Trials AFFIRM the role of rate: persistent AF patients do fine on rate control, but only if they can

Shelley Wood

March 18, 2002

Atlanta, GA - Rate control is at least as good as rhythm control for patients with persistent atrial fibrillation, according to two late-breaking sessions presented here at the American College of Cardiology 51st Annual Scientific Session. But experts caution that choosing rate over rhythm control is not a valid option for many patients suffering from persistent AF, while others may be eligible for new therapies such as pulmonary vein ablation.

Dr George Wyse (Univeristy of Calgary, AB) unveiled the much-anticipated results of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, while Drs Harry Crijns and Isabelle C Van Gelder (University Hospital, Maastricht, the Netherlands) shared the podium to present the smaller-scale Rate Control vs Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study.

The debate over rate versus rhythm in the treatment of atrial fibrillation (AF) has persisted due to the relative pros and cons of each therapeutic strategy. Standard practice has been to control sinus rhythm primarily through the use of antiarrhythmic drugs and cardioversion, which relieve symptoms and can retard or prevent progression to permanent AF. Rhythm control, however, carries some risk in that the standard antiarrhthymic drugs can themselves lead to arrhythmias. Rate control does away with the proarrhythmia risks, but allows AF to persist and does not eliminate AF symptoms, including palpitations, dyspnea, chest pain, fatigue, and fainting.

Rates and rhythms

The NHLBI-funded AFFIRM trial, conducted at 213 centers in the US and Canada, randomized a total of 4060 patients to rate control therapy using primarily digoxin (51% of patients), -blockers (49%), or calcium channel antagonists (41%), or to rhythm control using predominantly amiodarone (39%), sotalol (33%), and propafenone (10%). Ablation and pacemakers were given in the rhythm arm, if necessary. All patients enrolled in the trial were able to tolerate either rate or rhythm control therapy at baseline. The trial was conducted on an intention to treat basis.

"Obviously there were frequent changes in drug regimen throughout the study," Wyse said, noting that amiodarone was ultimately given to 60% of AFFIRM patients over the average 3.5 year follow-up period.

At follow-up, 60% of patients in the rhythm arm were in normal sinus rhythm - a surprisingly modest proportion, Wyse noted - while successful rate control was achieved in 80% of rate-control patients, Wyse reported. Warfarin use fell over the course of the study, but remained high in both groups, 85-90% in the rate group and 70% in the rhythm group. This was despite the fact that patients in the rhythm arm were permitted by study protocol to discontinue anticoagulation therapy after normal rhythm had been achieved and maintained for 1 month.

All-cause mortality, the primary endpoint of the study, was not significantly different between the two groups, said Wyse, although the survival curves did appear to separate at around 1.5-2 years in favor of the rate group. The authors saw no differences in several components of the secondary endpoint, including functional status, quality of life, or rate of ischemic stroke, although this last showed a trend favoring the rate group. Other factors also pointed to a superiority of rate over rhythm: death and disabling stroke, hospitalizations, or new arrhythmias also appeared to occur more often in the rhythm control group.

"We conclude that there is no survival benefit, but a possible slight increase in stroke risk with rhythm control," Wyse concluded. "The implications of these findings are that in an elderly population with stroke and death risk factors, the rate control strategy, which up until now has been considered by many physicians as second best, is at least as good as the rhythm control strategy and should be elevated to the status of a primary approach."

Rate affirmed, but for who?

Wyse emphasized some of the more important points of AFFIRM, pointing out that the lack of longer term anticoagulation therapy in the rhythm arm might account for the higher stroke rate, perhaps necessitating warfarin over a longer time period. He also emphasized that AFFIRM enrolled a wide cross-section of elderly people and as such the results were applicable to this group, but not younger patients.

Commenting on the AFFIRM results to heartwire , Dr Eric Prystowsky (St Vincent Hospital, Indianapolis, IN) pointed out that AFFIRM also excluded another important group of patients: those who were not able to get by with rate therapy alone.

"I'm worried that people will take the AFFIRM results and say, 'See? You don't need to have people in sinus rhythm.'"

In fact, says Prystowsky, the people who can't put up with their aberrant heart rhythms and related problems "never made it into the trial" because they could not get adequate relief from rate control: "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. So you have to be very careful and say if you can be well-controlled with rate and feeling fine, then maybe that's okay."

