Pharmacological Prevention of Atrial Fibrillation

Pharmacological Prevention of Atrial Fibrillation
Mattias F. Duytschaever, MD, PhD Electrophysiology Unit AZ St.Jan-Brugge University Hospital Ghent Hemmaridge Dimentja Fasit Haai_arki

Bruxelles 2008 Hemmaridge Dimentja Fasit Haai_arki

Pharmacological Prevention of AF
Outline of the Presentation Atrial Fibrillation: The Clinical Problem Changing Epidemiology of AF Impact on Morbidity and Mortality Pharmacological Prevention of AF Conventional Anti-arrhythmic Drugs New “Anti-arrhytmic drugs” for AF From Lone AF to Heart Failure New Dta

Atrial Fibrillation: The Clinical Problem
Clinically AF is a Multi-faceted Disease Parameters Par AF (N=1571) Pers AF (N=1167) Perm AF (N=1541) Age 64 ±13 66 ±12 71 ±11 Heart Failure 23% 35% 49% Valvular Heart Disease 19% 24% 40% Cardiomyopathy 7% 13% 16% This survey provides a unique snapshot of current AF management in 182 hospitals in the Euorepan Society of cardilology Discordance between guidelines and practice was found regarding several issues in stroke prevention and AADS Diabetes 15% 16% 22% Symptoms 77% 73% 55% LAD (mm) 43 ±7 46±8 51±17 Nieuwlaat et al, Eur Heart J 2005;26:2422 (Euro Heart Survey)

At 55y Life time risk for AF = 23.8%
Epidemiology of Atrial Fibrillation Prevalence (1 to 1.5%) and Incidence of AF Prevalence (%) Incidence/1000 person-years 17.8% Framingham Study Mayo Clinic Study CHS Rotterdam Study 60 Framingham Study (men) 15 CHS (men) Mayo Clinic (men) 40 10 20 5 Prevalence in the General Population 1 to 1,5% (Based on these data Estimated Prevalence Pool of 3 milj Europe, 2,3 in the US) Miyaska: cijfers bij dames ligt iets lager (niet geplot) Cijfers bij blanken ook hoger Rotterdam Study >55y: °Prevalence 5.5% °Life Time Risk to Develop AF was 23.8% >85 y: Prevalence 17.8% 40 50 60 70 80 40 50 60 70 80 90 Age (yrs) Age (yrs) At 55y Life time risk for AF = 23.8% Miyasaka et al, Circ 2006;114: Heeringa et al, EHJ 2006;27:

Epidemiology of AF is Changing
Estimated Prevalence Pool at 2050 Projected N of Pts with AF (millions) Age-adjusted Incidence/1000 person-year 4 7 2050: 5.6 million 6 3 3.68 5 4 3.04 2 2050:12 to 16 million 3 50% of AF>80y 2.3 2 Prevalence, Incidence and Life Time risk Data Go et al The ATRIA Study (1) 1990: Based upon Prevalence in adults (2) This estimated prevalence pool is calculated pure on the growing population size and the growing portion of elderly individuals Based upon Expected increase in Elderly Patients (twe 2 obvious reasons, however this study took not into account a third reason that could come up) (3) In 2050, 50% of affected individual is expected to be > than 80years Why would prevalence increase Well they analysed increase in prevalnece breween 1980 and 2000 (secular trends in Olmsted County) Incidence from 3% to almoalst 4% The Expected N will be 12 million (with same incidenec) or 15 million (if age-adjusted increase in incidence furter increases) Projected N of AF patients will increase by 3 fold anywhay: (1/3) growing population size (22%) (1/3) aging of the population (43%) (1/3) increase in age- and sex adjusted incidence/prevalence (35%) Why increase in age-and sex-adjusted incidence? Multifactorial: hypertension, diabetes, heart failure, myocardial infarction, valvular heart disease, obesity Relative Increase in Age-adjusted Incidence is 12.6% (from 3.0 to 3.6) Relative increase in obesity is 15% (from 10 tot 25% from 1980 to 2000) Framngham showed: relative hzard of incident AF was 1.5 for BMI >30 kg/m2 (cfr ook post CABG AF) 15% increase therefore would count for an estimated 7.5% incease in AF incidence Therefore the estimated trend in obesitycould accounbt for 60% of the estimlated incresae in age-adjusetd AF incidence 1 1 1990 2010 2030 2050 1980 1985 1990 1995 2000 Year Year Go et al, JAMA 2001;285:2370 Miyasaka et al, Circulation 2006;114:119

Incidence of AF 3-4% per year
Epidemiology of AF is Changing Temporal Relations of AF and CHF and their Joint Influence on Mortality (The Framingham Heart Study) Cumulative Incidence of AF in Pts with CHF Atrial Fibrillation and Heart Failure 0.4 Another Vicious Circle Incidence of AF 3-4% per year Heart 0.3 Failure • Neurohormonal remodeling • Atrial enlargement • Loss of atrial funct Underlying • Atrial hypertrophy • Non - physiologic HR Heart Disease • atrial pressure 0.2 • Irregular V response (AHT, LVH,VHD, • Atrial stretch • Loss of AV synchronicity age, • Atrial Fibrosis diabetes,..) • Electrical Remodeling Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. In pts with first CHF, the subsequent development of AF is associated with increased mortality Preexisting CHF adversely affected outcome for individuals for AF (compared to general AF) Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, D'Agostino RB, Murabito JM, Kannel WB, Benjamin EJ. Framingham Heart Study, 73 Mt Wayte Ave, Suite #2, Framingham, Mass , USA. BACKGROUND: Atrial fibrillation (AF) and congestive heart failure (CHF) frequently occur together, but there is limited information regarding their temporal relations and the combined influence of these conditions on mortality. METHODS AND RESULTS: We studied participants in the Framingham Study with new-onset AF or CHF. Multivariable Cox proportional hazards models with time-dependent variables were used to evaluate whether mortality after AF or CHF was affected by the occurrence and timing of the other condition. Hazard ratios (HRs) were adjusted for time period and cardiovascular risk factors. During the study period, 1470 participants developed AF, CHF, or both. Among 382 individuals with both conditions, 38% had AF first, 41% had CHF first, and 21% had both diagnosed on the same day. The incidence of CHF among AF subjects was 33 per 1000 person-years, and the incidence of AF among CHF subjects was 54 per 1000 person-years. In AF subjects, the subsequent development of CHF was associated with increased mortality (men: HR 2.7; 95% CI, 1.9 to 3.7; women: HR 3.1; 95% CI, 2.2 to 4.2). Similarly, in CHF subjects, later development of AF was associated with increased mortality (men: HR 1.6; 95% CI, 1.2 to 2.1; women: HR 2.7, 95% CI, 2.0 to 3.6). Preexisting CHF adversely affected survival in individuals with AF, but preexisting AF was not associated with adverse survival in those with CHF. CONCLUSIONS: Individuals with AF or CHF who subsequently develop the other condition have a poor prognosis. Additional studies addressing the pathogenesis, prevention, and optimal management of the joint occurrence of AF and CHF appear warranted. 0.1 Atrial fibrillation 2 4 6 8 10 Years Wang et al., Circulation 2003;107:2920

Impact of Atrial Fibrillation on Stroke
Stroke Prevention in AF is a Pressing Health Concern Yearly Risk of Stroke in Non-valvular AF is 5% AF is Associated with a 2 to 7-fold Increased Risk for Stroke The risk of Stroke increases Exponential with Age 20% of all Ischemic Strokes are Due to AF 40% of Patients with AF have Silent Brain Infarction In Patients with AF there is Twice as much Cognitive Dysfunction or Dementia Incidence of Dementia/1000 person-years 80 60 Men with AF 40 Previous Retrospective Studies: Backgound Rotterdam Study (1997) Now This is a longitudinal study in stroke free patients between 1986 and 2000 In AF twice as much CD Independent of stroke Silent cerabral infartion – variations in cerebral perfusion due to PIP Aims: To estimate the incidence of dementia after the first atrial fibrillation (AF), and its impact on survival in a community-based cohort. Methods and results: Olmsted County, Minnesota adult residents diagnosed with first AF during 1986–2000 were identified, and followed until The primary outcome was new detection of dementia. Interim stroke was censored in the analyses. Of 2837 subjects (71 ± 15 years old) diagnosed with first AF and without any evidence of cognitive dysfunction or stroke at the time of AF onset, 299 were diagnosed with dementia during a median follow-up of 4.6 years [interquartile (IQR) range 1.5–7.9 years], and 1638 died. The Kaplan–Meier cumulative rate of dementia was 2.7% at 1 year and 10.5% at 5 years. After adjustment for age and sex, dementia was strongly related to advancing age [hazard ratio (HR)/10 years, 2.8; 95% confidence interval (CI), 2.5–3.2], but did not vary with sex (P = 0.52). The occurrence of post-AF dementia was associated with significantly increased mortality risk (HR 2.9; 95% CI 2.5–3.3), even after adjustment for multiple comorbidities, and did not vary with age (P = 0.75) or sex (P = 0.33). Conclusion: Dementia appeared common following the diagnosis of first AF, and was associated with premature death. General Men 20 50 60 70 80 90 Age (yrs) Miyasaka et al, European Heart J 2007;28:

