The renin–angiotensin system (RAS) has an important role in many cardiovascular diseases, such as hypertension, left ventricular hypertrophy, atherosclerosis and heart failure, and lately its relationship with cardiac arrhythmias has also been investigated.1 Atrial fibrillation is the most frequently occurring sustained cardiac arrhythmia and its prevalence doubles with each advancing decade of age, from under 0.5% at 50–59 years of age to almost 9% at over 80 years of age.2 The lifetime risk of development of atrial fibrillation is one in four for men and women 40 years of age and older.3
In the past, atrial fibrillation was frequently a consequence of rheumatic heart disease.4 However, given the relative rarity of this condition in developed countries today, other risk factors are now more predominant. Today, hypertension is the most prevalent, independent and potentially modifiable risk factor for atrial fibrillation.2,5 Healey et al.6 found that the relative risk (RR) of developing atrial fibrillation in patients with hypertension was 1.4–2.1, which is modest compared with other conditions, such as heart failure (RR 6.1–17.5) and valvular disease (RR 2.2–8.3). However, due to the high prevalence of hypertension in the population today, it accounts for more cases of atrial fibrillation than other risk factors. In hypertensive individuals, age, left atrial chamber diameter and left ventricular mass have been identified as independent risk factors for chronic atrial fibrillation.7
We have previously also shown that hypertensive patients included in the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial with new-onset diabetes had a significantly higher event rate of new-onset atrial fibrillation, with a hazard ratio (HR) of 1.49 (1.14–1.94; p=0.0031) compared with patients without diabetes; this may explain the concomitant high risk of hospitalisation for heart failure in some of these patients.8
Renin–Angiotensin System and Atrial Fibrillation
Initially, RAS is activated as a compensatory mechanism in the body, e.g. in heart failure, but with progression of the disease it may have a more detrimental role. RAS blockers such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are important parts of the treatment regimens for heart failure and hypertension.
Atrial fibrillation itself causes atrial electrical and structural remodelling, including atrial dilatation and fibrosis development, which may facilitate recurrence and perpetuation of the atrial fibrillation. Patients with atrial fibrillation have been shown to have increased levels of angiotensin II type 1 (AT1) receptors in the left atrium,9 and angiotensin II, via AT1 receptors, can stimulate cardiac fibroblast growth and increase collagen synthesis in cardiac tissue.10 RAS may therefore promote atrial and ventricular arrhythmias due to increased cardiac hypertrophy, fibrosis and heterogeneity of the cardiac tissue.10 Other electrophysiological effects of RAS activation have also been suggested, e.g. experimental results have shown that RAS may have direct pro-arrhythmic effects on membrane and ion channels and that increased oxidative stress is likely to contribute to an increased arrhythmic incidence.11,12 ACEIs may reduce the level of angiotensin II, and the pro-arrhythmic effects mediated by AT1-receptors may be prevented by ARBs, as shown in Figures 1 and 2.13
In a recent meta-analysis, Sneider et al. 14 investigated the effects of RAS inhibition for the prevention of atrial fibrillation, aiming to define when RAS blockade is most effective. Twenty-three randomised studies with a total of 87,048 patients were included: six hypertension trials, two with patients with myocardial infarction, three with patients with heart failure (all primary prevention), eight after cardioversion and four on medical prevention of paroxysmal atrial fibrillation (secondary prevention).14 As shown in Figure 3, RAS blockade with ACEI or ARB reduced the odds ratio (OR) for atrial fibrillation by 32% (OR 0.68 [0.22–0.43)]; p<0.00001), with ACEIs and ARBs having similar effects. In primary prevention, RAS blockade was most effective in patients with left ventricular hypertrophy and/or heart failure. In secondary prevention, RAS blockade reduced the odds for atrial fibrillation recurrence after cardioversion by 45% (OR 0.55 [0.34–0.89]; p=0.01) and on medical therapy by 63% (OR 0.37 [0.27–0.49]; p<0.00001). However, no effect was found in those with the most refractory atrial fibrillation. The authors concluded that RAS blockade should be considered as an additional treatment option for the prevention of atrial fibrillation.14
Trials Investigating Atrial Fibrillation Using Renin–Angiotensin System Blockade
Hypertensive patients have an increased risk of developing atrial fibrillation, and atrial fibrillation increases the cardiovascular morbidity and mortality risk in hypertensive patients. Antihypertensive treatment is effective in reducing the risk of atrial fibrillation by its blood pressure reduction per se, but blockers of RAS, such as ACEIs and ARBs, also seem to reduce the incidence of atrial fibrillation, e.g. by attenuating changes in cardiac structure and function.
