Atrial Fibrillation: What Have Recent Trials Taught Us Regarding Pharmacologic Management of Rate and Rhythm Control?

Transcription

1 REVIEW Atrial Fibrillation: What Have Recent Trials Taught Us Regarding Pharmacologic Management of Rate and Rhythm Control? JAMES A. REIFFEL, M.D. From the Department of Medicine, Division of Cardiology, Electrophysiology Section, Columbia University Medical Center, New York, New York The management of atrial fibrillation (AF) focuses on control of heart rate, correction of rhythm disturbance, prophylaxis of thromboembolism, treatment of underlying disorders, and pathophysiologic mechanisms, and more recently on costs, hospitalizations, and other AF consequences. The goals of therapy are to reduce morbidity and mortality and improve quality of life (QOL). Several large studies have examined the relative efficacy of rhythm- versus rate-control strategies with respect to these outcomes, and have largely failed to demonstrate a survival advantage with either approach by intention-to-treat analysis both in patients with and without heart failure (HF). However, the results do not support the hypothesis that rate control is preferable as first-line therapy for AF with respect to survival and do not disprove the hypothesis that maintenance of sinus rhythm is preferable to the continuation of AF, particularly if rate control fails to restore adequate QOL or if selective approaches are employed. Many post hoc analyses and substudies have assessed QOL, functional status, and exercise tolerance, with the majority demonstrating important benefits associated with achievement of rhythm control. Moreover, some subanalyses and additional trials have suggested that sinus rhythm can be associated with longer survival, including in patients with HF. In addition, ATHENA demonstrated that a drug, dronedarone, could improve the composite endpoint of cardiovascular hospitalizations and all-cause mortality in a carefully selected, high-risk, nonpermanent AF population, in addition to its recognized reduction in AF. This review examines the clinical outcomes of several important AF trials, discusses the limitations in applying the major morbidity/mortality findings to everyday clinical practice, and summarizes the lessons learned. (PACE 2011; 34: ) atrial fibrillation, rate control, rhythm control, quality of life Introduction Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance experienced by patients and encountered by physicians 1 and is currently estimated to affect between 2.3 Disclosure statement: Dr. Reiffel has been an investigator in multiple trials reviewed in this manuscript; and, with respect to the agents used in these trials, he has also performed research studies supported by, served as an advisor to, and/or has served on a Speaker s Bureau supported by the following pharmaceutical manufacturers during the past 3 years: Sanofi-Aventis, GlaxoSmithKline, CV Therapeutics, Cardiome, Gilead, Merck, Boehringer Ingleheim, and Xention Discovery. Dr. Reiffel received no financial support for the preparation of this manuscript and the editorial content is entirely his own. Address for reprints: James A. Reiffel, M.D., Professor of Clinical Medicine, Columbia University, 161 Fort Washington Avenue, New York, NY Fax: ; jar2@columbia.edu Received March 31, 2010; revised August 10, 2010; accepted September 6, doi: /j x and 5.1 million people in the United States alone, numbers that are expected to reach 5.6 to 15.9 million by the year ,3 The overall prevalence of diagnosed AF has been estimated at 1% in the general population, with rates increasing with age (>7% and >10% in women and men 80 years old, respectively) and with the severity of heart failure (HF). 2,4 AF often is associated with underlying structural heart disease: hypertension ( 50% of AF patients), coronary artery disease (25%), HF (23% to 29%), and valvular heart disease (17%). 5 Symptoms of AF may include palpitations, angina, dyspnea, lightheadedness (and, rarely, syncope), chronic fatigue, and impaired exercise tolerance. These symptoms are also common in patients with significant underlying structural heart disease, including HF, and are thus nonspecific to AF; however, AF may be asymptomatic. Reduced ventricular compliance, as is associated with both systolic and diastolic ventricular dysfunction, often magnifies the severity of symptoms. Irrespective of symptoms, AF leads to considerable health concerns. All-cause mortality C 2010, The Author. Journal compilation C 2010 Wiley Periodicals, Inc. PACE, Vol. 34 February

2 REIFFEL is increased by 1.5- to 1.9-fold compared with individuals in sinus rhythm. 6 Hospitalizations for AF have increased significantly in the United States in recent years, increasing two- to threefold between 1985 and 1999 (to more than 2.2 million annually). 7 Clinically, AF can decrease cardiac output; can induce cardiomyopathy and HF, particularly when ventricular rates are rapid; can worsen the quality of life (QOL) in patients with prior HF; and can increase the long-term risk of stroke Further, AF is associated with a significant economic burden. 13,14 Therapeutic strategies targeting improved longevity and/or QOL in patients with AF include both rate and rhythm-control approaches. Accordingly, several major studies have examined rate versus rhythm strategies for the treatment of AF Notably, these studies, using thenavailable antiarrhythmic therapies, were unable to demonstrate a survival advantage to a rhythmcontrol approach. Nor have subsequent trials with other drug or nonpharmacologic therapies. Nonetheless, the results should not be interpreted to indicate that rate control is therefore as preferable a first-line therapy for AF as is the pursuit of sinus rhythm. A rhythm-control strategy does not ensure the attainment of sinus rhythm or the outcomes that might accrue from it. This review examines these and other important AF trials to assess the lessons learned from them, their limitations, and their applications to clinical practice, and contrasts, where appropriate, results in patients with and without HF. Because these trials have been largely pharmacotherapy trials, rather than ablation trials and as pharmacotherapy, not ablation, is the firstline approach to AF management in the most recent American College of Cardiology/American Heart Association/European Society of Cardiology [ACC/AHA/ESC] AF guidelines ablation trials are not considered in this manuscript. Ideally, the true comparison of drug versus ablation therapy will come from the ongoing CAtheter ablation versus antiarrhythmic drug therapy for Atrial fibrillation (CABANA) trial. 