter

99 Yearly CV morbidity and mortality Yearly cardiovascular event rate in RACE I and II studies % endpoint 5 Pacemaker Adverse drug effects Major bleeding Thrombo-embolism Heart failure CV mortality 0 rate control RACE I rhythm control lenient rate control RACE II strict rate control Van Gelder, N Engl J Med 2002; N Engl J Med 2010

100 Determinants of mortality in ACTIVE-W De Caterina Eur Heart J 2010

101 Dronedarone does not increase all cause mortality HR 0.84 (95% CI , p=0.18) Hohnloser et al New Engl J Med 2009

102 Dronedarone reduces cardiovascular death 29% 0.71 (95% CI, 0.51 to 0.98; P = 0.03) Hohnloser et al New Engl J Med 2009

103 Dronedarone reduces 1 st hospitalization due to CV events: 26% 0.74 (95% CI, 0.67 to 0.82; P <0.001)

104 The AF epidemic 18 Number of persons with AF (millions) ,1 5,9 5,1 5,6 6,7 6,1 7,7 6,8 8,9 7,5 10,2 8,4 11,7 9,4 13,1 10,3 14,3 11,1 15,2 15,9 11,7 12,1 16 million AF patients in USA 25 million AF patients in Europe Year Miyasaka, Olmsted County Study, Circulation 2006