Prystowsky believes patients with AF should first receive rate control. "And if rate control does not provide symptom relief, which it doesn't in 25-30% of my patient population, then that person is not a candidate for just leaving them in AF and controlling rate," he states. "That's one of my concerns with AFFIRM. The results from AFFIRM only relate to the type of patients who were included in the study."

Prystowsky on PV ablation, rate, and rhythm control

Prystowsky himself spent Monday morning in a session concurrent to the late-breakers debating whether pulmonary vein ablation (PVA) should be considered early in treating all patients with paroxysmal atrial fibrillation. Reaching a middle ground with protagonist Dr J Marcus Wharton (Durham, NC), Prystowsky concurred that PVA may indeed be an important strategy, particularly in younger people potentially facing a lifetime on drugs for AF. But, as he emphasized to heartwire , the person being considered for rhythm control, be it through anti-arrhythmic medications and conversion, or a newer therapy like PVA, is symptomatic.

"One of the reasons I like ablation, is that if you truly cure someone, a major advantage is that they go off anticoagulants," explains Prystowsky. "So I think ablation in the future is going to gain more and more acceptance as a mode of therapy. The issue here is which patients are the best candidates right now for early therapy with ablation with current technology and knowledge? There are a lot of younger people with AF who I think should be offered ablation very high up the list as one of the early options."

Prystowsky reiterates that the patients included in AFFIRM were admitted on the grounds that they would do fine on rate control. "So you could argue that the AFFIRM patients may not be your best candidates for ablation either. It's all those thousands, maybe a million patients who don't do feel good with a rate control philosophy who might be candidates for ablation."

In terms of the relative costs of therapy, the drugs used for rate control are "far cheaper" than those used for rhythm control, says Prystowsky. "On a cost-basis, all things being equal without more frequent visits to the doctor, costs would be less with rate control than rhythm control." There is currently no longer-term data on cost efficacy of PVA in AF specifically, he says, but other ablation data gives some clues. "If you look at analyses that have been done and published for WPW syndrome and AV node re-entry on drug therapy versus nonpharmacologic, it takes several years, depending on which drugs you use. But after 4 or 5 years, it's cheaper to do the ablation."

Commenting to the press on the role that PVA might one day play in the treatment of AF, Wyse stated that most of the studies of focal PVA or PV isolation are of relatively young people, usually with paroxysmal AF. Moreover, he says, "we don't know what the long-term recurrence rate is... I think it's premature to use the word 'curative' since you cannot be sure that you have actually cured AF. So while we all encouraged that these techniques might one day be curative, they're not 'curative' yet." Wyse believes that for the majority of patients, including elderly patients, PVA still needs to be further defined.

Several studies of PVA and pulmonary vein isolation as a treatment for AF are being presented at the ACC over the next 2 days.

-SW

Rate not a loser in RACE?

The second late-breaker addressing the issue of rate versus rhythm was based on the hypothesis that rate control using medical therapy would prove inferior to rhythm control using repeat electrical cardioversion (ECV) in tandem with antiarrhythmic drugs. The primary endpoint of the study was a composite of cardiovascular death, hospitalization for heart failure, thromboembolic complications, severe bleeding, pacemaker implantation, or severe drug side effects.

Over an average of 3 years follow-up, Crijns, Van Gelder and colleagues found no differences in mortality between the 256 patients randomized to the rate control group and the 266 patients randomized to rhythm control, although the composite primary endpoint was reached in 17.2% and 22%, respectively.

 
Rate control therapy is not inferior to rhythm control therapy in patients with persistent AF. Rate control is an attractive alternative for patients with a high risk of AF occurrence.
 

The differences, explained Felder, lay in some of the nonfatal endpoints: patients in the rhythm group experienced more thromboembolic complications, more heart failure, and more adverse drug effects. In a subgroup analysis, patients with hypertension randomized to the rhythm group showed a particularly high incidence of the combined primary endpoint at 30.8%, compared to hypertensives in the rate-control group.

"This may indicate that hypertensive patients may do better with rate control," Gelder told delegates, adding that this observation was a post hoc hypothesis and needed to be tested in further studies.

"We conclude that rate control therapy is not inferior to rhythm control therapy in patients with persistent atrial fibrillation," Gelder summarized. "The clinical implications of this study are that rate control is an attractive alternative for patients with a high risk of atrial fibrillation occurrence."

In the question period following RACE, Gelder agreed with what Wyse had already stated; that oral anticoagulation might need to be extended in patients with persistent AF.

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