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Circulation. 2005;111:3141-3150
doi: 10.1161/CIRCULATIONAHA.104.485565
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(Circulation. 2005;111:3141-3150.)
© 2005 American Heart Association, Inc.

Controversies in Cardiovascular Medicine

Is rate control or rhythm control preferable in patients with atrial fibrillation?

Rate Control Is Preferable to Rhythm Control in the Majority of Patients With Atrial Fibrillation

Rodney H. Falk, MD, FRCP

From Harvard Vanguard Medical Associates (R.H.F.), Boston, Mass, and Beth Israel Deaconess Medical Center (P.Z.), Boston, Mass.

Reprint requests to Rodney H. Falk, MD, Harvard Vanguard Medical Associates, 133 Brookline Ave, Boston, MA 02215 (e-mail rfalk{at}partners.org); or Peter Zimetbaum, MD, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd, Boston, MA 02215 (e-mail pzimetba@BIDMC.harvard.edu).


*    Introduction
up arrowTop
 *Introduction
down arrowLessons From the Multicenter...
 down arrowConclusions
 down arrowReferences
 

"...but to his surprise — the more he looked — the more Piglet wasn’t there."

— A.A. Milne, The House at Pooh Corner

The management of patients with atrial fibrillation has been the subjects of intense investigation over the past 2 decades. In the 1980s and early 1990s, large clinical trials of anticoagulant therapy for stroke prevention were performed. These consistently demonstrated that atrial fibrillation confers a significant and ongoing stroke risk and that anticoagulant therapy significantly reduces this risk.1–10 Warfarin subsequently became a standard of therapy for patients with atrial fibrillation, whether paroxysmal, persistent, or permanent.

If patients with atrial fibrillation had a high stroke risk compared with those in sinus rhythm, then logic appeared to dictate that restoration and maintenance of sinus rhythm should reduce the likelihood of thromboembolism and hence obviate the need for long-term warfarin anticoagulation. Perhaps driven in part by this belief, new atrial antiarrhythmic drugs were introduced during this period, and there was an increasing use of such drugs among patients with atrial fibrillation.11 A decade after the trials of anticoagulation in atrial fibrillation, several international trials were implemented to determine whether heart rate control would result in a similar outcome to the outcome after a strategy of restoration and maintenance of sinus rhythm.12–15 Analysis of these trials demonstrated no benefit either in mortality or in a combined end point of mortality and morbidity. These results are generally interpreted as showing that either rate control or rhythm control is a suitable strategy in a patient with atrial fibrillation, and there has therefore been a rethinking of the appropriate way in which to treat a patient with atrial fibrillation when the options include control of either rate or rhythm. In the treatment of atrial fibrillation, as with most things in medicine, one size does not fit all, and it must be recognized that there are some patients in whom trials of pharmacological rate control may be ineffective for the complete control of symptoms. These patients most certainly deserve vigorous attempts at maintaining sinus rhythm; however, these patients represent a small minority of patients with atrial fibrillation and are not the topic of the current discussion. It is therefore my purpose in this debate to demonstrate that rate control, by virtue of its relative simplicity, is superior to rhythm control in the management of the majority of patients with atrial fibrillation and should therefore be the method of choice. Furthermore, as with Piglet, the well-known character from the children’s story featured in the introductory quote to this argument, the more one looks in an attempt to prove the benefits of rhythm control over rate control, the more they are not there.


*    Lessons From the Multicenter Trials of Rate Versus Rhythm Control
up arrowTop
 up arrowIntroduction
 *Lessons From the Multicenter...
down arrowConclusions
 down arrowReferences
 
The results of the recently published trials of management strategies in atrial fibrillation have become a stimulus for the renewed debate concerning whether or not it is worthwhile to attempt to restore sinus rhythm (Table 1). As such, they deserve careful scrutiny to determine whether they have definitively answered the question of the best strategy or whether further trials, perhaps in specific patient subgroups, are needed.


