Disappointing results for valsartan (Diovan)

FLORENCE, ITALY. It is now generally accepted that there is a connection between atrial fibrillation (AF) and the renin-angiotensin-aldosterone system (RAAS). Aldosterone causes inflammation and fibrosis of the heart tissue by direct action on the mineralocorticoid (MC) receptors in the myocardium; this results in both electrical and structural remodeling of the atria. Aldosterone also causes an increased level of reactive oxygen species in the heart, promotes the loss through the urine of potassium and magnesium, and is associated with an unbalanced (overly sympathetic) autonomic nervous system.

Not surprisingly, several researchers have speculated if blocking the action of the RAAS would prevent, or at least reduce, the frequency of afib episodes. Angiotensin II type 1 receptor antagonists (AT1R) are potent blockers of MC receptors and thus should, in theory, reduce the adverse effects of aldosterone on the heart. There is also evidence that AT1R antagonists, specifically valsartan (Diovan) reduces plasma aldosterone levels. A group of Italian researchers (GISSI-AF investigators) now report on a large clinical trial aimed at determining if valsartan is effective in preventing the recurrence of AF.

The trial involved 1442 AF patients who were randomized to receive 320 mg/day of valsartan (gradual dose increase over 4 weeks) or a placebo for one year. All participants were in sinus rhythm at the start of the trial, but 88% had undergone an electrical or pharmacological cardioversion within 2 weeks prior to randomization. The majority (85%) of participants had reasonably well-controlled hypertension, 16% had diabetes, 57% were taking ACE inhibitors, 35% were on amiodarone, and 32% had been prescribed a class I antiarrhythmic (flecainide, propafenone, disopyramide). After 8 weeks, when all participants (except placebo group) were on the full dose of valsartan, 42.7% in the valsartan group and 44% in the placebo group had experienced recurrence of afib. Corresponding percentages after one year was 51.4% and 52.1%. More than one episode during the year was recorded by 26.9% in the valsartan group and in 27.9% in the placebo group. None of the above differences were statistically significant. The conclusion was that treatment with valsartan does not reduce the incidence of AF in this patient population.

Valsartan for prevention of recurrent atrial fibrillation. New England Journal of Medicine, Vol. 360, April 16, 2009, pp. 1606-17
Gillis, AM. Angiotensin-receptor blockers for prevention of atrial fibrillation – a matter of timing or target? New England Journal of Medicine, Vol. 360, April 16, 2009, pp. 1669-70

Editor’s comment: It is fairly conclusive that valsartan did not prevent the recurrence of afib episodes in this fairly unhealthy group of afibbers. In other words, it did not reverse existing electrical and structural remodeling. However, this does not mean that valsartan or other AT1R antagonists could not be effective in preventing the remodeling from starting or progressing in the first place. Hopefully, primary prevention trials will be conducted to prove or disprove this possibility.