International Journal of Cardiology 120 (2007) 85 – 91 www.elsevier.com/locate/ijcard

Candesartan in the prevention of relapsing atrial fibrillation☆ Arnljot Tveit a,⁎, Irene Grundvold b , Mona Olufsen a , Ingebjørg Seljeflot c , Michael Abdelnoor c , Harald Arnesen b,c , Pal Smith a a

Department of Internal Medicine, Asker and Baerum Hospital, 1309 Rud, Norway b Department of Cardiology, Ulleval University Hospital, 0407 Oslo, Norway c Center for Clinical Research, Ulleval University Hospital, 0407 Oslo, Norway Received 20 June 2006; accepted 10 August 2006 Available online 17 November 2006

Abstract Background: Several studies have indicated that treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs) may reduce the incidence of atrial fibrillation (AF) in hypertensive patients and patients with left ventricular dysfunction. However, there is limited data on the effect of ACE-inhibitors and ARBs in patients undergoing electrical cardioversion for persistent AF. We hypothesized that treatment with the ARB candesartan, without adjunct antiarrhythmic therapy, would reduce the recurrence rate of AF after successful cardioversion. Methods: In a double blind, placebo-controlled study, 171 patients with persistent AF were randomized to receive candesartan 8 mg once daily (n = 86) or placebo (n = 85) for 3–6 weeks before and candesartan 16 mg once daily or placebo for 6 months after electrical cardioversion. Primary endpoint was recurrence of AF. Results: A total of 68 patients in the candesartan group and 69 patients in the placebo group were successfully cardioverted. Forty-eight patients (71%) in the candesartan group and 45 (65%) in the placebo group had a recurrence of AF during 6 months follow-up. Median time to recurrence was 8 and 9 days in the candesartan and placebo groups, respectively. The differences between the groups were not statistically significant. Conclusion: Treatment with the ARB candesartan for 3–6 weeks before and 6 months after electrical cardioversion had no effect on the recurrence rate of AF. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Atrial fibrillation; Electrical cardioversion; Angiotensin II type 1 receptor blocker

1. Introduction With a prevalence of about 1% in the general population, atrial fibrillation (AF) is the most frequent arrhythmia encountered in clinical practice [1]. Recent studies have ☆ Grant support: This study was sponsored by the Regional Health Corporation of Eastern Norway, and the Medical Research Foundation, Asker and Baerum Hospital, Norway. AstraZeneca, Molndal, Sweden provided the study medication, and AstraZeneca, Oslo, Norway, supported the study with a grant to cover for laboratory analyses. ⁎ Corresponding author. Department of Internal Medicine, Asker and Baerum Hospital, P.O.Box 83, N-1309 Rud, Norway. Tel.: +47 971 71 773; fax: +47 67 55 09 93. E-mail address: [email protected] (A. Tveit).

0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.08.086

indicated that ventricular rate control and antithrombotic therapy may be the preferred strategy for most patients [2,3]. However, a “rhythm control” strategy with restoration and maintenance of sinus rhythm is still widely used in symptomatic AF patients. Invasive treatment strategies involving radiofrequency ablation are improving, but have so far been more successful in patients with paroxysmal AF [4]. In patients with persistent AF, electrical cardioversion is the preferred treatment to restore sinus rhythm. It is safe and highly effective, but AF recurrence rates are high, especially during the first weeks [5]. Several studies have indicated that treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs) may reduce the