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  		TABLE 1. Summary of Features of Each Rate vs Rhythm Trial

AFFIRM Trial
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, performed in North America, evaluated mortality as a primary end point when the strategies of rate versus rhythm control in atrial fibrillation were compared.12–15 Of the 4000 patients who were enrolled, no difference could be determined between these 2 strategies, although there was a trend toward a higher mortality rate in the rhythm-control group. The trial enrolled patients deemed to be at high risk for stroke on the basis of their age or underlying disease. It must be stressed that AFFIRM was a comparison of treatment strategies in a high-risk population with current or past atrial fibrillation. Patients with paroxysmal atrial fibrillation or those recently cardioverted from atrial fibrillation were eligible to participate, and this resulted in 52% of enrollees (1055/2027) who were randomized to rate control being in sinus rhythm at the time of randomization. Although many of these patients reverted transiently or permanently to atrial fibrillation during the study, it is conceivable that the failure to show a benefit of one or another strategy was related to a dilution of numbers by having patients in sinus rhythm in the rate-control group and patients who could not maintain sinus rhythm in the rhythm-control group. Despite these potential limitations, AFFIRM was a large study, and the strategy of attempted sinus rhythm maintenance showed no advantage either in the primary end point or in any prespecified secondary end points, including quality of life, stroke, or worsening functioning class.

RACE Trial
The Rate Control versus Electrical Cardioversion (RACE) trial, although smaller than AFFIRM (n=522), differed from it in only enrolling patients with persistent atrial fibrillation.13 Eligibility required a patient to have had a prior cardioversion and to be back in atrial fibrillation at the time of randomization. Subjects were either randomized to a strategy of repeat cardioversion(s) and antiarrhythmic drugs to maintain sinus rhythm or to rate control, which was almost exclusively pharmacological. The primary end point was a composite of cardiovascular death, heart failure, thromboembolism, bleeding, pacemaker insertion, or severe side effects of antiarrhythmic drugs. The end point did not differ between the 2 groups at a mean follow-up of 2.3 years. Although it is unclear how many of the rate-control patients crossed over to the rhythm-control group, there were only 26 patients in the rate-control group who were in sinus rhythm at study end, 13 of whom had been cardioverted during the study for intolerable cardiovascular symptoms. Analysis of quality of life, a secondary end point in RACE, showed no difference between these 2 strategies.

Two much smaller pilot trials have also addressed rate versus rhythm control. The Strategies of Treatment of Atrial Fibrillation (STAF)14 and Pharmacological Intervention in Atrial Fibrillation (PIAF)15 trials were both pilot trials designed to test the feasibility of a larger trial. These both demonstrated very similar outcomes between rate and rhythm strategies but, in light of the AFFIRM and RACE trials, neither proceeded into a full-scale study.

Why Do Patients With Atrial Fibrillation Develop Symptoms?
Before treatment is prescribed for a patient with new-onset atrial fibrillation, a thoughtful analysis is required to examine why any symptoms or clinical deterioration might have occurred. Symptoms in a patient presenting with new-onset atrial fibrillation should not be attributed simply to the loss of the atrial contribution to ventricular filling, because other culprits may be the predominant factor, the most obvious of which is a rapid ventricular response associated with the untreated arrhythmia. In the absence of AV nodal blocking agents, the mean resting ventricular response to atrial fibrillation is {approx}110 to 125 bpm,16–19 and this may increase considerably during exertion. As heart rate increases, the percentage of time spent in diastole is shortened. Because diastolic dysfunction is a feature of many diseases associated with atrial fibrillation,20 a rapid ventricular rate can precipitate or aggravate heart failure. If the rate remains uncontrolled for a longer period of time, tachycardia-mediated cardiomyopathy may occur.21 Although tachycardia-mediated cardiomyopathy is considered uncommon, there may be an unrecognized spectrum of subtle left ventricular dysfunction (diastolic as well as systolic) that is produced by atrial fibrillation. Thus, control of the ventricular rate should play a central role in the management of atrial fibrillation, because it can improve symptoms of heart failure by lengthening diastole, may decrease the likelihood of tachycardia-related systolic dysfunction, and can abolish the sensation of tachycardia or palpitations associated with the rapid rate. In addition to slowing the ventricular rate, the relative regularization of the ventricular response that may occur with such agents as verapamil or diltiazem,22,23 or the absolute regularization that follows AV nodal ablation may also have some role in improving hemodynamics and providing a sense of wellbeing.24–27