Impact of Atrial Fibrillation on Stroke
Long-Term Outcome in Pts with Lone AF: a 30-year Follow-Up Study Survival Free of Stroke/TIA (%) Survival Free of Death (%) 100 96% 100 92% observed 89% 85% 94% 80 80 68% 88% 86% 72%* 60 60 expected expected 57% 40 observed 40 20 Interaction of Lone AF with ageing and developing risk factors Predictors for stroke and detah: Older Age >45y (multivariate) st episode of AF (3623) 76 pts with lone AF (2%) 44.2+/-11.7y, 78% male, FU 25+/ permanent, 71 recurrent 22 out of 71 with 30y cumulative probbability of 29% progressie naar permanent AF (low risk of progression) Invasive therapies shoud be reserved for symptomatic patients, After a young patient with lone atrial fibrillation ages or develops hypertension, heart failure, or diabetes, thromboembolic risk increases. Therefore, screening for comorbidities is essential in this group Overall Survivial: duidelijk Stroke: Initial 25y similar risk (After a young patient with lone atrial fibrillation ages or develops hypertension, heart failure, or diabetes, thromboembolic risk increases. Therefore, screening for comorbidities is essential in this group, however everybody becomes old) mean age 74y 17 developed stroke/TIA over 30-years (5 strokes –12 TIA) 7 recurrent, 10 permanent 7 embolic, 10 non-embolic All pts who developed stroke/TIA had developed >1 RF for Trombo-embolism Chf 4, Hypertensie 12, Diabetes 3 (also in the age and sex matched population denk ik dan) (relatie met development of permanent AF?) 25 year is misschien geen gerusstelling voor man van 40 jaar? 20 10 20 30 10 20 30 Years Years Jahangir et al, Circulation 2007;115:

Impact of Atrial Fibrillation on Mortality
Mortality in AF Cases and Controls (Framingham Study) AF (men) Control (men) Relative Risk of Mortality Total deaths 4 59.2* 34.3 Deaths for CVS causes 2 49.9* 21.2 Similar results in female The mortality rate of pts with AF is about double that of SR patients Twice as likely to die k.o.m. Average time to death 5.9yr* 7.7yr Framingham Manitoba Whitehall Kannel et al, NEJM 1982;306:1018 Fuster et al, Circulation 2006;108:1979

Does Atrial Fibrillation Increase Mortality in Heart Failure? Survival (%) 100 Sinus Rhythm 80 60 AF at Baseline 40 Data van Middelkauf. Sudden death In this study indpeendent risk factor and arrhythmic death Prognostic significance of atrial fibrillation in advanced heart failure. A study of 390 patients. Middlekauff HR, Stevenson WG, Stevenson LW. Department of Medicine, UCLA School of Medicine. BACKGROUND. Atrial fibrillation is common in advanced heart failure, but its prognostic significance is controversial. METHODS AND RESULTS. We evaluated the relation of atrial rhythm to overall survival and sudden death in 390 consecutive advanced heart failure patients. Etiology of heart failure was coronary artery disease in 177 patients (45%) and nonischemic cardiomyopathy or valvular heart disease in 213 patients (55%). Mean left ventricular ejection fraction was / Seventy-five patients (19%) had paroxysmal (26 patients) or chronic (49 patients) atrial fibrillation. Compared with patients with sinus rhythm, patients with atrial fibrillation did not differ in etiology of heart failure, mean pulmonary capillary wedge pressure on therapy, or embolic events but were more likely to be receiving warfarin and antiarrhythmic drugs and had a slightly higher left ventricular ejection fraction. After a mean follow-up of 236 +/- 303 days, 98 patients died: 56 (57%) died suddenly, and 36 (37%) died of progressive heart failure. Actuarial 1-year overall survival was 68%, and sudden death-free survival was 79%. Actuarial survival was significantly worse for atrial fibrillation than for sinus rhythm patients (52% versus 71%, p = ). Similarly, sudden death-free survival was significantly worse for atrial fibrillation than for sinus rhythm patients (69% versus 82%, p = ). By Cox proportional hazards model, pulmonary capillary wedge pressure on therapy, left ventricular ejection fraction, coronary artery disease, and atrial fibrillation were independent risk factors for total mortality and sudden death. For patients who had pulmonary capillary wedge pressure of less than 16 mm Hg on therapy, atrial fibrillation was associated with poorer 1-year survival (44% versus 83%, p = ); however, in the high pulmonary capillary wedge pressure group, atrial fibrillation did not confer an increased risk (58% versus 57%). CONCLUSIONS. Atrial fibrillation is a marker for increased risk of death, especially in heart failure patients who have lower filling pressures on vasodilator and diuretic therapy. Whether aggressive attempts to maintain sinus rhythm will reduce this risk is unknown 20 P=0.0013 10 20 30 40 50 FU (weeks) Middlekauff et al., Circulation,1991;84:40 Wellens et al., EHJ 2006;27:2740

Studies Adressing Mortality Risk of CHF Pts with AF at Baseline Study N of AF EF(%) BB ACE/ARB Mortality RR P-value V-HeFT II (1993) 107/795 (FU 30m) 30% 0% 50% 20% vs 21% 0.76 0.18 Stevenson (1996) 140/750 (FU>24m) <40% 0% 60% 34% vs 25% 1.12 n.s. SOLVD (1998) 419/6517 (FU 33.4m) <35% 20% 50% 34% vs 23% 1.34 0.002 All Studies show that AF at Baseline is associated with Increased Mortality. However studies disagree on whether AF is an independent Predictor? Or just a marker of CHF Clinical Message: AF is associate with mortality (do not forget this message) still a matter of debate whetehr AF at baseline is a predicoe VHEFT II study (vasodilator heart failure trial) neutral effect STEVENSON ET AL; « af IMPROVES chf » en SOLVD : Dries et al, JACC, 1998, Retrospective SOLVD trial, 419 patients with AF, mild to moderate heart failure. Increased risk of death due to pump failure (in Middlekauf study, increased risk of death by sudden death). SR 23% mort, AF 34% mort Clear Independent Risk factor (RR 1.34): due to mild to moderate heart failure? COMET: Comet: also increased mortality if AF at baseline (N.R.) however, by multivariate anlysis, no longer an independent risk factor. CHARM Programme: Charm: also increased mortality if AF at baseline (N.R.) by multivariate anlysis, an independent risk factor. Howvever: stronger risk factor if moderate heart failure COMET (2005) 600/3029 (FU 58m) <35% 100% 90% N.R. (higher) 1.07 0.38 670/7599 (FU 37.7m) <40% 55% 55% 37% vs 28% 1.38 <0.001 CHARM (2006) 478/7599 (FU 37.7m) >40% 55% 20% 24% vs 14% 1.80 <0.001 Neuberger et al, Eur H Journal, 2007;Sept 13