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incidence of AF in hypertensive patients [6,7], patients with heart failure [8–10] and after myocardial infarction [11]. Three randomized, open-label studies have shown that treatment with ACE-inhibitors or ARBs in addition to amiodarone may reduce the recurrence rate of AF after electrical cardioversion as compared to amiodarone alone [12–14]. Moreover, animal studies have suggested that the ARB candesartan may prevent both electrical and structural remodelling induced by AF. Thus, candesartan prevented shortening of the atrial effective refractory period during rapid atrial pacing in dogs [15]. Furthermore, when treated with candesartan, dogs with sustained AF developed significantly less interstitial atrial fibrosis than controls [16]. In the present study we hypothesized that treatment with candesartan, without adjunct antiarrhythmic therapy, would reduce the recurrence rate of AF after successful electrical cardioversion. 2. Materials and methods 2.1. Patient population Patients of either gender aged 18 years or above were eligible if they had electrocardiographically documented AF of more than 48 hours duration and were scheduled for electrical cardioversion. Any of the following conditions would exclude a patient from the study: Hypersensitivity or contraindication to any ARB or any ACE inhibitor; current treatment with an ACE inhibitor or ARB; antiarrhythmic medication including sotalol (other beta-blockers were not regarded as antiarrhythmic agents); significant renal artery stenosis and any medical condition in which administration of a vasodilator is contraindicated; serum creatinine N 225 μmol/L or serum potassium N 5.5 mmol/L or serum sodium b 128 mmol/L; severe hepatic dysfunction; lifelimiting disease or substance abuse which may affect participation; previous cardioversion for atrial fibrillation within the last month; thyrotoxicosis; systolic blood pressure b 100 mmHg; hypertension requiring intensified treatment prior to cardioversion; pregnancy or lactation. All patients provided written, informed consent in accordance with the revised Declaration of Helsinki before enrolment. 2.2. Study protocol and follow-up The study was designed as a randomized, double blind and placebo-controlled study, conducted at 2 study centers (Asker and Baerum Hospital and Ulleval University Hospital). At baseline, full clinical status, electrocardiogram (ECG), echocardiography and blood sampling were performed. Blood pressure was measured both in the sitting and in the supine position after 10 min rest. By the use of consecutively numbered sealed envelopes, eligible patients were randomized to receive tablets of candesartan 8 mg or matching placebo once daily. The placebo tablets had exactly the same

ingredients as active tablets except for the candesartan component. Both active and placebo tablets were manufactured by AstraZeneca, Molndal, Sweden, and were identical in appearance, taste and smell. Treatment was given for 3– 6 weeks before cardioversion, depending on the time needed on warfarin treatment to maintain an international normalized ratio (INR) N 2.0 for a minimum of 3 weeks. After 1 week on study medication, patients were seen for ECG, and measurement of blood pressure, serum-creatinine and serum-potassium. Electrical cardioversion was performed under propofol anesthesia. A maximum of 4 direct current R-wave synchronized monophasic discharges were given in the following sequence: 200 J, 360 J and 360 J with anterolateral electrode position, then 360 J with anteroposterior electrode position until sinus rhythm was restored. Patients who failed to convert to sinus rhythm, or relapsed to AF prior to hospital discharge, discontinued study medication. Electrocardiographic and echocardiographic examinations were performed before discharge, 4 hours after cardioversion. Successfully cardioverted patients received candesartan 16 mg o.d. or matching placebo from the day after cardioversion for the rest of the follow-up period of 6 months, or until relapse of AF was documented. Patients were seen for ECG, measurement of blood pressure and blood sampling at 1 and 6 weeks, 3 and 6 months after cardioversion, or at any time if they had symptoms indicating a recurrence of AF. Echocardiography was performed at 6 weeks and 6 months after cardioversion. All patients were asked to return the study medication not used to the hospital pharmacies when their participation in the study was ended. Patient compliance was evaluated by tablet counting, dividing the number of used tablets on the expected number of used tablets calculated from time on study medication. Adverse events were recorded as spontaneously reported by the patient and/or reported in response to an open question from the study personnel: ‘Have you had any health problems since your previous visit?’. The following protocol amendments were made during the course of the study: 1) Patients on ACE-inhibitors or ARBs were allowed to participate provided they had no heart failure or other strong indication for this medication. In these patients the ACE-inhibitor or ARB was discontinued, and a wash-out period of 2 weeks was necessary before randomisation. An alternative antihypertensive medication was given in these patients, preferably a calcium channel antagonist or a betablocker, whichever most suitable for each patient. 2) Biphasic discharges were allowed for electrical cardioversion because of a higher success rate. A maximum of 4 biphasic shocks were given in the following sequence: 150 J, 270 J and 270 J with anterolateral electrode position, then 270 J with anteroposterior electrode position until sinus rhythm was restored. The study was approved by the Regional Ethics Committee and the Norwegian Medicines Agency, and registered at the website ClinicalTrials.gov.

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Fig. 1. Flow chart. n = number of patients.