Rhythm Control in Atrial Fibrillation: A Strategy That Is Difficult to Obtain Consistently
One reason rate control is a preferred strategy in atrial fibrillation is that rhythm control is not an easy goal to achieve in many patients. Why might this be so? As with many other forms of arrhythmia, atrial fibrillation is associated with and precipitated by a number of underlying types of heart disease. The abnormalities responsible for the maintenance of atrial fibrillation are complex and represent a combination of the primary pathology responsible for the arrhythmia20 and cellular, subcellular and molecular changes that result from the fibrillation itself.28–40 Although the underlying pathology both precipitates and perpetuates the arrhythmia, the secondary changes produced by atrial fibrillation may progress with time and lead to further likelihood of perpetuation ("atrial fibrillation begets atrial fibrillation"41). Simply restoring sinus rhythm does not affect the underlying pathology initially responsible for the arrhythmia, and it is therefore not surprising that atrial fibrillation has a high recurrence rate unless antiarrhythmic therapy is administered; however, as discussed below, the use of antiarrhythmic drugs is a 2-edged sword, because none of these drugs are free of side effects, and none comes close to having 100% efficacy.42 Thus, before a patient is subjected to a potentially harmful agent to restore and maintain sinus rhythm, every effort should be made to ensure that heart rate during atrial fibrillation has been controlled adequately, because this may result in symptom improvement and obviate the need to use an antiarrhythmic drug.

What Is the Optimal Heart Rate in Atrial Fibrillation?
Unfortunately, there is a lack of uniform definition of heart rate control in atrial fibrillation, although it is generally agreed that rate control must exist both at rest and during normal daily activities. Patients in atrial fibrillation demonstrate greater maximum and minimum heart rates during normal daily activities than do similar patients in sinus rhythm, and the assessment of an "optimal" heart rate in patients with atrial fibrillation must take into account the potential need for a slightly faster resting heart rate at rest than might be seen in sinus rhythm that results from the loss of the atrial contribution to ventricular filling. There have been several small trials of individual negative chronotropic agents for ventricular rate control in persistent atrial fibrillation that used exercise testing as a goal to determine optimal heart rate control. These studies have been reviewed recently by Bjerregaard and coworkers.43 The predominant drugs studied were digoxin, various ß-blocking agents, and the nondihydropyridine calcium channel blocking agents verapamil and diltiazem. ß-Blocking agents and verapamil or diltiazem are more effective than digoxin for controlling heart rate, particularly during activity, although digoxin has a synergistic effect with each of the other classes of drugs. Few studies have directly compared the efficacy of heart rate control during daily activity with that during exercise using multiple drug regimens. Farshi et al44 performed a crossover study in 12 patients treated with digoxin 0.25 mg/d, diltiazem CD 240 mg/d, atenolol 50 mg/d, or a combination of each of the latter 2 drugs with digoxin. Digoxin alone provided the least effective mean peak ventricular rate during exercise of 175 bpm and a daytime mean heart rate of 85±20 bpm. The combination of atenolol and digoxin resulted in a significantly lower peak heart rate during exercise than did the other therapies and was the most effective in blunting heart rate peaks during daily activities. Despite a mean decrease of 49 bpm during exercise compared with digoxin alone, the digoxin-atenolol combination had no effect on exercise tolerance compared with any other combination. This contrasts with some other studies of ß-blocking agents in which vigorous blunting of peak heart rate was associated with a decrease in exercise tolerance. Thus, the use of currently available negative chronotropic agents results in reasonably good heart rate control in the majority of patients, although care must be taken not to overtreat.

The AFFIRM study was the first large study to attempt to formally define and institute criteria for a controlled ventricular response in atrial fibrillation.12,45 Adequate rate control was defined not only as a controlled resting heart rate but also as the absence of excessive heart rate elevation with a modest level of exercise and/or during daily activities. Specifically, for the goal of adequate heart rate control to be achieved, patients were required to have a ventricular response of ≤80 bpm at rest and to have either a maximum heart rate of <110 bpm during a 6-minute walk on a flat surface or an average heart rate during 24-hour ambulatory monitoring <100 bpm with no heart rate >110% of maximal predicted age-adjusted exercise heart rate. With these criteria, the overall success rate for heart rate control ranged from 38% with calcium channel blockers alone to 76% in a small group of patients who were treated with a combination of ß-blocker, calcium channel blocker, and digoxin. The overall success rate for heart rate control 2 months after entering the AFFIRM study among patients who were in atrial fibrillation at the time of that visit was {approx}63%, and control gradually improved throughout the study to a maximum of 86% at rest, 90% with exercise, and 78% overall at the 5-year mark.45 Although these data may raise some concerns about the 22% to 37% of patients without "adequate rate control," the criteria for rate control were based on prospectively defined criteria. It is possible that this definition was too rigid and that patients who fell outside this definition of "rate control" were not harmed in any way. To attempt to answer this question, Cooper et al45 analyzed patients in the rate-control arm of the AFFIRM study who were in atrial fibrillation both at baseline and at 2 months. Patients were grouped by quartile of achieved heart rate at rest and with exercise. The heart rate quartiles at rest (n=680) were 44 to 69, 70 to 78, 79 to 87, and 88 to 148 bpm, respectively, and with exercise (n=349), the rates were 53 to 82, 83 to 92, 93 to 106, and 107 to 220. No difference was found in survival free from cardiac hospitalization or in overall survival among quartiles, which suggests that at least in the median-term follow-up of the AFFIRM study, vigorous attempts at rate control to these predefined criteria may not have been necessary in every patient.45 Therefore, rate control in atrial fibrillation may not necessarily require a rigid titration of medications to a particular heart rate goal, provided that prolonged periods of excessive or symptomatic tachycardia can be avoided.

