Role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the management of atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common clinical arrhythmia, and is difficult to treat. Current treatment strategies are far from optimal. Antiarrhythmic drug therapy to maintain sinus rhythm is limited by inadequate efficacy and potentially serious side effects. New areas of research include targeting the AF substrate and examining whether drugs can produce atrial structural and/or electrophysiological remodelling, and whether this results in a reduction in AF burden. There are two approaches to the treatment of AF. The first approach is cardioversion and treatment with antiarrhythmic drugs to maintain sinus rhythm. The other approach is the use of rate-controlling drugs allowing AF to persist. In both approaches, the use of anticoagulant drugs is recommended. There is an increasing interest in novel therapeutic approaches that target AF-substrate development. Recent trials suggest that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor II blockers (ARBs) may be useful, particularly in patients with left ventricular hypertrophy, hypertension, chronic heart failure and left ventricular dysfunction. While experimental studies have shown that the pathogenic structural and electrical remodelling of the atria are prevented by inhibition of angiotensin II, the clinical potential and mechanisms of this approach are still under active investigation. The present article will discuss information pertaining to the mechanism of action and clinical use of ACEIs and ARBs in AF. It will also review the current data on the use of ACEIs and ARBs in a high-risk group of AF patients (heart failure, hypertensive with left ventricular hypertrophy, and myocardial infarction), together with the potential benefit of this class type of pharmacological therapy in direct current cardioversion and after radiofrequency catheter ablation.

Atrial fibrillation (AF) is associated with a high risk of stroke and death; however, its management remains a difficult clinical problem. Before initiating specific treatment of AF, treatable causes must first be reliably ruled out. Furthermore, the chances of maintaining a sinus rhythm must be individually weighed against the potential complications and risks of an antiarrhythmic therapy. Cardiovascular diseases (ie, myocardial infarction [MI], heart failure and hypertension), which are associated with an activation of the renin-angiotensin system (RAS), can induce AF which is not only initiated by mechanical distension of the atria, but also by increased atrial expression and response to RAS components. This initiates an inflammatory signal cascade, oxidative stress and consequently, myolysis and interstitial fibrosis. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) reduce morbidity and mortality in patients with heart failure (1) and/or systolic dysfunction after MI (2), and are quite effective in the treatment of hypertension. Experimental and clinical trials (3) suggest that these medications may prevent the development and/or recurrence of AF. It is well known that angiotensin II is important in the regulation of blood pressure, fibroblast proliferation and cardiac hypertrophy, with subsequent benefits in controlling AF. A recent meta-analysis (4) suggested RAS inhibition suppresses AF in patients with left ventricular (LV) dysfunction and LV hypertrophy (LVH).

Radiofrequency catheter ablation of AF has evolved into a highly effective and safe procedure. Nevertheless, the immediate and long-term success of AF ablation is often offset by the recurrence of AF (5). There is growing evidence, both from animal and clinical studies, of the involvement of the angiotensin system in the pathophysiology of AF. Angiotensin-converting enzyme (ACE) expression is increased in atrial biopsies of patients with AF (6) and angiotensin II concentrations are increased in animal models of AF (7,8). Previous studies (9,10) have shown that ACEIs diminish the incidence of AF after MI and in the setting of heart failure, and that ARBs reduce the recurrence of AF after cardioversion for persistent AF. Identifying risk factors for AF development after ablation and whether ACEIs and ARBs can reduce the AF recurrence after radiofrequency catheter ablation has also been studied (5).

POTENTIAL MECHANISMS

There are several potential mechanisms by which inhibition of the RAS with ACEIs and ARBs may reduce AF. In animal models, ACEIs and ARBs appear to prevent AF by attenuating changes in cardiac structure and function (11), preventing left atrial dilation, atrial fibrosis and conduction velocity (12). Experimental data show that ACEIs decrease angiotensin II concentration which stimulates mitogen-activated protein kinases, which in turn activate fibrosis formation and lead to conduction heterogeneity and induction of AF. On the other hand, AF induces atrial dilation, atrial stretch and atrial secretion of ACEs.

Remodelling in AF

It is well known that AF tends to become permanent with time, illustrated by the fact that it becomes more difficult to maintain sinus rhythm when AF has been present for a long time. Atrial remodelling plays a part in this process and has been studied in experimental models.

