a Division of Cardiology and Cardiovascular Surgery, Institute of Medicine, Chung-Shan Medical University Hospital, Taichung, Taiwan
b National Yang-Ming University, School of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
* Correspondence to: Kwo-Chang Ueng, MD, Division of Cardiology, Chung-Shan Medical University Hospital, Taichung, 110, Sec. 1, Chien-Kuo N. Rd., Taichung, Taiwan. Tel: 886-4-2253-2603; Fax: 886-4-2252-3626
E-mail address: ueng.kc{at}msa.hinet.net
Received 28 April 2003; revised 22 July 2003; accepted 14 August 2003
Abstract
Aims This study aimed to assess whether enalapril could improve cardioversion outcome and facilitate sinus rhythm maintenance after conversion of chronic atrial fibrillation (AF).
Methods and results Patients with chronic AF for more than 3 months were assigned to receive either amiodarone (200mg orally 3 times a day; group I: n=75) or the same dosage of amiodarone plus enalapril (10mg twice a day; group II: n=70) 4 weeks before scheduled external cardioversion. The end-point was the time to first recurrence of AF. In 125 patients (86.2%), AF was converted to sinus rhythm. Group II had a trend to a trend to a lower rate of immediate recurrence of AF than group I did (4.3% vs 14.7%, P=0.067). KaplanMeier analysis demonstrated a higher probability of group II remaining in sinus rhythm at 4 weeks (84.3% vs 61.3%, P=0.002) and at the median follow-up period of 270 days (74.3% vs 57.3%, P=0.021) than in group II.
Conclusion The addition of enalapril to amiodarone decreased the rate of immediate and subacute arrhythmia recurrences and facilitated subsequent long-term maintenance of sinus rhythm after cardioversion of persistent AF.
Key Words: Atrial fibrillation Remodelling Angiotensin-convertingenzyme inhibitor
1. Introduction
Atrial fibrillation (AF), the most common sustained arrhythmia in the elderly, increases the risk of stroke and it and also itis an independent predictor of mortality.13Transthoracic electrical cardioversion of AF is one of the most widely used and effective treatments for restoration of sinus rhythm.4,5However, it it has a limited success rate and a high recurrence rate, which is only partially affected by anti-arrhythmic treatment.6,7Clinical observations have demonstrated that the recurrence of AF is frequently clustered within the first month after cardioversion.8,9Most of the recurrences are probably due to electrical and structural remodelling, caused by changes in the refractory period of atrial muscle8,10,11and atrial fibrosis with intra-atrial conduction disturbances.
Recently, several studies1214have demonstrated that the atrial angiotensin system may play an important role as a mediator of atrial remodelling in AF. A recent study15supporting this notion showed that there was a lower recurrence rate of AF and a longer time to first arrhythmia recurrence in patients with AF lasting more than 7 days who were treated with amiodarone and irbesartan. However, the effect of angiotensin converting enzyme (ACE) inhibitor on cardioversion outcome and subsequent maintenance of sinus rhythm in patients with persistent AF lasting more than 3 months is not known. Therefore, the aim of the current study was to investigate in a prospective, controlled fashion whether the ACE inhibitor enalapril facilitates maintenance of sinus rhythm in patients receiving electrical cardioversion of chronic AF.
2. Methods
2.1. Patient population
From May 2001 to January 2003, 180 consecutive patients with persistent AF for more than 3 months by serial electrocardiograms (ECG) were prospectively included. All of the patients were in stable cardiac condition. Written informed consent was obtained from all patients before they entered the study. Underlying heart disease was determined from the patient's history, physical examination, chest X-ray film, transthoracic and/or transoesophageal echocardiogram and, if available, coronary angiography. Patients with any of the following conditions were excluded from the study: age younger than 18 years; significant rheumatic stenosis; a left atrium size larger than 6.0cm in long axis view; myocardial infarction within 6 months or unstable angina; severe uncontrolled heart failure (New York Heart Association functional class IV); heart surgery within the last 6 months; a previous adverse reaction to amiodarone or enalapril; significant thyroid, pulmonary, hepatic or renal disease; a history of thromboembolism within 6 months; pregnancy or fertile female; significant electrolyte imbalance; QT prolongation (i.e. corrected QT more than 0.45s); sick sinus syndrome; significant alterations of the atrioventricular conduction; an implanted pacing device.