21 Similarly, because this manuscript is meant to deal primarily with major outcome benefits regarding the treatment approaches to AF, rather than to individual antiarrhythmic drug efficacy endpoints such as time to first AF recurrence, it also does not consider drug-by-drug efficacy trials targeting this type of endpoint. Initial Considerations: Treatment Goals, Interpreting Trials, and Selecting Therapeutic Strategies The clinical consequences of untreated AF are well known and treatment goals target their reduction. Potential target outcomes include improvements in symptoms and QOL, prevention of disease progression, reduction of adverse clinical and economic outcomes, and, if possible, reducing the incidence of premature death. Treatment strategies for AF are focused on three main goals: control of heart rate, correction of the rhythm disturbance, and prophylaxis of thromboembolism. 22 Although rate or rhythm control often is chosen as the primary focus of therapy, these strategies are not mutually exclusive; rate control during recurrences is a required part of a rhythm-control strategy, and some agents, such as sotalol, amiodarone, and dronedarone may alter both inseparably. The choice of a rate- or rhythm-control strategy as a primary goal is dependent on multiple factors, including the duration and pattern of AF, the type and severity of symptoms, the presence of cardiovascular disease, intrinsic atrioventricular node function status, and the safety profiles of the treatments under consideration. Some of these factors are reviewed in more detail in a recent Controversies In Cardiovascular Medicine debate. 23 Notably, a rate- versus rhythm-control strategy is not required for all AF patients. For example, infrequent, transient, minimally symptomatic episodes that might last for only minutes, months apart, probably do not require treatment. Moreover, recurrences of this type during drug therapy may not constitute treatment failure. Similar infrequent but longer episodes may be best treated with only cardioversion, as needed. However, since AF begets AF through adverse remodeling, there must come a point where treatment of some intermittent pattern may benefit what could be a progressive disorder. Hence, therapy (drug or otherwise) must be matched to presentation characteristics and be focused on appropriate target goals while, at the same time, minimizing the potential for adverse events. In addition, treatment of underlying disorders and the atrial pathophysiologic changes that may be consequent to them (e.g., electrical and structural remodeling) 24,25 should also be pursued. To this end, so-called upstream therapies may be helpful, including treatment with angiotensinconverting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), statins, omega 3 fish oil, and other agents in selected populations Further, prophylaxis of thromboembolism must also be considered, irrespective of rate- or rhythm-control treatment strategy; the need for anticoagulation therapy is based on the overall risk of stroke not on the restoration or maintenance of sinus rhythm, regardless of whether it is by a pharmacologic or an ablative approach. Finally, in addition to survival and QOL, our 248 February 2011 PACE,Vol.34

3 REVIEW OF RECENT TRIALS IN AF current state of medical costs and payments necessitates yet another treatment goal: that of reducing the personal and societal economic burden of AF. (Note, while antithrombotic therapy for prevention of stroke and systemic embolism in AF is also a pharmacologic therapy, it is not a focus of review in this manuscript.) The determination of whether maintenance of sinus rhythm should be the optimal goal for patients with AF requires an evaluation of the effects of achieving normal sinus rhythm on both survival and QOL. Between 2000 and 2003, five significant prospective trials AFFIRM, RACE, PIAF, HOT CAFE, and STAF were conducted for the purpose of comparing rhythm- and rate-control strategies These trials included patients with a history of HF or reduced left ventricular ejection fraction (LVEF) but were not specific for them (Table I). Their findings were later confirmed in a large series of HF patients with the Atrial Fibrillation-Congestive Heart Failure (AF-CHF) trial. 29 Each of the six trials failed to show a survival benefit associated with rhythm-control strategies. Notably, this should not be taken to indicate that rate-control strategies are equivalent to maintenance of sinus rhythm. It merely suggests that, using intent-to-treat (ITT) analyses of the therapies employed at the time of each trial, the rhythm- and rate-control strategies appeared to be equivalent with regard to effects on mortality. Moreover, because rhythm control did not carry a statistically significant excess risk over rate control in these studies, the results do not support rate control as a sufficient strategy when it does not restore adequate QOL to patients with AF. To this point, patients who were enrolled in these trials would presumably have been unwilling to participate if they previously remained symptomatic on prior rate-control therapy; this, in fact, was our experience while enrolling in the AFFIRM trial, and, to this point, the percentage of HF patients (commonly severely symptomatic in AF) enrolled in these trials prior to AF-CHF was not high (see below and Table I). Of course, if antiarrhythmic therapy fails to achieve sinus rhythm, it, too, will fail to restore adequate QOL to the patient with symptomatic AF. Importantly, each of the above trials had primary outcome endpoints of mortality or a composite including mortality. In clinical practice, a change in the pattern of AF from frequent and