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Retrospective analyses of certain trials on Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) suggest that these medications may prevent the development or recurrence of atrial fibrillation (AF). Atrial fibrillation is associated with a higher risk of stroke, death, and heart failure. It is therefore important to understand the effect of these agents on the occurrence of AF and their potential use as antiarrhythmic agents.
ACEIs and ARBs likely prevent AF by reversing changes in cardiac structure and function. Left ventricular hypertrophy and left atrial enlargement are elements of cardiac remodeling that are frequent complications of hypertension and heart failure and these changes are strongly associated with the development of clinical AF.
Enlargement of the left atrium and increased atrial pressure may promote the development and maintenance of AF by triggering premature atrial beats, slowing atrial conduction velocity, and providing a greater area for re-entry.
In animal models of heart failure, ACEIs and ARBs reduced certain aspects of cardiac remodeling such as left atrial dilatation and dysfunction, fibrosis, and shortening of the atrial effective refractory period (1,2,3,4) which should, in turn, lead to a reduction in AF. Indeed, the greater the effectiveness of these agents in patients with heart failure and left ventricle dysfunction the greater the reduction in AF is among patients with more severely impaired ejection fraction. This fact suggests that the benefit of ACEIs and ARBs may be related to an improvement in cardiac hemodynamics and a reduction in left ventricular and left atrial wall stress.
In addition, ACEIs and ARBs may have specific properties that help prevent AF with a specific mechanisms related to the inhibition of the renin-angiotensin-aldosterone. Indeed, irbesartan has been shown to possess direct anti-arrhythmic properties (5) while, in animal models, the antiarrhythmic effect observed with ACEIs and ARBs was not seen with hydralazine and isosorbide mononitrate (3).
In a recent metanalysis of 11 trials for a total of 56,308 patients (6), the use of ACEIs or ARBs reduced the relative risk of developing AF by 28% (95% confidence interval [CI] = 15% to 40%, p <0.0002). There were similar benefits seen with ACEIs (relative risk reduction [RRR] =28%, 95% CI 7% to 44%, p <0.01) and ARBs (RRR = 29%, 95% CI 16% to 40%, p <0.0002). The majority of these trials included in this analysis were post-hoc reports of randomised trials designed to assess outcomes other than AF. Thus, one must note however that these data may be prone to multiple-testing error and data-derived emphasis biases.
Heart failure. In four trials studying ACEIs or ARBs in patients with heart failure (6), there was an overall 44% relative risk reduction in the development of AF (p <0.007, 95% CI 15% to 63%). There appeared to be a relationship between the relative risk reduction of AF and LV ejection fraction.
Hypertension. The three hypertension trials (6) did not demonstrate a consistent reduction in AF with ACEIs and ARBs. The overall apparent lack of AF prevention in the hypertension trials may reflect the less severe hemodynamic abnormalities in these patients. In patients treated for hypertension, a reduction in AF was seen only in one trial evaluating subjects with established LV hypertrophy. Secondary prevention of AF following cardioversion. Two small prospective unblind randomised trials (7,8) showed a 48% reduction (CI 21-65) of the recurrence of AF (absolute recurrence rate of 18% and 36% in treated and control arms respectively) in patients following electrical cardioversion. This reduction was apparent within weeks of the cardioversion.
It is premature to recommend an ACEI or ARB solely for the prevention or treatment of AF, but these data raise the possibility of an added benefit in patients receiving either agent for heart failure or hypertension.
ACEI or ARB could be administered during the peri-procedural period of an electrical cardioversion of AF to decrease the recurrence rate which is maximal shortly after cardioversion. Additional prospective research is required to empirically determine the impact of the use of ACEIs or ARBs in patients with AF.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
Both ACEIs and ARBs are effective at preventing the development of AF. This effect appears to be most clearly seen in patients with systolic LV dysfunction and clinical heart failure. Limited data suggests that ACEIs and ARBs reduce AF following cardioversion.
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7. Madrid AH, Bueno MG, Rebollo JMG, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation. Circulation 2002;106:331– 6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12119249&query_hl=16
8. Ueng KC, Tsai TP, Yu WC, et al. Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation. Results of a prospective and controlled study. Eur Heart J 2003;24:2090–8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14643269&query_hl=18
Dr M. Brignole Lavagna, Italy Member of the Education Committee of the ESC and member of the Committee for Scientific Initiatives of EHRA