Version July 2025
INTRODUCTION —
Initial studies suggested that angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and (possibly) aldosterone antagonists might either prevent new onset and recurrent atrial fibrillation (AF) or reduce the rate of major adverse cardiovascular outcomes in these patients. However, the available data do not support the use of these drugs solely for these purposes.
In this topic, ACE inhibitors and ARBs collectively will be referred to as "angiotensin inhibition."
POSSIBLE MECHANISMS —
Proposed mechanisms of benefit from angiotensin blockade included direct effects on the structural and electrical properties of the atria, as well as the indirect influence of improved control of heart failure and hypertension, both of which are known risk factors for atrial fibrillation (AF) [1].
●(See "The electrocardiogram in atrial fibrillation".)
●(See "Epidemiology, risk factors, and prevention of atrial fibrillation".)
●(See "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Renin-angiotensin system'.)
The following observations supported the proposed mechanisms:
●Reduction in atrial stretch — Atrial stretch, due to increased left atrial (LA) pressure, is associated with changes in the refractory period and conduction properties of atrial myocardium. These abnormalities provide both potential triggers and the substrate for the initiation and perpetuation of AF. The hemodynamic effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) improve ventricular function and reduce LA pressure and wall stress [2].
●Prevention of atrial fibrosis — Fibrosis in the atrial myocardium may be an important component of the substrate necessary for AF. Atrial fibrosis is stimulated by elevated levels of angiotensin-II [3] and reduced by treatment with ACE inhibitors [4,5].
●Prevention of electrical remodeling and direct antiarrhythmic effects — Direct effects of angiotensin blockade on ion channels and electrophysiologic properties have been suggested [6], though data from both animal and human studies are conflicting and inconclusive.
PREVENTION OF NEW ONSET AF —
In post-hoc analyses of randomized trials and observations from nonrandomized studies, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) was associated with reduced incidence of new atrial fibrillation (AF) in a variety of settings including the treatment of left ventricular systolic dysfunction or hypertension, and after coronary artery bypass graft surgery (CABG).
The following findings were noted in a 2010 meta-analysis of data from 26 randomized trials [7]:
●ACE inhibitors and ARBs reduced the risk of AF development (odds ratio [OR] 0.65, 95% CI 0.55-0.76); the benefit was equivalent with the two classes of drugs.
●In patients with heart failure with reduced ejection fraction, the mean rate of AF development was 50 percent lower among patients treated with ACE inhibitors or ARBs; however, this finding was not statistically significant and the possibility of a small increase in AF development could not be excluded (95% CI 0.19-1.16).
●The effect of ACE inhibitors and ARBs was greater in preventing recurrent AF (OR 0.45, 95% CI 0.31-0.65) compared with preventing new-onset AF (OR 0.80, 95% CI 0.70-0.92)
The meta-analysis was limited by the inclusion of post-hoc analyses of randomized trials performed for reasons other than prevention of AF (eg, heart failure, post-myocardial infarction [MI], or hypertension), heterogeneity, and the likely presence of publication or ascertainment bias.
Patients with left ventricular systolic dysfunction or heart failure — In the TRACE trial of patients with left ventricular systolic dysfunction and sinus rhythm after an acute myocardial infarction, trandolapril therapy was associated with a significantly reduced incidence of subsequent AF at two- to four-year follow-up (2.8 versus 5.3 percent with placebo) [8].
Similar findings were noted in retrospective analyses from the randomized trials SOLVD and Val-HeFT, which enrolled patients with chronic left ventricular systolic dysfunction, almost all of whom had ischemic heart disease [9,10]. In the SOLVD trial, enalapril significantly reduced the incidence of subsequent AF at a mean follow-up of 2.9 years (5.4 versus 24 percent with placebo, hazard ratio 0.22). (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".)