Antiarrhythmic Drugs: An Armamentarium With a Plethora of Side Effects
Antiarrhythmic drugs have been used for many years to restore and maintain sinus rhythm; however, the use of these drugs has drawbacks, because none are free of side effects (cardiac or noncardiac), and none comes close to having 100% efficacy. Thus, their use requires a careful assessment of the risks and benefits of each agent and must be tailored to the individual patient’s medical condition. Furthermore, no guarantee of safety or efficacy of any one drug in an individual patient can be given.

The currently available antiarrhythmic agents are associated with a plethora of significant side effects, both cardiac and noncardiac. Agents that prolong repolarization (predominantly the class 3 agents sotalol and dofetilide and class 1 agents such as quinidine, disopyramide, and procainamide) are associated with a risk of torsade de pointes, which may be fatal.46–48 The absence of early proarrhythmia with these agents is no guarantee of freedom from late proarrhythmia, which may be precipitated by a fall in potassium, the development of bradycardia, or worsening renal function.49 In the setting of prior myocardial infarction with ventricular ectopy, the use of the class 1C agent flecainide was associated with an increased risk of sudden death.50 Although introduced after the Cardiac Arrhythmia Suppression Trial (CAST) study, propafenone has electrophysiological properties similar to flecainide, and it is likely that it would have had the same adverse effect. Thus, both propafenone and flecainide are considered to be contraindicated in patients with atrial fibrillation and ischemic heart disease.51 The use of the 1C agents may also cause atrial fibrillation to organize to atrial flutter with a relatively slow atrial rate, resulting in 1:1 AV nodal conduction. Because of the "use-dependent" properties of these drugs (whereby their electrophysiological effect is heightened in the setting of an increased depolarization rate), atrial flutter with 1:1 conduction is commonly associated with a markedly widened QRS. This can result in ventricular dyssynergy and the potential for cardiovascular collapse. To minimize this occurrence, it is advisable to prescribe the class 1C agents in conjunction with an AV nodal blocking agent, thereby increasing the number of drugs a patient takes.

Amiodarone, the most effective atrial arrhythmic drug, also prolongs the QT interval but appears to have a very low risk of torsade de pointes. Unfortunately, the low risk of proarrhythmia with amiodarone is offset by its numerous side effects, which necessitated discontinuation in 18% of patients over 16 months in the Canadian trial of amiodarone for atrial fibrillation52 and in up to 23% of patients in other clinical trials.53 The long-term discontinuation rate is even greater owing to the cumulative toxicity of the drug. Pulmonary fibrosis due to amiodarone, although rare, is a serious complication. Although it often reverses after the drug is stopped, the fibrosis may progress, and fatal cases have been reported. Hypothyroidism is commonly induced by amiodarone, and amiodarone-induced hyperthyroidism, although less common, is a difficult to treat complication of this drug. Liver function test abnormalities are common, and on occasion, significant hepatotoxicity may occur. Perhaps the most common, troublesome, and potentially dangerous side effect of amiodarone is its interaction with warfarin. Amiodarone decreases total warfarin requirements, but because of its complex pharmacokinetics and an unpredictable time course, the international normalized ratio (INR) may suddenly elevate after apparently being stable for a number of weeks after the initiation of amiodarone in a patient taking warfarin.54