2.3. Study endpoints and definition of terms The primary endpoint of the study was recurrence of AF during 6 months follow-up after successful electrical cardioversion. Secondary endpoint was time to recurrence of AF. Cardioversion was deemed successful if sinus rhythm was established and maintained for at least 2 hours. Complete shock failure was defined as no sinus beats recorded throughout the course of electrical cardioversion. Relapse of AF was defined as first ECG-recorded episode of AF. 2.4. Statistics The sample size was calculated in advance on the basis of an assumed 40% reduction in AF recurrences, from 60% in the placebo group to 36% in the candesartan group. Given a two-sided probability of 0.05 and a power of 80%, the number of patients needed in each treatment group was calculated to be 68. The observation time was 6 months per patient, or until AF recurred. Data are expressed as median or mean ± standard deviation (SD) for continuous variables, and frequencies were measured for categorical variables. Continuous variables were examined for statistical significance by a Students t test or the Mann– Whitney U-test. Categorical data were compared by the chi-

square test or Fisher's exact test. Time to relapse of AF was compared using the log rank test. A 2-sided p-value of b 0.05 was considered significant. 3. Results 3.1. Patient characteristics Recruitment was initiated May 2001 and stopped December 2004. A total of 262 patients were screened, and 171 were subsequently randomized to receive candesartan (n = 86) or placebo (n = 85) (Fig. 1). There were no significant differences between the groups regarding baseline characteristics (Table 1). The duration of AF before randomisation was unknown in 95 patients (56%), and known in 76 patients (40 in the candesartan group and 36 in the placebo group; median 11 weeks and 10 weeks, respectively). Seventy-one percent of the patients had AFrelated symptoms (exercise intolerance 52%, palpitations 39%, dyspnoea 37%, fatigue 37% and dizziness 18%), with no significant differences between the groups. Six patients were currently on an ACE-inhibitor or ARB, 3 in each group. Twelve patients were withdrawn from the study before cardioversion (6 in the candesartan group and 3 in the placebo group because of spontaneous conversion to sinus rhythm, 2 in

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Table 1 Baseline characteristics of the study population

Table 2 Results of electrical cardioversion

Candesartan Placebo

Medical history Age (years) Sex (women/men) Body weight (kg) Body mass index (kg/m2) Hypertension (%) Coronary heart disease (%) Diabetes (%) Chronic obstructive pulmonary disease (%) Lone atrial fibrillation (%) Current cigarette smoking (%) Medication Digitoxin (%) Beta-blockers (%) Calcium channel blockers Verapamil (%) Other (%) Diuretics (%) Statins (%) Blood pressure and heart rate Systolic (mmHg) Diastolic (mmHg) Ventricular rate (beats per minute) Echocardiogram Left atrial diameter (long axis view, mm) Left atrial area (apical four-chamber view, cm2) Right atrial area (apical four-chamber view, cm2) Interventricular septum thickness (diastole, mm) Left posterior wall thickness (diastole, mm) End-diastolic left ventricular dimension (mm) End-systolic left ventricular dimension (mm) Fraction of shortening (%)

p

n = 86

n = 85

64 ± 10 23/63 84 ± 14 26 ± 3 24.4 9.3 8.1 5.8

63 ± 11 16/69 86 ± 15 27 ± 4 35.3 9.4 5.9 8.3

0.223 0.217 0.398 0.373 0.120 0.980 0.563 0.535

51.1 10.5

44.7 18.8

0.398 0.114

12.8 36.0

12.9 36.5

0.977 0.954

32.6 12.8 9.3 14.0

36.5 8.2 10.6 12.9

0.591 0.332 0.779 0.846

134 ± 17 83 ± 9 85 ± 18

135 ± 18 83 ± 9 85 ± 15

0.641 0.799 0.968

46.7 ± 5.4 27.1 ± 5.3

45.8 ± 5.7 0.312 26.9 ± 5.2 0.735

23.7 ± 5.3

22.8 ± 4.6 0.251

11.0 ± 1.6

11.2 ± 2.2 0.447

10.8 ± 1.9

11.0 ± 2.1 0.495

50.2 ± 5.4

50.2 ± 5.8 0.989

34.8 ± 6.5

35.5 ± 6.4 0.552

30.5 ± 7.3

29.3 ± 7.3 0.338

Candesartan Placebo Electrical cardioversion Cardioversion waveform, mono-/biphasic Number of shocks Total energy (Joules) Failed electrical cardioversion Complete shock failure AV nodal escape rhythm Immediate relapsing atrial fibrillation Successful cardioversion Number of shocks, successfully cardioverted Total energy (Joules), successfully cardioverted SR at 1 week SR at 6 weeks SR at 3 months SR at 6 months