A smaller reduction in the incidence of new AF with the ARB candesartan was noted in the CHARM trials [11]. Among 7601 patients enrolled in the three trials, 6379 patients did not have AF at baseline. At a median follow-up of 38 months, candesartan produced a reduction in the incidence of new AF (5.6 versus 6.7 percent, adjusted P value 0.039).
Patients with hypertension — Some [12-16], but not all [17-19], studies comparing ACE inhibitors or ARBs to other classes of drugs in patients with hypertension have shown a lowering of the risk of development AF. A 2010 meta-analysis included six hypertension trials; analysis of these six trials found no significant reduction in the risk for AF with angiotensin inhibition [20].
The role of angiotensin blockade in the treatment of hypertension is discussed separately. (See "Hypertension in adults: Initial drug therapy".)
Patients with other risk factors for atrial fibrillation — The issue of whether these therapies might prevent the development of AF in patients with risk factors other than left ventricular dysfunction, heart failure, or hypertension, such as diabetes or coronary artery disease, has not been well studied. (See "Epidemiology, risk factors, and prevention of atrial fibrillation".)
Coronary artery bypass graft — The possible role of these therapies for the prevention of AF in patients undergoing cardiac surgery is discussed elsewhere. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Strategies with uncertain or no proven benefit'.)
PREVENTION OF RECURRENT AF
Patients with cardiovascular disease — Multiple small studies have demonstrated reduction in recurrent atrial fibrillation (AF) with use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), but these findings have not been confirmed in larger, better powered studies.
In small trials that enrolled fewer than 200 patients, ACE inhibitors or ARBs in combination with amiodarone reduced the rate of recurrent AF compared with amiodarone alone [21-25]. In a small trial of 62 patients with hypertension or heart disease, ramipril reduced AF recurrence compared with placebo [25]. In a small trial comparing telmisartan to carvedilol in hypertensive patients with prior AF, patients treated with telmisartan had less recurrence of AF despite similar blood pressure reduction between the two agents [26]. However, these results from smaller studies were not confirmed in the GISSI-AF trial, which randomly assigned 1442 patients in sinus rhythm, with a history of symptomatic AF, to receive either valsartan or placebo [27]. All patients had underlying cardiovascular disease, diabetes, or left atrial enlargement.
Valsartan did not prevent recurrent AF in GISSI-AF. At one-year follow-up, there was no difference in the proportion of patients who had more than one episode of AF (51 versus 52 percent, adjusted hazard ratio 0.97, 95% CI 0.83-1.14) or in the median time from randomization to the first recurrence of AF (295 versus 291 days), between valsartan compared with placebo. Although 57 percent of patients were taking an ACE inhibitor and 70 percent were taking antiarrhythmic drugs at baseline that were continued throughout the trial and might have confounded the results, the outcomes in subgroup analysis were similar in the patients who were or were not being treated with such agents.
Another possible contributor to the lack of benefit in GISSI-AF was a low prevalence of heart failure/left ventricular dysfunction (8 percent) as the benefit may be greatest in patients with these conditions [28].
Prevention of recurrent AF was also analyzed in the ACTIVE I study, which randomized 9016 patients with a history of AF, stroke risk factors, and a systolic blood pressure of at least 110 mmHg to either irbesartan 300 mg once daily or placebo. Patients who received irbesartan in ACTIVE I were not significantly more likely to be in sinus rhythm at subsequent follow-up, regardless of whether they were initially in AF at baseline or in sinus rhythm at baseline (RR 0.97, 95% CI 0.85-1.10). Similarly, the ANTIPAF study, a randomized study of placebo versus olmesartan in patients with documented paroxysmal AF, demonstrated no benefit in regard to recurrent AF episodes in patients randomized to olmesartan [29].
Post-catheter ablation — The data are mixed as to whether ACE inhibitors/ARBs reduce AF after radiofrequency catheter ablation procedures: A significant benefit was seen in some [30], but not other [31,32] studies. (See "Atrial fibrillation: Catheter ablation".)