How Common Are Potential Contraindications to Atrial Antiarrhythmic Drugs?
The potential for side effects of atrial antiarrhythmic drugs is increased in the setting of comorbidities. In a study of 723 Canadian patients with paroxysmal atrial fibrillation entered into a prospective registry between 1991 and 1996, Humphries et al55 noted that 56% had documented structural heart disease, including 22% with left ventricular systolic dysfunction. When they sought the presence of a clinical feature that was specified as a contraindication, warning, or precaution to a specific drug in the 1996 Canadian Compendium of Pharmaceuticals and Specialties, the percentage of patients who fell into at least 1 such category among the most commonly prescribed drugs (flecainide, quinidine, sotalol, amiodarone, and propafenone) ranged from 36% for quinidine to 58% for flecainide. Although, as the authors appropriately point out, these were only potential limitations to drug use and do not necessarily preclude therapy based on good clinical judgment, these data certainly underscore the complexities of prescribing antiarrhythmic drugs, even before the efficacy of the agents is entered into the equation.

Safety of Negative Chronotropic Agents Compared With Antiarrhythmic Agents
In contrast to the common adverse effects of antiarrhythmic agents, the 3 main classes of negative chronotropic agents (digoxin, ß-blockers, and the nondihydropyridine calcium channel blockers verapamil and diltiazem) have a good safety profile. The digitalis glycosides, of which digoxin is used almost exclusively, have been available for more than 2 centuries, and the outstanding clinical observations of Sir William Withering in the 18th century laid the foundation for the understanding of digoxin toxicity. With the introduction of the measurement of serum digoxin levels, classic digoxin toxicity decreased considerably. Digoxin has a synergistic negative chronotropic effect with drugs in the other classes,44 and when used in appropriate doses and with recognition of the verapamil-digoxin interaction (which leads to elevated digoxin levels), it has proved to be a safe, useful, and enduring adjunct to ventricular rate control. ß-Blockers and calcium channel blockers are similarly remarkably safe agents. Indeed, ß-blockers have a well-known cardioprotective effect, and in selected cases of atrial fibrillation with left ventricular dysfunction, their use may be associated with an improvement in ejection fraction.56,57 Although the calcium channel blockers demonstrate a negative inotropic effect in vitro, this is uncommonly seen in the clinical setting, provided that this class of drug is not given to patients with uncompensated heart failure.

Why Cannot Anticoagulation Be Discontinued in a Patient With a History of Paroxysmal or Persistent Atrial Fibrillation Once Sinus Rhythm Has Been Restored?
One argument in favor of the use of antiarrhythmic drugs in atrial fibrillation is that restoration of sinus rhythm may render unnecessary the need for continued anticoagulation. Until recently, it was considered safe to discontinue warfarin anticoagulation once a patient had been cardioverted from atrial fibrillation and had apparently remained in sinus rhythm for a period of 30 to 90 days. Some guidelines suggested that anticoagulation could be discontinued in such patients,58 thereby implying an advantage of rhythm control over rate control in terms of the risks and inconvenience of long-term anticoagulation. The trials of rate versus rhythm control permitted discontinuation of anticoagulation in the rhythm-control group once sinus rhythm was (or at least appeared to have been) maintained; however, in each of the trials, the stroke/thromboembolism rate was the same or slightly higher in the rhythm-control group than in the rate-control group, with a difference that approaches statistical significance when the data are pooled (Table 2). This consistent demonstration that rhythm control is associated with an ongoing risk of thromboembolism underscores the need for warfarin to be continued for a longer period than was previously believed necessary after apparently successful cardioversion.


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  		TABLE 2. Stroke Rates in the 4 Rate vs Rhythm Trials

The risk of ongoing stroke among patients with a history of atrial fibrillation who subsequently appear to be in sinus rhythm is probably related to recurrent episodes of paroxysmal atrial fibrillation. The patient may be asymptomatic during recurrent episodes, but the atrial fibrillation retains the risk of thrombus formation and subsequent thromboembolism. In the Prevention of Atrial Fibrillation after Cardioversion (PAFAC) trial, 1182 patients with persistent AF were cardioverted and then randomized to receive either placebo, verapamil, or a combination of quinidine with verapamil.59 Daily transtelephonic monitoring was performed in each patient for a mean follow-up of 266 days and a total of >191 000 ECGs. Recurrence of atrial fibrillation, documented by transtelephonic monitoring, occurred in 67% of patients. Remarkably, the documented recurrence of atrial fibrillation occurred without symptoms in close to 70% of these patients.

