GRöNINGEN, NETHERLANDS—Although controlling sinus rhythm has long been the primary goal when treating patients with atrial fibrillation, two recent studies have demonstrated that ventricular rate control is an acceptable alternative for persistent, recurrent arrhythmia—and may even be preferable in some patients.

Dutch researchers hypothesized that since the benefits of rhythm control can be offset by life-threatening cardiovascular events, and since these events are often caused by an underlying cardiovascular abnormality, rhythm control does not determine prognosis and may not be any better than rate control.[1] Similarly, North American investigators theorized that because atrial fibrillation is often poorly responsive to antiarrhythmic drugs, control of the ventricular response rate might simplify therapy and allow the use of less toxic drugs.[2]

THE DUTCH EXPERIENCE

To test their theory, Isabelle C. Van Gelder, MD, PhD, and colleagues conducted a multicenter randomized study comparing the long-term effects of rate control and rhythm control in 522 patients with persistent atrial fibrillation. The rate-control group (n = 256) was treated with one or all of the following: digitalis, a calcium-channel blocker, and a ß-blocker to achieve a target resting heart rate of 100 beats per minute. If patients did not respond to treatment, cardioversion or atrioventricular node ablation and implantation of a pacemaker were performed. The rhythm-control group (n = 266) underwent electrical cardioversion followed by sotalol administration. If atrial fibrillation recurred within six months, cardioversion was repeated and sotalol replaced by flecainide or propafenone. If the arrhythmia recurred within six months of this second treatment, a loading dose of amiodarone was given and cardioversion was repeated.

From four weeks before until four weeks after electrical cardioversion, all patients received an oral anticoagulant. This therapy could be stopped and changed to aspirin after one month if sinus rhythm was established. Patients younger than 65 in the rate-control group could also take aspirin if no underlying cardiac disease was present.

The primary composite end point was heart failure, thromboembolic complications, bleeding, the need for a pacemaker, severe adverse effects of antiarrhythmic drugs, or death from cardiovascular disease. Follow-up lasted a mean of 2.3 years.

OUTCOMES SIMILAR

By the end of the study, patients in the rhythm-control group had undergone a median of two electrical cardioversions, and 39% had sinus rhythm. In the rate-control group, 10% of patients had sinus rhythm. Of these, half had received electrical cardioversion because of intolerable symptoms, and half had had spontaneous cardioversion.

A primary end point event occurred in 17.2% of the rate-control group and in 22.6% of the rhythm-control group. Thirty-five patients (21 in the rhythm-control group and 14 in the rate-control group) experienced thromboembolic complications. Pacemakers were implanted in three patients in the rate-control group and in eight patients in the rhythm-control group. The rate of death from cardiovascular causes was similar in both groups.

In the rhythm-control group, morbidity and mortality were similar regardless of whether sinus rhythm was restored, suggesting that cardiovascular risk is not reduced with rhythm control. The investigators proposed that rate control be considered for management of persistent atrial fibrillation earlier in the treatment process than it is currently used.

According to lead author Dr. Van Gelder, one population that would benefit from rate control is asymptomatic patients with hypertension, since both her study and the North American trial, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), found an excess number of primary end point events in patients with hypertension.

AFFIRM

The AFFIRM investigators performed a study similar to that of Dr. Van Gelder and colleagues. They enrolled 4,060 patients with atrial fibrillation, who were then randomized to receive antiarrhythmic drugs (n = 2,033) or rate-controlling drugs (n = 2,027), along with anticoagulants as needed. Although nonpharmacologic therapies could be used when drugs failed, very few patients were treated with these therapies. The primary end point was overall mortality.

Patients were followed for a mean of 3.5 years. During the study, 594 patients were switched from the rhythm- to the rate-control group; in comparison, 248 were switched from the rate- to the rhythm-control group. More deaths occurred in the rhythm-control group than the rate-control group, but this difference did not reach significance. Additionally, patients in the rhythm-control group were more likely to be hospitalized and have adverse drug events than those in the rate-control group.