protracted to rare and brief would constitute clinical success but would be considered irrelevant in trials focused upon a mortality endpoint or in most prior AF trials where time to first recurrence has been the most Table I. Frequency of Heart Failure History and Measurements of Impaired Ventricular Systolic Function in Important AF Trials Patients with a Patients Trial History of HF LVEF or Alternative (N) ATHENA 29% 4% with LVEF < 35% 4,628 AFFIRM 9% Mean LVEF 54% (26% < 50%) 4,060 AF-CHF 100% Mean LVEF 28% (100% < 35%) 1,367 J-Rhythm 30% Mean LVEF 66% 823 Safe-T Excluded class III/IV; Mean LVEF 50% % HF class I/II RACE 19% 30% fractional shortening 522 Diamond AF 100% 77% WMI < CHF-Stat (AF subgroup) 100% Mean LVEF 25% 103 CTAF HF not listed 6% LVEF < 50% 403 PIAF HF excluded EF not stated 252 HOT-CAFÉ 99% Mean fractional shortening 31% 205 STAF HF history not listed 14% LVEF < 45% 200 AF-CHF = Atrial Fibrillation and Congestive Heart Failure; AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; ATHENA = A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patients with Atrial fibrillation/atrial flutter; J-Rhythm = Japanese Rhythm Management Trial for Atrial Fibrillation; Safe-T = Sotalol Amiodarone atrial Fibrillation Efficacy Trial; RACE = RAte Control versus Electrical cardioversion; Diamond AF = Danish Investigations of Arrhythmia and Mortality ON Dofetilide atrial fibrillation; CHF-Stat (AF subgroup) = Congestive Heart Failure: Survival Trial of Antiarrhythmic Therapy; CTAF = Canadian Trial of Atrial Fibrillation; PIAF = Pharmacologic Intervention in Atrial Fibrillation; HOT-CAFÉ = HOw to Treat Chronic Atrial Fibrillation; STAF = Strategies of Treatment of Atrial Fibrillation; EF = ejection fraction; HF = heart failure; LVEF = left ventricular ejection fraction; WMI = wall motion index. PACE,Vol.34 February

4 REIFFEL common primary endpoint. Similarly, so would be the reduction in outcome events associated with AF, such as hospitalization, even if the time to the first AF episode or the total number of AF episodes were not changed. The complete absence of AF recurrence may be unachievable and impractical, whereas fewer and shorter AF episodes and fewer AF consequences would appear to be a more realistic goal from the standpoint of everyday clinical practice, analogous to treatment goals in angina pectoris especially in the highly symptomatic coronary artery disease patient. With AF, survival remains an important criterion of success for any treatment, but by itself is not a sufficient measure. The QOL of patients with AF is poorer than that of the overall population, and, regardless of the fact that QOL across the spectrum of AF, as with coronary heart disease, shows substantial interpatient variability, QOL in AF was reported to be even worse, overall, than that of patients with coronary heart disease. 30 In addition, AF often leads to or worsens HF, which may further impair QOL, decrease productivity, increase resource utilization, and increase morbidity rates. QOL is a subjective measure that is affected by many consequences of AF and the specific therapies applied, and the patient s QOL may be affected by the symptoms of AF on a day-to-day basis. In addition, reducing the risk of thromboembolism and stroke may be one of the most important considerations for improving QOL and one that resonates as strongly with patients as does the potential for reducing the risk of premature death. Finally, as with all medical decisions, costs must be considered, and reduced economic burden is another important measure of treatment success. Economic burden can be influenced and measured by hospitalizations, treatment costs, costs related to complications, QOL issues, and the functional status of patients. Healthcare costs are approximately five times higher for patients with AF than for those without it, and hospitalizations are a key contributor. 13,14 A Contemporary Look at Important Clinical Trials of (or of Relevance to) the Pharmacotherapy of AF This section summarizes several noteworthy observations that have been published based on data from key trials of relevance to AF, in addition to the primary efficacy and safety findings. The results provide additional insight on whether sinus rhythm may afford important survival and/or QOL benefits for patients with AF. Effects on Mortality AFFIRM The AFFIRM study (N = 4,060) compared survival with rhythm- versus rate-control strategies in patients with AF and a high risk of stroke or death. 17 At 5 years, the ITT analysis showed that the overall mortality rate (primary endpoint) was 23.8% in the rhythm-control group and 21.3% in the rate-control group (P = 0.08). Interestingly, the rates of cardiovascular death (9% and 10%, respectively) and vascular death (3% and 3%, respectively) were comparable between the two treatment arms, but the rate of noncardiovascular death was significantly higher in the rhythm-control group (12% vs 8% for rate control; P = ). 31 The difference between treatment groups in noncardiovascular mortality being the primary endpoint was driven primarily by pulmonary and cancer-related deaths. The drug used most commonly in the rhythm-control arm was amiodarone ( two-thirds of the cases). The primary analysis, which addressed mortality, did not assess changes in QOL (see below). In AFFIRM, the largest AF trial to its time, only 9% of enrollees had a history of HF and only 26% had an LVEF <50% (mean LVEF 54%). Consequently, it could be considered that its results may not be applicable to a HF population. Moreover, comparisons of rhythmand rate-control strategies in AFFIRM are limited by the constraints of the prespecified ITT analysis. 17 Throughout AFFIRM, many patients in the rhythm-control arm remained in AF (e.g., 17.6%, 26.7%, and 37.4% at 1, 3, and 5 years, respectively). Conversely, many patients in the rate-control arm had paroxysmal AF (PAF) and were in fact in sinus rhythm for some or most of the time even without an antiarrhythmic drug. At 5 years, for example, 34.6% of patients in the rate-control group were in sinus rhythm. Thus, the AFFIRM study compared treatment algorithms based on currently available therapies and strategies, not outcomes based on whether a patient was in AF or sinus rhythm. Although the use of antiarrhythmic drugs increased the risk of death by 49% after adjusting for the presence of sinus rhythm (P = ), the presence of sinus rhythm was associated with a better survival rate (P < ). 32 These results suggest that the antiarrhythmic drugs used in AFFIRM (mainly amiodarone) were neither highly efficacious nor safe, at least in its patient population. Given amiodarone s commonplace use for AF in patients with HF, this safety observation should be of great relevance to its further use in such patients. Moreover, given amiodarone s superior efficacy in AF compared with other agents, such as 250 February 2011 PACE,Vol.34

