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provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 45, No. 4, 2005 © 2005 by the American College of Cardiology Foundation ISSN 0735-1097/05/$30.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2004.09.076 Acute Myocardial Infarction Antiarrhythmic Effect of After Acute Myocardial Infarction Results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) Trial John McMurray, MD,* Lars Køber, MD,† Michele Robertson, BSC,‡ Henry Dargie, MB, CHB,* Wilson Colucci, MD,§ Jose Lopez-Sendon, MD,ʈ Willem Remme, MD,¶ D. Norman Sharpe, MD,# Ian Ford, PHD‡ Glasgow, United Kingdom; Copenhagen, Denmark; Boston, Massachusetts; Madrid, Spain; Rhoon, the Netherlands; and Auckland, New Zealand

OBJECTIVES Whether beta-blockers reduce atrial arrhythmias and, when added to an angiotensin- converting enzyme (ACE) inhibitor, ventricular arrhythmia is unknown. BACKGROUND Ventricular and atrial arrhythmias are common after acute myocardial infarction (AMI) and are associated with a poor prognosis. Angiotensin-converting enzyme inhibitors reduce the incidence of both types of arrhythmia. METHODS The antiarrhythmic effect of carvedilol was examined in a placebo-controlled multicenter trial, the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRI- CORN) study, which enrolled 1,959 patients with reduced left ventricular systolic function after AMI, 98% of whom were treated with an ACE inhibitor. RESULTS The incidence of atrial fibrillation/flutter was 53 to 984 (5.4%) in the placebo group and 22 to 975 (2.3%) in the carvedilol group, giving a carvedilol/placebo hazard ratio (HR) of 0.41 (95% confidence interval [CI] 0.25 to 0.68; p ϭ 0.0003). The corresponding rates of ventricular tachycardia/flutter/fibrillation were 38 to 984 (3.9%) and 9 to 975 (0.9%) (HR 0.24, 95% CI 0.11 to 0.49; p Ͻ 0.0001). CONCLUSIONS Carvedilol has a powerful antiarrhythmic effect after AMI, even in patients already treated with an ACE inhibitor. Carvedilol suppresses atrial as well as ventricular arrhythmias in these patients. (J Am Coll Cardiol 2005;45:525–30) © 2005 by the American College of Cardiology Foundation Cardiac arrhythmias are common early after myocardial infarc- atrial arrhythmias in higher risk post-MI patients (18–21). tion (MI) and portend a poor prognosis (1–4). Elevated It is not known whether beta-blockers, added to ACE sympathetic nervous system activity is one contributory mech- inhibitor treatment, will further reduce arrhythmias in these anism and, by counteracting this, beta-adrenoceptor antago- patients. nists may reduce cardiac electrical instability (5–8). Most The Carvedilol Post-Infarct Survival Control in Left Ven- tricular Dysfunction (CAPRICORN) study was a multina- See page 531 tional prospective, randomized, event-driven, mortality/ attention has been paid to ventricular arrhythmias, and these morbidity trial carried out in patients with recent acute MI and were the focus of previous studies of the antiarrhythmic action left ventricular systolic dysfunction (22,23). All patients were of beta-blockers after MI (9–13). It is also recognized, how- expected to be treated with an ACE inhibitor (and 98% were). ever, that atrial fibrillation (AF) results in a worse outcome Patients were blindly allocated to placebo or carvedilol. This after MI, although no placebo-controlled trial has examined analysis describes the effect of carvedilol on the risk of atrial and whether beta-blockers reduce the risk of atrial arrhythmias in ventricular arrhythmias. this setting (2,4,14–17). METHODS More recently, angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce both ventricular and The CAPRICORN trial. The design and primary results of the CAPRICORN trial have been described in detail

From the *Department of Cardiology, Western Infirmary, Glasgow, United elsewhere (22,23). Briefly, 984 patients were allocated to Kingdom; †Department of Cardiology, Gentoffe University Hospital, Copenhagen, placebo and 975 were allocated to carvedilol between 3 to 21 Denmark; ‡Robertson Centre for Biostatistics, University of Glasgow; Glasgow, days post-MI (mean 10 days) and followed for an average of United Kingdom; §Boston University Medical Center, Boston, Massachusetts; ʈDepartment of Cardiology, Hospital University, Madrid, Spain; ¶Sticares Founda- 1.3 years. All prespecified end points (death and certain tion, Rhoon, the Netherlands; #Department of Medicine, University of Auckland, types of cardiovascular hospitalization) were adjudicated by Auckland, New Zealand. The CAPRICORN study was funded by GlaxoSmithKline a blinded end point committee. and Roche Pharmaceuticals. Manuscript received June 2, 2003; revised manuscript received August 26, 2004, Arrhythmia analysis. Cardiac arrhythmias were not a pre- accepted September 2, 2004. specified end point in the CAPRICORN trial. This analysis 526 McMurray et al. JACC Vol. 45, No. 4, 2005 Antiarrhythmic Effect of Carvedilol February 15, 2005:525–30