Among patients with paroxysmal atrial fibrillation, even "successful" drug therapy may be associated with episodes of asymptomatic atrial fibrillation. The Suppression of Paroxysmal Atrial Tachyarrhythmias (SOPAT) trial was a sister study to PAFAC.60 The design was similar, except that patients with paroxysmal arrhythmias (predominantly atrial fibrillation) were recruited. A total of 1012 patients with symptomatic paroxysmal atrial fibrillation were treated with either a combination of quinidine and verapamil, sotalol, or placebo. Daily transtelephonic ECG transmissions were performed for at least 1 minute for a total of >179 000 recordings. Atrial fibrillation was documented in 13 410 episode recordings (representing 7% of the total recordings), and fewer than half of the episodes were associated with symptoms. At the end of 1 year, approximately half of the drug-treated patients had experienced recurrences of symptomatic arrhythmia or had discontinued therapy owing to side effects. From these results, it is clear that antiarrhythmic therapy with these "classic" class 1A and class 3 agents is poorly effective for long-term maintenance of sinus rhythm and is associated with a high proportion of asymptomatic arrhythmia.

Thus, from the standpoint of antithrombotic therapy, clinical trials point to the need for continued warfarin anticoagulation in patients at risk of stroke. Because paroxysmal atrial fibrillation is as strong a risk factor for embolic stroke as persistent/permanent atrial fibrillation, warfarin anticoagulation should be continued indefinitely even when antiarrhythmic therapy is used, both because of the likelihood of silent episodes of paroxysmal atrial fibrillation and because of the poor long-term efficacy of most antiarrhythmic drugs for the maintenance of sinus rhythm.

Are There Any Proven Subgroups in Which Maintenance of Sinus Rhythm Produces Better Results Than Rhythm Control?
Symptoms may not be the only criterion for restoration of sinus rhythm, and it has been suggested that in a subgroup of patients with congestive heart failure, rhythm control may be superior to rate control. A recent retrospective study may throw some light on this question. Al-Khatib et al61 performed a retrospective analysis of 1009 patients with atrial fibrillation and heart failure enrolled in the Duke University database between 1995 and 2001. All 1009 patients had a discharge diagnosis of atrial fibrillation along with clinical evidence of heart failure, some with an ejection fraction of <50%. Two thirds of the patients had, or had previously had, severe heart failure, defined as class III or class IV, and 30% were classified as having nonischemic cardiomyopathy on the basis of coronary angiography. Although therapy was nonrandomized and based on the preference of the treating physician, exactly half of the patients fell into the rhythm-control and rate-control groups, respectively. After adjustment for differences in baseline characteristics and medications, no significant differences in mortality were found between patients treated with rhythm control and those treated with rate control. Thus, within the limitations of a retrospective study, rhythm control failed to improve survival even in a group of patients with a high prevalence of severe congestive heart failure.

Quality of Life and Cost-Effectiveness
The AFFIRM trial primary end point was mortality, and the end point in RACE was a composite of mortality and serious events, yet neither trial demonstrated the superiority of rhythm control over rate control. Mortality and other morbid end points can be equivalent between 2 treatment strategies, yet quality of life may be superior in one or the other group. (Indeed, in some heart failure trials of positive inotropes, active therapy was associated with a higher mortality yet a better quality of life.62) Quality of life in the small PIAF study was assessed by the Medical Outcomes Short Form health survey (SF-36).63 At baseline, scores on all 8 scales in both groups were reduced compared with normal subjects. At the end of the observation period, improvement was seen in both patient groups, and no difference was found between the rate- or rhythm-control strategy. The RACE investigators, who also used the SF-36 survey, obtained a very similar result.64 Thus, no argument can be made that restoration of sinus rhythm improves quality of life.

In the absence of any proven benefit of a strategy of attempted restoration of sinus rhythm for a patient with atrial fibrillation, a comparison of cost-effectiveness of the 2 strategies is of interest. A detailed cost-effectiveness analysis from the RACE trial has shown the advantage of rate over rhythm control; the overall strategy of rate control was cheaper than that of rhythm control, and the cost saving per avoided end point was calculated as {approx}25 000 Euros.65 The AFFIRM investigators also performed a cost-effectiveness analysis. Patients in the rate-control group used fewer resources, such as hospital days, cardioversions, and emergency department visits. Utilizing a sensitivity analysis, the estimated cost savings per patient treated with rate control ranged from $2189 to $5481 per person.66 Thus, in contrast to the absence of a difference in quality of life between the 2 strategies, rate control is a less costly strategy than rhythm control in the treatment of atrial fibrillation.

