An Argument for Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation
The age-old and common-sense argument that if you were born in sinus rhythm you should probably try to remain so has seemingly lost some vigor with the results of recent randomized studies.1–6 These trials have convincingly demonstrated that in a select population of patients, a strategy of rhythm control with antiarrhythmic drugs confers no mortality benefit over a rate-control strategy. These studies have also demonstrated no quality-of-life benefit associated with a strategy of maintenance of sinus rhythm in this patient population.
The question therefore remains, is there any reason to maintain sinus rhythm? The answer is “yes,” given the fundamental observation that atrial fibrillation (AF) is an independent predictor of mortality in virtually every study that has monitored this end point.7–13 Unselected population-based studies (most notably, the Framingham Heart Study) have identified an increased mortality risk associated with AF, particularly in women.14 The Centers for Disease Control and Prevention analyzed national and state mortality statistics for patients with AF in 1999.15 They identified 67 875 deaths in which AF was a contributing cause, with an age-adjusted death rate of 24.7/100 000 population. Patients aged ≥75 years represented 84% of these deaths and those aged ≥85 years represented 47.4%. Studies of selected populations with coronary and noncoronary cardiomyopathy, congestive heart failure, hypertrophic obstructive cardiomyopathy, and sinoatrial dysfunction have all demonstrated an increased mortality risk associated with AF.7–13
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, the largest of the recent trials of rhythm control compared with rate control, demonstrated a statistically insignificant trend toward increased mortality in the rhythm-control arm (Table 1). Excess mortality in the rhythm-control arm was largely associated with noncardiovascular disease.5 Further analysis of this study determined that the presence of AF at the time of study termination was a more potent predictor of mortality than treatment strategy.6 This finding suggests that although sinus rhythm is preferable to AF, our methods of maintaining sinus rhythm may themselves contribute to overall mortality.
Why Doesn’t Rhythm Control Reduce Mortality?
It seems obvious that the maintenance of sinus rhythm should be associated with reduced mortality. AF is associated with increased risk of stroke, congestive heart failure, and cardiomyopathy and may be associated with tachycardia-induced tachyarrhythmias. Strategies for rhythm control have not shown a reduction in overall mortality for a multitude of reasons. These trials have been performed in patient groups at high risk for stroke but have not mandated the continuation of anticoagulation. A major contribution of these studies has been to show the importance of continued anticoagulation regardless of the use of antiarrhythmic therapy. This imperative likely exists because these medications do not confer complete suppression of AF. In fact, studies of rhythm control versus rate control have shown at best a 60% suppression of AF in the rhythm-control group (Table 1). Indeed, the Strategies of Treatment of Atrial Fibrillation multicenter pilot study (STAF), which randomized 200 patients to a strategy of rhythm control versus rate control, found that all but 1 of the end points of death or thromboembolism reached in the rhythm-control group occurred during AF.3
The best available agent for rhythm control is amiodarone. In the Canadian Trial of Atrial Fibrillation, amiodarone was compared with propafenone and sotalol for suppression of AF. Amiodarone was associated with a 35% rate of AF recurrence at 16 months compared with a 63% rate of recurrence with the other study drugs.16,17 The rates of stroke and intracranial hemorrhage were less in the amiodarone-treated group than in the other antiarrhythmic therapies.
Antiarrhythmic medications are also associated with a significant risk of proarrhythmic and noncardiovascular toxicities. The careful use of these medications as demonstrated in AFFIRM can minimize this risk but does not eliminate it entirely.17 The problem lies with incomplete data for the effects of rhythm control in large groups of AF patients not represented in current clinical studies and the profound limitations of the tools currently available to maintain sinus rhythm.
Can We Generalize the Results of Rate Versus Rhythm Control Trials to All AF Patients?
AF is unlikely to be one disease. It is likely that lone AF in the 50-year-old male with vagal triggers is a very different disease in both mechanism and natural history than the same arrhythmia in a 75-year-old with longstanding hypertension and congestive heart failure. It seems logical that the apoptosis and fibrosis that naturally occur with aging would lead to different mechanisms of AF that are age dependent. Concomitant disease may further complicate the underlying substrate.
Randomized controlled trials have largely represented patients with at least 1 risk factor for stroke who were candidates for participation in a randomized trial. In general, younger patients with lone and highly symptomatic AF, the elderly over 80 years of age, and those patients with concomitant congestive heart failure were not included. These neglected groups constitute a significant proportion of patients with AF. Lone AF represents 15% to 20% of the AF population, and those over the age 80 years represent 35%.18 Consequently, at least 50% of the 3.3 million adults who will have AF in the United States by the year 2025 will not be represented in the previously cited trials. It is inappropriate to generalize the results of AFFIRM and other such rhythm- versus rate-control trials to this large group of patients. Should we relegate the asymptomatic 50-year-old male with a normal heart and persistent AF to chronic AF? One could argue that we won’t make him feel better by restoring sinus rhythm; however, we may prevent the progressive atrial remodeling (electrophysiological and anatomic) that occurs with chronic AF. These chronic changes that occur with the development of chronic AF will likely disqualify this patient from or reduce the effectiveness of developing and potentially curative therapies.