ALDOSTERONE INHIBITION —
Data from animal and human studies suggest that mineralocorticoid receptor antagonists may reduce the risk of recurrent AF [33-40]. Supportive studies of specific drugs are summarized as follows:
●Eplerenone – In the randomized EMPHASIS-HF trial, eplerenone reduced new onset AF in patients with heart failure with reduced ejection fraction and mild heart failure symptoms [35]. In a small study, eplerenone was associated with decreased AF recurrence after catheter ablation for long-standing persistent AF [36].
●Spironolactone – In the TOPCAT trial of spironolactone in patients with heart failure with preserved ejection fraction, spironolactone did not reduce the incidence of AF [37] (see "Treatment and prognosis of heart failure with preserved ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Secondary therapy (MRA)'). A 2016 meta-analysis suggested reduced AF in patients treated with aldosterone antagonists based on three randomized controlled trials and two observational studies, although this effect was evident for eplerenone but not spironolactone [38].
●Finerenone – In a secondary analysis of the randomized FIDELIO-DKD trial of patients with chronic kidney disease and type 2 diabetes, those assigned the mineralocorticoid receptor antagonist finerenone had a lower incidence of new-onset atrial fibrillation or flutter compared with placebo (hazard ratio 0.71; 95% CI 0.53-0.94) [39].
●Meta-analysis of mineralocorticoid receptor-antagonists – In a 2019 meta-analysis of 24 studies (representing both randomized and observational studies, with a total of 7914 patients), aldosterone-antagonist-treated patients had reduced AF occurrence compared with control patients (odds ratio 0.55; 95% CI 0.44-0.70), regardless of the particular mineralocorticoid receptor antagonist used [40].
Although there is potential benefit to the use of aldosterone inhibitors in heart failure patients, we do not recommend aldosterone inhibitors specifically for prevention of new or recurrent AF. The details of mineralocorticoid receptor antagonists in heart failure are presented separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.)
PREVENTION OF CARDIOVASCULAR EVENTS —
As discussed in the sections on prevention above, the benefit of either angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARB) therapy for the prevention of new or recurrent atrial fibrillation (AF) is uncertain. The question of whether ARB therapy reduces the rate of major adverse cardiovascular events in patients with AF was addressed in the ACTIVE I trial, which enrolled individuals with either permanent AF or at least two episodes of intermittent AF (in the previous six months) from the ACTIVE A and ACTIVE W trials [41]. (See 'Prevention of recurrent AF' above and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Introduction'.)
Mean reductions in systolic and diastolic blood pressures were 2.9 and 1.9 mmHg greater in the irbesartan group. At a mean follow-up of 4.1 years, there was no difference in the rates of the first combined coprimary outcome of stroke, myocardial infarction, or death from vascular causes (5.4 percent per 100 person-years in both groups); nor in the rates of the second combined coprimary outcome, including the components of the first coprimary outcome plus the rate of hospitalization for heart failure (7.3 and 7.7 percent per 100 person-years in the irbesartan and placebo groups, respectively).
A Swedish registry study of patients followed after acute myocardial infarction showed that use of ACE inhibitors and ARBs did reduce all-cause mortality, but did not reduce the incidence of new-onset AF [42]. In another study of 1110 patients with AF and hypertension evaluated in the emergency department, treatment with either ACE inhibitor or ARB was associated with lower rates of subsequent all-cause death, cardiovascular death, and major adverse events, compared with patients not treated with these agents [43].
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".)
SUMMARY AND RECOMMENDATIONS
●Prevention of atrial fibrillation – For patients at risk for atrial fibrillation (AF) but without another indication for angiotensin blockade, we recommend not initiating therapy with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker solely to prevent new onset AF. (See 'Prevention of new onset AF' above.)
●Prevention of AF recurrence – In patients with a history of AF, we recommend not treating with an ACE inhibitor or ARB for the sole purpose of preventing recurrent AF. (See 'Prevention of recurrent AF' above.)