2.2. Study protocol and follow-up (Fig. 1)
Patients with AF lasting more than 3 months were admitted to the hospital for external cardioversion after at least 4 weeks of adequate treatment with warfarin at a dosage adjusted to achieve an international normalized ratio of two or more. Patients were randomized in an open-label fashion into two groups. Patients received either oral amiodarone 200mg three times daily alone or amiodarone 200mg three times daily plus enalapril 10mg twice daily 4 weeks before electrical cardioversion. To control blood pressure, enalapril 10mg was administered at twice daily and could be increased to 20mg twice daily in patients with hypertension. Electrical cardioversion was scheduled after 4 weeks of randomization.
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2.3. Definition of terms
Cardioversion was deemed successful if sinus rhythm was established and maintained for at least 2min. Total shock failure was defined as no any sinus beat emerges throughout the course of electrical cardioversion. After the ultra-short IRAF period, relapses of AF within 4 weeks were deemed as subacuterecurrences.
2.4. End-point of the study
The end-point was the length of time to a first electrocardiographically confirmed recurrence of AF or atrial flutter. Only episodes lasting longer than 10min (as indicated by the history) were considered to be clinically significant. For the purpose of the end-point, the beginning of the follow-up was considered to be the day of the scheduled electrical cardioversion (day 0). Patients in whom sinus rhythm was not achieved were classified as having had a recurrence on day 0.
2.5. Statistics
The sample size was calculated to provide the study with 80% power for a two-sided alpha level of 0.05, assuming a 50% relapse free rate in the amiodarone group and a 70% relapse free rate in the amiodarone plus enalapril group within 1 year after cardioversion.
Parametric data are expressed as the mean±SD or numbers and percentages of patients. Continuous variables were compared between two treatment groups using the unmatched t- test, and categorical data by the chi-square test with Yates correction or Fisher's exact test as appropriate. Estimates of the proportion of patients remaining in sinus rhythm over time were constructed using the method of KaplanMeier and compared using the log-rank test. To find variables possibly related to recurrence of AF, log-rank comparisons of KaplanMeier curves were also used for an univariate assessment of the prognostic value of potential risk factors, such as age, sex, left atrial size, left ventricular ejection fraction, the presence or absence of underlying cardiac disease, and the duration of AF prior to cardioversion, measured at study entry. Subsequently, variables with a P value <0.20 were selected for multivariate Cox proportional hazards regression analysis. The assumption of proportional hazards was checked by estimating plots of the logarithm of the cumulative hazard. The risk reductions of AF relapse after electrical cardioversion were calculated in the form of hazard ratios and 95% CIs from Cox's proportional hazards models. The risk reduction for amiodarone plus enalapril against amiodarone alone was calculated as 100x (1-hazard ratio). The principal evaluation of efficacy of both treatment modalities in the prevention of AF recurrence after cardioversion was made from all patients who received electrical cardioversion. For patients who were lost to follow-up, events were censored at the last visit. A P value less than 0.05 was considered statistically significant.
3. Results
3.1. Patients characteristics
Among the 180 patients, 159 patients were randomized to participate in the present study. Within 4 weeks after randomization, eight patients (two in the amiodarone group, six in the amiodarone plus enalapril group) were withdrawn from the study because of pharmacological side effects (slow ventricular response in three patients with treatment of amiodarone and dry cough in six patients with treatment of enalapril). In six patients, sinus rhythm was documented at the time of the scheduled electrical cardioversion, of whom three were in the amiodarone group and three were in the amiodarone plus enalapril group. These patients were excluded from analysis. Finally, 145 patients wereanalyzed. Among these patients, 75 were assigned to amiodarone, and 70 to amiodarone and enalapril. The baseline demographic and clinical characteristics and the concomitant cardiovascular medications are shown in Table 1. The median duration of AF before attempted cardioversion was 34 months (range, 4 to 144), with no differences among the groups. For patients treated with enalapril, the daily dose of enalapril ranged from 20 to 40mg, with 27.1% of the patients receiving 40mg. Final systolic blood pressure values were similar between the amiodarone group and amiodarone plus enalapril group (129±15 vs 127±18mmHg, P=0.553).
