7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation : E Kevin Heist, MD, PhD : Samuel L vy, MD, Hugh Calkins, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 25, 2023. 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 Mechanisms proposed to explain the benefit of angiotensin blockade found in the early studies included the direct effects of angiotensin blockade on the structural and electrical properties of the atria, as well as the indirect influence of improved control of heart failure and hypertension (in patients with these conditions), both of which are known risk factors for atrial fibrillation (AF) [1]. (See "The electrocardiogram in atrial fibrillation" and "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Renin-angiotensin system'.) The following observations supported the proposed mechanisms: https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 1/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate 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) result in improved ventricular function and also reductions in 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], but data from both animal and human studies have been conflicting and inconclusive. Canine work has suggested direct inhibition of triggering of atrial arrhythmias by ACE inhibitors and ARBs [7]. PREVENTION OF NEW ONSET AF Post-hoc analyses of randomized trials and observations from nonrandomized studies have suggested that angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) reduce the incidence of new atrial fibrillation (AF) in a variety of settings including the treatment of left ventricular 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 [8]: ACE inhibitors and ARBs significantly reduced the risk of the development of AF (Odds Ratio [OR] 0.65, 95% CI 0.55-0.76); the benefit was equivalent with the two classes of drugs. The benefit of ACE inhibitors and ARBs appeared large in patients with systolic heart failure (OR 0.50), but the result was not statistically significant (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 to new-onset AF (OR 0.80, 95% CI 0.70-0.92) However, the strength of the conclusions from the meta-analysis is weakened due 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. https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 2/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Left ventricular dysfunction or heart failure In the TRACE trial of patients with left ventricular 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) [9]. Similar findings were noted in retrospective analyses from the randomized trials SOLVD and Val- HeFT, which enrolled patients with chronic left ventricular dysfunction, almost all of whom had ischemic heart disease [10,11]. 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" and "Management and prognosis of asymptomatic left ventricular systolic dysfunction", section on 'ACE inhibitors'.) A smaller reduction in the incidence of new AF with the ARB candesartan was noted in the CHARM trials [12]. 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). Hypertension Some [13-17], but not all [18-20], 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 of trials with substantial heterogeneity found no significant reduction in the risk for AF [21]. The role of angiotensin blockade in the treatment of hypertension is discussed separately. (See "Choice of drug therapy in primary (essential) hypertension".) 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 'Ineffective or possibly effective therapies'.) PREVENTION OF RECURRENT AF 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 https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 3/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate 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 [22-26]. A small study of ramipril versus placebo in hypertensive patients demonstrated reduced AF recurrence with ramipril [26] and a small randomized study comparing telmisartan to carvedilol in hypertensive patients with prior AF demonstrated less recurrence of AF in patients treated with telmisartan, despite similar blood pressure reduction between the two agents [27]. However, these results from smaller studies were not confirmed in the GISSI-AF trial, which randomly assigned 1442 patients with a history of symptomatic AF and in sinus rhythm to receive either valsartan or placebo [28]. All patients had underlying cardiovascular disease, diabetes, or left atrial enlargement. GISSI-AF found that valsartan did NOT prevent recurrent AF. At one-year follow-up, there was no significant difference between valsartan or placebo 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). 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), since the meta-analysis cited above found that the benefit was greatest in patients with these conditions [29]. Prevention of recurrent AF with irbesartan 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 mm Hg 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, p = 0.61). 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 [30]. Aldosterone inhibition and atrial fibrillation There are data from animal and human studies to suggest that spironolactone, an aldosterone antagonist, may reduce the risk of recurrent AF [31,32]. Supportive studies of specific drugs are summarized as follows: https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 4/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Eplerenone A newer aldosterone antagonist, eplerenone, was shown in the randomized EMPHASIS-HF study to reduce new onset AF in patients with systolic heart failure and mild heart failure symptoms [33]. Eplerenone was also shown in a small study to decrease AF recurrence after catheter ablation for long-standing persistent AF [34]. Spironolactone In the TOPCAT randomized trial of spironolactone in patients with heart failure with preserved ejection fraction, spironolactone did not reduce the incidence of AF [35] (see "Treatment and prognosis of heart failure with preserved ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Mineralocorticoid receptor antagonists'). A 2016 meta-analysis did suggest reduced AF in patients treated with aldosterone antagonists based on three randomized controlled trials and two observations studies, although this effect was evident for eplerenone but not spironolactone [36]. 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 resulted in a lower incidence of new-onset atrial fibrillation or flutter compared with placebo (hazard ratio 0.71; 95% CI 0.53-0.94) [37]. Meta analysis of aldosterone-antagonists A 2019 meta-analysis of 24 studies (representing both randomized and observational studies, with a total of 7914 patients) demonstrated a significant reduction in AF occurrence in aldosterone-antagonist-treated patients compared with control patients (odds ratio 0.55; 95% CI 0.44-0.70), with significant AF reduction demonstrated in randomized and observational studies, and regardless of the particular aldosterone antagonist used [38]. Although there appears to be 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'.) Catheter ablation of atrial fibrillation The data are mixed as to whether ACE inhibitors/ARBs reduce AF after radiofrequency catheter ablation procedures: A significant benefit was seen in some [39], but not other [40,41] studies. (See "Atrial fibrillation: Catheter ablation".) PREVENTION OF CARDIOVASCULAR EVENTS https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 5/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate 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 issue of whether ARB therapy can reduce 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 [42]. (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 significant difference in the rates of the first combined coprimary outcome of stroke, myocardial infarction, or death from vascular causes for the irbesartan compared with placebo groups (5.4 percent per 100 person- years in both groups), and there was no significant difference in the rates of the second combined coprimary outcome, which included 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 two 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 [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 (Grade 1B). (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 (Grade 1B). (See 'Prevention of recurrent AF' above.) https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 6/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. 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The effects of statins and renin-angiotensin system blockers on atrial fibrillation recurrence following antral pulmonary vein isolation. J Cardiovasc Electrophysiol 2007; 18:942. 42. ACTIVE I Investigators, Yusuf S, Healey JS, et al. Irbesartan in patients with atrial fibrillation. N Engl J Med 2011; 364:928. 43. Batra G, Lindhagen L, Andell P, et al. Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Are Associated With Improved Outcome but Do Not Prevent New-Onset Atrial Fibrillation After Acute Myocardial Infarction. J Am Heart Assoc 2017; 6. Topic 935 Version 27.0 Contributor Disclosures E Kevin Heist, MD, PhD Equity Ownership/Stock Options: Oracle Health [Device diagnostics]. Consultant/Advisory Boards: Biotronik [Cardiac resynchronization therapy and atrial fibrillation]; Boston Scientific [Cardiac resynchronization therapy and atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Hugh Calkins, MD Grant/Research/Clinical Trial Support: Adagio Medical [Atrial fibrillation]; Boston Scientific [ARVC]; Farapulse [Atrial fibrillation]; Medtronic [Atrial fibrillation]. Consultant/Advisory Boards: Abbott [Atrial fibrillation]; Atricure [Atrial fibrillation]; Biosense Webster [Catheter ablation]; Boston Scientific [ARVC and atrial fibrillation]; Medtronic [Atrial fibrillation]; Sanofi [Atrial fibrillation]. Other Financial Interest: Atricure [Lecture honoraria]; Biosense Webster [Lecture honoraria]; Boston Scientific [Lecture honoraria]; Medtronic [Lecture honoraria]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 10/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 11/11