Valsartan for Atrial Fibrillation?
Abstract & commentary
By John P. DiMarco, MD, PhD
Source: The GISSI-AF Investigators. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med. 2009;360: 1606-1617.
It has been postulated that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II-receptor blockers (ARBs) decrease the risk of developing atrial fibrillation both indirectly by better control of hypertension and heart failure and directly by effects on fibrosis, inflammation, and atrial remodeling. In this study, the GISSI-AF investigators report a controlled, randomized trial using the ARB valsartan in patients with atrial fibrillation. Patients were eligible for inclusion in the study if they had two or more episodes of symptomatic atrial fibrillation in the previous six months or had been successfully cardioverted from atrial fibrillation within the previous fourteen days. Patients were required to have a risk factor for stroke including at least one of the following conditions: heart failure or left ventricular dysfunction, hypertension with or without left ventricular hypertrophy, diabetes, prior stroke or peripheral artery disease, coronary artery disease, or left atrial dilatation. Patients were maintained on a stable regimen for the treatment of atrial fibrillation and other cardiac disorders for a minimum of one month before enrollment. Patients were permitted to continue other cardiac medications that had been started earlier, including ACE inhibitors, antiarrhythmic drugs, and beta adrenergic blockers. Patients enrolled were randomly assigned to receive either valsartan or matching placebo. The initial dose of active study drug was 80 mg daily for two weeks. The dose was then increased to 160 mg daily for two weeks and, finally, increased to 320 mg daily. Patients who could not tolerate a daily dose of 160 mg or more had their study drug discontinued. Follow-up was obtained by office visits periodically during the year of the study. All patients also were provided with a transtelephonic monitoring device, which they could use to transmit a 30-second electrocardiogram either with the occurrence of symptoms or routinely at least once per week.
The study had two primary endpoints: time to recurrence of atrial fibrillation and the proportion of patients who had more than one episode of atrial fibrillation during one year follow-up. Secondary endpoints included: total number of episodes of atrial fibrillation, hospitalization for any reason, hospitalization for a cardiovascular event, death, and thromboembolic events.
The study enrolled 1,442 patients at 114 centers over a 2.5-year period. The valsartan and placebo groups were similar in terms of their baseline characteristics. Hypertension was present in 85.4%, diabetes in 14.6%, and heart failure in 7.9%. At the time of randomization, 35% of the patients were receiving amiodarone, 57% were receiving ACE inhibitors, 34% were on a beta blocker, and 57% were on a vitamin K antagonist. The target dose of 320 mg of valsartan or matching placebo was achieved in 84% of the patients, with no difference between the two groups. Only five patients in each group could not tolerate a daily dose of 160 mg.
Valsartan had no significant effect on atrial fibrillation. At one year, there was no difference in the recurrence of atrial fibrillation between the two groups (51.4% valsartan vs. 52.1% placebo). After adjustment for baseline variables, the adjusted hazard ratio was 0.97 (96% confidence interval, 0.83 to 1.14; p = 0.73). The median time from randomization to the first occurrence of atrial fibrillation was 295 days in the valsartan group and 271 days in the placebo group. Recurrent episodes of atrial fibrillation were noted in 27% of the valsartan patients and 28% of the placebo group. There was also no difference between the groups in the frequency or duration of atrial fibrillation events. There were no significant differences between all-cause hospitalizations, cardiovascular hospitalizations, or deaths. The authors did note a slight excess in the number of thromboembolic events in the valsartan group (10 vs. 2), but considered this due to chance. Subgroup analyses showed that the hazard ratios for the first occurrence of atrial fibrillation were similar in all predefined subgroups. The study drug was well tolerated. One patient in the valsartan group had severe hypotension and one had renal dysfunction plus hyperkalemia.
The authors conclude that daily valsartan added to standard therapy in patients with a history of atrial fibrillation does not reduce the incidence of recurrent atrial fibrillation compared to placebo therapy.
A number of studies on the use of both ACE inhibitors and ARBs in patients with heart failure have reported a decreased incidence of AF as a secondary endpoint. A recent meta-analysis by Healey et al (J Am Coll Cardiol. 2005;45:1832-1839), reported that therapy with ACE inhibitors and ARBs resulted in relative risks for developing atrial fibrillation of 0.72 and 0.71, respectively. In a retrospective analysis from the AFFIRM trial, ACE inhibitor or ARB use associated with less atrial fibrillation recurrence in patients with heart failure or decreased ventricular function. Only an insignificant trend was seen in the whole AFFIRM population. (Heart Rhythm. 2004;1:669-675.). Blockade of the renin-angiotensin-aldosterone system in experimental models of heart failure has had favorable effects on atrial electrical and structural remodeling. In this randomized trial, adding an ARB to standard therapy in patients with atrial fibrillation did not decrease the risk of recurrence. The current study results should be a significant disappointment to clinicians caring for patients with atrial fibrillation. The ARB, when added to other therapy, did not change the risk for recurrent atrial fibrillation or diminish the number or recurrent episodes, but the follow-up was only a year. There remains the strong possibility that use of ACE inhibitors or ARBs in patients with hypertension or heart failure, if started early in the course of their disease before they develop atrial fibrillation, may still prove to be a correct strategy.