Stimulation of angiotensin II production promotes cardiac fibrosis, contributing to LV remodelling following MI (13), and rapid atrial stimulation can increase plasma angiotensin II concentrations (14). Also, preliminary clinical data show that ARBs can prevent AF episodes via their influence on atrial remodelling. The determining factor of both electrical and structural remodelling is the rapidity of the atrial rhythm of the AF itself. In an experimental model (15) of persistent AF, electrical remodelling was found to accompany structural remodelling; the structural remodelling is a reaction of adaptation similar to that observed in hibernating myocardium during ischemia and aims to prolong cellular viability by decreasing atrial contractility. Another aspect of structural remodelling is the activation of fibroblasts with the formation of fibrosis with resulting heterogeneity of the conduction tissue. Because atrial remodelling causes an increase in ACE and angiotensin II concentrations, it has been proven (16) that ACEIs and ARBs can reduce fibroblast growth. Therefore, ACEI and ARB therapy has clinical applications in preventing new-onset AF and reducing recurrent AF. Based on findings of the relationship of the RAS to the development of atrial electrical remodelling and fibrosis (both of which promote AF), studies (14) have been performed evaluating pharmacological blockage of the RAS to reduce AF.

Role of inflammation or fibrosis in the initiation and perpetuation of AF

Much attention has been devoted in the past few years to assess the role of inflammation in AF. Angiotensin II regulates cardiac fibroblast proliferation (17), it binds to angiotensin II type 1 receptors and stimulates fibrous tissue formation by promoting transforming growth factor (TGF)-β1 synthesis which could be of particular importance in promoting atrial fibrosis (18). Selective cardiac overexpression of TGF-β1 in transgenic mice causes atrial fibrosis, with predisposition to AF (19). Atrial TGF-β1 is activated during the development of congestive heart failure CHF with subsequent development of AF (20). Cardiac-specific ACE overexpression produces atrial enlargement and AF (21), consistent with an angiotensin II/fibrosis/AF link. In an experimental CHF model (18), ACEIs inhibited fibrosis and reduced AF duration. Also, there is evidence for a role of angiotensin II in mediating inflammatory responses, which may additionally be involved in AF (22).

The contribution of the inflammatory cascade to the onset of AF is suggested by the high incidence of AF in postoperative cardiac surgeries (23–26). Studies (27,28) have suggested that inflammation leads to ‘atrial myocarditis’, with subsequent electrical and structural atrial changes resulting in initiation and maintenance of AF. Also, left atrial dysfunction has been described in patients with increased C-reactive protein but without AF, suggesting that inflammation per se affects left atrial function (26,29).

Patients with a longer duration of AF have a greater elevation in C-reactive protein levels and subsequently greater atrial structural remodelling evidenced by larger left atrial diameter (30,31). Markers of platelet activation assessed by soluble P-selectin levels have also been shown to be elevated within 12 h in patients with persistent AF and return to normal levels on resolution to normal sinus rhythm (26).

ACEIs and CHF link in AF

Hemodynamic effects of ACEIs include systemic arteriolar dilation and increased large artery compliance that decrease systolic blood pressure. In CHF, RAS inhibition reduces after-load, left atrial pressure and systolic wall stress, consequently leading to an improvement in cardiac function (32). Acutely raised blood pressure increases atrial vulnerability by shortening refractory periods (33), possibly by opening stretch-activated channels. Atrial stretch is not the only determinant of the AF substrate in CHF because it can still be induced despite reversal of atrial dilation after recovery from tachypacing-induced CHF (34).

ROLE OF ACEIs AND ARBs IN DIFFERENT AF SUBSETS

The initial basic science and clinical trial data suggest that modulation of RAS may be an effective treatment for AF. However, serious issues remain to be clarified: Do these drugs have a clinically meaningful impact on AF burden? If there is an impact, is it similar in all AF patients or just in certain subsets? Do ACEIs and ARBs have similar benefits?