number of combined outcomes, taking account of death or Abbreviations and Acronyms an arrhythmia. ACE ϭ angiotensin-converting enzyme Statistical analysis. All analyses were carried out on an AE ϭ adverse event intention-to-treat basis. All outcomes were analyzed using a ϭ AF atrial fibrillation time-to-first-event approach. The statistical significance of CAPRICORN ϭ Carvedilol Post-Infarct Survival Control in Left Ventricular treatment comparisons was based on the log-rank test. Hazard Dysfunction trial ratios (HR) and 95% confidence intervals (CIs) were derived CI ϭ confidence interval from the fitting of Cox proportional hazards regression models DIAMOND-MI ϭ Danish Investigations of Arrhythmia with treatment assignment as the only factor. Cumulative and Mortality on Dofetilide- incidence curves, which adjust for competing risks for censor- Myocardial Infarction study HR ϭ hazard ratio ing due to all-cause mortality, were used to show the accrual of MI ϭ myocardial infarction events with time in the two treatment groups (24). SAE ϭ serious adverse event The distribution of age at baseline is presented as mean TRACE ϭ Trandolapril Cardiac Evaluation and the range and categorical baseline characteristics are study shown as percentages. was, therefore, a post-hoc, though blinded, one. One end RESULTS point committee member (J.M.) reviewed all adverse and serious adverse event reports (AEs and SAEs) without The baseline characteristics of the patients randomized in knowing treatment allocation. All events thought to be CAPRICORN are shown in Table 1. A total of 9% of related to an arrhythmia were assigned to one of the patients (89 placebo group, 81 carvedilol group) were following categories, which were decided upon before the recorded as having a prior or ongoing history of AF/atrial analysis was undertaken: flutter, and 1.1% were identified as having had ventricular tachycardia (2 placebo group, 0 carvedilol group) or fibril- Atrial arrhythmias: 1) any report of supraventricular ectopic lation (14 placebo group, 6 carvedilol group). beats, atrial tachycardia, atrial flutter, AF, or any other A total of 96 patients (5%) were treated with an antiar- “supraventricular tachycardia,” excluding sinus tachycar- rhythmic drug at the time of randomization, and, in 95 of dia; 2) AF/atrial flutter only. these 96, the treatment used was amiodarone (59 placebo Ventricular arrhythmias: 1) any report of ventricular ectopic group, 36 carvedilol group). beats, ventricular tachycardia, ventricular fibrillation, or ventricular flutter; 2) “malignant” ventricular arrhyth- Table 1. Baseline Characteristics of Patients mias only (i.e., ventricular tachycardia, ventricular fibril- Placebo Carvedilol (975 ؍ n) (984 ؍ lation, and ventricular flutter). (n Arrhythmias were identified and characterized according to Mean (range) age (yrs) 63 (25–90) 63 (29–88) the AE narrative, and electrocardiogram confirmation was Males (%) 74 73 not available. Past medical history (%)* Prior arrhythmias. Information on prior arrhythmias was MI 29 31 Angina 54 57 collected in two ways. Investigators were asked to complete a Hypertension 52 55 “medical history” form at the screening visit. This form sought Diabetes mellitus 23 21 information on prior or ongoing problems. Investigators were Coronary revascularization 11 12 also asked to complete a “signs and symptoms” baseline visit Atrial fibrillation/flutter 9 8 form at the time of randomization, designed to identify any Ventricular fibrillation 1.4 0.6 Site of AMI (%) changes in the patients’ clinical condition from screening. The Anterior 54 59 baseline visit usually occurred on the same date as screening, Inferior 21 21 but could take place later. Because Ͼ5% of patients have a Other 25 20 previous or ongoing atrial arrhythmia recorded at their screen- Treatment for index AMI (%) ing visit, two sets of analyses were performed. The main Thrombolysis/primary PCI 47 45 Intravenous diuretic 33 35 analysis used all randomized patients. A separate analysis was Medication at randomization (%) carried out in the subset of patients without a history of atrial Amiodarone 6 4 arrhythmias. A similar secondary analysis was performed for Other antiarrhythmic drug Ͻ10 patients with prior or recent ventricular arrhythmias. ACE inhibitor 97 98 Combined outcomes. To take account of the issue of Aspirin 86 86 Warfarin 5 5 “competing risks,” in relation to the different survival rates *Past or ongoing. in the two treatment groups (whereby deceased patients ACE ϭ angiotensin-converting enzyme; AMI ϭ acute myocardial infarction; cannot be at risk of an arrhythmia), we also examined a MI ϭ myocardial infarction; PCI ϭ percutaneous coronary intervention. JACC Vol. 45, No. 4, 2005 McMurray et al. 527 February 15, 2005:525–30 Antiarrhythmic Effect of Carvedilol