Significance of AF in Heart Failure (1) New onset (Incident) AF is an Independent Risk Factor for Increased Mortality (“pre-terminal phenomenon”) Swedberg et al., Eur Heart J 2005;26:1303 (COMET) Wang et al., Circulation 2003;107:2920 (Framingham) (2) Prevalent AF is an Independent Risk Factor in Mild-to-moderate CHF Olsson et al., JACC 2006;47:1997 (CHARM) Crijns et al., Eur Heart J 2000;21:1238 (PRIME II) (3) Prevalent AF is an Independent Risk Factor in Ischemic Heart Failure Pedersen et al., Eur Heart J 2006;27:2866 (DIAMOND) Wellens et al., Eur Heart J 2006;27:2740 These conclusions talk about true signigficance of AF and why studies are differing Comet: (1) increasde mortality if AF at baseline, however, by multivariate anlysis, no longer an independent risk factor. (2) On the other hand, new onset AF was associated wtih markdly increasde risk for subsesequent mortlaity (3) Similar indings by Wang et al. DIAMOND COMET: Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET. Swedberg K, Olsson LG, Charlesworth A, Cleland J, Hanrath P, Komajda M, Metra M, Torp-Pedersen C, Poole-Wilson P. Department of Medicine, Sahlgrenska University Hospital/Ostra, SE Goteborg, Sweden. AIMS: Atrial fibrillation is common in patients with chronic heart failure (CHF). We analysed the risk associated with atrial fibrillation in a large cohort of patients with chronic heart failure all treated with a beta-blocker. METHODS AND RESULTS: In COMET, 3029 patients with CHF were randomized to carvedilol or metoprolol tartrate and followed for a mean of 58 months. We analysed the prognostic relevance on other outcomes of atrial fibrillation on the baseline electrocardiogram compared with no atrial fibrillation and the impact of new onset atrial fibrillation during follow-up. A multivariate analysis was performed using a Cox regression model where 10 baseline covariates were entered together with study treatment allocation. Six hundred patients (19.8%) had atrial fibrillation at baseline. These patients were older (65 vs. 61 years), included more men (88 vs.78%), had more severe symptoms [higher New York Heart Association (NYHA) class] and a longer duration of heart failure (all P < ). Atrial fibrillation was associated with significantly increased mortality [relative risk (RR) 1.29: 95% CI ; P < ], higher all-cause death or hospitalization (RR 1.25: CI ), and cardiovascular death or hospitalization for worsening heart failure (RR 1.34: CI ), both P < By multivariable analysis, atrial fibrillation no longer independently predicted mortality. Beneficial effects on mortality by carvedilol remained significant (RR 0.836: CI ; P = ). New onset atrial fibrillation during follow-up (n = 580) was associated with significant increased risk for subsequent death in a time-dependent analysis (RR 1.90: CI ; P < ) regardless of treatment allocation and changes in NYHA class. CONCLUSION: In CHF, atrial fibrillation significantly increases the risk for death and heart failure hospitalization, but is not an independent risk factor for mortality after adjusting for other predictors of prognosis. Treatment with carvedilol compared with metoprolol offers additional benefits among patients with atrial fibrillation. Onset of new atrial fibrillation in patients on long-term beta-blocker therapy is associated with significant increased subsequent risk of mortality and morbidity Aims Atrial fibrillation (AF) is a risk factor for death in patients with a myocardial infarction, but highly variable results are reported in patients with heart failure. We studied the prognostic impact of AF in heart failure patients with and without ischaemic heart disease. Methods and results During a period of 2 years, 3587 patients admitted to hospital because of heart failure were included in this study. All patients were examined by echocardiography and the presence of AF was recorded. Follow-up was available for 8 years. Twenty four percent of those discharged alive from hospital had AF. After 4 and 8 years of follow-up, mortality was higher in patients with AF than in patients without, 56 vs. 52% and 77 vs. 73%, respectively. Cox multivariable regression analysis showed a small but significant importance of AF for long-term mortality [hazard ratio (HR) 1.12, 95% confidence limits (CI), 1.02–1.23, P=0.018]. There was a significant interaction between the importance of AF and the presence of ischaemic heart disease (P=0.034). In patients with AF at the time of discharge and ischaemic heart disease, HR was 1.25 (95% CI: 1.09–1.42) and P<0.001; in patients with AF at discharge and without ischaemic heart disease, HR was 1.01 (95% CI: 0.88–1.16) and P=0.88. Conclusion AF is associated with increased risk of death only in patients with ischaemic heart disease. This finding may explain the variable results of studies of the prognosis associated with AF in heart failure.

Challenges of Therapies in AF
Clinical Objectives for Therapy of AF Prevention of Stroke Preservation/improvement of LV Function Relief of Symptoms Reduction in Mortality The AF treatment guidelines have been revised recently, but new information is emerging at such a rapid rate that the guideline process can not keep up with the pace The Preferred Strategy would be Pharmacological Rhythm Control, if Obtained Effectively and Safe

Importance of Sinus Rhythm!!
Rhythm vs Rate Sinus vs AF Cumulative Mortality (%) Endpoint Free Survival (%) Sinus Rhythm 100 30 n:352 25 80 Atrial Fibrillation n:306 20 Rhythm Control 60 15 Rate Control 40 10 AFFIRM STAF 5 20 12 24 36 48 60 5 10 15 20 25 30 35 FU (months) FU (months) Survival in CHF and AF (%) Survival in CHF and AF (%) Voor non CHF liggen de curves op elkaar en hoog bovenaan. These data of the SPAF trial suggest that in patients with AF and CHF the risk of AARD may outweigh the potential benefit of Maintaining Sinus rhythm. N:1330. Met AARD en CHF, RR op cardiac mortality x4.7, RR op aritmic death x3.7 AARD quiniidine 127, procainamide 57, disopyramide 15, flecainide 35, encainamide 20, amiodarone 7 DIAMOND: retrospective analysis of patients with AF at baseline in the 2 DIAMOND trials (CHF and postMI). 506 patients. Placebo: 34% conversion naar SR en 42% maintenance, 116 doden; Dofetilide: 59% conversion, 79% maintenance, 111 doden. 56% was in NYHA III-IV in beide groepen, 12% b-lyse in beide groepen. Besluit; Dof is effectief, sinus ritme is beter, hoewel meer SR in dofetilde is de survival gelijk. Besluit of hypothese: in de non responders (ptn die in AF blijven ondanks Dofetilide) is er oversterfte aanwezig. Background— In patients with left ventricular dysfunction, atrial fibrillation and flutter (AF and AFl, respectively) are common arrhythmias associated with increased morbidity and mortality. The present study investigated the potential of dofetilide in AF-AFl patients with left ventricular dysfunction to restore and maintain sinus rhythm, which might reduce mortality and hospitalizations. Methods and Results— In the Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies, 506 patients were in AF-AFl at baseline. Over the course of study, cardioversion occurred in 148 (59%) dofetilide- and 86 (34%) placebo-treated patients. In these patients, the probability of maintaining sinus rhythm for 1 year was 79% with dofetilide versus 42% with placebo (P<0.001). Dofetilide had no effect on all-cause mortality, but restoration and maintenance of sinus rhythm was associated with significant reduction in mortality (risk ratio [RR], 0.44; 95% CI, 0.30 to 0.64; P<0.0001). In addition, dofetilide therapy was associated with a significantly lower risk ratio versus placebo for either all-cause (RR, 0.70; 95% CI, 0.56 to 0.89; P 0.005) or congestive heart failure (RR, 0.69; 95% CI, 0.51 to 0.93; P 0.02) rehospitalization. Conclusions— Dofetilide is safe and increases the probability of obtaining and maintaining sinus rhythm in patients with structural heart disease. The present study suggests that restoration of sinus rhythm is associated with improved survival. 1330 patients enrolled in SPAF, If AARD: In patients with No CHF: relatiev risk of cardiac death: 0.7 (no increased risk) In patients with CHF: relative risk of cardiac death: 4.7 relative risk of aritmic death: 3.7 Echter Singh et al. Have shown that Amiodaroen is Safe (NEJM 1995) 100 100 Sinus Rhythm Amiodarone 80 80 60 60 Placebo Atrial Fibrillation 40 40 CHF-STAT 20 20 CHF-STAT 12 24 36 12 24 36 FU (months) FU (months)

Conventional Antiarrhythmic Drugs for AF
Vaughan Williams Classification of Antiarrhythmic Agents Fuster et al., JACC 2001, page 1-70