Role of ACEIs/ARBs in preventing new-onset AF

Experimental and observational studies (35,36) in animal and human models support the role of ACEIs and ARBs in the prevention of AF. Enalapril attenuates ventricular tachypacing-induced changes in angiotensin II, mitogen-activated protein kinase, and atrial remodelling in dogs (37,38). Previous meta-analyses from randomized clinical trials have reported the role of ACEIs and ARBs in the prevention of AF (3,9,41–43). In the Captopril Prevention Project (CAPPP) trial (44) and the Swedish Trial in Old Patients with Hypertension-2 (STOP H-2) trial (39), ACEIs did not provide any significant benefit over the use of conventional antihypertensive treatments in the prevention of AF. In the CAPPP trial, captopril was administered one to two times per day and because of the short duration of action of captopril, these patients may have received an insufficient dose. In the STOP H-2 trial, 46% of all patients were receiving more than one antihypertensive drug and only 61.3% of patients in the ACEIs group were still taking their randomly assigned treatment at the end of the trial. In the Losartan Intervention for Endpoint reduction in Hypertension (LIFE) trial (40), new-onset AF was significantly reduced by losartan-based treatment compared with atenolol-based antihypertensive treatment with similar blood pressure reduction (42). The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial (41) did not show any benefit of valsartan over amlodipine. This may be, in part, attributed to the significantly higher baseline blood pressure among the patient group treated on valsartan than those on amlodipine. In the Candesartan and Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) (45) and The Gruppo Italiano per la Studio della Strptochinasi nell’ Infarto Miocardio-3 (GISSI-3) (3) trials, there was no significant protective effect of ACEIs and ARBs on new-onset AF. In the Valsartan Heart Failure trial (Val-HeFT) (46), the addition of valsartan to the standard therapy decreased new-onset AF. In two placebo-controlled trials, the Studies of Left Ventricular Dysfunction (SOLVD) (9) and the Trandolipril Cardiac Evaluation (TRACE) (47) study, the occurrence of AF decreased in patients receiving ACEIs and ARBs (42).

A meta-analysis of the above nine randomized clinical trials showed an 18% risk reduction in new-onset AF, and in the five primary prevention trials there was a 31% risk reduction in the incidence of AF (42). However, ARBs did not have a significant protective effect compared with ACEIs; this finding is different from results of a previous meta-analysis in which ACEIs and ARBs were equally efficacious (42,43).

AF and chronic heart failure (Table 1)

TABLE 1.

Clinical trials of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with atrial fibrillation (AF) and and congestive heart failure (CHF)

Author (reference)	Drug (class)	Number of patients randomized	Mean follow-up	Mean LVEF, %	Rate of AF in control group, %	Main findings
Van den Berg et al (49)	Lisinopril (ACEI)	30	84 days	N/A	64	More patients in SR six weeks postcardioversion; P = Not significant
Vermes et al (9)	Enalapril (ACEI)	374	3.3 years	27	24	Reduced new-onset AF (P<0.0001)
Cohn (46)	Valsartan (ARB)	4409	2 years	28	8	Lower AF incidence (P<0.0002)
Anique et al (45)	Candesartan (ARB)	5518	3.2 years	39	8	Candesartan reduced the incidence of AF in patients with symptomatic CHF

LVEF Left ventricular ejection fraction; SR Sinus rhythm; Val-HeFT Valsartan Heart Failure Trial; N/A Not available

AF is frequent in patients with chronic heart failure. Experimental and clinical studies have demonstrated that blocking the RAS may prevent AF. In the CHARM study (45,48), the effects of the ARB candesartan on cardiovascular mortality and morbidity were evaluated in a broad spectrum of patients with symptomatic chronic heart failure. Seven thousand six hundred one patients with symptomatic heart failure and reduced or preserved left ventricular systolic function were randomly assigned to candesartan or placebo in the three component trials of the CHARM study. The major outcomes were cardiovascular death or chronic heart failure, hospitalization and all-cause mortality. Median follow-up was 37.7 months. The study showed that treatment with the ARB candesartan reduces the incidence of AF in a large population of patients with symptomatic heart failure, although there was not statistically significant effect heterogeneity between CHARM subgroups; however, the significant effect was found only in patients with LV dysfunction. In patients with preserved LV systolic function, the effect was negligible and not statistically significant. In four trials (9,49) studying ACEIs and ARBs in patients with chronic heart failure there was an overall 44% RR reduction in the development of AF, there was also a relationship between the RR reduction and LV ejection fraction. In the SOLVD substudy, patients had the most severely impaired LV function (mean LVEF 26.7%) and the largest reduction in AF (RR reduction 78%). As mean LVEF in heart failure studies increased, the RR reduction with therapy decreased (in Val-HeFT: mean LVEF 28%, RR reduction 23%; in the CHARM trial: mean LVEF 39%, RR reduction 18%).