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3.4. Subacute recurrence of atrial fibrillation
At the 4-week follow-up visit, 40 patients had a recurrence of AF. Recurrence of AF within 4 weeks occurred in 11 patients of the amiodarone plus enalapril group, as compared with 29 patients in the amiodarone group. KaplanMeier analysis demonstrated that the probability of remaining in sinus rhythm at 4 weeks was higher among the patients assigned to amiodarone plus enalapril (84.3%) than among those assigned to amiodarone alone (61.3%, P=0.002). For the patients treated with enalapril, the hazard ratio for a recurrence of AF was 0.31, reflecting a 69% reduction in the risk of subacute recurrence of AF within 4 weeks after cardioversion (95% CI 0.11 to 0.87; P=0.026). After the Cox proportional model was applied, correcting for those confounding factors (i.e. left atrial size, or the left ventricular ejection fraction), the hazard ratio was 0.37, reflecting a 63% reduction (95% CI 0.12 to 1.15; P=0.041). In addition, APBs count was significantly fewer in patients receiving enalapril during 24-h Holter recording at 4-week follow-up than those not receiving enalapril (80±176 vs 205±414 APBs, P=0.038).
3.5. Long-term outcome
After a median follow-up period of 270 days (range, 61 to 575), KaplanMeier analysis (Fig. 2A) showed that the amiodarone plus enalapril group had a higher incidence of patients remaining in sinus rhythm (74.3% vs 57.3%,P=0.021). Moreover, the most important variable shown to independently influence late outcome by multivariate analysis was left atrial size >40mm prior to cardioversion. Fig. 2B and Fig. 2C clearly show that enalapril plus amiodarone was superior to amiodarone alone after cardioversion in subgroup patients with left atrial size >40mm (hazard ratio 0.48; 95% CI 0.25 to 0.91; P=0.026).
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4. Discussion
4.1. Major findings
This study has demonstrated that treatment with enalapril decreased the rate of immediate and subacute arrhythmia recurrences and could significantly enhance long-term outcome in patients with long-standing AF after cardioversion. The combination of enalapril and amiodarone was well tolerated and did not increase the risk of electrical cardioversion complications.
4.2. Atrial premature beats and relapse of arrhythmia
The present study and previous studies9,16have found that all IRAF episodes were triggered by APBs. Atrial ectopy clearly remained potentially important as a trigger for reinitiation of AF. The ability of APBs to induce AF depends on their timing and location relative to electrical heterogeneity gradients.17,18The potential importance of ectopic activity in AF has acquired great significance with the recent recognition of the important role of ectopic beats originating from the great venous tissues.1921When a vulnerable substrate exists, the occurrence of AF requires a trigger, generally provided by ectopic beats. Enalapril might may suppress the APBs, probably by its modifying the sympathetic tone22,23and/or decreasing Na+/Ca2+exchanger activity.2426Webster et al.27also observed that ACE inhibition was associated with a trend toward reduction of the frequency of APBs over time in addition to a decrease in atrial pressure. In the present study, we showed that patients treated with enalapril had significantly fewer APBs within 2min following cardioversion and at the 4-week follow-up, and also, these patients had less recurrences of AF.