Efficacy of Class IC and III to Prevent Persistent AF Predictors for Recurrence Maintenance of Sinus Rhythm SR (%) 100 Male Gender Amiodarone 80 Age >75 Sotalol 60 Amiodarone Sotalol Digoxin Propafenone 40 LA <52 LVEDD 20 25% Duration>1year 100 200 300 400 500 0.001 0.01 0.1 1 10 100 Days of Follow-up Absence of Recurrence Duytschaever et al., PACE 1999 CTAF, Roy et al., NEJM, 2000

Template _1 4/14/2017 9:23 PM Review of RCTs on Prevention of Recurrence of AF after DCC RCT included into analysis AF Recurrence Total 44 Class IA Class IC Metoprolol Class III Amio Dofetilide Sotalol Q vs Class I Q vs Sotalol Amio vs Class I Amio vs Sotalol Sotalol vs Class I No. of patients 11,322 Placebo controlled 25 Active comparator 14 Persistent AF 38 (60% pts) PAF/recent onset 6 Despite Good Raprot EF > 50% 41 Lone AF 1 Follow-up 1 year 0.5 1 1.5 2 Odds Ratio (95% CI) Lafuente-Lafuente C, et al, Arch Intern Med 2006;166:719-28 12 9 20 8

Primary Endpoint (Death)
Conventional Antiarrhythmic Drugs for AF Rhythm Control v Rate Control (The AFFIRM Trial) 4060 patients, FU 5 year Paroxysmal or Recurrent Persistent Asymptomatic AF > 65 yr or Other RF for Stroke or Death Rhythm Control : cardioversion, antiarrhythmic drugs, Stop coumadin if SR Rate Control : heart rate from 80/’ en 110/’ ; continued coumadin Cumulative Mortality (%) 30 25 Rate Control Rhythm Control P=0.08 n:352 n:306 20 15 10 5 Years (%) 1 2 3 4 5 Primary Endpoint (Death) Wyse et al. NEJM 2002

Primary Endpoint (Cardiovascular Death)
Conventional Antiarrhythmic Drugs for AF Rhythm Control v Rate Control (The AF-CHF Trial) Primary Endpoint (Cardiovascular Death) 1376 patients, FU >2 year LVEF ≤ 35% and NYHA II-IV AF ≥ 6 h within last 6 months or one episode ≥ 10 min within 6 months and prior D/C shock 82% amiodarone (rhythm control) Roy et al, NEJM 2008;358:

Class I and III Drugs are Not Safe (Certainly not in CHF) Survival in Patients with CHF and AF (%) Survival in Patients with CHF and AF (%) No Antiarrhythmic Drugs 100 100 Placebo 90 80 80 60 Antiarrhythmic Drugs (Quinidine, Procainamide, Disopyramide, Flecainide, Encainide) Amiodarone 70 40 Voor non CHF liggen de curves op elkaar en hoog bovenaan. These data of the SPAF trial suggest that in patients with AF and CHF the risk of AARD may outweigh the potential benefit of Maintaining Sinus rhythm. N:1330. Met AARD en CHF, RR op cardiac mortality x4.7, RR op aritmic death x3.7 AARD quiniidine 127, procainamide 57, disopyramide 15, flecainide 35, encainamide 20, amiodarone 7 DIAMOND: retrospective analysis of patients with AF at baseline in the 2 DIAMOND trials (CHF and postMI). 506 patients. Placebo: 34% conversion naar SR en 42% maintenance, 116 doden; Dofetilide: 59% conversion, 79% maintenance, 111 doden. 56% was in NYHA III-IV in beide groepen, 12% b-lyse in beide groepen. Besluit; Dof is effectief, sinus ritme is beter, hoewel meer SR in dofetilde is de survival gelijk. Besluit of hypothese: in de non responders (ptn die in AF blijven ondanks Dofetilide) is er oversterfte aanwezig. Background— In patients with left ventricular dysfunction, atrial fibrillation and flutter (AF and AFl, respectively) are common arrhythmias associated with increased morbidity and mortality. The present study investigated the potential of dofetilide in AF-AFl patients with left ventricular dysfunction to restore and maintain sinus rhythm, which might reduce mortality and hospitalizations. Methods and Results— In the Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies, 506 patients were in AF-AFl at baseline. Over the course of study, cardioversion occurred in 148 (59%) dofetilide- and 86 (34%) placebo-treated patients. In these patients, the probability of maintaining sinus rhythm for 1 year was 79% with dofetilide versus 42% with placebo (P<0.001). Dofetilide had no effect on all-cause mortality, but restoration and maintenance of sinus rhythm was associated with significant reduction in mortality (risk ratio [RR], 0.44; 95% CI, 0.30 to 0.64; P<0.0001). In addition, dofetilide therapy was associated with a significantly lower risk ratio versus placebo for either all-cause (RR, 0.70; 95% CI, 0.56 to 0.89; P 0.005) or congestive heart failure (RR, 0.69; 95% CI, 0.51 to 0.93; P 0.02) rehospitalization. Conclusions— Dofetilide is safe and increases the probability of obtaining and maintaining sinus rhythm in patients with structural heart disease. The present study suggests that restoration of sinus rhythm is associated with improved survival. 1330 patients enrolled in SPAF, If AARD: In patients with No CHF: relatiev risk of cardiac death: 0.7 (no increased risk) In patients with CHF: relative risk of cardiac death: 4.7 relative risk of aritmic death: 3.7 Echter Singh et al. Have shown that Amiodaroen is Safe (NEJM 1995) 60 20 50 90 180 270 360 450 540 630 12 24 36 Follow-up (days) Follow-up (months) Flaker et al.(SPAF), JACC, 1992 Singh et al.(CHF-STAT),Circulation, 1998

Class I and III Drugs are Not Effective Nor Safe Efficacy Safety % of Sinus Rhythm Number of Deaths 169 75 160 130 129 60% 140 113 120 50 100 52 81 Cancer 40% 80 23 39 Pulmonary 25 Mode of death analysis (in the era w/o heart failure w/o class IC) All deaths underwent blinded review by the AFFIRM event committee Intention to treat vs on treatment analysis Cordarone theory (more cordarone in the rhyhtm control arm) In rhythm control cordarone was ultimately prescribed in 60% of the patients Cancer death (vnl pulmonary cancer ) Pulmonary death (vnl pneumonia (3 cordaronepneumonitis) Similar results (increased cancer death and pulmonary deaths) were found in the EMIAT and AVID trial Warfarin therory (more warfarin in the rate control) Warfarin antineoplastic Earlier bleeding from a neoplastic site may have enhanced early detection of cancer Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. As shown in Table 1, the difference in noncardiovascular death rates between the rhythm-control and rate-control treatment arms was a result of significant differences in pulmonary causes (39 [4%] versus 23 [3%], Figure 3, P=0.04) and cancer-related death (81 [6%] versus 52 [4%], Figure 4, P=0.01). Lung cancer was the most common type of malignancy responsible for death and demonstrated a sizable disparity between groups: 30 in the rhythm-control group and 12 in the rate-control group. Only 3 deaths were caused by amiodarone pulmonary toxicity. Most pulmonary deaths were caused by pneumonia. Similar death rates were observed between treatment arms for other noncardiovascular causes Steinberg JS, Sadaniantz A, Kron J, Krahn A, Denny DM, Daubert J, Campbell WB, Havranek E, Murray K, Olshansky B, O'Neill G, Sami M, Schmidt S, Storm R, Zabalgoitia M, Miller J, Chandler M, Nasco EM, Greene HL. Division of Cardiology, St Luke's-Roosevelt Hospital Center and Columbia University, New York, NY 10025, USA. BACKGROUND: Expectations that reestablishing and maintaining sinus rhythm in patients with atrial fibrillation might improve survival were disproved in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. This report describes the cause-specific modes of death in the AFFIRM treatment groups. METHODS AND RESULTS: All deaths in patients enrolled in AFFIRM underwent blinded review by the AFFIRM Events Committee, and a mode of death was assigned. In AFFIRM, 2033 patients were randomized to a rhythm-control strategy and 2027 patients to a rate-control strategy. During a mean follow-up of 3.5 years, there were 356 deaths in the rhythm-control patients and 310 deaths in the rate-control patients (P=0.07). In the rhythm-control group, 129 patients (9%) died of a cardiac cause, and in the rate-control group, 130 patients (10%) died (P=0.95). Both groups had similar rates of arrhythmic and nonarrhythmic cardiac deaths. The numbers of vascular deaths were similar in the 2 groups: 35 (3%) in the rhythm-control group and 37 (3%) in the rate-control group (P=0.82). There were no differences in the rates of ischemic stroke and central nervous system hemorrhage. In the rhythm-control group, there were 169 noncardiovascular deaths (47.5% of the total number of deaths), whereas in the rate-control arm, there were 113 noncardiovascular deaths (36.5% of the total number of deaths) (P=0.0008). Differences in noncardiovascular death rates were due to pulmonary and cancer-related deaths. CONCLUSIONS: Management of atrial fibrillation with a rhythm-control strategy conferred no advantage over a rate-control strategy in cardiac or vascular mortality and may be associated with an increased noncardiovascular death rate. 60 37 35 40 20 Cardiac Vascular Non Cardiovascular Rate 310 † Rhythm 352 † Steinberg et al, Circulation 2004;109:1973

