Statin Therapy for the Prevention of Atrial Fibrillation Trial (SToP AF trial)

Abstract

Background Inflammation and oxidative stress are associated with atrial fibrillation (AF). Statins have antioxidant and anti-inflammatory properties. We tested if atorvastatin reduced AF recurrence after DC cardioversion (CV) by modifying systemic oxidative stress and inflammation. (NCT00252967) Methods and Results In a randomized, double-blinded, placebo-controlled trial, patients with atrial fibrillation/flutter (AF) were randomized to receive either atorvastatin 80 mg (n=33) or placebo (n=31) before CV. Treatment was continued for 12 months or until AF recurred. Serum oxidative stress markers (ratios of oxidized to reduced glutathione and cysteine, derivatives of reactive oxygen species, isoprostanes) and inflammatory markers [ high sensitivity C- reactive protein (hs-CRP), interleukin-6 (IL-6), interleukin-1β(IL-1β), tumor necrosis factor-α (TNFα)] were measured at baseline and on follow-up. AF recurred in 22 (66.7%) of atorvastatin and 26 (83.9%) of placebo group (p=0.2). The adjusted hazard ratio of having recurrence on atorvastatin versus on placebo was 0.99 (95% CI: 0.98-1.01, p=0.3). There was no significant difference in the time to recurrence using Kaplan-Meier survival estimates (median (IR): 29 (2-145) days vs. 22 (7-70) days, p=0.9). While no significant effect was seen on oxidative stress, 2 of 4 inflammatory markers, IL-6 (adjusted OR: 0.59, 95% CI: 0.35-0.97, p= 0.04) and hs-CRP (adjusted OR: 0.59, 95% CI: 0.37-0.95, p=0.03) were significantly lowered with atorvastatin. Cholesterol levels significantly decreased with atorvastatin (p=0.03). Conclusions High dose atorvastatin did not reduce the recurrence of AF after CV. It reduced selective markers of inflammation without affecting systemic oxidative stress. Failure of atorvastatin to prevent AF recurrence may be due to its failure to affect oxidative stress.

Atrial Fibrillation: Antiarrhythmic Therapy

“…100 In the statin therapy for the prevention of atrial fibrillation trial, 64 patients were randomized to atorvastatin or placebo starting 1 week before cardioversion, then continued for 12 months. 101 There was no significant reduction in AF recurrence between the groups. A meta-analysis of 4 trials including the ones described earlier, analyzing 424 patients, demonstrated no benefit for statins in preventing AF recurrence.…”

Atrial Sources of Reactive Oxygen Species Vary With the Duration and Substrate of Atrial Fibrillation

“…33 However, as shown in Figure 7, Rac1 activity was not increased in RA samples from patients with persistent AF, and atorvastatin did not cause a mevalonate-reversible reduction in superoxide production in this group, in agreement with studies indicating little or no beneficial effect of statins in the secondary prevention of AF or in disease states (eg, heart failure) associated with atrial structural remodeling. [12][13][14][15] It should be noted that our studies in human atrial tissue are limited to samples of the RA appendage. Although the similarities in the findings obtained in human and goat RA myocardium in the presence of longstanding AF suggest that the goat is a representative model of human AF, we cannot be certain that the human LA myocardium would show the same results.…”

“…[7][8][9] In humans, NOX2-containing NADPH oxidases are the main source of ROS production in both right atrial (RA) homogenates and isolated myocytes, 6 and RA NADPH-stimulated superoxide production is independently associated with an increased risk of developing AF after cardiac surgery. 10 Statins prevent AF-induced early electric remodeling in dogs 9 and reduce the occurrence of postoperative AF in patients undergoing cardiac surgery 11 but are less effective in the secondary prevention of AF [12][13][14] or in the presence of significant atrial structural remodeling (eg, in heart failure 15 ). By inhibiting HMG CoA reductase, statins prevent the isoprenylation of Rac1 and reduce ROS formation by NADPH oxidases in cardiac tissue.…”

Serum Levels of Vitamin E Are Associated With Early Recurrence of Atrial Fibrillation After Electric Cardioversion

“…This suggestion could explain why statins, which inhibit NOX2 activation, are effective in AF primary prevention and less effective in secondary prevention, where other sources of reactive oxygen species are associated with AF. 32 The use of markers of antioxidant status or oxidative stress may also help in identifying patients at high risk of AF recurrence. Finally, vitamin E supplementation could represent an interesting therapeutic option that should be considered in future trials in patients with persistent AF undergoing cardioversion.…”