Introduction

Basic studies have demonstrated that angiotensin II blockade can inhibit atrial electrical remodeling that occurs with atrial fibrillation (AF).¹ Inhibition of AF by renin angiotensin blockade could occur by other potential mechanisms including decreasing inflammation, atrial structural remodeling and fibrosis, and decreasing left atrial pressure and dilatation that may lead to stretch activated arrhythmias.² Although several studies suggest that angiotensin II blockade can prevent AF, many studies were small, retrospective analyses of large studies including meta-analyses, performed in combination with amiodarone, and/or allowed concomitant therapy with ACE inhibitors.^2-6 The majority of previous studies were performed in patients with structural heart disease, and little data are available in patients with lone AF.⁵

Methods

ANTIPAF investigated the effect of olmesartan medoxomil in patients with paroxysmal AF (ECG documented within 6 months before randomization) and without structural heart disease. The intention-to-treat population included 425 patients randomized to placebo or 40 mg a day of olmesartan in a prospective, randomized, placebo controlled trial. Concomitant therapy with ACE inhibitors, angiotensin receptor blockers and antiarrhythmic agents were not allowed. The primary endpoint was AF burden (percentage of days with documented episodes of paroxysmal AF) during a 12 month follow-up period. Secondary outcome endpoints, included quality of life, time to first AF recurrence, time to persistent AF and number of hospitalizations. A total of 87,818 daily transtelephonic recordings (mean of 207 per patient) were analyzed. Recordings were made independent of symptoms.

Results

Medical therapy was balanced between the two study groups and systolic and diastolic blood pressures were not different. The primary endpoint of AF burden was not different between the olmesartan (15.1%) and placebo (14.7%) groups (p=0.770). Secondary outcome endpoints were not different. The time to prescription recovery with amiodarone was earlier in the placebo group (p=0.022).

Conclusion

The angiotensin receptor blocker, olmesartan, was not effective in suppressing AF burden, time to first AF recurrence or time to persistent AF, when compared to placebo.

Perspective

Olmesartan blocks the actions of angiotensin II and theoretically angiotensin receptor blocking agents should inhibit electrical and structural remodeling that can occur with persistent AF.¹ There have been a number of studies to suggest that angiotensin II blockade may be beneficial in the suppression of AF.² However, most of these trials were small, retrospective, post-hoc analyses of trials suggesting that angiotensin II blockade would suppress the development of AF or studied the addition of angiotensin II blockade in combination with amiodarone.^3,4 In addition, most patients had structural heart disease. Meta-analyses of these studies suggested that angiotensin II blockade might suppress AF particularly in heart failure patients.⁵ Two large prospective trials, GISSI AF6 and ACTIVE I,⁷ showed not benefit of angiotensin receptor blockade in suppressing AF recurrences in the first study or clinical endpoints in the second study. Both of these large trials were limited in that ACE inhibitors were continued in about 55% of patients, possibly limiting any potential benefit of an angiotensin receptor blocker.

ANTIPAF,⁸ performed in paroxysmal AF patients without structural heart disease, adds to the continued saga suggesting that angiotensin II blockade is ineffective in suppressing AF as measured by burden, first AF recurrence or time to persistent AF. Although the findings may be limited to the study population (PAF without structural heart disease), it had the advantage over GISSI AF and ACTIVE I in that competing ACE inhibition was not allowed. Clinically this study adds to other large prospective studies, GISSI AF and ACTIVE I, suggesting that angiotensin II receptor blockers, as monotherapy, have failed to demonstrate any clinically meaningful benefit in the suppression of AF recurrences. ANTIPAF, GISSI AF, and ACTIVE 1 are reminders that positive experimental studies, encouraging case series, post-hoc studies, and meta-analyses are no substitute for well-designed large prospective-randomized, placebo-controlled trials. If these drugs are useful in combination with other antiarrhythmic drugs or in selected patient subgroups (post-cardioversion, with associated hypertension or congestive heart failure) still has not been demonstrated in large, prospective, controlled clinical trials. In the meantime, angiotensin II inhibitors should be continued to be used for other approved clinical purposes, such as the treatment of hypertension and improving survival in patients with left ventricular dysfunction.

References

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3. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002;106:331-336
4. Yin Y, Dalal D, Liu Z, et al. Prospective randomized study comparing amiodarone vs. amiodarone plus losartan vs. amiodarone plus perindopril for the prevention of atrial fibrillation recurrence in patients with lone atrial fibrillation. Eur Heart J 2006;27:1841-1846.
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8. Goette A, Schon N, Kirchof P, et al. Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) Trial. Circ Arrhythm Electrophysiol 2012;5:43-51.