These findings led the investigators to conclude that rhythm control offers no survival advantage to patients with atrial fibrillation such as those enrolled in AFFIRM. Nevertheless, there may still be instances when rhythm control is preferable. According to D. George Wyse, MD, a member of the AFFIRM writing group and a Professor of Cardiology and of Pharmacology and Therapeutics at the University of Calgary in Alberta, this would include “younger patients who are highly symptomatic [as well as] patients with their first episode and little or no structural heart disease.”

“The main message,” said Dr. Wyse, “is that rate control has been underappreciated as primary therapy, and one should not persist with the rhythm control approach when it is not going well in AFFIRM-type patients.”

RISK FACTORS AND ANTICOAGULANTS

There are many theories as to why rhythm control did not equate to lower cardiac risk in the two studies. Data from the Dutch trial suggest that cessation of anticoagulant therapy in patients with risk factors for stroke is associated with stroke occurrence despite a normal sinus rhythm. The protocol for this study allowed anticoagulant therapy to be discontinued after one month of normal sinus rhythm. Six thromboembolic events occurred after anticoagulants had been discontinued; in five of these six cases, the patient had normal sinus rhythm at the time of the event.

Similarly, most of the strokes in AFFIRM occurred in patients with either suboptimal or discontinued anticoagulation. Thus, the AFFIRM investigators arrived at a similar conclusion—that anticoagulants should not be discontinued in patients at risk for stroke.

END POINT EVENTS

In the Dutch study, female sex was associated with a higher incidence of primary end point events in the rhythm-control group. In AFFIRM, the point estimate of the hazard ratio for the primary end point (death) comparing rhythm control to rate control was virtually identical for both sexes. In an editorial, Rodney H. Falk, MD, a Professor of Medicine at Boston University School of Medicine, noted that sex was not prespecified for analysis in the Dutch study.[3] Nevertheless, he pointed out that in the rate-control group, women had fewer end point events than men did. This implies, said Dr. Falk, that the higher female incidence of end point events in the rhythm-control group may have been the result of an interaction between treatment and sex, and not of sex alone. He added, however, that because cardiac histories were not examined in the study, firm conclusions cannot be drawn; it may simply be that some of the women were predisposed to additional events.

Both studies found that rhythm control was associated with poorer outcomes in patients with hypertension. For example, among the hypertensive patients in the Dutch trial, the risk of a primary end point event was almost twice as high in the rhythm-control group than in the rate-control group. In AFFIRM, the hazard ratio for death was much lower in the rate-control group than in the rhythm-control group.

“Our hypothesis was that rate control was not inferior to rhythm control. … Nevertheless, we did not expect the excess number of end points in patients with hypertension and females randomized to the rhythm-control strategy,” said Dr. Van Gelder, who is an Associate Professor of Cardiology at University Hospital, Groningen, in the Netherlands.

When asked about the importance of cardiovascular abnormalities and risk factors in determining prognosis, Dr. Van Gelder admitted that it was difficult to say but noted, “80% of patients had underlying heart disease [and] 90% had stroke risk factors.”

Dr. Falk observed that hypertension is the most common cause of left ventricular hypertrophy, and left ventricular hypertrophy in turn is associated with an increased risk of drug-related arrhythmias.

USING RHYTHM CONTROL

Because the Dutch study included only patients who had recurrent atrial fibrillation after cardioversion, its findings may not apply to patients having their first episode of atrial fibrillation.

For this group, Dr. Van Gelder said, therapy should consist of “one electrical cardioversion, … probably with prophylactic antiarrhythmic drugs afterwards (or even started shortly before cardioversion in the hospital) to improve maintenance of sinus rhythm.” However, she added, “in elderly asymptomatic patients, acceptance of [atrial fibrillation] may be a first option.”

Dr. Van Gelder also stressed the need for improved monitoring of anticoagulation to prevent thromboembolic events and “improvement of methods to maintain sinus rhythm after cardioversion, especially in symptomatic younger patients—either with more effective and safe antiarrhythmic drugs or invasive methods like pacing and radiofrequency ablation to prevent atrial fibrillation.”

—Gale Jurasek

References
1. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347:1834-1840.
2. The AFFIRM Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825-1833.
3. Falk RH. Management of atrial fibrillation—radical reform or modest modification? N Engl J Med. 2002;347:1883-1884.

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