ACC/AHA/ESC 2006 guidelines for the management of AF Paroxysmal or Recurrent Persistent AF Permanent AF No Symptoms Symptoms Antico and Rate Control Antico and Rhythm Control Antico and Rate Control Fuster et al, Circulation 2006;108:1979

ACC/AHA/ESC 2006 guidelines for the management of AF No Heart Disease Coronary Artery Disease Heart Failure or Hypertension with LVH Flecainide Sotalol Sotalol Amiodarone Catheter Ablation Catheter Ablation Catheter Ablation Amiodarone Amiodarone Fuster et al, Circulation 2006;108:1979

“Antiarrhythmic” Drugs for AF
Template _1 4/14/2017 9:23 PM Disopyramide Amiodarone Class IA Quinidine b-Blocker Antiarrhythmic Agents Sotalol Class III Propafenone Class IC Dofetilide Flecainide New Class III Agents Substrate therapies Novel Drugs Connexin modulators b-Blocker SAC Blockers Atrial repolarisation delaying agents Azimlide (Porcter and Gamble): Iks blocker: disappointing outcome in ALIVE study post infraction and in pts with persistent Afib (A-STAR, A-COMET) Tedisamil (Solvay): multiple K blocker, side effcects (diaree tot VT) ACEI ARB Statins PUFAs Azimilide Tedisamil Ranolazine Na+/H+ Inhibitors Dronedarone Adenosine Agonist Pirfenidone Na+/Ca2+ Inhibitor Multi-channel blockers ARDAs (Vernakalant, AVE0118) ARDAs Savelieva and Camm, Europace 2008; 28

Novel “Antiarrhythmic” Drugs for AF
Pharmacological Modulation of Atrial Conduction (Rotigaptide) Modulation of Gap Junctions Inter Cellular Uncoupling 16 Weeks AF Figure 6. ZP123 inhibits acidosis-induced conduction slowing. Contours illustrate propagation from a point stimulus proceeding in an elliptical pattern. Action potential upstrokes (inset) recorded from 5 sites ( ) along the transverse axis of propagation illustrate relative conduction delay between recording sites. In the absence of ZP123 (A and B), acidosis produced significant slowing of conduction. In contrast, pretreatment with ZP123 (C and D) preserved conduction during acidosis. ZP123 attenuates acidosis-induced CV slowing while producing no change in pattern of propagation. L indicates longitudinal CV; T, transverse CV Pharmacological modulation of cardiac gap junctions to enhance cardiac conduction: evidence supporting a novel target for antiarrhythmic therapy. Eloff BC, Gilat E, Wan X, Rosenbaum DS. The Heart and Vascular Research Center and the Department of Biomedical Engineering, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio , USA. BACKGROUND: Disease-induced alterations of cardiac gap junctions lead to intercellular uncoupling, which is an important mechanism of arrhythmogenesis. Therefore, drugs that selectively open gap junctions potentially offer a novel strategy for antiarrhythmic therapy. Because the peptide ZP123 was found to increase conductance between paired myocytes, we hypothesized that ZP123 would suppress acidosis-induced gap junction closure in the intact heart. METHODS AND RESULTS: High-resolution optical mapping was used to measure conduction velocity (CV) and action potential duration from ventricular epicardium of Langendorff-perfused guinea pig hearts at baseline (pH 7.4) and during 45 minutes of perfusion with acidotic (pH 6.0) Tyrode's solution with (n=8) and without (control, n=7) ZP123 (80 nmol/L). Acidosis produced conduction slowing transverse (29.1+/-0.1 to 16.8+/-0.2 cm/s, P<0.0001) and longitudinal (47.2+/-2.4 to 33.2+/-4.8 cm/s, P<0.0001) to cardiac fibers. Importantly, ZP123 inhibited conduction slowing during acidosis by approximately 60%. The peak effect of ZP123 was achieved after 16 minutes of acidosis, consistent with inhibition of uncoupling. ZP123 did not affect Na+ current in isolated myocytes, additionally affirming that preservation of CV was attributable to the compound's action on gap junctions. ZP123 had no effect on CV in the absence of acidosis, suggesting that drug activity targets gap junctions under metabolic stress. Action potential duration heterogeneity was significantly reduced by ZP123 (6.7+/-0.8 ms) compared with controls (9.7+/-3.1 ms, P<0.05), presumably by enhancing cell-to-cell coupling. CONCLUSIONS: These data suggest that ZP123 significantly attenuates gap junction closure during acidosis. Preservation of intercellular coupling diminished CV slowing and heterogeneous repolarization, eliminating arrhythmogenic substrates. Eloff et al., Circulation, dec 2003

Late and Early Class III Drugs (Experimental) S1 S1 S2 “Late” versus “ Early “ Class III Drugs 400 142 Control Sinus Rhythm 186 d-Sotalol ‘Early’ Class III AAD Ito 102 After 24 h of AF Control ICa IKur 118 d-Sotalol IKs IKr Therefore we tested the effect of d-Sotalol on refractoriness, before and after AF-induced electrical remodeling. This slide shows the effect of an intravenous dose of 6mg/kg, on the atrial refractory period during regular slow pacing with a cycle length of 400 msec. In a control, sinus rhythm goat, d-sotalol prolonged AERP markedly from 142 to 186 msec. After 24 hours of AF, AERP has shortened to 102 msec. d-Sotalol prolonged AERP to 118 msec. After 48 hours of AF, AERP had further shortened to 74 msec. Now d-sotalol hardly exerted any effect on the AERP that had prolonged to 78 msec. Furthermore we observed that d-sotalol was never capable of preventing induction of AF. So we believe that there is a loss of effect of d-sotalol on refractoriness by atrial fibrillation. 74 Control After 48 h of AF 100 200 300 400 ms 78 d-Sotalol Duytschaever et al., Cardiovascular Research, 2005,67:69-76

Template _1 4/14/2017 9:23 PM Savelieva and Camm, Europace 2008; 31

‘Early’ Class III Drugg AVE0118 (IKur Blocker) AVE 0118 (3mg/kg/h) Δ AERP (ms) ms Remodeled Atria 220 QT-time * * 200 60 * * 180 * 40 AERP400 160 140 Background— Currently available antiarrhythmic drugs are only moderately effective against atrial fibrillation (AF) and may cause ventricular proarrhythmia. AVE0118 is a blocker of atrium-specific early K+ currents (IKur/Ito). Methods and Results— Effects of intravenous AVE0118 and dofetilide on atrial effective refractory period (AERP) and inducibility of AF were measured before and after 48-hours of AF-induced electrical remodeling in the goat. During persistent AF (53±19 days), the cardioversion efficacy and effects on atrial wavelength of AVE0118, dofetilide, and ibutilide were evaluated. QT durations were measured during atrial pacing and persistent AF. After 48 hours of AF, the effect of dofetilide on AERP was reduced, and induction of AF was not prevented. In contrast, the class III action of AVE0118 was enhanced, and AF inducibility decreased from 100% to 32% (P<0.001). At 1, 3, and 10 mg · kg–1 · h–1, AVE0118 terminated persistent AF in 1 of 8, 3 of 8, and 5 of 8 goats, respectively. Dofetilide and ibutilide terminated AF in 1 of 5 and 2 of 7 goats. AVE , 1.5, and 5 mg/kg prolonged the AERP during AF and increased the fibrillation wavelength from 6.7±0.6 to 8.5±0.5, 9.7±0.5, and 11.2±0.9 cm (P<0.01). Whereas dofetilide and ibutilide prolonged QT duration, AVE0118 had no appreciable effect. Conclusions— AVE0118 markedly prolongs the AERP during AF without affecting QT duration. Cardioversion of AF was due to an 2-fold increase in fibrillation wavelength. Atrium-selective class III drugs like AVE0118 may be a promising new option for safe and effective cardioversion of AF. 20 120 100 200 250 300 350 400 -20 -10 10 20 30 Pacing Cycle Length (ms) Time (min) Blaauw et al, Circulation Oct 2004