4.3. ACE inhibitors and immediate relapse of atrial fibrillation
The natural history of AF is characterized by a gradual worsening with time. Atrial fibrillation itself alters atrial electrophysiology (termed atrial electrical remodelling, mainly shortening of atrial effective refractory period), and causes atrial dilatation (structural remodelling), which facilitates the perpetuation of AF itself.7,2830Nakashima et al.12reported that captopril prevented atrial electrical modelling induced by a relatively brief period (6h) of rapid atrial pacing in a dog model. However, a recent manuscript by Shinagawa et al.31have has already shown that enalapril has no effect on longer-term (7 days) electrical remodelling, as might occur with persistent AF. In the present study, patients were in AF for more than 3 months before cardioversion. Thus, it is unlikely that the electrophysiologic effects of ACE inhibitors on electrical remodelling have contributed to the beneficial outcome. In the present study, the finding that treatment with enalapril only resulted in marginal effect on IRAF may be explained as a net result by the persistence of electrical remodelling despite treatment of enalapril and positive effect of enalapril on structural remodelling and fewer APBs during this period.
4.4. ACE inhibitors and subacute recurrence of atrial fibrillation
Most of the benefit of enalapril occurred during the first 4 weeks after conversion. After that, the two curves seem to be parallel. The mechanisms of treatment with enalapril causing this result remain to be understood. In a goat model of AF, changes in atrial refractory periods were no longer evident 1 week after recovery of sinus rhythm.11Everett et al.32demonstrated that complete reversal of electrical remodelling occurred 7 to 14 days after cardioversion of persistent AF in a canine model. However, gross and ultrastructural changes persisted, as did vulnerability to induce AF. Our previous work33also demonstrated that complete reversal of atrial electrical remodelling following cardioversion of chronic AF in humans happened on the third day after cardioversion. However, the present study, as well as previous clinical observation,8has demonstrated that the persistence of atrial vulnerability to fibrillation after cardioversion continues to increase within 2 to 4 weeks after reversal of electrical remodelling. Thus, subacute recurrence of AF within first 4 weeks after electrical cardioversion must be due to a distinct arrhythmogenic mechanism other than electrical remodelling.
Atrial fibrosis could cause circumscribed electrophysiological inhomogeneities of the atria allowing the induction of AF. A recent study by Shi et al.13has shown that experimental congestive heart failure induced by right ventricular pacing creates dilatation of both atria and atrial fibrosis (structural remodelling), which is correlated with vulnerability to AF. In this work, they demonstrated the ability of enalapril to regress atrial fibrosis and reduce associated AF promotion in the setting of congestive heart failure. These findings, suggestinged that the blockade of the atrial tissue ACE is associated with inhibition of collagen type I synthesis. Enalapril has been shown to attenuate arrhythmogenic atrial structural remodelling in an experimental heart failure model.14The ACE inhibitor trandolapril reduced the incidence of AF in post-myocardial infarction patients with left ventricular dysfunction.34However, most patients included in the present study had a nearly normal left ventricular ejection fraction and were predominantly in the New York Heart Association class III. Thus, the results from heart failure models may not allow to really allow to explain the findings in patients without overt heart failure.
Recent studies have demonstrated changes in atrial expression/activity of ACE,35angiotensin II receptors,36and bradykinin metabolism37in persistent AF patients with normal left ventricular function. An ACE-dependent change in the amounts of activated extracellular signal-regulated kinases and bradykinin in atrial interstitial cells contributes to the development of atrial fibrosis, which provides a pathophysiologic substrate for AF. Atrial dilatation is another example of structural remodelling. It is an important independent factor to predict the early recurrence of AF, potentially promoting AF by activating stretch-operated channels and/or by increasing atrial mass. Previous report indicated that atrial dilatation increased the vulnerability of AF and opposed the successful maintenance of sinus rhythm.28A recent study by our group38also showed that the increased inhomogeneity in atrial electrophysiological properties during atrial dilatation contributed to the inducibility of AF. Thus, atrial dilatation could play an important role in arrhythmogenesis in clinical settings. In the current study, we demonstrated that the patients with left atrial dimension larger than 40mm was the only clinical parameter to predict of relapse into AF. Treatment with enalapril significantly reduced the recurrence of AF in these patients. These findings suggested potential reversibility of structural remodelling as a therapeutic benefit of ACE inhibition to reduce relapse into AF.
