GISSI-AF- Valsartan does not reduce recurrent AF

The angiotensin receptor blocker (ARB) valsartan did not significantly reduce either primary end point in GISSI-AF; that is, time to the first recurrence of atrial fibrillation (AF) or the proportion of patients with one or more episodes of AF during the one-year follow-up period.

Animal models show that blockade of the RAAS using angiotensin-converting enzyme (ACE) inhibitors or ARBs has favourable effects on atrial remodelling (which in turn predisposes to AF).

The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Atrial Fibrillation (GISSI-AF) trial was designed to discover whether addition of the ARB valsartan to the treatment regimen of AF patients could reduce the rate of recurrence of AF¹.

For inclusion in the trial, patients had to be 40 years or more, with at least two documented episodes of symptomatic AF in the previous six months or cardioversion 140-48 hours before randomisation. Additionally, patients had to have heart failure, left ventricular dysfunction, a history of hypertension, type 2 diabetes or stroke, coronary artery disease or left atrial dilatation. Treatment regimens were continued unaltered, with the exception of addition of the study drug.

In all, 1,442 patients were enrolled from 114 centres:722 patients were randomised to valsartan treatment (starting at 80 mg daily and up-titrated gradually to 320 mg daily) and 720 to placebo.

Duration of follow-up was one year. Patients were given a trans-telephonic monitoring device, to transmit a 30-second ECG at least once a week and if symptoms occurred to the co-ordinating centre. The primary end points were the time to first recurrence of AF and the proportion of patients who had one or more episodes of AF during follow-up.

Patients were well matched at baseline, with a mean age of 68 and just over 60% male patients. Eighty-five percent of patients had a history of hypertension, and blood pressure at inclusion was approximately 139/82 mmHg. Forty percent had had two or more episodes of AF over the past six months, and nearly 90% had had cardioversion in the previous fortnight.

At one year, 371 patients (51.4%) in the valsartan group and 375 patients (52.1%) in the placebo group had had a recurrence of AF (hazard ratio 0.98, p=0.83); median times to first recurrence of AF were 295 days in the valsartan group compared with 271 days in the placebo group.

More than one episode of AF occurred in 194 patients (26.9%) in the valsartan group and 201 (27.9%) of placebo group patients (odds ratio 0.95, p=0.66). Of the 1,254 patients who were in sinus rhythm at week 8, there were no significant differences between the treatment groups with respect to the rate of recurrence of AF (42.7% in the valsartan group and 44.0% in the placebo group, HR=0.96, p=0.62). There was no significant difference in the rate of symptomatic AF (24.0% in the valsartan group and 23.1% in the placebo group, p=0.77).

In this study, addition of valsartan to the treatment of patients with a history of AF associated with cardiovascular disease, diabetes or left atrial enlargement did not reduce the risk of first recurrence or multiple recurrences of AF. These findings were consistent across all predefined subgroups. However, a more pronounced effect of these agents has been demonstrated in other primary prevention trials.