The recurrence of atrial fibrillation (AF) after cardioversion may be partially related to a process known as remodeling – the electrical, mechanical and structural properties of the atrial tissue are altered in a progressive and irreversible manner resulting in a more favourable substrate for AF. From animal models, blockade of the rennin-angiotensin-aldosterone system (RAAS) has been shown to alter the remodeling process in a beneficial manner.
The GISSI-AF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Atrial Fibrillation)study was a prospective, multi-centre, randomised, double-blind, placebo controlled trial. It assessed whether the addition of the AIIRB valsartan to established treatments could reduce the recurrence of AF in patients with a history of arrhythmia. Patients were eligible if they were at least 40 years of age and had had 2 or more episodes of symptomatic atrial fibrillation in the previous 6 months or a successful cardioversion (electrical or pharmacological) 48 hours-14 days before randomisation. Patients had to have been in sinus rhythm for a minimum of 48 hours prior to enrolment. Participants were also required to have been on a stable regimen for treatment for atrial fibrillation or other cardiac conditions for 1 month.
1442 patients were randomly assigned to either valsartan (n=722) or placebo (n=720). Study visits were scheduled at 2, 4, 8, 24 and 52 weeks with follow up concluding at 1 year. An ECG was performed at each visit and to increase the likelihood of AF being detected patients were provided with a transtelephonic device with instructions to activate this if symptoms occurred. Additionally they were to activate this device on a weekly basis – regardless of symptoms – and a 30 second ECG was sent to both the co-ordinating centre and the responsible physician. The study was designed with 2 primary end-points: time to first recurrence of AF and the proportion of patients who had more than 1 episode of AF in the follow up period. Secondary end-points included: total number of episodes of AF/patient, hospitalisation for any reason, hospitalisation for a cardiovascular event, the composite of death and thromboembolic events, number of patients in sinus rhythm at each study visit, duration of and ventricular rate at the first recurrence of AF and a safety profile.
AF recurred in 371/722 patients (51.4%) in the valsartan group compared to375/720 (52.1%) in the placebo group (adjusted hazard ratio (HR) 0.97, 96%CI 0.83-1.14, p = 0.73). 194/722 (26.9%) in the valsartan arm and 201/720 (27.9%) in the placebo arm (adjusted odds ratio 0.89, 99% CI 0.64-1.23, p = 0.34 had more than one episode of AF. The results were similar in all the pre-defined sub-groups including those who were not receiving ACE inhibitors.
These results provide demonstrate that valsartan did not prevent the recurrence of AF in this population. However there are some important caveats. The majority of the study population had reasonably well controlled hypertension (85%), 57% were already taking ACE inhibitors and >70% were taking a Class I or III anti-arrhythmic agent for the prevention of atrial fibrillation. In addition, 88% had undergone cardioversion (either electrical or pharmacological) in the 2 week period preceding randomisation. These factors would suggest that the substrate for AF was well established in the population studied, and that it may have been too late for medication to make a noticeable difference. Previous studies have suggested that patients with LV dysfunction or hypertrophy benefit the most from use of ACE inhibitors or AIIRBs for prevention of AF. However in this study population only 8% of patients had either heart failure or ventricular systolic dysfunction and data on presence of left ventricular hypertrophy were not provided. Finally, this was a study of the secondary prevention of AF and it is possible that the greatest benefit from ACE inhibitors and A II RBs will be in the prevention of new onset AF (‘primary’ prevention) since it may be that these drugs can prevent but not reverse the structural remodelling that acts as a substrate for AF.
The GISSI-AF Investigators. Valsartan for Prevention of Recurrent Atrial Fibrillation. N Engl J Med 2009;360:1606-17
Gillis AM (ed). Angiotensin Receptor Blockers for Prevention of Atrial Fibrillation – A Matter of Timing or Target? N Engl J Med 2009;360:1669-71