5 REVIEW OF RECENT TRIALS IN AF propafenone and sotalol in the CTAF trial 33 and dronedarone in the DIONYSOS trial, 34 it seems we have no current antiarrhythmic pharmacological approach that simultaneously maximizes efficacy and safety hopefully, an attainable goal of both further drug development and of ablative approaches for AF. The above-noted results from AFFIRM should not be extrapolated to all patients with AF, independent of the small proportion with HF. Approximately 60% of the population was male, and most had persistent AF (69%) rather than PAF (31%). Very few had lone AF (12%). 17 Because the trial was performed in a relatively elderly population (mean age, 70 years), most of whom had additional risk factors for stroke and death, the findings cannot be generalized to younger, healthier patients. A retrospective subanalysis of data from AFFIRM suggests that younger patients (<65 years of age) and those with a history of HF may derive a greater survival benefit with rhythmcontrol drugs. 32 However, no mortality benefit was observed in patients with HF receiving rhythm control (vs rate control) in the AF-CHF study (see below). 35,36 RACE The RACE trial (N = 522) compared rhythm versus rate control strategies among patients with persistent AF, some with mild to moderate HF. 18 Nineteen percent had a history of HF and by echocardiography, the mean percent fractional shortening was 30%. The primary endpoint was a composite outcome measure that included cardiovascular death, hospitalizations for HF, thromboembolic complications, severe hemorrhage, pacemaker implantation, and severe adverse events. Overall, no difference was observed between the treatment arms with respect to the study s primary endpoint. Similar to the AFFIRM study, patients who were in sinus rhythm at 1 month had the option to discontinue treatment with anticoagulants or switch to aspirin, and this aspect of the study design could have produced a bias in the observed rates of thromboembolic events. However, in a subanalysis, patients who remained in sinus rhythm while receiving rhythm control and anticoagulation treatment did not have a better prognosis for survival. 37 Although the overall primary composite endpoint rates were similar between patients successfully treated with rhythm control and those who were in AF at study end, the individual component rates were different. Specifically, a post hoc analysis showed that, compared with patients in AF at the end of the study, those in sinus rhythm had lower incidence rates of cardiovascular mortality (0% vs 9.5%), progression of HF (2.1% vs 4.8%), bleeding (0% vs 4.8%), and pacemaker implantation (2.1% vs 6.0%) but higher incidence rates of thromboembolic complications (10.6% vs 7.1%) and adverse drug effects (8.5% vs 3.6%). 38 These data suggest that several clinically important outcomes may improve when sinus rhythm is achieved and maintained, including a reduction of HF progression (which would be expected to result in reduced hospitalization and costs), and/or that patients in whom sinus rhythm can be maintained represent a healthier population, regardless of which treatment strategy is employed. An analysis of events versus specific therapies used has not been presented for RACE. STAF The STAF pilot trial (N = 200) compared rhythm- versus rate-control strategies among patients with persistent AF. 19 The trial report did not provide data on the percent of patients with a history of HF; only 14% had an LVEF < 45%. There was no significant difference between the treatment groups with respect to the primary endpoint, which was a composite of death, stroke or transient ischemic attack, systemic embolism, and cardiopulmonary resuscitation. The primary endpoint occurred in nine of 100 patients in the rhythm-control group and 10 of 100 in the ratecontrol group. Of note, only one of the 19 patients was in sinus rhythm at the time of the primary outcome event (P = 0.049). This suggests that intractable AF is associated with greater morbidity and mortality and that sinus rhythm can be of benefit in reducing morbidity and mortality and/or that it can only be attained in patients with lesssevere disease and intrinsically better outcomes. This interpretation is supported by observations from the DIAMOND, CHF-STAT, and possibly the J-Rhythm trials. 16,39,40 (The STAF trial was too small to assess outcomes versus a specific therapy and too small to do a HF subanalysis.) Trials with More Direct Relevance to HF Patients with AF DIAMOND DIAMOND was a trial that assessed survival exclusively in HF patients (mean wall motion index by echocardiography was reduced with 77% having a value < 0.8), with and without coronary disease, treated with dofetilide versus placebo. 16 An AF substudy, DIAMOND AF (N = 506), investigated the potential of dofetilide to restore and maintain sinus rhythm in patients with AF or atrial flutter. Mortality was a secondary outcome. Differences in favor of dofetilide were observed for the primary endpoint: conversion to sinus rhythm occurred in 44% of dofetilide-treated patients and PACE,Vol.34 February

