No reason for rhythm: AFFIRM and RACE trials support rate control as equivalent strategy in AF

Shelley Wood

December 04, 2002

Boston, MA - Rate control can be considered a "primary approach" in the treatment of atrial fibrillation (AF), while rhythm control, if used, can be abandoned early if need be, according to the results of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) and Rate Control vs Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) trials. Both studies, first presented at the 2002 American College of Cardiology meeting, found a strategy of rate control to be at least as good as rhythm control for patients with persistent AF.

"In this study of patients with AF and risk factors for stroke, the strategy of restoring and maintaining sinus rhythm had no clear advantage over the strategy of controlling the ventricular rate and allowing atrial fibrillation to persist," the AFFIRM investigators concluded.

The studies have now been published in the New England Journal of Medicine[1,2].

Old assumptions

For years, physicians have assumed that rhythm controlusing antiarrhythmic drugs such as amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, sotalol, etc, with cardioversion as necessarywould be preferable since this strategy was believed to reduce symptoms, improve exercise tolerance, and lower risk of stroke. By contrast, rate control has been considered a secondary strategy for AF, using antrioventricular nodal blocking agents or ablation of the AV junction and pacemaker implantation to control ventricular response.

As Dr Michael E Cain (Washington University School of Medicine, St Louis, MO) points out in a Perspective accompanying the papers, "Over time, a low rate of efficacy, side effects, and ventricular proarrhythmia dampened enthusiasm for the use of antiarrhythmic drugs in patients with AF and finally led to randomized trials comparing the 2 approaches"[3].

The randomized trials

The largest of these trials to date is AFFIRM, a 4060-patient trial conducted at 213 centers in the US and Canada looking at all-cause mortality. In Europe, the RACE study addressed a composite of cardiovascular mortality and other adverse events in 522 patients. Results from both studies were previously reported by heartwire .

In AFFIRM, 356 out of 2033 patients randomized to rhythm control died over the average follow-up of 3.5 years, compared with 310 out of 2027 in the rate control group (p=0.08). Also, more rhythm control patients were hospitalized and/or had adverse drug effects. Crossover rate was significantly greater among rhythm control patients, "in keeping with the fact that antiarrhythmic drug therapies frequently fail."

Of note, the trend toward increased mortality in the rhythm control group of AFFIRM did not begin to emerge until almost the second year of follow-up, hinting that problems associated with rhythm control might continue to increase over time. "Patients with atrial fibrillation often need treatment for decades, not years," the AFFIRM investigators note. "The adverse effects due to the most commonly used drug, amiodarone, might be reasonably expected to increase with longer use."

Adverse outcomes in AFFIRM

End point Rate group, No. (%) Rhythm group, No. (%)
Death 310 (25.9) 356 (26.7) 0.08
Death, disabling stroke, anoxic encephalopathy, major bleeding, cardiac arrest 416 (32.7) 445 (32.0) 0.33
Hospitalization after baseline 1220 (73.0) 1374 (80.1) <0.001

In RACE, led by Dr Isabelle C Van Gelder (University Hospital, Groningen, the Netherlands), the primary end point of cardiovascular death, heart failure, thromboembolic complications, bleeding, pacemaker implantation, or severe adverse drug effects occurred in 60 out of 266 patients randomized to rhythm control, compared with 44 of 256 in the rate control group. The rate of death was similar in the 2 groups of RACE patients, but thromboembolic complications and adverse drug reactions were greater in the rhythm control group. Of note, events in the rhythm control group were more common among female patients and patients with hypertension. A strong trend toward increased mortality among rhythm control patients with hypertension was also seen in AFFIRM.

In both the RACE and AFFIRM trials, ischemic strokes were more common in patients not on anticoagulation or with suboptimal INRs. "On the basis of these data, rate control can now be considered a primary approach to the treatment of AF, and rhythm control, if used, can be abandoned early if it is not fully successful," Cain commented.

Practical implications

In an accompanying editorial, Dr Rodney H Falk (Boston University School of Medicine) warns that the findings of excess end points among women in RACE should be "interpreted with caution" since it was not a prespecified analysis, women overall had fewer end points than did men, and the observation could have been due to chance[4]. The findings, however, underscore "the importance of hypertension as a risk factor for atrial fibrillation and the need to consider it when choosing a treatment strategy," Falk writes.

More important, Falk says, is how to integrate the RACE and AFFIRM findings into clinical practice. "At first glance, it may seem that the results render an attempt at cardioversion obsolete, since the quality of life, the risk of stroke, and mortality were not affected by an attempt to maintain sinus rhythm." However, he continues, all of the patients in RACE and most of the patients in AFFIRM had already had an episode of AF before enrollment, pointing to a "propensity for recurrent arrhythmia." As such, the findings from these trials do not necessarily apply to people with a first episode of arrhythmia.

Falk adds another "word of caution," saying that while AFFIRM and RACE are "landmark" trials, "there remains a substantial proportion of patients in whom atrial fibrillation causes symptoms despite pharmacologic attempts to control heart rate." For these patients, Falk says, "the goal is still maintenance of sinus rhythm, and the quest for better drugs and techniques to achieve this goal will, and should, continue."

Falk's points echo those of Dr Eric Prystowsky (St Vincent's Hospital, Indianapolis, IN) who commented on the AFFIRM results to heartwire when they were first presented, noting that the AFFIRM population excluded those who couldn't get by on rate therapy alone. "These are the people that I get calls from every single day in my practice who say 'I can't stand these palpitations,' even though their rate is under wonderful control. . . . If rate control does not provide symptom relief, which it doesn't in 25% to 30% of my patient population, then that person is not a candidate for just leaving them in AF and controlling rate," Prystowsky stated.

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