Supraventricular arrhythmias. ANY SUPRAVENTRICULAR ARRHYTHMIA. Among carvedilol-treated patients, 26 of 975 (2.7%) had a report of a supraventricular arrhythmia compared with 54 of 984 (5.5%) of placebo-treated patients, representing a carvedilol/placebo HR of 0.48 (95% CI 0.30 to 0.76; log-rank p ϭ 0.0015). After excluding patients with a history of AF/atrial flutter, 19 of 894 (2.1%) of carvedilol- treated patients and 32 of 895 (3.6%) of placebo-treated patients had a report of a supraventricular arrhythmia after randomization: HR 0.59 (95% CI 0.33 to 1.03; p ϭ 0.062).

AF/ATRIAL FLUTTER. The comparable rates of AF/atrial flutter in the carvedilol and placebo groups were 22 of 975 Figure 2. Survival free of any ventricular arrhythmia. Dotted line ϭ (2.3%) and 53 of 984 (5.4%), respectively, representing an placebo; solid line ϭ carvedilol. HR of 0.41 (95% CI 0.25 to 0.68; p ϭ 0.0003) (Fig. 1). After excluding patients with a history of AF/atrial flutter, Arrhythmias and sudden death. Table 3 shows the rela- 16 of 894 (1.8%) carvedilol-treated patients and 31 of 895 tionship between arrhythmias and death from any cause and (3.5%) placebo patients had a report of AF/atrial flutter after those adjudicated as sudden. Patients who experienced an ϭ randomization: HR 0.51 (95% CI 0.28 to 0.93; p 0.025). arrhythmia were more likely to die and to have their mode Ventricular arrhythmias. ANY VENTRICULAR ARRHYTHMIA. of death classified as “sudden.” There was a nonsignificant Among carvedilol-treated patients, 26 of 975 (2.7%) had a trend for fewer sudden deaths in the carvedilol group, report of a ventricular arrhythmia compared with 69 of 984 especially in patients with an arrhythmia. (7.0%) placebo-treated patients, representing an HR of 0.37 (95% CI 0.24 to 0.58; p Ͻ 0.0001) (Fig. 2). Among carvedilol- treated patients, there were 4 episodes of ventricular fibrilla- DISCUSSION tion/flutter, 6 of ventricular tachycardia, and 19 of other In this retrospective, but blinded, analysis of the CAPRI- ventricular arrhythmias (premature beats, couplets, and so on). CORN trial, carvedilol was shown to have a striking effect, In the placebo group, these numbers were 17, 27, and 38, not only on the incidence of ventricular arrhythmias but also respectively. on the risk of atrial arrhythmias. After excluding patients with a history of ventricular The occurrence of AF after MI is associated with a worse fibrillation/tachycardia, 25 of 969 (2.6%) carvedilol-treated clinical outcome, including a higher mortality (2–4,14–17). patients and 66 of 968 (6.8%) placebo-treated patients had This is the case generally and also in patients with significant a report of a ventricular arrhythmia after randomization: left ventricular systolic dysfunction after infarction. For exam- Ͻ HR 0.37 (95% CI 0.23 to 0.59; p 0.0001). ple, the Trandolapril Cardiac Evaluation (TRACE) investiga- “MALIGNANT” VENTRICULAR ARRHYTHMIAS. The compa- tors found that AF was an independent predictor of both a rable rates of ventricular tachycardia, ventricular fibrillation, higher in-hospital and long-term mortality (4). In the or ventricular flutter were 9 of 975 (0.9%) in the carvedilol TRACE study, the risk of developing AF, over a mean group and 38 of 984 (3.9%) in the placebo group, repre- follow-up of 2.2 years, was reduced in the ACE inhibitor ϭ ϭ senting an HR of 0.24 (95% CI 0.11 to 0.49; p Ͻ 0.0001). group (n 22, 2.8%) compared with the placebo group (n Combined outcomes. Table 2 shows the combined out- 42, 5.3%) (21). comes of death or an arrhythmia. Carvedilol reduced the Whether beta-blockers reduce the risk of atrial arrhythmias risk of all combined outcomes analyzed, including the after MI has not been tested in a double-blind prospective, outcome of death or any reported arrhythmia. randomized, placebo-controlled trial, particularly in patients already treated with an ACE inhibitor. This analysis of the CAPRICORN trial suggests that carvedilol markedly sup- presses atrial arrhythmias in these patients. It is of interest to compare these findings with the recent Danish Investigations of Arrhythmia and Mortality on Dofetilide-Myocardial Infarc- tion (DIAMOND-MI) study, which examined the effect of a new class III antiarrhythmic agent in similar patients with those enrolled in the TRACE and CAPRICORN trials (25). In the DIAMOND-MI study 58% of patients were treated with an ACE inhibitor and 36% with a beta-blocker at the time of randomization (25). The risk of developing AF or atrial Figure 1. Survival free of atrial fibrillation or atrial flutter. Dotted line ϭ flutter, over a mean follow-up of 1.25 years, in patients in sinus placebo; solid line ϭ carvedilol. rhythm at baseline was 14 of 705 (2.0%) in the placebo group 528 McMurray et al. JACC Vol. 45, No. 4, 2005 Antiarrhythmic Effect of Carvedilol February 15, 2005:525–30