6 REIFFEL 14% of placebo-treated patients over the course of the study (P < 0.001). The 1-year probabilities of maintaining sinus rhythm were 79% and 42%, respectively (P < 0.001). There was no significant difference in mortality rate between the two treatment groups, dofetilide versus placebo. However, regardless of treatment, the mortality rate was significantly lower in patients who experienced restoration and maintenance of sinus rhythm than in those who did not convert to sinus rhythm (risk ratio: 0.44; 95% confidence interval [CI] 0.30 to 0.64; P < ). (See Fig. 1 for results by treatment group.) These data seem consistent with the expectation that in patients with HF, sinus rhythm can improve survival if its benefits are not offset by drug-related adverse events; however, the complex interaction between AF, more severe HF, and death confound any simple relationship analysis. It is on the basis of this trial that dofetilide became one of the recommended agents for AF in patients with HF in the ACC/AHA/ESC guidelines. However, this DIAMOND trial report did not include data specific to QOL or hospitalization. CHF-STAT The CHF-STAT trial included a subgroup of 103 patients who had both AF and HF at baseline. The mean LVEF in this CHF-STAT subgroup was 25%. For this subgroup, Deedwania and colleagues 39 observed the effects of amiodarone versus placebo in converting and maintaining sinus rhythm relative to survival patterns. Sixteen of 51 amiodarone-treated patients (31.4%) and four of 52 patients receiving placebo (7.7%) converted to and remained in sinus rhythm for the duration of the study (P = 0.002). Although no difference in mortality rate was noted between the two treatment groups overall, the survival rate was significantly higher among amiodarone-treated patients who converted to and remained in sinus rhythm (n = 16) than for amiodarone-treated patients who remained in AF (n = 35; P = 0.04). These results reinforce the DIAMOND observations, though they have the same confounding interrelationships. The trial was too small, however, to truly assess the risk versus benefit profile of amiodarone in this setting and did not focus on hospitalizations, QOL, or costs. J-Rhythm The J-Rhythm trial 40 assessed rhythm versus rate control in 823 Japanese patients with PAF and 163 patients with persistent AF. Thirty percent had a history of HF, although the mean LVEF was normal. The primary endpoint was a composite of all-cause mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for HF requiring intravenous administration of diuretics, and physical or psychological disablement requiring discontinuation of therapy. Maintenance of sinus rhythm occurred more frequently in the rhythm-control group and resulted in a better event-free survival rate than in the rate-control group (85% vs 78%). However, the difference in rates between the groups was significant only for patients with PAF (P = ). Figure 1. DIAMOND: Survival rates for patients treated with dofetilide (A) or placebo (B) who converted or did not convert to sinus rhythm (SR). 16 AF-CHF More recently, the AF-CHF trial compared rhythm control versus rate control in 1,367 patients with AF, Classes II IV HF, and an LVEF 35%. 36 The mean LVEF was 28%. Patients assigned to rhythm control received direct current cardioversion and antiarrhythmic therapy, primarily with amiodarone (82% of cases). Rate-control strategies consisted of β-blockers 252 February 2011 PACE,Vol.34

7 REVIEW OF RECENT TRIALS IN AF and digoxin, with pacemaker therapy and atrioventricular node ablation when necessary. As in previous rate- versus rhythm-control studies, using an ITT analysis 35,36 there was no difference between the two strategies in terms of cardiovascular deaths, the primary endpoint, or predefined secondary endpoints of death from any cause; worsening HF; stroke; and the composite endpoint of cardiovascular death, stroke, and hospitalization. Data on outcomes for patients who achieved normal sinus rhythm are not yet available for this trial, though at 4 years of follow up, 73% of patients in the rhythmcontrol group were maintained in sinus rhythm. 36 Perhaps importantly, like AFFIRM, the principal antiarrhythmic drug chosen was amiodarone. It is therefore implicit that the results might have been different, as they were in the drug-arm patients in DIAMOND who attained sinus rhythm with dofetilide, had a less-toxic agent been available and utilized. ATHENA and ANDROMEDA ATHENA Most recently, results from the ATHENA trial were published. 41 Although ATHENA was not a rate- versus rhythm-control trial, its results hold relevance to the pharmacotherapy of AF in the current era, especially if the results of the ratecontrol arms in such trials are loosely viewed as akin to what might occur in a placebo-treated arm of a randomized, antiarrhythmic, drug versus placebo trial. In particular, ATHENA provides insight into another relevant clinical endpoint (hospitalizations), as well as additional data regarding mortality outcomes on antiarrhythmic drug therapy. ATHENA was a multicenter trial in which 4,628 patients with PAF or persistent AF and high-risk markers for stroke or death were randomized to receive dronedarone or placebo. Dronedarone is a benzofuran derivative with a pharmacologic profile resembling that of amiodarone, but with different relative effects on individual ion channels. Dronedarone s halflife is approximately 24 hours, which reduces its accumulation in tissue, and it appears to have a reduced risk of thyroid and pulmonary toxicity, compared with amiodarone. 41 In ATHENA, patients with classes I III HF were eligible for enrollment (29% of patients had a history of HF) but those with class IV HF or recently decompensated HF were excluded from participation. Only 4% had an LVEF < 35%. The ATHENA population was in many respects similar to that of AFFIRM, but it did have a higher percentage with a HF history and an older mean age (Table II). The primary endpoint and the corresponding results of ATHENA contrast notably to those of prior antiarrhythmic trials in AF patients. In ATHENA, patients were followed for a mean of 21 months; the primary outcome was the first hospitalization due to cardiovascular hospitalization or death in the ITT population, and secondary outcomes were death from any cause, death from cardiovascular causes, and hospitalization due to cardiovascular events in the ITT population. The primary outcome occurred in 734 patients (31.9%) in the dronedarone group and in 917 patients (39.4%) in the placebo group, with a hazard ratio (HR) Table II. Contrasting Results in Atrial Fibrillation: What Is the Message? Trial Patients Drug Outcome AFFIRM 17 ATHENA 41 AF Age 65 years or above with additional risk factor(s) and a recent episode. Mean age 69 years; 61% male; 51% HTN; 26% CAD; 9% HF; mean LVEF: 54%. AF Age 75 years, or 70 or above with additional risk factor(s) and a recent episode. 