Template _1 4/14/2017 9:23 PM Vernakalant Hydrochloride for Conversion of AF AF Termination (%) 60 Vernalkalant (n=75/145) RSD 1235 Phase 3 randomised plaebo-controlled trial N=226, AF 3 h-7 d N=116, AF 8-45 d N=62, AFL RSD mg/kg vs placebo 1o EP: cardioversion within 90 min 52% 40 20 Placebo (n=3/75) 4% 20 40 60 80 100 Time (min) For AF <7 days Odds of conversion=24 (95% CI, 7-84) Conversion rates for AF >7 days and AFL: 8% and 2.5% No drug related torsades de pointes Roy et al. Circulation 2008, 117: 33

New “Class III” Agents for AF
Template _1 4/14/2017 9:23 PM Dronedarone (Post-Hoc Analysis) ADONIS (N=630, follow-up 1 year) EURIDIS and ADONIS Meta-analysis Time to AF Recurrence Time to First CV Hospitalization or Death Placebo 0.4 Placebo 0.8 Dronedarone 400 mg BID Dronedarone 400 mg BID 0.7 0.3 0.6 HR=0.80 p=0.16 95%CI=[0.59; 1.09] 0.5 Cumulative incidence 0.4 0.2 Cumulative Incidence 0.3 Similar to amioadorne, a mulichannel blocker, Lacks its iodine substituent (radical) Classical AADS study with the EP being sinus rhythm EURIDIS (Eurpean) and Adonis (Afro-australian-american) showed that dronedarone is better than placebi in prevention of recurrence 0.2 0.1 0.1 0.1 Log-rank test results: p=0.0017 Few adverse events 0.0 0.0 0.0 60 60 120 180 240 300 360 60 120 180 270 360 Time (days) Time(days) ? ATHENA Singh BN et al, NEJM 2008 Hohnloser. Presented at Heart Rhythm Society 2008; May 2008; San Francisco, CA (A). 35

R New “Class III” Agents for AF ATHENA and Trial Design
Template _1 4/14/2017 9:23 PM ATHENA and Trial Design N=4628 patients with a history of paroxysmal or persistent AF Age ≥ 75 years with or without additional risk factors Age ≥ 70 years and ≥ 1 risk factor (hypertension, diabetes, prior stroke/TIA, LA ≥ 50 mm, LVEF ≤ .40) R Dronedarone (400 mg bid) Placebo Phase III RCT: Minimum follow-up 12 months Primary EP: time to Death or Cardiovascular Hospitalisation J Cardiovasc Electrophysiol. 2008;19:69-73. 36

Template _1 4/14/2017 9:23 PM ATHENA: Patient Characteristics Placebo (N=2327) Dronedarone (N=2301) Age (yrs) 72+/-9 72+/-9 Female gender 45% 49% AF at baseline 25% 25% 61% 58% Structural Heart Disease Arterial Hypertension 86% 87% Coronary Heart Disease 32% 29% Valvular Heart Disease 16% 17% NYHA III/IV 22% 20% EF<0.35 4% 4% Lone AF 6% 6% 37

Template _1 4/14/2017 9:23 PM ATHENA: Baseline Medications Placebo (N=2327) Dronedarone (N=2301) Betablocker 71% 71% Ca-antagonists 13% 14% Digoxin 13% 14% 69% 70% ACE/ARB Statins 39% 38% Vit.K anatagonists 60% 61% Aspirin 44% 44% 38

Template _1 4/14/2017 9:23 PM ATHENA: Primary Outcome Time to first cardiovascular hospitalization or death Cumulative Incidence (%) 50 HR=.76 P<.001 40 30 Placebo 20 Dronedarone 10 6 12 18 24 30 Months Patients at risk Placebo Dronedarone Mean follow-up 21  5 months. Hohnloser. Presented at Heart Rhythm Society 2008; May 2008; San Francisco, CA (A). 39

Template _1 4/14/2017 9:23 PM ATHENA: Fatal Outcomes Outcome Placebo (N=2327) Dronedarone (N=2301) Hazard Ratio 95% CI P Value All death 139 116 0.84 .18 Non-CV death 49 53 1.10 .65 CV death 90 63 0.71 .03 Cardiac non-arrhythmic death 18 17 0.95 .89 Cardiac arrhythmic death 48 26 0.55 .01 Vascular non-cardiac 24 20 .57 Hohnloser. Presented at the Heart Rhythm Society. May San Francisco, California (A). 40

Template _1 4/14/2017 9:23 PM ATHENA: Non-Fatal Outcomes Outcome Placebo (N=2327) Dronedarone (N=2301) Hazard Ratio 95% CI P Value Primary outcome 917 734 0.76 <.001 First hospitalization for CV reasons 859 675 0.75 AF 510 335 0.63 CHF 132 112 0.86 .221 ACS 89 62 0.70 .030 Syncope 32 27 0.85 .542 Ventricular arrhythmia or non-fatal cardiac arrest 12 13 1.09 .828 Hohnloser. Presented at the Heart Rhythm Society. May San Francisco, California (A). 41

ATHENA: Summary Dronedarone Significantly Prolongs Time to Cardiovascular Hospitalisation or Death in Moderate to High Risk Elderly AF Pts All Cause Mortality was Not Increased in Pts Receiving Dronedarone Cardiovascular Mortality (Specifically Arrhythmic Death) was Lower in the Dronedarone Compared to the Placebo Group The Reduction in CV Hospitalisation was Mainly Due to Fewer Admissions for AF and Acute Coronary Syndromes Discontinuation of Study Drug Was Similar in Both Groups Indicating Good Tolerability of Dronedarone The Development Portfolio of this Drug is Practically Complete

Template _1 4/14/2017 9:23 PM Increased Mortality after Dronedarone Therapy for Severe Heart Failure After inclusion of 627 patients (310 in the dronedarone group and 317 in the placebo group), the trial was prematurely terminated beacuse of increased early mortality related to the worsening of heart failure (inappropriate discontinuation of ACEI deu to increase in creatinine?) Background Dronedarone is a novel antiarrhythmic drug with electrophysiological properties that are similar to those of amiodarone, but it does not contain iodine and thus does not cause iodine-related adverse reactions. Therefore, it may be of value in the treatment of patients with heart failure. Methods In a multicenter study with a double-blind design, we planned to randomly assign 1000 patients who were hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction to receive 400 mg of dronedarone twice a day or placebo. The primary end point was the composite of death from any cause or hospitalization for heart failure. Results After inclusion of 627 patients (310 in the dronedarone group and 317 in the placebo group), the trial was prematurely terminated for safety reasons, at the recommendation of the data and safety monitoring board, in accordance with the board's predefined rules for termination of the study. During a median follow-up of 2 months, 25 patients in the dronedarone group (8.1%) and 12 patients in the placebo group (3.8%) died (hazard ratio in the dronedarone group, 2.13; 95% confidence interval [CI], 1.07 to 4.25; P=0.03). The excess mortality was predominantly related to worsening of heart failure — 10 deaths in the dronedarone group and 2 in the placebo group. The primary end point did not differ significantly between the two groups; there were 53 events in the dronedarone group (17.1%) and 40 events in the placebo group (12.6%) (hazard ratio, 1.38; 95% CI, 0.92 to 2.09; P=0.12). More increases in the creatinine concentration were reported as serious adverse events in the dronedarone group than in the placebo group. Conclusions In patients with severe heart failure and left ventricular systolic dysfunction, treatment with dronedarone was associated with increased early mortality related to the worsening of heart failure. (ClinicalTrials.gov number, NCT [ClinicalTrials.gov] .) ANDROMEDA Study; Kober et al. NEJM 2008, 358: 43

