Observational Study Finds Possible Long-Term Mortality Advantage for Rhythm Control Drugs In Atrial Fibrillation Reply

Challenging a decade-old influential trial, a large observational study of patients with atrial fibrillation (AF) suggests that rhythm control drugs may outperform rate control drugs after 4 years.

Raluca Ionescu-Ittu and colleagues analyzed data from 26,130 patients 66 years or older diagnosed with AF in Quebec, Canada. Patients were followed for a mean of 3.1 years and for a maximum of 9 years. In apparent agreement with the AFFIRM trial, the investigators observed a small early increase in mortality associated with rhythm control therapy, followed by similar mortality between the groups until year 4. After year 4, however, mortality was lower in the rhythm control arm.

Total unadjusted mortality

  • Rhythm control: 48.3%
  • Rate control: 50.1%

Unadjusted mortality at 5 years:

  • Rhythm control: 41.7%
  • Rate control: 46.3%

Adjusted hazard ratios for rhythm control at:

  • 6 months: 1.07 (1.01-1.14)
  • 1 year: 1.03 (0.95-1.11)
  • 3 years: 0.95 (0.90-1.02)
  • 5 years: 0.89 (0.81-0.96)
  • 8 years: 0.77 (0.62-0.95)

The authors point out numerous differences between their study population and the AFFIRM study population, including the fact that their subjects were older, were more likely to be female and to have CHF, and were more likely to receive beta-blockers in the rate control group. Acknowledging the limitations of observational studies, they write that “the long-term benefits of rhythm control drugs in AF found in this study need to be assessed in future studies.”

In an accompanying editorial, Thomas Dewland and Gregory Marcus write that the results of the observational study are “provocative” but “insufficient to recommend a universal rhythm control strategy for all patients with AF.” They remind their readers, however, “that no clinical trial has definitively shown that maintenance of sinus rhythm is inferior to rate control, and expert consensus recommends a rhythm control strategy for individuals with arrhythmia-attributable symptoms.”

Here is the press release from Archives:

Study Examines Comparative Effectiveness of Rhythm Control vs Rate Control Drug Treatment on Mortality in Patients with Atrial Fibrillation

CHICAGO – An observational study that examined the comparative effectiveness of rhythm control vs. rate control drug treatment on mortality in patients with atrial fibrillation (a rapid, irregular heart beat) suggests there was little difference in mortality within four years of treatment, but rhythm control may be associated with more effective long-term outcomes, according to a report published Online First by Archives of Internal Medicine, a JAMA Network publication.

AF affects approximately 2.3 million Americans and 250,000 Canadians, and the condition has a complex therapy that may involve rate control agents, antiarrhythmic drugs, anticoagulant drugs and/or ablative techniques (use of a catheterization procedure to eliminate the anatomic source of the atrial fibrillation), according to study background.

“Controversy continues concerning the choice of rhythm control vs. rate control treatment strategies for atrial fibrillation (AF). A recent clinical trial showed no difference in five-year mortality between the two treatments. We aimed to determine whether the two strategies have similar effectiveness when applied to a general population of patients with AF with longer follow-up,” the authors write as background.

Raluca Ionescu-Ittu, Ph.D., of the Harvard School of Public Health, Boston, and colleagues used population-based databases from Quebec, Canada, from 1999 to 2007 to select patients 66 years or older hospitalized with AF who did not have AF-related drug prescriptions in the year before they were hospitalized but received one within seven days of discharge.

“We found that with increasing follow-up time the mortality among the patients who newly initiated rhythm control therapy gradually decreased relative to those who initiated rate control drugs, reaching 23 percent reduction after eight years of follow-up,” the authors comment.

The researchers note that recent clinical trials comparing the two treatments “concluded that there are no differences in mortality between the two treatment strategies.”

“For the first four years after treatment initiation, our results in a population-based sample are similar to the results from the recent clinical trials. In addition, we found a tendency toward a long-term protective effect for rhythm control drugs. The long-term benefits of rhythm control drugs in AF found in this study need to be assessed in future studies,” the researchers conclude.

(Arch Intern Med. Published online June 4, 2012. doi:10.1001/archinternmed.2012.2266.)

Editor’s Note: This research was supported by grants from the Canadian Institutes for Health Research (CIHR) to principal investigators. Some authors also disclosed support and affiliations. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Can Observational Data Trump Randomized Clinical Trial Results?

In an editorial, Thomas A. Dewland, M.D., and Gregory M. Marcus, M.D., M.A.S., of the University of California, San Francisco, write: “How do we best interpret this unexpected result given contrary evidence from prior randomized trials?”

“Although the findings of Ionescu-Ittu et al are provocative, they are insufficient to recommend a universal rhythm control strategy for all patients with AF. Randomization is a powerful tool that unfortunately cannot be reliably reproduced with statistical modeling,” the authors conclude.

(Arch Intern Med. Published online June 4, 2012. doi:10.1001/archinternmed.2012.2332.)

Editor’s Note: Dr. Marcus is a consultant for In-Carda Therapeutics and has received research support from St. Jude Medical, Astellas and Gilead. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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