Methods for maintenance of sinus rhythm are particularly important in the elderly. The risk of AF-related stroke increases with age, with 1 in 4 strokes occurring in those >80 years of age directly attributable to AF.19 The absence of stroke reduction associated with rhythm control strategies is likely related to the ineffectiveness of these therapies. Specifically, all available antiarrhythmic drugs are associated with at least a 25% to 50% yearly recurrence of AF.16 These recurrences often occur with a controlled ventricular response and are asymptomatic. The elderly represent a group both at high risk of stroke and frequently intolerant of warfarin. Elderly patients who are started on warfarin therapy at the time of AF diagnosis frequently have it discontinued owing to the development of a risk of falls, bleeding, or difficulty with medication compliance. The effective suppression of AF in this group may reduce the risk of stroke. The combination of amiodarone and a pacemaker in the setting of sinoatrial dysfunction often proves a very effective method of AF suppression.20
The congestive heart failure population is another underrepresented group in currently analyzed clinical trials. The increased mortality associated with AF in patients with left ventricular dysfunction and congestive heart failure has been demonstrated conclusively.21 Amiodarone has been shown to reduce mortality in patients with congestive heart failure who were converted to sinus rhythm in the Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT) trial.22 A similar finding was demonstrated in the DIAMOND (Danish Investigation of Arrhythmia and Mortality on Dofetilide) study, in which restoration and maintenance of sinus rhythm with dofetilide in patients with AF and congestive heart failure was associated with a reduction in mortality and hospitalization rates.23 In the AFFIRM study, the subset with preexisting congestive heart failure (23% of population) demonstrated a trend toward improved mortality in the rhythm-control arm. The HOT CAFÉ (Rate Control vs Rhythm Control in Patients With Nonvalvular Persistent Atrial Fibrillation: The Results of the Polish How to Treat Chronic Atrial Fibrillation Study) study noted a significantly increased mean left ventricular fractional shortening in the rhythm-control group compared with the rate-control group.7 The potential benefits of improved left ventricular function in the absence of clinical congestive heart failure will likely require longer follow-up to realize the absolute benefits of rhythm control. A definitive answer to the question of the importance of maintaining sinus rhythm in patients with congestive heart failure should be provided by the Canadian Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial.24
Nonpharmacological therapies to maintain sinus rhythm represent the most hopeful option for reducing the mortality and morbidity of AF. The percutaneous isolation of the pulmonary veins to isolate triggers of AF, in some instances coupled with linear lesions to modify the atrial substrate for arrhythmia perpetuation, has proven increasingly successful. It is premature to call this procedure curative, but rates of significant reduction in AF frequency approach 70% to 80%25–28 (Table 2). A recent study of pulmonary vein isolation coupled with left atrial linear lesions in patients with impaired left ventricular function (left ventricular ejection fraction <45%) and congestive heart failure reported a 78% rate of sinus rhythm maintenance at 12 months of follow-up.27 There was a significant improvement in left ventricular ejection fraction, a decrease in left ventricular dimensions, and improvement in exercise capacity and quality of life. These findings were present in patients regardless of the adequacy of rate control before ablation, determined by a 48-hour Holter study. This observation raises the question of whether factors other than ventricular rate (eg, irregularity of rhythm, loss of atrial contribution to filling) contribute to congestive heart failure.29 These findings are consonant with results of Pappone et al,25 who showed improved survival and quality of life after pulmonary vein isolation. Unqualified enthusiasm for the percutaneous management of AF must be tempered by the 1% risk of stroke, 4% risk of pulmonary vein stenosis, and development of left atrial–esophageal fistula associated with this procedure.30,31 The surgical approach to sinus rhythm maintenance is also rapidly evolving. Variations on the operative MAZE procedure have consistently demonstrated 80% reductions in the recurrence of AF. This procedure is generally reserved for patients already undergoing CABG or valve surgery.32
Costs and Quality of Life
There is no question that we need to reduce the healthcare costs associated with AF. In a retrospective analysis of 3 federally funded US databases, approximately 350 000 hospitalizations, 7 million office visits, and 542 000 emergency department visits were attributable to AF annually.33 Overall, total inpatient and outpatient costs for AF were approximately $6.42 billion. The cost analysis of the AFFIRM study found the rate-control strategy to be more cost-effective than the rhythm-control strategy.34 A large percentage of the costs comprised hospital admissions. Improvements in methods for rhythm control that lead to long-term suppression or cure of AF will undoubtedly prove cost-effective compared with long-term rate control, particularly in young individuals. The real cost savings associated with long-term maintenance of sinus rhythm will be achieved over decades with reductions in congestive heart failure and stroke and improvement in function that will translate into more work days and better quality of life.