There have been few prospective studies on the development of atrial fibrillation, but there are several secondary analyses of large randomised trials. In a meta-analysis by Sneider et al.,14 no significant reduction in the OR for atrial fibrillation was detectable in hypertension trials (OR 0.89 [0.75–1.05]; p=0.17). However, there was significant heterogeneity between trials, and the Losartan Intervention for Endpoint Reduction in Hypertension study (LIFE)15 and the VALUE16 trials, both testing the effect of ARBs, detected significant reductions in the rates of new-onset atrial fibrillation (see Table 1).
In the LIFE study, treatment with an ARB (losartan) significantly reduced the incidence of new-onset atrial fibrillation, with an RR of 0.67 (0.55–0.83; p<0.001) compared with treatment with a beta-blocker (atenolol), despite similar blood pressure reduction.15 Patients with new-onset atrial fibrillation in the LIFE population had an approximately two-fold increased risk of cardiovascular events, an approximate three-fold increased risk of fatal and non-fatal stroke and a five-fold increased rate of hospitalisation for heart failure.15 The ARB (losartan) was also more effective than the beta-blocker (atenolol) treatment in reducing the risk of a combined end-point of cardiovascular morbidity and mortality as well as stroke and cardiovascular death in hypertensive patients with electrocardiographic left ventricular hypertrophy and atrial fibrillation.17
In the VALUE trial there was a modest but significant reduction of new-onset atrial fibrillation from 4.34% after treatment with a calciumchannel blocker (amlodipine) to 3.67% after treatment with the ARB (valsartan), giving a significant unadjusted HR of 0.843 (0.713–0.997; p=0.0444) in favour of RAS blockade.16 Blood pressure lowering in the VALUE trial was slightly greater with the calcium-channel blocker than with the ARB, which suggests that mechanisms beyond blood pressure control may have contributed to the beneficial effects of the ARB.
In contrast to these observations, two general hypertension trials, the Captopril Prevention Project (CAPPP)18 and the Swedish Trial in Old Patients with Hypertension-2 (STOP-2),19 found no reduction in atrial fibrillation with treatment with ACEIs compared with beta-blockers, calcium-channel blockers and diuretics. However, in these oldest trials, sensitivity and accuracy for the detection of new-onset atrial fibrillation are poor, being mainly ascertained as adverse event reports. To compare, if the effect on atrial fibrillation in the VALUE trial was based merely on adverse event rates, no effect of ARB would have been detected,20, 21 and therefore definite conclusions about the preventative effect of ACEIs cannot be drawn. In Figure 4, risk reduction with blockers of RAS in large hypertension and heart failure trials are shown.
Trials Including Patients with High Cardiovascular Risk
The Heart Outcomes Prevention Evaluation (HOPE) study included patients with high cardiovascular risk without heart failure and left ventricular systolic dysfunction and randomised the patients to treatment with an ACEI (ramipril) or placebo.22 No statistically significant difference in the proportion of patients who developed atrial fibrillation was found between the ACEI and placebo arms, and treatment with ACEI had no protective effect on the development of atrial fibrillation (OR 0.92 [0.68–1.24]; p=0.57).22 In the Telmisartan Randomized Assessment Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND), patients intolerant to ACEIs with cardiovascular disease or diabetes with end-organ damage were randomised to treatment with ARB (telmisartan) or placebo, and no significant effect on new-onset atrial fibrillation was found. One hundred and eighty-two patients (6.4%) treated with ARB compared with 180 patients (6.3%) treated with placebo developed new-onset atrial fibrillation, with an HR of 1.02 (0.83–1.28; p=0.829).23 However, HOPE22 and TRANSCEND23 were not ‘pure’ hypertension trials, although they included a large number of hypertensives (~50% in HOPE, ~76% in TRANSCEND) as hypertension was one qualifying risk factor, and this may explain why these trials failed to detect a beneficial effect of RAS blockade.