42% age 75 years and above; 63% male; 86% HTN; 30% CAD; 29% HF; 4% with LVEF < 35%. Amiodarone (67%) Dronedarone No survival benefit versus rate control. Trend toward increased mortality (P = 0.08) (non-cv). No difference in CV mortality. Reduced CV hospitalization and mortality (composite endpoint) and CV mortality. AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; ATHENA = A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patients with Atrial fibrillation/atrial flutter; CAD = coronary heart disease; CV = cardiovascular; HF = heart failure; HTN = hypertension; LVEF = left ventricular ejection fraction. PACE,Vol.34 February

8 REIFFEL for dronedarone of 0.76 (95% CI 0.66 to 0.84; P < 0.001). This difference was largely due to a reduction in hospitalization related to AF and included fewer patients admitted with acute AF and hemodynamic decompensation, fewer patients admitted for cardioversion or to change antiarrhythmic therapy, and, no doubt, fewer patients admitted with symptoms from rapid AF, as dronedarone does slow the ventricular response to AF. Therefore, its benefit may have been both from rhythm control and, in some patients, from rate control. In addition, there were 63 deaths from cardiovascular causes (2.7%) in the dronedarone group and 90 (3.9%) in the placebo group (HR, 0.71; 95% CI 0.51 to 0.98; P = 0.03). This was largely due to a reduction in the rate of death from arrhythmia with dronedarone. 41 Further, there was a nonsignificant (P = 0.24) reduction in total mortality (relative risk, 0.86) in the dronedarone arm (that contrasts with the amiodarone experience in AFFIRM). Contributing to this may have been fewer coronary artery deaths, as acute coronary syndrome was reduced in the dronedarone arm versus placebo in ATHENA, or fewer stroke deaths, as a retrospective analysis 42 suggested a reduction of stroke in the dronedarone arm versus placebo, or other factors. Notably, had ANDROMEDA not been performed first, which led to careful exclusion criteria due to HF for ATHENA, it is possible that the beneficial mortality trend in ATHENA might not have occurred. Interestingly, both active and placebo arms demonstrated a lower-than-expected mortality rate in ATHENA. (See Fig. 2 for results by treatment group.) In terms of safety, the dronedarone group had higher rates of adverse events, including bradycardia, QT-interval prolongation, nausea, diarrhea, rash, and increased serum creatinine levels (that were not associated with renal failure), but the rates of thyroid- and pulmonary-related adverse events were not significantly different between the two groups. One significant limitation of the ATHENA trial is that the rate of premature discontinuation of dronedarone was high (30.2%). This may have resulted in an underestimation of both the benefit and the incidence of adverse events with this drug. When considering the ATHENA trial, we also must consider in conjunction the ANDROMEDA trial. 43 ANDROMEDA compared HF hospitalization and mortality in patients with advanced HF (LVEF < 35% plus recent decompensation leading to hospitalization) without any AF requirement. ANDROMEDA was stopped prematurely by the Data Safety Monitoring Board due to an increased event rate with dronedarone versus placebo (with a relative mortality risk of 2.13). Consequent to ANDROMEDA, ATHENA specifically excluded patients who had either hemodynamic instability or severe (New York Heart Association [NYHA] class IV) HF (see above). It therefore appears that dronedarone increases cardiovascular mortality among patients with advanced and recently decompensated HF, but reduces cardiovascular hospitalization with a trend toward lower cardiovascular mortality in patients with AF and less-severe HF. 41 These endpoints were attained without the toxicity associated with amiodarone, as thyroid, pulmonary, hepatic, and other severe organ compromise have not been noted in the clinical trials with dronedarone. However, of note, follow-up periods in the dronedarone trials published to date have not exceeded 3 years. Thus, these two dronedarone trials taken together suggest that for many patients with HF (excluding those with class IV or recent decompensation), as well as for patients with other high-risk markers (as were used in the enrollment criteria for ATHENA and that are now part of the drug s Food and Drug Administration [FDA]-approved indication, see below), dronedarone should be a first-line consideration for AF when rhythm control is the strategy chosen. Dronedarone not only can reduce AF episodes but also reduce the composite of hospitalization and cardiovascular mortality that can be associated with them. It should be noted that these endpoints have not yet been demonstrated as clinically significant in a clinical trial of any other antiarrhythmic drug currently available. 44 Conversely, if dronedarone were used for patients with AF without high-risk markers (that would be an off-label use in the United States), one should also recall that the true long-term safety profile of this agent still remains to be verified with longer follow-up observation periods than exist at present a factor to consider when deciding upon it versus a class IC agent or sotalol, which have been available for decades. The mechanism of excessive risk with dronedarone in ANDROMEDA remains speculative but could include an adverse interaction with dronedarone and the typical modes of death (bradycardia, electromechanical dissociation) seen in hospitalized patients with severe HF, 45 as dronedarone can demonstrate negative chronotropic and dromotropic actions, as well as a higher discontinuation rate of ACE inhibitors and ARBs, agents which increase survival in HF patient, in the dronedarone arm compared with the placebo arm. Discontinuations occurred because of a then-underappreciated action of dronedarone that of altering renal tubular handling of creatinine, such that serum levels can rise although glomerular filtration rate is unchanged, which, if misinterpreted as a reduction in renal 254 February 2011 PACE,Vol.34

