ATLANTA — For patients with permanent atrial fibrillation, lenient control of heart rate does not result in worse outcomes than stricter control, a multicenter, randomized trial showed.
Through three years, the rate of adverse outcomes was similar in the two groups (12.9% with lenient control and 14.9% with strict control), establishing noninferiority for the lenient approach, according to Isabelle Van Gelder, MD, of University Medical Center Groningen in the Netherlands, and colleagues.
The lenient group achieved its heart rate targets with significantly fewer total healthcare visits (75 versus 684, P<0.001), Van Gelder reported at the American College of Cardiology meeting here. The results were published simultaneously online in the New England Journal of Medicine.
“Lenient rate control is more convenient, since fewer outpatient visits, fewer examinations, lower doses of rate-control drugs, and less of the combination of drugs are needed,” Van Gelder said in her presentation.
“Therefore, lenient rate control may be adopted as the first-choice rate-control strategy in patients with permanent atrial fibrillation, and this applies to both high- and low-risk patients.”
Ralph Brindis, MD, MPH, a cardiologist at Kaiser Permanente in Oakland, Calif., and president-elect of the ACC, said at a press briefing at which the results were discussed that “the concept that you actually as a clinician can feel comfortable having a patient at a higher resting heart rate is huge.”
He added, however, that choice of treatment needs to be patient-focused, “because if the patient is not doing well with a high resting heart rate, or with exercise heart rate goes way up, then that’s a patient we might clearly want to be more aggressive with.”
Van Gelder said the results call into question existing guidelines. Recommendations from the ACC, American Heart Association, and European Society of Cardiology advise strict heart rate control — a heart rate less than 80 beats per minute at rest and less than 110 bpm during moderate exercise — to improve outcomes. That advice is not based on clinical evidence.
Van Gelder said she thinks the guidelines should be changed to reflect the new findings.
But Brindis disagreed, pointing to the relatively small number of patients included in the study.
“I don’t think I would change our guidelines at this time,” he said, adding, however, that “I find [the study] a little freeing.”
To see whether more lenient control — a heart rate less than 110 bpm at all times — would work as well as strict control at preventing cardiovascular morbidity and mortality, Van Gelder and colleagues undertook the RACE II trial at 33 centers in the Netherlands.
All 614 patients had permanent atrial fibrillation for up to 12 months (median three months), were 80 or younger (mean age 68), and had a mean resting heart rate greater than 80 bpm at baseline.
The two groups of patients were well-matched at baseline, except for a higher prevalence of coronary artery disease and statin use, and higher diastolic pressure, in the lenient group.
During a dose-adjustment phase, patients in both groups were given one or more negative dromotropic drugs until the heart rate target or targets were achieved. At the end of this phase, the mean resting heart rate was 93 bpm in the lenient group and 76 bpm in the strict group (P<0.001).
Nearly all of the patients in the lenient group (97.7%) reached their target, compared with just 67% of the strict group (P<0.001).
The primary endpoint was a composite of cardiovascular death, heart failure hospitalization, stroke, systemic embolism, major bleeding, arrhythmic events, life-threatening adverse effects from the rate-control drugs, and implantation of a pacemaker or cardioverter-defibrillator.
Through follow-up lasting two to three years, 12.9% of the patients in the lenient group and 14.9% in the strict group reached that endpoint (absolute difference -2%, 90% CI -7.6% to 3.5%). Because the upper bound of the confidence interval was less than 10%, noninferiority of the lenient approach was established.
Rates of most of the components of the primary endpoint were also similar in the two groups. The lone exception was stroke, which occurred less frequently in the lenient group (1.6% versus 3.9%; HR 0.35, 95% CI 0.13 to 0.92).
Ralph Sacco, MD, a neurologist at the University of Miami in Florida, said there was no clear explanation for the difference in stroke risk, although it could have something to do with the increased number of visits in the strict group.
“Obviously, when there’s closer follow-up and closer observation, it may be that investigators more easily recorded vascular symptoms including stroke,” said Sacco, incoming president of the AHA.
Van Gelder noted that the numbers of strokes were low, precluding firm conclusions.
Symptoms of atrial fibrillation, hospitalizations, and adverse events occurred at similar rates in the two groups.
In an editorial that accompanied the NEJM article, Paul Dorian, MD, of St. Michael’s Hospital in Toronto, noted a number of limitations in the study: It is possible that rapid ventricular rates may take many years to result in cardiac deterioration, illness, or death, and thus, the benefits of strict rate control might take decades to become apparent. The subgroup that may have a particular benefit from strict rate control — patients with atrial fibrillation who have very rapid ventricular responses — may have been underrepresented. The data on symptoms and quality of life were somewhat limited. As in all randomized trials, selection bias might have limited enrollment to patients who were relatively well.
Nevertheless, he wrote, “a heart-rate target of less than 110 beats per minute at rest, although it may make physicians feel uncomfortable, is probably as useful as the current guideline-recommended target heart rates at rest and during exercise, at least in the medium term.”
Sacco noted that if clinicians don’t have to worry about rate control, they can concentrate on controlling other risk factors and oral anticoagulation.
“If we now know that a lenient rate control is as good as strict rate control, if not slightly better for stroke risk, I think that’s one less thing we have to be focused on.”
The study was supported by the Netherlands Heart Foundation and unrestricted educational grants from AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Medtronic, Roche, and Sanofi Aventis France (paid to the Interuniversity Cardiology Institute of the Netherlands).
Van Gelder reported receiving consulting fees from sanofi-aventis, Boehringer Ingelheim, and Cardiome, grant support from Medtronic, Biotronik, and St. Jude Medical, and lecture fees from sanofi-aventis, Boehringer Ingelheim, and Medtronic. Her co-authors reported relationships with Boehringer Ingelheim, sanofi-aventis, AstraZeneca, St. Jude Medical, Boston Scientific, Medapharma, Merck, Medtronic, Biosense Webster, Amgen, Pfizer, Biosite-Inverness, and Menarini.
Dorian reported receiving consulting fees from Sanofi, Boehringer Ingelheim, Cardiome, and St. Jude Medical, and grants, honoraria, and payment for the development of educational programs from Sanofi and Boehringer Ingelheim.