In the recently presented Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE I), treatment with an ARB (irbesartan) in high-normotensive patients with atrial fibrillation reduced the secondary end-point of heart-failure hospitalisation compared with placebo during 4.5 years of follow-up with a hazard ratio of 0.86 (0.76–0.98; p=0.018), despite only a -3 (2.91)/-2 (1.88) mmHg reduction in blood pressure.24 Although irbesartan failed to reduce the primary composite end-point of stroke, myocardial infarction and vascular death in atrial fibrillation patients randomised to treatment, it did reduce the secondary end-point of heart-failure hospitalisations by 14%, which may be of importance in this large high-risk population. Preventing the progression from high blood pressure to atrial fibrillation to heart failure may be of great importance not only for patients, but also for healthcare systems.
Post-myocardial Infarction Trials
Two studies examining the effect of RAS blockade on the development of atrial fibrillation after myocardial infarction are included in the meta-analysis by Schneider et al.,14 and no beneficial effect of ACEI treatment was detectable overall (OR 0.72 [0.41–1.27]; p=0.26). In the Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico-3 (GISSI-3) trial,25 patients given randomised treatment with both nitrates and ACEIs (lisinopril) during the first 24 hours of a myocardial infarction were less likely to develop atrial fibrillation (OR 0.76 [0.65–0.89]), but no significant reductions in atrial fibrillation were found comparing ACEI-and non-ACEI-treated patients. However, most patients in this trial had no evidence of heart failure at the time of the myocardial infarction.25 In the smaller TRAndolapril Cardiac Evaluation (TRACE) study,26 only subjects with evidence of heart failure were included, and the follow-up was much longer (two to four years) and showed a significant reduction of 55% for new-onset atrial fibrillation following myocardial infarction after treatment with the long-acting ACEI (trandolapril) (RR 0.45 [0.26–0.76]; p<0.01).
Heart Failure Trials
Atrial fibrillation is a common finding in patients with heart failure, its prevalence increases with the severity of the disease, and development of atrial fibrillation in patients with congestive heart failure worsens the prognosis. A sub-study of the Studies of Left Ventricular Dysfunction (SOLVD)27 investigated the effect of ACEI, whereas in the Cardiovascular Health and Age Related Maculopathy (CHARM) Study28 and Valsartan Heart Failure Trial (Val-HeFT) study29 the effects of ARBs were studied, and all demonstrated a significant reduction in new-onset atrial fibrillation. The SOLVD study,27 including patients with the most severely impaired left ventricular function, showed the largest reduction in atrial fibrillation, with an HR of atrial fibrillation of 0.22 (0.11–0.44; p<0.0001), whereas reductions in atrial fibrillation rates were more modest in CHARM (OR 0.802 [0.650–0.990]; p=0.039)28 and in Val-HeFT (HR 0.63 [0.49–0.81]; p=0.0003).29 In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) database, patients with congestive heart failure or impaired left ventricular function who were on ARB or ACEI treatment had a lower recurrence rate of atrial fibrillation.30 In the meta-analysis by Schneider et al.,14 a significant beneficial effect of RAS inhibition was found in heart failure trials (OR=0.52 [0.31–0.87]; p=0.01).
Post-operative atrial fibrillation is a common complication of cardiac surgery and is associated with increased morbidity, mortality, longer hospital stays and higher costs. In a prospective study of 128 patients undergoing cardiac surgery (coronary artery bypass and/or valve surgery), there was a significantly reduced post-operative atrial fibrillation occurrence in patients treated with an ACEI together with an ARB (candesartan) compared with a control group (12 and 10% versus 33%), with a p-value of 0.02 and 0.01, respectively.31 However, in a real randomised trial the patients should only use one specific ACEI with a definite dose, and the drugs should have been started at the same time. Differences in prevalence of hypertension and a possible beta-blocker withdrawal effect should also have been evaluated.