9 REVIEW OF RECENT TRIALS IN AF Figure 2. ATHENA: Kaplan-Meier cumulative indices of the primary and secondary outcomes. Composite cumulative incidence of first hospitalization due to cardiovascular events or death from any cause (Panel A), cumulative incidence of death from any cause (Panel B), cumulative incidence of death from cardiovascular causes (Panel C), and cumulative incidence of first hospitalization due to cardiovascular events (Panel D). 41 function, could have led physicians to reduce ACE inhibitors and ARBs inappropriately. Notably, the negative dromotropic effect of dronedarone has been demonstrated in a reduction of the ventricular rate during AF. 46,47 Consequent to ATHENA and ANDROMEDA, in July 2009, the United States FDA approved dronedarone for marketing with an indication to reduce the risk of hospitalization in patients with AF or atrial flutter and associated cardiovascular risk factors (e.g., age > 70 years, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or larger, or LVEF of 40% or less) who have had at least one recent episode and who are in sinus rhythm or will be cardioverted. 48 It should be noted that dronedarone is contraindicated in patients with NYHA class IV HF or NYHA classes II III HF with a recent decompensation requiring hospitalization or referral to a specialized HF clinic (Fig. 3). This FDA approval reflects the observation that no other antiarrhythmic agent, aside from dronedarone in the ATHENA trial, has been shown in a large, randomized trial to prevent hospitalizations due to cardiovascular events or death 41 and contrasts starkly to the amiodarone experience in AFFIRM, which enrolled a similar patient population. More recently, dronedarone has been approved in Europe for the reduction of AF and for rate reduction in AF. Taken in concert with the STAF and DIAMOND data, ATHENA suggests that the attainment and maintenance of sinus rhythm in high-risk AF patients can be PACE,Vol.34 February

10 REIFFEL Figure 3. A proposed role for dronedarone as a first-line agent for AF as stratified by the categories of the ACC/AHA/ESC algorithm and in keeping with its specific approved indication. 44 associated with a reduced mortality, if adverse outcomes from the therapy used do not offset it. Effects on QOL, Functional Status, and Exercise Tolerance The primary objective of most of the previously mentioned trials was to assess mortality, either alone or as part of a composite endpoint. However, because AF significantly impairs QOL, patients perception of QOL may be independent of the objective measures of disease severity that have traditionally been employed as primary outcome parameters in clinical trials. 49 In light of this, many post hoc analyses and substudies have assessed QOL, functional status, and exercise tolerance, and the majority of these analyses suggest that there are important benefits associated with rhythm-control strategies aside from survival considerations. 15,20,40,50 58 These may be more applicable to the wider world of AF patients who have reduced QOL and bothersome symptoms, despite the absence of markers of high mortality/stroke risk or of HF. However, included in this series is the small-scale HOT-CAFÉ trial (see below). For several reasons, caution should be used when interpreting QOL data. Both patient and physician expectations with respect to symptoms, QOL, and adverse effects can differ depending on whether a rate-control or rhythmcontrol strategy is pursued, potentially leading to subject bias. In addition, the choice of a specific rate-control or rhythm-control agent, as well as the dose of the agent, can affect QOL results. So can confused expectations when symptoms may be the result of AF or of HF. Further, bias may exist with respect to patient selection (e.g., the ability to maintain sinus rhythm may be selective for less sick patients and thus lead to better outcomes). HOT CAFÉ The HOT-CAFÉ trial was a small-scale (N = 205) study that compared rhythm- versus ratecontrol strategies in patients with persistent AF. 20 It enrolled patients with HF history (99% of subjects) and a mean percent fractional shortening of 31% by echocardiography. Rates for the primary endpoint, a composite of death, thromboembolic complications, and intracranial or other major hemorrhage, did not differ significantly between the two treatment groups. However, at the end of the study, maximal workload, assessed by a treadmill test, and exercise duration were significantly better among patients in the rhythmcontrol arm (both P < 0.001). Both rhythm and rate control similarly prevented the development of recurrent and/or progression of HF. Maintenance of Sinus Rhythm and Progression of AF or Resolution of its Atrial Alterations If sinus rhythm can improve the decreased QOL and increased mortality that can be 256 February 2011 PACE,Vol.34

11 REVIEW OF RECENT TRIALS IN AF associated with AF, then one would also hope that sinus rhythm could beneficially impact on the commonly encountered progression of AF over time. Although results from the studies reviewed herein suggest that there are benefits to achieving sinus rhythm with respect to QOL and can be with regard to overall mortality, cardiovascular mortality, and cardiovascular hospitalization using currently available approaches, it is more difficult to assess the role of sinus rhythm control in preventing the natural progression of AF from the initial episode to permanent AF. Dittrich and colleagues 59 showed that the duration of AF predicts whether sinus rhythm will be maintained at 1 month after successful initial cardioversion. In their study, maintenance of sinus rhythm at 1 month was more likely in patients with an AF duration of <3 months than in those with AF duration of >12 months (P < 0.05), suggesting a relative urgency for treatment. This is consistent with the hypothesis that there is greater potential for reverse remodeling and long-term maintenance of normal sinus rhythm when normalization is achieved early in the course of treatment. In addition, the PAF 2 trial showed that after ablation and pacing therapy, pharmacologically controlled sinus rhythm lowered the risk of progression from PAF to permanent AF by 57% (P = 0.02). 