Might Catheter Ablation of Atrial Fibrillation Provide a Better Outcome Than Antiarrhythmic Therapy?
The criticism of antiarrhythmic drug therapy as the preferred therapy for atrial fibrillation is based on the side effects of these drugs. Therefore, if it were possible to maintain sinus rhythm without the use of antiarrhythmic drugs, might a primary approach stressing restoration of sinus rhythm become more attractive? Catheter ablation of atrial fibrillation, more precisely termed catheter-based isolation of the pulmonary veins, is an increasingly used procedure for patients with symptomatic arrhythmia. It has been suggested that this technique is highly successful when performed by experienced operators, although the long-term efficacy is not perfect, and severe side effects can occur in a small minority of patients. In a nonrandomized study, Pappone et al67 compared outcomes among 589 patients who had undergone radiofrequency ablation for atrial fibrillation with outcomes among 582 patients who had received drug therapy. The authors suggested that restoration of sinus rhythm by pulmonary venous isolation was associated with a subsequent survival rate equivalent to age-matched patients in the general population with atrial fibrillation. In contrast, patients treated with antiarrhythmic drugs had a worse survival than the same age-matched population. Although these data raise interesting questions, it is uncertain whether the 2 populations (ablation versus drug therapy) are precisely comparable, and it is hard to accept that they can be extrapolated to the vast majority of patients with atrial fibrillation. Most patients with atrial fibrillation have underlying structural heart disease, and on the basis of that disease alone, they would be anticipated to have a worse survival than randomly selected age-matched patients in the general population. This would suggest that the patients in the study by Pappone et al67 do not represent the average patient with atrial fibrillation, and on the basis of this selected, nonrandomized population, it is premature to conclude that attempted maintenance of sinus rhythm by radiofrequency catheter pulmonary venous isolation has a salutary effect on mortality among patients with atrial fibrillation. Furthermore, there are few centers in the world that have the numerical experience with this procedure approaching that of the group in the study by Pappone et al,67 and it is likely that the efficacy of the procedure is lower and its side effects are higher in centers that do not have dedicated, high-volume electrophysiological expertise.

Does Radiofrequency Ablation Abolish the Likelihood of Asymptomatic Paroxysmal Atrial Fibrillation?
As noted above, paroxysmal atrial fibrillation is common among patients with prior persistent atrial fibrillation or prior episodes of paroxysmal atrial fibrillation even when sinus rhythm appears to have been maintained by antiarrhythmic drugs. For this reason, long-term warfarin is now recommended in most patients who have had 1 or more episodes of atrial fibrillation and who are considered to be at thromboembolic risk because of age or underlying heart disease. To date, no studies have evaluated the safety of discontinuing warfarin after (apparently) successful catheter ablation of atrial fibrillation. In an attempt to determine whether catheter ablation abolishes paroxysmal atrial fibrillation, Oral et al68 recorded daily, randomly transmitted 3-minute ECG strips from 60 patients with a history of paroxysmal atrial fibrillation who had remained asymptomatic for at least 6 months after radiofrequency pulmonary vein isolation. Patients transmitted once-daily ECGs for a mean of 25 days and whenever they experienced symptoms that might represent arrhythmia recurrence. During the 1-month transmittal period, 7 patients (12%) developed symptoms and transmitted ECGs, all of which documented recurrent atrial fibrillation. Only 1 random asymptomatic transmission documented atrial fibrillation. On the basis of these results, the authors concluded that asymptomatic atrial fibrillation is uncommon among patients with paroxysmal atrial fibrillation who have undergone pulmonary venous ablation and who have remained asymptomatic for at least 6 months; however, these conclusions are questionable, because the duration of monitoring (3 minutes every 24 hours) would certainly have missed the vast majority of short episodes of asymptomatic atrial fibrillation. Furthermore, it is striking that 12% of subjects developed symptoms of atrial fibrillation once they had been given a monitor, despite apparent freedom from symptoms for a mean time greater than 1 year after ablation. As the authors point out, it is possible that participation in the clinical trial heightened patients’ awareness of minor symptoms of atrial fibrillation, thereby making it more likely that they would transmit a recording. These observations, in my opinion, point to the likelihood of ongoing (albeit less symptomatic) episodes of atrial fibrillation in a significant number of patients after pulmonary venous ablation and underscore the probable need for continued anticoagulation in this group despite the clinical benefit gained from the procedure in terms of improvement of symptoms.

