NEJM: Novartis' Diovan fails to prevent a-fib recurrence

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Treatment with Novartis' Diovan (valsartan) does not reduce the incidence of recurrent atrial fibrillation (AF), according to results of the GISSI-AF trial published in the April 16 issue of the New England Journal of Medicine. Experimental studies suggest that angiotensin II-receptor blockers (ARBs) can influence atrial remodeling, and some clinical studies suggest that they may prevent AF. Based on this data, the GISSI-AF investigators conducted a randomized, prospective, placebo-controlled, multicenter trial to test whether the ARB valsartan could reduce the recurrence of AF.

The researchers enrolled 1,442 patients who were in sinus rhythm but had had either two or more documented episodes of atrial fibrillation in the previous six months or successful cardioversion for AF in the previous two weeks. To be eligible, patients also had to have underlying cardiovascular disease, diabetes or left atrial enlargement. Patients were randomly assigned to receive valsartan or placebo.

The authors wrote that the two primary end points were the time to a first recurrence of AF and the proportion of patients who had more than one recurrence of AF over the course of one year.

The GISSI-AF investigators reported that AF recurred in 51.4 percent in the valsartan group, as compared with 52.1 percent in the placebo group. More than one episode of AF occurred in 26.9 percent in the valsartan group and in 27.9 percent in the placebo group. They also found that the results were similar in all predefined subgroups of patients, including those who were not receiving angiotensin-converting-enzyme inhibitors.

The authors said that it seems unlikely that the expected benefit of ARB therapy would occur within the first few days of starting treatment. Early recurrences of atrial fibrillation after cardioversion are probably due to short-term electrical remodeling of atria, which tends to normalize within days or weeks if sinus rhythm is again restored. For this reason, they planned a secondary analysis that was limited to data on patients who were in sinus rhythm at the first follow-up visit, on day 15. This analysis did not show any effect of valsartan on the recurrence of AF.

They noted that the "significant excess of thromboembolic events in the valsartan group was unexpected," and may be a "chance finding." Of note, the rate of thromboembolic events in the placebo group in our trial was much lower than expected and was lower than previously reported rates in similar patient populations.

They evaluated the potential benefit of adding 320 mg of valsartan daily to standard therapy in patients who had a history of AF associated with cardiovascular disease, diabetes or left atrial enlargement, according to the investigators. At one year, they found no significant reduction in the incidence of recurrent AF among patients receiving valsartan as compared with those receiving placebo, they noted.