60 The RACE trial demonstrated that maintenance of sinus rhythm was associated with reduced atrial size (remodeling) and improved left ventricular function (P < 0.05), two contributory factors to the presence of AF. 61 In HOT CAFE, only patients in the rhythm-control group had an increase in left ventricular fractional shortening (P < 0.001). 20 However, none of the above datasets have specifically contrasted outcomes in HF versus non-hf patients. Of related importance clinically, although several drug and ablation studies have shown that atrial size regresses toward normal and that atrial function improves with the attainment of sinus rhythm, complete normalization of size and full restoration of function do not generally occur. This has implications regarding the need for chronic antiarrhythmic therapy. In addition, few data exist regarding restoration of atrial secretory function and reduction in biochemical thrombogenic factors in patients who achieve and maintain normal sinus rhythm but may have residual atrial anatomic and mechanical dysfunction. Thus, discontinuation of anticoagulation should not be considered at this time for AF patients with a significant CHADS 2 score despite conversion to and maintenance of sinus rhythm. This is of particular relevance to the HF patient as HF, by itself, contributes a point to the CHADS 2 score. Conclusions: Lessons Learned The rate- versus rhythm-control clinical trials conducted in patients with AF do not show an advantage to rhythm control over rate control with regard to mortality using the therapies employed in the populations studied by ITT analysis. However, the trend results of the ATHENA trial may suggest that a survival benefit might have accrued if dronedarone had been available in them. DIAMOND, in which dofetilide showed no mortality difference in HF when compared with placebo, also raises the question of whether trials such as AFFIRM would have had different results had amiodarone been used more sparingly and dofetilide used more frequently. In addition, based on the available data, clear and thorough comparisons of outcomes between patients who achieve normal sinus rhythm and those who achieve rate control are not yet possible given the variety of limitations in the trials cited. For example, use of the ITT approach to data analysis is of only partial relevance to everyday practice, though it is the primary method and sometimes the only method of analysis reported in peerreviewed publications. ITT analysis is a potent statistical approach and certainly demonstrates what to expect when a strategy is employed. However, in practice, the success of therapy is not assessed by an intention to treat a patient; it is assessed by what happens when the patient is treated. That is, patients may be successfully treated with the first therapy; they may undergo a series of therapies before one is deemed successful; or they may crossover from one approach (e.g., drugs) to another (e.g., ablation). It is the final therapy that ultimately claims the benefit or the harm, rather than the initial therapy selected. Herein is the issue of a rate- versus rhythm-control study in contrast to whether the patient actually maintains sinus rhythm or not, and to what benefit and at what cost. It is therefore problematic that many patients will remain in AF despite treatment with the currently available antiarrhythmic drugs, and this lack of efficacy is frequently accompanied by adverse-event profiles that are less than ideal. It is noteworthy, therefore, that several non-itt analyses and/or substudies have found reductions in mortality and improvements in QOL, functional status, and exercise tolerance when sinus rhythm was achieved and maintained as noted in the DIAMOND AF and CHF-STAT trials (both studies enrolled HF patients) and that with some newer agents on the horizon (as demonstrated with dronedarone in ATHENA) this can also be demonstrated by ITT analysis in appropriately chosen patients. Hopefully, therapies now under investigation will also demonstrate PACE,Vol.34 February

12 REIFFEL the ability to reduce mortality and serious morbidity simultaneously with the suppression of AF. Improving QOL, reducing morbidity and mortality, and reducing hospitalization with its economic and emotional costs should now be the main objectives of AF treatment. To the extent that this appears possible with a pharmaceutical agent (dronedarone in ATHENA) and has not yet been prospectively demonstrated with a nonpharmacological approach, such observations will no doubt color the therapeutic algorithm in at least the decade to come. However, to the extent that QOL can be improved by ablative approaches in the symptomatic patient who fails antiarrhythmic drug therapy or chooses not to try it, nonpharmacologic therapies (that have not been the focus of this manuscript) should also be considered in the discussion with each patient. From a theoretical standpoint, early restoration and maintenance of sinus rhythm also may result in reversal of atrial remodeling and in slowing or preventing AF disease progression, and this merits additional consideration. Therefore, when considering the currently available options for treatment, it should be remembered that no single strategy is universally beneficial and treatment must be individualized for each patient. The development of new antiarrhythmic drugs with improved efficacy, safety, and tolerability profiles should facilitate a more meaningful and detailed assessment of the benefits of sinus rhythm-control strategies in patients with AF. Acknowledgments: The author received editorial support in the preparation of this manuscript from Mary Tom, Pharm.D., who was funded by sanofi-aventis, United States. 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