In patients after who have had successful cardioversion, recovery of normal atrial mechanical function was reported to occur from 1 to 4 weeks following after restoration of sinus rhythm.39,40Shi et al.13reported that experimental congestive heart failure causes mechanical abnormalities of both atria, which are correlated with atrial fibrosis. In this study, they demonstrated that enalapril significantly restored atrial emptying function and also reduced the vulnerability to AF. Regardless of the length of time course of the electrophysiological remodelling, it is likely that once a patient is restored to sinus rhythm, the time required for structural remodelling of the atria will likely be much slower than the electrophysiological remodelling of the individual atrial myocytes. We, therefore, believe that recurrence of AF after cardioversion is mostly attributed to atrial electrical and structural remodelling in different time courses, respectively. This may account for the different favourable effects of enalapril on IRAF and subacute recurrences after cardioversion of persistent AF. Besides, the finding that the beneficial role of enalapril seems to be weaning after 4 weeks may be in part attributed to arrhythmia relapse in three out of four patients with withdrawal of enalapril during late follow-up.
Although blood pressure control could be an important part of the mechanism for the benefit of enalapril on AF recurrence, there was similar proportion of hypertension and left ventricular hypertrophy. Also, there was no significant difference in blood pressure between the two groups at the randomization and after the follow-up. Therefore, it is less likely that lowering of blood pressure may play a role in the result of this study. Enalapril could have antiarrhythmic activity by means of other mechanisms. These include decrease of wall stress, improvement of left ventricular systolic function, decrease of end-diastolic left ventricular pressure and subsequently left atrial pressure, ß-blocking properties, and stabilization of electrolyte concentrations.
Recent multicentre, randomized studies41,42reveal that rhythm control offers no advantage over rate control in AF. The rhythm control strategy involved use of a wide range of potentially toxic antiarrhythmic drugs. These results reflect the limitations of current sinus rhythm maintenance therapy. However, novel approaches that may modify adverse structural remodelling were not investigated in these studies. Given the results from the present study and the study by Madrid et al.,15the addition of enalapril or irbesartan to amiodarone can achieve better maintenance of sinus rhythm than those with amiodarone alone during long-term follow-up. Of note, there is accumulating evidence that ACE inhibitor or angiotensin II type 1 receptor blocker treatmentimproves the prognosis in patients with underlyingcardiac disease. Therefore, the development of a new therapeutic target directed against the development of the AF substrate and atrial remodelling is likely to greatly alter the management strategy for these patients. However, further study must show whether such combination treatment can achieve lower complication, better quality of life, and better prevention of stroke and death than rate control can.
4.5. Limitations of the study
The study has several potential limitations: (1) Although combination therapy was superior to amiodarone alone, we cannot define the effects of monotherapy with enalapril because of study design; (2) We cannot exclude the possibility of a distortion in the estimate of the treatment effect (due to not including patients who spontaneously restored to sinus rhythm) in both groups; (3) The median follow-up period of the study was only 270 days that did not reach our presumed long-term follow up within 1 year. However, the KaplanMeier curves for both groups appeared to be parallel 6 months after cardioversion. Therefore, there is a reason to make our conclusion regarding the effect of enalapril on long-term follow-up; (4) Although a recovery from structural remodelling has been proposed as the major mechanism by which enalapril reduces subacute AF recurrences, no attempt was made to assess changes in atrial size and fibrosis in the current study, and further studies are necessary to address this question; (5) Hypertension may be associated with renin-angiotensin system activation. Many antihypertensive drugs can modify renin-angiotensin secretion. Diuretics could cause a rise in plasma renin activity, and the ß-blockers depress renin activity. Calcium channel blockade could have some effects on acute electrical remodelling. However, the percentage of patients using these agents was low and similar in both groups. It is unlikely that they may have played a role in the benefit of enalapril on AF recurrence.
5. Conclusion
Concomitant use of enalapril with amiodarone enhances cardioversion outcome in patients with long-lasting AF possibly mainly by attenuating adverse structural remodelling process and reducing APBs, thus reducing subsequent immediate and subacute arrhythmia relapses, and allowing more patients to remain in sinus rhythm.
Acknowledgments
We gratefully acknowledge the expert secretarial work of Wei-Heng Chi.
References
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