p

77 54/23 1.9 ± 1.0 452 ± 334

82 61/21 0.548 2.1 ± 1.2 0.340 517 ± 396 0.265

6 1 2 68 1.7 ± 0.9

12 0 1 69 1.8 ± 1.0

388 ± 277

411 ± 311 0.649

34 25 23 18

38 27 24 23

0.174

0.447 0.620

0.552 0.724 0.857 0.411

Data are expressed as mean values ± standard deviation (SD) or number of patients. AV = atrio-ventricular; SR = sinus rhythm.

shocks with a success rate of 83%, in contrast to a 100% success rate in 44 patients receiving biphasic shocks. There was a tendency towards fewer complete shock failures in the candesartan group (6 vs. 12), but the difference did not reach statistical significance. Ninety-three successfully cardioverted patients (68%) had a relapse of AF during the six-month follow-up after electrical cardioversion, 48 in the candesartan group and 45 in the placebo group. Three patients were withdrawn from the study during follow-up while still in sinus rhythm; 2 in the candesartan group because of adverse events and 1 patient in the placebo group who died. Thus, 41 successfully

Data are expressed as mean values ± standard deviation (SD) or number (%) of patients.

the candesartan group because of adverse events, and 1 in the candesartan group withdrew her consent). Median time from randomisation to cardioversion was 29 days in both groups. 3.2. Results of electrical cardioversion and follow-up Electrical cardioversion was successful in 137 of 159 patients (86.2%). Table 2 summarizes the results of electrical cardioversion in the two groups. The mean energy and number of shocks given were similar in the two groups, as were the proportions of patients receiving biphasic shocks. One hundred and fifteen patients received monophasic

Fig. 2. Survival free of AF. Kaplan–Meier curves for the probability of survival free of atrial fibrillation (AF). Time (days) from electrical cardioversion (EC) to first ECG-documented recurrence of AF.

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4. Discussion

Fig. 3. Blood pressure. Mean blood pressures at each study visit. EC = Electrical cardioversion; ⁎ p b 0.05 for differences between groups.

cardioverted patients completed 6 months follow-up in sinus rhythm (30%). The proportion of patients in sinus rhythm at each study visit is given in Table 2. Median time to relapse of AF was 8 days in the candesartan group and 9 days in the placebo group. Kaplan–Meier analysis showed no difference in the survival free of AF (log rank test had a Chi square of 0.648; p = 0.421)(Fig. 2). The mean arterial blood pressures did not differ significantly between the groups until 6 weeks after electrical cardioversion. However, at 6 weeks, 3 months and 6 months after electrical cardioversion the mean arterial blood pressures were lower in the candesartan group, with the greatest difference at 3 months (127 ± 18 mmHg vs. 141 ± 19 systolic and 73± 11 vs. 78± 7 diastolic; p = 0.01 and 0.04, respectively)(Fig. 3). Eight patients did not return their study medication. Based on tablet count the rest of the study population had a mean compliance of 98%. 3.3. Adverse events Forty-five randomized patients reported a total of 74 adverse events during the course of the study. Abdominal discomfort/nausea, dizziness, headache and presyncope/syncope were the most commonly reported adverse events, with no significant differences between the groups. Serious adverse events were reported in 8 patients, 3 in the candesartan group and 5 in the placebo group. In the candesartan group, 1 patient was hospitalized with abdominal pain and 1 because of symptomatic hypotension. One patient, allocated to candesartan, needed implantation of a permanent pacemaker because of persistent AV-nodal escape-rhythm and bradycardia after cardioversion. In the placebo group, 4 patients were hospitalized because of syncope, abdominal pain, quadriceps ligament rupture and gastrointestinal bleeding, respectively. One patient in the placebo group died suddenly, and autopsy revealed a ruptured thoracic aortic aneurysm.