Secondary Prevention of Atrial Fibrillation Following Cardioversion
The first report from post-cardioversion patients treated with RAS blockade demonstrated a beneficial but not significant effect of ACEI (lisinopril) treatment.32 Thirty patients with congestive heart failure and chronic atrial fibrillation were randomised in a double-blind, placebo-controlled study, and the maintenance of sinus rhythm was 71% in the ACEI group and 36% in the placebo group after subsequent cardioversion (p = non-significant).32 In a study by Ueng et al.,33 adding ACEI (enalapril) to amiodarone in patients scheduled for external cardioversion (about 30% with hypertension) decreased the rate of immediate (4.3 versus 14.7%; p=0.067) and subacute arrhythmia recurrences, and facilitated subsequent long-term maintenance of sinus rhythm (74.3 versus 57.3%; p=0.021) after cardioversion in patients with persistent atrial fibrillation. In a observational study, treatment with an ACEI decreased the number of cardioversion attempts required to achieve sinus rhythm.34
In a study by Madrid et al.,35 154 patients with persistent atrial fibrillation were randomised to treatment with an ARB (irbesartan) or placebo in addition to amiodarone three weeks before electrical cardioversion. Of these patients, about 40% had hypertension.35 Time to recurrence and the probability of remaining free of atrial fibrillation were greater in the group treated with ARB (irbesartan), and irbesartan was the only significant variable related to the maintenance of sinus rhythm after cardioversion in a multivariate analysis.35
The two-month recurrence rate of atrial fibrillation was 15% in a group of patients who underwent electrical cardioversion and were treated with ARB (irbesartan) compared with 37% in the placebo group (p=0.008).35 In another paper by Madrid et al.,36 ARB (irbesartan) in addition to amiodarone in 90 normotensive patients with ‘lone atrial fibrillation’ (absence of cardiac or extracardiac cause of atrial fibrillation) decreased the rate of atrial fibrillation in a dose-dependent manner. One limitation of these studies is that the effect of RAS blockade alone was not tested.
The first randomised, double-blind, placebo-controlled study to investigate the efficacy of an ARB (candesartan) to prevent recurrences of atrial fibrillation after electrical cardioversion and without anti-arrhythmic drugs was the Candesartan in the Prevention of Relapsing Atrial Fibrillation (CAPRAF) study.37 The recurrence rates of atrial fibrillation during follow-up (six months) were remarkably high (68%), and treatment with the ARB did not reduce the recurrence rate compared with placebo.37 The recently published GISSI-Atrial Fibrillation (GISSI-AF) trial showed no effect of treatment with ARB (valsartan) on the recurrence of atrial fibrillation compared with placebo (adjusted HR = 0.97 [0.83–1.14]; p=0.73) after one-year follow-up.38 Patients enrolled were in sinus rhythm but had had either two or more documented episodes of atrial fibrillation in the previous six months or successful cardioversion for atrial fibrillation in the previous two weeks.38,39 To be eligible, patients also had to have underlying cardiovascular disease, diabetes or left atrial enlargement.38,39 The recurrence rates in the placebo groups were also remarkably high (52.1%), which suggests that atrial fibrillation was very difficult to treat in these high-risk patients and that the high rates of atrial fibrillation relapse may be related to the low rate of concomitant use of anti-arrhythmic drugs, in particular amiodarone.38
Cardioversion from atrial fibrillation and atrial fibrillation recurrence rate were more successful in patients treated with RAS blockade than in the non-RAS-treated patients in an observational study of patients scheduled for elective pharmacological or electrical cardioversion (92 versus 82% and 17 versus 31%, respectively; p=0.026).40 In multivariate analysis, pre-treatment with RAS blockers, number of cardiac defibrillation (DC) shocks and left atrial size were independent predictors of atrial fibrillation recurrence rate (OR 0.33 [0.15–0.75]; p=0.008).40
However, RAS blockade treatment did not improve cardioversion success.40 The main limitations in an observational study such as this are the heterogeneity of age, underlying heart disease, atrial fibrillation types, medications and echocardiographic characteristics between the two treatment groups, which result from the nature of retrospective analysis.