Aldosterone antagonists ACE inhibitors and ARBs
Substrate Therapies for AF Template _1 4/14/2017 9:23 PM Atrial Remodeling Hypertension, heart failure AA effects (anti-fibrotic, antiarrhythmic?) Aldosterone antagonists Lipid-lowering effects Antiarrhythmic effects n-3 PUFA (fish oil) Reduction of BP, CHF MI, etc. Beta blockers Anti-inflammatory effects Corticosteroids Coronary artery disease Systemic atherosclerosis AA effects (antiinflammatory, antioxidant) Statins Hypertension Heart failure ACE inhibitors and ARBs Therapies Possible Target Prevention of Atrial Remodeling AF Disease Substrate Targets: Prevention of Heart Disease Prevent HD-induced Remodeling Prevent AF-induced Remodeling 45

Substrate Therapies for AF
Prevention of AF by Treating Heart Failure (Primary Prevention) ACE Inhibitors AR Antagonists SR (%) Cumulative Incidence of AF Enalapril (5% AF) 0.15 100 Placebo (8% AF) 80 Placebo (24% AF) 0.10 60 40 0.05 Valsartan (5.1% AF) Studies on pts with sinus rhyhtm at baseline SOLVD (similarly TRACE study) , SOLVD, AF at baseline excluded (maw incident AF or primary prevention) Ook bij ValHeFT AF at baseline exculded from the retro-sective anlysis (prospective CHARM) Retrospective Analysis SOLVD BACKGROUND: Atrial fibrillation (AF) is frequently encountered in patients with heart failure (HF) and is also a predictor of morbidity and mortality in this population. Recent experimental studies have shown electrical and structural atrial remodeling with increased fibrosis in animals with HF and have suggested a preventive effect of ACE inhibitors (ACEi) on the development of AF. To verify the hypothesis that ACEi prevent the development of AF in patients with HF, we conducted a retrospective analysis of the patients from the Montreal Heart Institute (MHI) included in the Studies Of Left Ventricular Dysfunction (SOLVD). METHODS AND RESULTS: Clinical charts were reviewed and serial ECGs interpreted by a single cardiologist blinded to drug allocation. Patients with AF or flutter on the baseline ECG were excluded. Baseline characteristics were obtained from the SOLVD databases. The mean follow-up was 2.9+/-1.0 years. Of the 391 patients randomly assigned at MHI, 374 were in sinus rhythm at the time of random assignment, with 186 taking enalapril and 188 taking placebo. Baseline characteristics were similar in the two groups except for a higher incidence of previous myocardial infarction in the enalapril group. Fifty-five patients had AF during the follow-up: 10 (5.4%) in the enalapril group and 45 (24%) in the placebo group (P<0.0001). By Cox multivariate analysis, enalapril was the most powerful predictor for risk reduction of AF (hazard ratio, 0.22; 95% CI, 0.11 to 0.44; P<0.0001). CONCLUSIONS: Treatment with the ACEi enalapril markedly reduces the risk of development of atrial fibrillation in patients with left ventricular dysfunction. ValHeFT. BACKGROUND: Atrial fibrillation (AF) in heart failure (HF) is generally considered a negative prognostic factor. Recent studies indicate that the incidence of AF might be decreased by renin angiotensin aldosterone system inhibitors. The identification of a treatment to prevent its occurrence is likely to improve patients outcome. The aims of these subanalyses of Val-HeFT were to assess (a) the effects of valsartan in the prevention of AF, (b) the independent predictors of this event, and (c) the prognostic role of AF occurrence. METHODS AND RESULTS: The occurrence of AF was evaluated based on adverse event reports in the patients with HF enrolled in Val-HeFT. Patients were randomized to valsartan or placebo on top of their prescribed treatments for HF. During the mean 23 months of follow-up, AF was reported in 287/4395 patients (6.53%) in sinus rhythm at baseline, of whom 113/2205 (5.12%) were allocated to valsartan and 174/2190 (7.95%) to placebo (P = .0002). Multivariable analysis showed that brain natriuretic peptide (BNP) levels at baseline above the median value (HR 2.28, 95% CI ), age over 70 years (HR 1.51, 95% CI ), male sex (HR 1.53, 95% CI ), and the valsartan treatment (HR 0.63, 95% CI ) were independently associated with AF occurrence. Cox multivariable regression analysis showed that occurrence of AF was independently associated with a worse prognosis, with the adjusted hazard risks for all-cause mortality and combined mortality/morbidity of 1.40 (95% CI ) and 1.38 (95% CI ), respectively. CONCLUSIONS: The results of the present study demonstrate that (a) adding valsartan to prescribed therapy for HF significantly reduces the incidence of AF by 37%; (b) BNP level and advanced age were the strongest independent predictors for AF occurrence; and (c) AF occurrence further worsens the outcome in patients with HF. 20 Years 1 2 3 4 5 6 12 18 24 Months FU 2.9y FU 23m (SOLVD) (ValHeFT) Vermes et al, Circulation 2003;107;2926 Maggioni et al, Am Heart J 2005;149:548

Prevention of AF by Treating Heart Failure (Primary Prevention) Let alone start of AADS (CHF-AF): If incident AF is so important shoud we do primary arrhythmia profyaixs in every heart failure patients If AF in the setting of heart failure: rate or rhythm control? Management of atrial fibrillation in patients with heart failure Heart Rhythm, Volume 4, Issue 3, Supplement 1, March 2007, Pages S28-S30 William G. Stevenson and Usha Tedrow Primary Arrhythmia Profylaxis in Heart Failure Patients With the courtesy of H Crijns

Prevention of AF by Treating Arterial Hypertension Patients with hypertension (%) 80 71 64.4 62.6 60 55 51 49 40 20 GLB.IRB 071221a_Irbe Hypertension is the commonest comorbidity associated with AF. In the AFFIRM study, hypertension was a primary diagnosis at enrollment in 51% patients and the prevalent diagnosis in 70%. At the same time, hypertension is a risk factor for stroke in patients with AF. PIAF RACE STAF AFFIRM overall AFFIRM predominant HOT CAFÉ AF populations Savelieva I & Camm AJ, not published.

Prevention of AF by Treating Hypertension (Secondary Prevention) N=250 Mild AHT and Documented AF in Previous 6 months Amiodarone 200 + Losartan 50mg Amlodipine 5mg Fogari et al Journal of Cardiovasc. Pharmacol 2006

Prevention of AF by Treating Hypertension (Primary Prevention) Stroke (%) New Onset AF (%) 8 10 7 RR: 0.67 [95% CI: ], p<0.001. Atenolol 6 8 5 Atenolol 6 4 4 3 Aggresive treatment of hypertension as treatment of AF Despite the importance of AHT the guidelines include 1 sentence about the treatment of AHT as option Madrid, 40% had AHT, effect irrespective of RR lowering effect Background— Data from studies of angiotensin-converting enzyme inhibitors provide evidence that the renin-angiotensin-aldosterone system plays a role as a mediator of atrial remodeling in atrial fibrillation. The present study has evaluated the effect of treatment with the angiotensin I type 1 receptor blocker irbesartan on maintaining sinus rhythm after conversion from persistent atrial fibrillation. Methods and Results— To be included in the present study, patients must have had an episode of persistent atrial fibrillation for >7 days. The patients were then randomized and scheduled for electrical cardioversion. Two groups of patients were compared: Group I was treated with amiodarone, and group II was treated with amiodarone plus irbesartan. The primary end point was the length of time to a first recurrence of atrial fibrillation. From a total of 186 patients assessed in the study, 154 were analyzed with the use of intention-to-treat analysis. Seventy-five patients were randomly allocated to group I and 79 to group II. After 2 months of follow-up in the intention-to-treat analysis, the group treated with irbesartan had fewer patients with recurrent atrial fibrillation (Kaplan-Meier analysis, 84.79% versus 63.16%, P=0.008). The Kaplan-Meier analysis of time to first recurrence during the follow-up period (median time, 254 days [range, 60 to 710]) also showed that patients treated with irbesartan had a greater probability of remaining free of atrial fibrillation (79.52% versus 55.91%, P=0.007). Conclusions— Patients treated with amiodarone plus irbesartan had a lower rate of recurrence of atrial fibrillation than did patients treated with amiodarone alone. 2 Losartan 2 Losartan 1 12 24 36 48 60 12 24 36 48 60 Months Months LIFE, Kjeldsen et al, JAMA, 2002; 288:1491 Wachtell et al, JACC; 2005; 45