To the best of our knowledge this is the first randomized, double blind, placebo-controlled study on the efficacy of an ARB to prevent recurrences of AF after electrical cardioversion. The recurrence rate of AF during 6 months follow-up was high (68%), and treatment with candesartan did not reduce the recurrence rate as compared to placebo. Several studies have indicated that ACE-inhibitors and ARBs may prevent development of new-onset AF in patients with hypertensive heart disease, heart failure and left ventricular dysfunction following myocardial infarction [6–9,11]. The patients in our study were relatively young, and about half the patients had “lone” fibrillation. Thus, one may speculate if an effect might have been found in patients with left ventricular disease. A small randomized, open label study showed that treatment with the ARB irbesartan plus amiodarone was associated with a reduction in AF recurrences after electrical cardioversion as compared to amiodarone alone also in patients with lone fibrillation [14]. Thus, there may be an anti-fibrillatory effect of ARBs in conjunction with amiodarone in patients without evidence of left ventricular disease. The lack of effect of candesartan in our study as compared to apparent effect of irbesartan in similar studies [13,14] could be explained by pharmacodynamic differences between the two substances. However, two studies have found an effect of candesartan both on electrical and structural remodelling [15,16]. In the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program, treatment with candesartan reduced the incidence of AF in a large, broadly-based, population of patients with symptomatic heart failure [10]. Hence, this suggests that candesartan possess anti-fibrillatory effects. In one small study, a dose-dependent effect of irbesartan was demonstrated, with a lower recurrence rate of AF after electrical cardioversion in patients treated with higher dosages as compared to lower dosages of irbesartan [14]. The dosages used in our study reflect the normally used dosages of candesartan in hypertension in Norway at the time this study was planned. Higher dosages of candesartan have been used in recent studies on heart failure and hypertension with good tolerability [17,18], and an effect by higher dosages of candesartan in preventing AF recurrences cannot be excluded. On the other hand, two patients were withdrawn from our study because of symptomatic hypotension, one receiving 8 mg of candesartan daily before cardioversion and one receiving 16 mg daily after successful cardioversion. Higher dosages may therefore induce tolerability issues. The significant reduction in blood pressure in the candesartan group as compared to the placebo group also supports the notion that the dosages used are ‘biologically active’. Reduction in blood pressure, as seen in the present study, has not been reported in other studies with ACE inhibitors or ARBs after electrical cardioversion [12,13], except for a reduction in diastolic blood pressure in one small study [14].

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While electrical remodelling is a relatively fast process, structural remodelling evolves more slowly over a few weeks or months, and a minimum of exposure time is probably needed for effective medication to reverse this process. In our study, median time on treatment before electrical cardioversion was 29 days in each group. At the time of electrical cardioversion there were no significant differences in blood pressures between the treatment and placebo groups. The differences became significant at 6 weeks after electrical cardioversion and doubling of the candesartan dose. This may indicate a slowonset of action from the study medication in these patients, in addition to the possible need for a higher dosage. Most recurrences were seen during the first 6 weeks after electrical cardioversion, and this may have preceded the potential effects on remodelling by candesartan in the present study. To our knowledge, no other study has analysed the effect of ARBs on the relapse rate of AF after electrical cardioversion without adjunct therapy with amiodarone. In other studies, both the treatment groups and control groups received amiodarone for several weeks before electrical cardioversion and during follow-up [12–14]. This treatment regimen might be responsible for the significantly higher proportion of patients remaining in sinus rhythm as compared to the results of our study. The fact that candesartan had no impact on relapse rate in our study raises the question whether there is a synergistic effect of ARBs and amiodarone. If so, the effect may be related to electrical remodelling. Another possible explanation of the combined effect of ACE-inhibitors/ARBs and amiodarone could be a ‘bridging’ effect of amiodarone, preventing early recurrences of AF after electrical cardioversion and providing time for the ACE-inhibitors/ARBs to reverse atrial remodelling. 4.1. Limitations of the study The number of patients in this study is relatively small, but the recurrence rates and time to recurrence are almost identical in the candesartan and placebo groups. We therefore doubt that a larger study would reveal a clinically relevant effect in this setting. The patients included are relatively young and healthy, and a clinically relevant effect in other patient groups cannot be excluded. Moreover, patients with symptomatic heart failure were not included in this study. However, based on the results of recent studies [2,3], rate control and not rhythm control is recommended in most patients with AF. Cardioversion strategies are used in selected patients, including young, healthy patients and highly symptomatic patients. Except for patients with heart failure, the patients in this study may therefore be representative for those patients selected for rhythm control and electrical cardioversion in the future. 5. Conclusion Treatment with the ARB candesartan for 3–6 weeks before and 6 months after electrical cardioversion for

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