AF and MI (Table 2)

TABLE 2.

Clinical trials of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers in patients with atrial fibrillation (AF) and myocardial infarction

Author (reference)	Drug (class)	Number of patients randomized	Mean follow-up	Mean LVEF, %	Rate of AF in control group, %	Patients with hypertension, %	Main findings
Pederson et al (47)	Trandolapril (ACEI)	1577	2 to 4 years	33	5	22	Reduced new-onset AF (P<0.05)
Pizetti et al (3)	Lisinopril (ACEI)	17,711	42 days	N/A	8	30	No significant reduction in AF with six weeks of ACEI therapy

LVEF Left ventricular ejection fraction; N/A Not available

Clinical trials have suggested that ACEIs prevent the development and/or recurrence of AF after MI. The TRACE trial (47) has shown that in patients with reduced LV function after MI, trandolapril reduces the frequency of AF. The same conclusion has been made in the SOLVD trial (9); a 78% reduction in the frequency of AF after MI was noted with enalapril compared with placebo. However, two studies examining the use of ACEIs following MI came to different conclusions regarding their utility in preventing AF. The GISSI-3 (3) trial has found no significant reduction in AF with six weeks of ACEI therapy initiated within 24 h of MI, whereas the TRACE (47) trial found a 48% RR reduction in patients treated with trandolapril, starting three to seven days following MI and followed for up to four years. The incidence of AF was higher in the GISSI-3 trial, which could be explained in part by the following: a larger study size because the number of patients with AF was more than 20 times that seen in the TRACE study; differences in the duration of follow-up periods; and the TRACE study enrolled only patients with LV dysfunction, whereas in the GISSI-3 (3) trial, 84% of patients had no evidence of CHF at the time of MI.

AF and hypertension (Table 3)

TABLE 3.

Clinical trials of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with atrial fibrillation (AF) and hypertension

Author (reference)	Drug (class)	Number of patients randomized	Mean follow-up	Rate of AF in control group, %	Main findings
Hansson et al (39)	Enalapril (ACEI)	10,985	5 years	8	Reduced AF incidence (P=0.018)
Hansson et al (44)	Captopril (ACEI)	6614	6.1 years	2	No difference in AF
Wachtell et al (40)	Losartan (ARB)	9193	4.9 years	6	Reduced composite primary end point: cardiovascular mortality, stroke and MI (P=0.0009)

MI Myocardial infarction

The effect of losartan compared with amlodipine (both associated with amiodarone) in preventing the recurrence of AF in hypertensive patients with a history of recent paroxysmal AF has been evaluated (47). Two hundred fifty mild hypertensive (systolic blood pressure greater than 140 mmHg and/or diastolic blood pressure greater than 90 mmHg) outpatients in sinus rhythm (with at least two electrocardiogram-documented episodes of symptomatic AF in the previous six months) were randomly assigned to losartan or amlodipine and were followed up for one year. Clinic blood pressure and a 24 h electrocardiogram were evaluated every month. Two hundred thirteen patients completed the study: 107 in the losartan group and 106 in the amlodipine group. The study revealed that using losartan in combination with amiodarone seemed more effective than the amlodipine/amiodarone combination in preventing new episodes of AF in hypertensive patients. The LIFE trial demonstrated a significant reduction in AF in patients with evidence of LV hypertrophy (38). Two other clinical trails showed different results to the LIFE trial; the CAPPP trial (44) and STOP-H2 (39) trial. Both clinical trials have studied general hypertensive populations. In both trials, there was no reduction in AF with ACEIs compared with beta-blockers, calcium channel blockers, and diuretics; this controversy can be explained by the fact that the LIFE trial (40) only enrolled hypertensive patients with LVH, whereas the CAPPP trial and STOP-H-2 trial enrolled general hypertensive patients regardless of the LVH. In both the SOLVD treatment and prevention trials, there was a small but statistically significant reduction in systolic and diastolic blood pressures during follow-up in the enalapril group compared with the placebo group (in SOLVD-Treatment, by 4.7 mmHg and 4.0 mmHg, respectively, and in SOLVD-Prevention, by 5.2 mmHg and 3.2 mmHg, respectively) (35).

AF and cardioversion (Table 4)

TABLE 4.

