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Angiotensin inhibition in the prevention of atrial fibrillation
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Angiotensin II has been shown to play a role in the cardiac remodeling that contributes to AF in both human and animal atrial models. It promotes vasoconstriction, sodium and water retention and cardiac hypertrophy, and results in structural changes due to fibroblast stimulation and increased fibrotic tissue.
Thus, it seems logical that a RAS inhibitor would be useful in AF prevention.
In addition to translational and mechanistic studies, post hoc analyses involving RAS inhibitors performed on HF (SOLVD-enalapril, Val-HeFT-valsartan, CHARM-candesartan) and MI trials (GISSI-3-lisinopril, TRACE-trandolapril) all demonstrated a significant reduction in new-onset AF, and patients with left ventricular systolic dysfunction (LVSD) derived the greatest benefit.
Several hypertension trials have examined the occurrence of new AF. For example, secondary analysis of the LIFE study revealed that new-onset AF occurred in 6.8% of patients treated with losartan (Cozaar, Merck) compared with 10.1% of those randomized to atenolol (HR 0.67, 95% CI: 0.55-0.83; P<.001). Furthermore, in the VALUE trial, the occurrence of new onset AF (a prespecified secondary endpoint) in patients treated with valsartan (Diovan, Novartis) was 3.67% compared with 4.34% in patients treated with amlodipine (HR 0.84, 95% CI: 0.713-0.997; P=.045). Lastly, the recent ONTARGET study, which evaluated telmisartan (Micardis, Boehringer Ingelheim), ramipril or the combination in high-risk patients, assessed new-onset AF as a secondary endpoint, and no difference was detected.
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Several metaanalyses evaluated the use of RAS inhibitors for AF prevention. Anand et al showed an 18% relative risk reduction in new-onset AF, with patients who had HF deriving the greatest benefit. In this analysis, ACE inhibitors (RR 0.75, 95% CI: 0.57-0.99) were more effective in preventing AF than ARBs (RR 0.81, 95% CI: 0.62-1.06). Healey et al also performed a metaanalysis with similar results, showing that RAS inhibitors reduced the risk of AF by 28% (95% CI: 15-40%, P=.0002); patients with impaired LV function benefited most. However, no difference was seen between ACE inhibitors (RRR 28%, 95% CI: 0.07-0.44, P=.01) and ARBs (RRR 29%, 95% CI: 0.16-0.40, P=.0002).
Prospective studies have also yielded positive outcomes. Ozaydin et al conducted a study (n=128) examining the use of an ACE inhibitor alone [lisinopril, n=80; cilazapril, n=7; ramipril and quinapril, n=4; perindopril (Aceon, Solvay), n=2; and fosinopril, n=1] and in combination with candesartan in postoperative cardiac patients. There was a 33% occurrence of AF in the control group, compared with the ACE inhibitor group (12%, P=.02) or the combination group (10%, P=.01).
GISSI-AF, the largest trial to date to prospectively assess the effect of RAS inhibition on AF prevention, was recently published in the New England Journal of Medicine. More than 1,400 high-risk patients with a prior history of AF were randomized to either valsartan or placebo. Primary outcomes were time to first recurrence of AF and the proportion of patients who had more than one recurrence over one year. After a one-year follow-up, valsartan did not show a reduction in recurrent AF (51.4% in valsartan group vs. 52.1% in the control group, and there was no difference in the time to first occurrence of AF, HR 0.97, 96% CI: 0.83-1.14; P=.83). Also, more than one AF recurrence was noted in 26.9% of valsartan-treated patients compared with 27.9% of the control patients (OR 0.89, 99% CI: 0.64-1.23; P=.34). As observed previously, although not statistically significant, in patients with HF, LVSD, or both, there was a trend toward benefit in the valsartan group (HR 0.81, 95% CI: 0.48-1.35; P=.41).
Although RAS blocking agents are routinely used in the management of many CV conditions including HF and ACS, current data do not support their use for the prevention of AF. The precise mechanism behind how RAS inhibitors can reduce the occurrence of AF is unclear, although it does appear that patients with impaired LVSD obtain better outcomes likely resulting from attenuation of cardiac remodeling. The robust GISSI-AF investigation failed to illustrate an overall benefit with valsartan. However, there are ongoing studies in high-risk populations, including those with diabetes and those who have undergone cardiac surgery that will further clarify the role of RAS inhibition in AF prevention.
Antoine Jenkins, PharmD, BCPS, is a Clinical Pharmacist, OSF St. Francis Medical Center, Peoria, Ill.
Rhonda Cooper-DeHoff, PharmD, MS, Associate Professor, University of Florida College of Pharmacy, Gainesville, is Cardiology Today’s regular Pharmacology Consult columnist and a member of the CHD and Prevention section of Cardiology Today’s editorial board.
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