Natural Hx and Progression of AF
Substrate Therapies for AF Prevention of Progression of AF (No Structural Heart Disease) Natural Hx and Progression of AF Study # pts Follow-up Progression UK general practice, 2005 525 1st PAF age yrs 2.7 yrs; 1606 person-yrs 70/418 (17%) progression increased risk of mortality 1.5 ( ) Tokyo study, 1995 137 new onset PAF 1 year 30/137 (22%) CARAF, 2001 560 men, 339 women 1st AF 4.14 yrs 19%; time to progression 1138 days (men), 1092 days (women) CARAF, 2005 757 new onset PAF 8 (2-11) yrs 8.6% by 1 year; 25% by 5 yrs; probability of any AF 63% by 5 yrs Danish study, 1986 426 1st PAF 9 (0-24) yrs 141 (33%) Parkinson, 1930 200 PAF 10 yrs 25% Tokyo study, 2004 171 PAF 14 yrs 132/171 (77%) (5.5%/year 51

Secondary Prevention in The Absence of Heart Disease After ECV of Persistent AF In Paroxysmal AF SR (%) SR (%) Amiodarone+ Irbesartan Amiodarone+ Losartan 20 40 60 80 100 20 40 60 80 100 Amiodarone Amiodarone Of course in HF this does have an effect However alsi in AHT clear effect and benefit of ARB >BB (fogari after ECV, Life study) evidence of more than anti-AHT efefct However also in Mild Heart disease persistent AF after ECV (satins, ACE, ARB? Fish oil) Paroxysmal AF - Three prospective trials in CV of lone persitent AF One population based cohort study in peopele >65y and look at incident AF ARB also in paroxysmal lone AF : Yin etal European heart journal Abstract AIMS: This study aimed to assess whether enalapril could improve cardioversion outcome and facilitate sinus rhythm maintenance after conversion of chronic atrial fibrillation (AF). METHODS AND RESULTS: Patients with chronic AF for more than 3 months were assigned to receive either amiodarone (200mg orally 3 times a day; group I: n=75) or the same dosage of amiodarone plus enalapril (10mg twice a day; group II: n=70) 4 weeks before scheduled external cardioversion. The end-point was the time to first recurrence of AF. In 125 patients (86.2%), AF was converted to sinus rhythm. Group II had a trend to a trend to a lower rate of immediate recurrence of AF than group I did (4.3% vs 14.7%, P=0.067). Kaplan-Meier analysis demonstrated a higher probability of group II remaining in sinus rhythm at 4 weeks (84.3% vs 61.3%, P=0.002) and at the median follow-up period of 270 days (74.3% vs 57.3%, P=0.021) than in group II. CONCLUSIONS: The addition of enalapril to amiodarone decreased the rate of immediate and subacute arrhythmia recurrences and facilitated subsequent long-term maintenance of sinus rhythm after cardioversion of persistent AF. PMID: [PubMed - indexed for MEDLINE] The aim of this study was to investigate the effect of statin therapy on arrhythmia recurrence in patients with lone atrial fibrillation (AF). From July 1998 to December 1999, 62 patients with lone persistent AF lasting 3 months underwent successful external cardioversion. After a mean follow-up of 44 months, 85% had recurrence of AF. The use of statins was associated with a significant decrease in the risk of arrhythmia recurrence after successful cardioversion of AF. The result of this retrospective study demonstrates that the use of statins in patients with lone AF was associated with a significant decrease in the risk of arrhythmia recurrence after successful cardioversion. BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is particularly common in the elderly. Although effects of fish intake, including potential antiarrhythmic effects, may favorably influence risk of AF, relationships between fish intake and AF incidence have not been evaluated. METHODS AND RESULTS: In a prospective, population-based cohort of 4815 adults > or =age 65 years, usual dietary intake was assessed at baseline in 1989 and Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches (fish burgers) did not. AF incidence was prospectively ascertained on the basis of hospital discharge records and annual electrocardiograms. During 12 years' follow-up, 980 cases of incident AF were diagnosed. In multivariate analyses, consumption of tuna or other broiled or baked fish was inversely associated with incidence of AF, with 28% lower risk with intake 1 to 4 times per week (HR=0.72, 95% CI=0.58 to 0.91, P=0.005), and 31% lower risk with intake > or =5 times per week (HR=0.69, 95% CI=0.52 to 0.91, P=0.008), compared with <1 time per month (P trend=0.004). Results were not materially different after adjustment for preceding myocardial infarction or congestive heart failure. In similar analyses, fried fish/fish sandwich consumption was not associated with lower risk of AF. CONCLUSIONS: Among elderly adults, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower incidence of AF. Fish intake may influence risk of this common cardiac arrhythmia. Lone AF is associated with inflammation (CRP increased in lone AF, biopsy, CRP in persistent AF hoger dan paroxysmal etc…) Statins have an antiinflammatory action, they decrease CRP indpendent of cholesterol AIMS: The purpose of this trial was to compare the long-term efficacy of low-dose amiodarone with losartan and perindopril (both combined with low-dose amiodarone) for the prevention of atrial fibrillation (AF) recurrence in patients with lone paroxysmal AF. METHODS AND RESULTS: One-hundred and seventy-seven patients with lone paroxysmal AF were randomly assigned to three treatment groups: group 1 received low-dose amiodarone alone, group 2 received low-dose amiodarone plus losartan, and group 3 received low-dose amiodarone plus perindopril. Left atrial diameter was measured with transthoracic echocardiogram at baseline and 6, 12, 18, and 24 months after randomization. The primary endpoint was the incidence of AF documented by 12-lead ECG or Holter after 14 days and within 24 months after randomization. The primary endpoint was reached in 24 patients (41%) in group 1, 11 (19%) in group 2, and 14 (24%) in group 3 (P = 0.02). The Kaplan-Meier survival analysis demonstrated a significant reduction in AF recurrence in group 2 (P = 0.006, log-rank test) as well as in group 3 (P = 0.04, log-rank test) when compared with group 1. No difference in the AF recurrence-free survival was found between group 2 and group 3. After 24 months follow-up, the left atrial diameter in group 2 and group 3 was significantly smaller than that in group 1 (36 +/- 2.3 and 35 +/- 2.4 vs. 38 +/- 2.4 mm, P < for both comparisons). CONCLUSION: The results of this study suggest that the combination of perindopril or losartan with low-dose amiodarone is more effective than low-dose amiodarone alone for the prevention of AF recurrence in patients with lone paroxysmal AF. Adding losartan or perindopril to amiodarone can inhibit left atrial enlargement in this group of patients. P:0.007 P:0.006 60 120 180 240 300 360 180 360 540 720 * Days Days Madrid et al, Circulation 2002;106:331 Yin et al, Eur Heart J 2006;27;1841

ACTIVE Study Dose-adjusted OAC (INR 2.0–3.0) ACTIVE Investigators, Lancet 2006;367: Yes ACTIVE W R Irbesartan (150–300 mg/day) Clopidogrel (75 mg/d) + ASA (75–100 mg/day) n = Willing/able to take OAC Patients with AF R ACTIVE I Clopidogrel (75 mg/day) + ASA (75–100 mg/day) Placebo No R ACTIVE A Placebo + ASA (75–100 mg/day) Primary endpoint: Stroke, MI, CV death, Systemic Emboli

AF During the Next Half Decade Atrial fibrillation will become much more common Conventional therapies are only modesty effective New “safer” variations of conventional therapies are almost available Drugs with novel antiarrhythmic actions are in development New targets that prevent substrate development or suppress triggers will become available The rate versus rhythm debate will reignite Mortality and morbidity will improve

Pharmacological Prevention of Atrial Fibrillation

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