Clinical studies of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with atrial fibrillation (AF) and cardioversion

Author (reference)	Drugs (class)	Number of patients randomized	Mean follow-up	Rate of AF in control group, %	Main findings
Madrid et al (36)	Amiodarone and irbesartan (ARBs)	154	254 days	29	Improved SR maintenance (P=0.007)
Ueng et al (51)	Amiodarone and enalapril (ACEIs)	125	270 days	43	Improved SR maintenance (P=0.021)

SR Sinus rhythm

The pharmacological mechanism by which ACEIs and ARBs facilitate direct current cardioversion is through attenuation of the atrial structural changes that form the substrate for AF perpetuation. ACEIs and ARBs appear to play a beneficial role by preventing immediate recurrence of AF within 5 min of cardioversion and/or early recurrence of AF within the first four weeks following cardioversion (51). This is of a particular importance because AF recurrence frequently occurs during the first few weeks after cardioversion. Prospective randomized studies (52) have shown that the addition of ACEIs or ARBs to amiodarone reduces the recurrence rate of AF after electrical cardioversion. Recently, two randomized trials were designed to test whether ACEIs (51) or ARBs (53) would reduce the recurrence of AF in patients following electrical cardioversion (most patients in those trials had hypertension with preserved LV function). Both studies showed a significant reduction in AF with treatment, which was apparent within weeks of the cardioversion. The limitations of those two studies were that they were small, had a short follow-up period and although randomized, they were not placebo-controlled.

Recent work suggests that intravenous ibutilide can significantly improve the success rate of cardioversion; however, the use of the drug in patients with low ejection fractions (less than 20%) is contraindicated (54,55), and, as all antiarrhythmic therapy, long-term use may induce proarrhythmic effects which is not recommended.

ACEIs, ARBs and outcome after AF catheter ablation

In a recent study of 234 patients, ACEIs and ARBs showed no potential to improve catheter ablation outcome of AF (56). A possible explanation might be the preserved LV function in the examined cohort. Meta-analyses examining the beneficial effects of ACEIs and ARBs on AF (42,43,56) have shown that AF prevention is greatest in patients with LV dysfunction and is not constantly observed in patients with normal LV function. Therefore, it cannot be excluded that performing the same study in patients with impaired left ventricular function might lead to different results (56). In addition, previous studies on AF prevention by anti-inflammatory and RAS modulating drugs were predominantly conducted in populations at risk of AF and not in populations with existing AF.

DISCUSSION

There is strong evidence that the actions of ACEIs have a negative inotropic effect and may lead to a reduction in atrial pressure because atrial myocardium contains both angiotensin I and II receptors (12,53,57,58). These receptors exert significant positive inotropic effects on atrial myocardium, and this effect is mediated both directly and through release of catecholamines at the angiotensin II receptor site. Angiotensin II exerts its inotropic effect only on atrial tissue and not ventricular myocardium. Blocking its effects by ACEIs would lead to a negative inotropic effect, which, in turn, could make atrial tissue less prone to development of AF (55). It is the realization that anticoagulation therapy alone is not sufficient for the management of AF that has prompted clinical trials to compare the two main approaches used in the treatment of AF: rate control versus rhythm control. In the rhythm control strategy, the focus is to establish and maintain sinus rhythm with the use of antiarrhythmic drugs. In the simpler rate control approach, emphasis is placed on controlling the ventricular response of AF. There are potential benefits and risks with both of these therapeutic methods. It has been argued that antiarrhythmic agents eliminating, or at least substantially reducing the frequency and duration of atrial fibrillation, might not just alleviate symptoms and improve functional capacity but might also lower the risk of stroke, death and obviate the inherent risk of anticoagulation. Interestingly, potential advantages of the rate control approach are primarily derived from the elimination of the untoward consequences of antiarrhythmic drugs, namely their many side effects and particularly their serious proarrhythmic potential. The ACEIs and ARBs have the potential to prevent AF by reversing changes in cardiac structure and function. The clinical antiarrhythmic actions of ACEIs and ARBs are mediated by the prevention of structural remodelling (LVH and left atrial enlargement), which is a frequent complication of hypertension and chronic heart failure and has a strong association with the development of AF (59). Enlargement of the left atrium and increased atrial pressure may promote the development and maintenance of AF by triggering premature atrial beats (60), slowing atrial conduction velocity and providing a greater area for re-entry (61). In animal models of chronic heart failure, ACEIs and ARBs reduce aspects of cardiac remodelling (such as left atrial dilation, dysfunction, fibrosis, and shortening of the atrial effective refractory period) (12), which should in turn lead to a reduction in AF (62). Although there is a substantial heterogeneity between clinical trials (which is partially explained by differences in patient population and LV function), a clinically significant reduction in AF has been documented in patients treated with either ACEIs or ARBs. The reduction in AF with ACEIs and ARBs appears to be related, in part, to the hemodynamic effects of these drugs; however, these two classes of agents may also possess specific properties that prevent new-onset or recurrent AF. Currently, there are insufficient prospective double-blinded trial data with no solid clinical evidence to recommend ACEI or ARB treatment solely for AF prevention.