There is currently no uniformly accepted AF-specific tool with which to assess quality of life.35 Application of less specific tools has in composite demonstrated no improvement in quality of life in rhythm- versus rate-control studies; however, the Rate Control versus Electrical Cardioversion (RACE) study has demonstrated that as with the issue of mortality, quality of life is better in patients who maintain sinus rhythm, regardless of which study arm of a protocol they are assigned.36 Recent data from the Sotalol Amiodarone Atrial Efficacy Trial (SAFE-T) demonstrated a significant improvement in quality of life and exercise capacity associated with the maintenance of sinus rhythm.36a
We Need a New Paradigm for the Prevention and Treatment of AF
Studies demonstrating no survival advantage to sinus rhythm maintenance over AF must be regarded as an indictment of our treatments more than a rationale for acceptance of continuous AF. The fundamental conclusion we should derive from the current state of the debate of rhythm versus rate control is that we need a new paradigm for our thinking about patients with AF. First, we need to target prevention. Next, we need to improve our methods of management to improve efficacy, safety, and quality of life for patients while reducing costs to the healthcare system.
It is possible that improved management of hypertension will reduce the number of patients predicted to have AF in the coming decades. ACE inhibitors and angiotensin II type 1 receptor blockers have been demonstrated to reduce the development of atrial fibrosis and atrial remodeling.37 In a pooled analysis of randomized controlled trials of ACE inhibitors and angiotensin II type 1 receptor blockers, the incidence of new-onset and recurrent AF was significantly reduced in patients taking these medications.38 Whether the use of antialdosterone agents, which have been associated with decreased atrial fibrosis, will prove to be an additional preventative therapy needs to be tested.
Better and Safer Medications
There is a need for antiarrhythmic drugs with better efficacy and greater safety. Current strategies include the development of antiarrhythmic drugs with effects limited to atrial tissue to reduce the development of ventricular arrhythmias.39,40 Genetic screening of patients to prospectively identify ion channel abnormalities that may predispose to proarrhythmic toxicity of antiarrhythmic medications may prove feasible and may help direct therapy of AF.
Frequent interrogation of atrial diagnostic parameters in implanted devices can provide information about the frequency and duration of AF recurrences. Ultimately, we will be able to monitor these device patients on a continuous basis through wireless technology. Those at high risk for anticoagulation-related complications or those on the lower-risk side for stroke who still meet requirements for anticoagulation (eg, 65 years old with treated hypertension) may be maintained safely with no warfarin but with antiarrhythmic medications. If recurrences are documented, anticoagulants can be administered until sinus rhythm is restored. The development of rapidly acting anticoagulants with efficacy and safety equivalent to warfarin will make such an approach very practical. It is likely that for some patients (eg, those with diffuse atheromatous disease), AF is a marker but not the sole risk factor for stroke, and anticoagulants should never be stopped. This approach will need to be tested in a randomized controlled study but is needed given the limitations of chronic anticoagulation in this population.
Better and Safer Procedures
Safer and more efficacious refinements of the percutaneous procedure for AF ablation are under constant development. New energy sources will likely reduce the risk of pulmonary vein stenosis and provide more complete electrical isolation of the pulmonary veins.
A completely epicardial approach to the MAZE procedure holds great promise. A thoracoscopic-guided procedure with the avoidance of cardiopulmonary bypass, pulmonary vein stenosis, and stroke risk associated with an endocardial catheter-based procedure, coupled with the potential stroke risk reduction of a left atrial appendectomy, may prove a successful strategy for AF management.41
Evaluation of Cost-Effective Management Strategies
We need to test and implement management strategies to reduce the costs associated with AF. This involves improved compliance with anticoagulation guidelines to reduce the incidence of thromboembolic complications. Strategies to avoid unnecessary hospital admissions for components of AF management, including cardioversion and antiarrhythmic drug initiation, have proved safe and highly effective.42–45
As Sir Thomas Lewis noted in 1912, “Most hearts which develop fibrillation of the auricles maintain this mechanism to the end of the chapter; it is essentially a chronic and terminal malady. But from time to time transient attacks are seen, and in some patients paroxysms of fibrillation of a few hours, days or weeks duration are noted. The affection, when it takes this form, is generally classed as paroxysmal tachycardia.”46 He went on to say, “There is no ailment in which such success can be achieved, no other cardiac disease which may be so speedily benefited, as the well-managed case of auricular fibrillation. As a direct result of active treatment the moribund may be restored and many years may be added to their lives.” Sir Lewis was referring to the use of digoxin for rate control of chronic AF. He did not have high hopes for the maintenance of sinus rhythm, let alone a curative solution for AF. Nearly a century later, we have not improved much on Lewis’ original characterization of AF. We now recognize the importance of isolated atrial ectopy, particularly arising from the pulmonary veins in the initiation of paroxysmal AF.47 We are just beginning the process of targeting our therapies to the diverse mechanisms of this disease. The generalization of one management strategy for AF would represent a step back we should not be willing to take. Ultimately, a combination of the above strategies may bring us full circle to what our common sense has always told us: if you were born in sinus rhythm, you should probably try to remain so.
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