In a recently published study by Belluzzi et al.,41 cardioversion was chemically achieved with propafenone in patients with lone atrial fibrillation and then randomised to treatment with ACEI (ramipril) or placebo. A beneficial effect of RAS inhibition was detected after a three-year follow-up despite no anti-arrhythmic drugs being used after cardioversion.41 Atrial fibrillation relapses were observed in three patients treated with ACEI (ramipril) and in 10 patients allocated to placebo (p<0.03), which may be due to the fact that included patients with lone AF were comparably healthy and recurrence rates in the placebo group were low (32%).41
In a meta-analysis by Sneider et al.,14 an overall significant reduction in the risk of atrial fibrillation recurrence after cardioversion (electrical or chemical) with use of ACEIs or ARBs found (OR 0.55 [0.34–0.89]; p=0.01). The data suggest that a beneficial effect of RAS inhibition may not be present in patients with the most refractory disease, in particular in the absence of adequate concomitant treatment with anti-arrhythmic drugs (amiodarone, propafenone).
Secondary Prevention of Atrial Fibrillation by Medical Therapy
There are some studies examining the effects of RAS blockade on the recurrence of atrial fibrillation in patients with paroxysmal atrial fibrillation. In a study by Yin et al.,42 patients with lone atrial fibrillation showed that combinations of amiodarone with ARB (losartan) or ACEI (perindopril) were more effective in preventing atrial fibrillation recurrence compared with amiodarone alone, without any difference between the ACEI and the ARB. Adding an RAS blocker to amiodarone may inhibit left atrial enlargement in this group of patients. Fogari et al. have published three studies on atrial fibrillation development in patients with hypertension. The first study showed that recurrence of atrial fibrillation is lower with treatment with ARB (losartan) and amiodarone than with calcium-channel blocker (amlodipine) and amiodarone.43 The second study compared the effects of ARB (valsartan), ACEI (ramipril) and calcium-channel blocker (amlodipine), and a lower recurrence of atrial fibrillation was found with RAS blockade (ARB and ACEI) compared with amlodipine despite similar blood pressure lowering, suggesting beneficial effects of RAS inhibition beyond blood pressure lowering.44
The third study, in hypertensive patients with diabetes, demonstrated that ARB/calcium-channel blocker (valsartan/amlodipine) is superior to beta-blocker/calcium channel blocker (atenolol/amlodipine), despite similar effects on peripheral blood pressure.45 The beneficial effects of ARB/calcium-channel blocker (valsartan/amlodipine) were more pronounced in those patients concurrently treated with amiodarone or propafenone than in patients treated with other anti-arrhythmic drugs or without anti-arrhythmic treatment.45 In a meta-analysis by Sneider et al.,14 four studies examining the effect of treatment with RAS blockade on the recurrence of atrial fibrillation in patients with paroxysmal atrial fibrillation were included. A significant reduction in the recurrence of atrial fibrillation with ACEI or ARB treatment (OR 0.37 [0.27–0.49]; p<0.00001) was found in those patients with paroxysmal atrial fibrillation.
Atrial fibrillation heightens the risk of cardiovascular morbidity and mortality. Prevention and new treatment regimens of atrial fibrillation are needed, considering the growing elderly population and limited efficacy, costs and significant side effects of current anti-arrhythmic drugs and catheter ablation procedures. The evidence to support using ACEIs and ARBs as anti-arrhythmic therapy in patients with atrial fibrillation is still not solid. However, in view of a possible beneficial effect and a low incidence of side effects, treatment with RAS blockade may be tried in patients at high risk of developing atrial fibrillation or in patients having recurrent atrial fibrillation, especially in patients with other indications for their use (e.g. hypertension, heart failure and diabetes). Aggressive treatment of hypertension, especially with a blocker of RAS, may postpone or prevent atrial fibrillation development and reduce thromboembolic complications. Focus on primary prevention of atrial fibrillation with optimal antihypertensive treatment may reduce morbidity, mortality and healthcare expenditure.