In three large trials (39,40,44) of ARBs and ACEIs in a hypertensive population, the average rate of AF development in the non-ACEI arm was 5% (annual rate of 1%), which is almost double the rates seen in the Heart Outcomes Prevention Evaluation (HOPE) study (annual rate of 0.5%) (63). Potential explanations for lower than expected AF rates include selection of patients with no history of heart failure and relatively low rates of patients with a history of hypertension (less than 50% at randomization) and a mean blood pressure of 139/80 mmHg.

In the SOLVD trials, patients treated with enalapril were less likely to be hospitalized with atrial tachyarrhythmias than patients treated with placebo. Furthermore, analysis has identified an association between ACEI treatment and hospitalization with atrial tachyarrhythmias in patients with LV dysfunction (35). These findings are in agreement with previous observations suggesting a preventive role for ACEIs on atrial tachyarrhythmias in patients with LV dysfunction. In a retrospective analysis of the TRACE study (35), trandolapril intitiated immediately after MI in patients with LV dysfunction was associated with a reduction in the incidence of AF (48). The high-risk HOPE study participants without a known history of heart failure or LV dysfunction had a low rate of new-onset AF and ramipril did not significantly reduce the risk of AF over the 4.5-year follow-up period. A previous meta-analysis (43,63) of the randomized clinical trials demonstrated a reduction of new AF with ACEIs and ARBs (RR 0.72; 95% CI 0.60 to 0.85); however, it did not include HOPE, the fourth largest trial of ACEIs and ARBs reporting AF outcomes. The RR for the development of AF (analyzing only the ACEIs trials) is 0.75 (95% CI 0.60 to 0.94) and 0.73 (95% CI 0.63 to 0.86) when ARB trials are included. When ACEI trials involving patients with LV dysfunction (SOLVD [9] and TRACE [47]) are excluded from the re-analysis, the results are no longer statistically significant (RR 0.92; 95% CI 0.80 to 1.05) (61). For the ARB trials that did not involve patients with LV dysfunction, the RR is 0.58 (95% CI 0.33 to 1.00). Furthermore, when both ARB and ACEI trials are categorized based on the underlying patient population, the reduction in AF was seen in trials involving patients with LV dysfunction (RR 0.55; 95% CI 0.39 to 0.79) (61). The benefit seen in AF reduction by the use of ACEIs and ARBs is likely to be greater in those patients with LV dysfunction and may not be applicable in those with preserved LV systolic function. It is likely that ACE inhibition in the setting of normal LV function does not reduce the incidence of new-onset AF. However, because of the lack of power in the HOPE study, a moderate but clinically significant treatment effect cannot be clearly excluded (63), and further prospective randomized studies of ACEIs and ARBs in patients with normal LV function are required.

Despite the growing body of evidence to support the role of drugs with anti-inflammatory and/or RAS modulating properties on AF treatment and recurrence, it should not be overlooked because there are also numerous studies that could not find a preventive effect on AF occurrence (44,56,63). These conflicting data may, in part, be related to profound differences in study populations such as differences in AF history and predisposing diseases. Furthermore, there was great variance in study protocols that could contribute to controversial results (56). Among others, the sample size, follow-up duration, drug dose, duration of drug application, and method to assess occurrence of AF varied widely. Further information will be available in The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) (64).

CONCLUSION

Clinical trials demonstrate the beneficial effects of ACEI and ARB treatment in patients with high-risk factors for AF (eg, heart failure, hypertension with LVH, and MI with LV dysfunction). ACEIs and ARBs prevent the development of new-onset AF and reduce its potential recurrence in high-risk individuals. Furthermore, they appear to have particular importance in preventing the recurrence of AF after direct current cardioversion.