Ablate and Pace: The Optimal Rate-Controlling Procedure in Atrial Fibrillation?
Recent data from a trial of patients with an implantable defibrillator have indicated that permanent right ventricular pacing is more likely to be associated with the development of congestive heart failure than when patients are permitted to remain in sinus rhythm.69 Because right ventricular pacing may increase left ventricular dyssynergy, and improvement of LV dyssynergy may decrease heart failure, concern has recently been expressed about the use of AV nodal ablation with right ventricular pacing for patients with atrial fibrillation and a poorly controlled heart rate. A meta-analysis of 21 studies of AV nodal ablation and pacemaker insertion performed for medically refractory atrial tachyarrhythmias (97% of which were atrial fibrillation) included 1181 patients and demonstrated improvement in quality of life, treadmill exercise duration, ejection fraction, and New York Heart Association class and showed a decrease in hospital visits.70 Early concerns about the provocation of fatal polymorphic ventricular tachycardia after this procedure appear to be assuaged by the authors’ finding of a low mortality on follow-up. As the authors of this meta-analysis point out, the use of baseline pacing rates of 80 to 90 bpm for 1 to 2 months after ablation appears to prevent this uncommon but serious proarrhythmic complication.

Further evidence that right ventricular pacing does not worsen left ventricular function in the majority of patients with atrial fibrillation comes from the Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT).71 Ninety-nine patients with permanent atrial fibrillation who had mild to moderate symptoms at the time of presentation and who also had an ability to successfully achieve rate control with pharmacological therapy were randomized to either pharmacological therapy or AV nodal ablation with right ventricular pacing. Not surprisingly, given the ability of all patients to achieve adequate pharmacological rate control and the presence of a mean baseline ejection fraction of 55% to 57%, exercise time did not differ between the 2 groups 12 months after randomization. According to the CAST quality-of-life questionnaire, patients with AV nodal ablation had a significant improvement in symptoms, but these results need to be interpreted cautiously because 2 other "arrhythmia nonspecific questionnaires" showed no difference in quality of life. Importantly, AV nodal ablation with pacing did not cause any deterioration in left ventricular function. Thus, the AIRCRAFT results confirm that pharmacological therapy is effective for symptom control and that rate regularization, such as occurs with ventricular pacing (and that is one of the purported benefits of sinus rhythm restoration), may play only a small part in symptom control. The difference in outcome in terms of quality of life between the prospective AIRCRAFT trial and the "ablate and pace" meta-analysis almost certainly represents different patient populations, with the AIRCRAFT patients being, by virtue of entrance criteria, less sick than the usual patients who are considered for ablation and pacing (ie, drug-refractory symptomatic atrial fibrillation, often with a decreased ejection fraction). For patients with a significantly reduced ejection fraction and refractory atrial fibrillation and for whom concern still exists that right ventricular pacing may not be the optimal mode, biventricular pacing, with or without AV nodal ablation, has been shown to be successful both in terms of rate control and in improving symptoms and ventricular function.72,73


*    Conclusions
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 up arrowIntroduction
 up arrowLessons From the Multicenter...
 *Conclusions
down arrowReferences
 
Careful analysis of published data to date does not support a routine strategy of restoration of sinus rhythm in the majority of patients with atrial fibrillation. Large clinical trials have consistently shown that ventricular rate control is equally (or more) effective than rhythm control in terms of survival, quality of life, and multiple other end points. Currently available antiarrhythmic drugs have a relatively low efficacy in maintaining sinus rhythm and have the potential for serious cardiac and noncardiac side effects, which contrasts with the low side effect profile and (in the case of ß-blockers) cardioprotective effect of rate-controlling agents. Catheter isolation of the pulmonary veins is quite effective in skilled hands in highly selected patients, but it is not proven to reduce the risk of thromboembolism, and the procedure has an uncertain long-term efficacy, particularly when episodes of asymptomatic atrial fibrillation are considered. In contrast, the well-established ablate-and-pace method for ventricular rate control in drug-refractory patients is a relatively simple and very safe procedure that is associated with a clear-cut improvement in the quality of life in previously symptomatic patients and that may be associated with an improvement in ejection fraction in patients with previously poorly controlled rate and impairment of ventricular function. Thus, in this era of increasing awareness of the side effects of antiarrhythmic drugs and the undocumentable benefit of restoration of sinus rhythm, the physician faced with a patient with atrial fibrillation should consider ventricular rate control first to fulfill the primary precept of all physicians: "First, do no harm."


*    Footnotes
 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.


*    References
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 up arrowLessons From the Multicenter...
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