Table 2. Combined Outcomes of Death or Arrhythmia Subjects With Event Carvedilol/Placebo Hazard Ratio Log-Rank /(975 ؍ Carvedilol (n CI) p Value %95) (984 ؍ Outcome Placebo (n Death or SV arrhythmia 133/187 0.70 (0.56, 0.88) 0.0016 Death or SV arrhythmia (excluding patients with a history of AF/AFL) 112/152 0.72 (0.57, 0.92) 0.0090 Death or AF/AFL 129/186 0.68 (0.55, 0.85) 0.0008 Death or AF/AFL (excluding patients with a history of AF/AFL) 109/151 0.71 (0.55, 0.91) 0.0057 Death or any ventricular arrhythmia 138/201 0.67 (0.54, 0.84) 0.0003 Death or any ventricular arrhythmia (excluding patients with a history 137/197 0.68 (0.54, 0.84) 0.0004 of VT/VF) Death or a malignant ventricular arrhythmia 123/173 0.70 (0.56, 0.89) 0.0028 Death or any arrhythmia 154/233 0.64 (0.52, 0.79) Ͻ0.0001

AF/AFL ϭ atrial fibrillation/atrial flutter; CI ϭ confidence interval; SV ϭ supraventricular; VT/VF ϭ ventricular tachycardia/ventricular fibrillation.

and 5 of 690 (0.7%) in the dofetilide group (approximately 65% That the substantial reduction in “malignant” ventricular risk reduction, p ϭ 0.09) (25). arrhythmias did not translate into a clearly significant reduction The effect of beta-blockers on ventricular arrhythmias in the in sudden death (placebo 69 of 984 [7%], carvedilol 51 of 975 post-MI setting is more clearly established. Both substudies of [5%]; p ϭ 0.098), as reported in the main CAPRICORN trial the large beta-blocker secondary prevention trials and indepen- results paper (23), might, at first sight, seem surprising. dent studies showed significant reductions in all grades of However, with only 120 sudden deaths in total, we had low ventricular arrhythmias with , , and meto- statistical power to detect such a treatment effect. Furthermore, prolol (9–13,26–29). None of these studies, however, focused any such treatment effect might have been diluted by nonar- on patients with substantial left ventricular systolic dysfunction; rhythmic causes of sudden death such as bradycardia/asystole, indeed, it seems that high-risk patients were excluded from pulmonary embolism, reinfarction leading to catastrophic these studies (22,23). Furthermore, these studies were con- pump failure, stroke, and other noncoronary vascular events ducted before the benefits of ACE inhibitors, one of which is (e.g., aortic aneurysm rupture) the risk of which may not be to reduce ventricular arrhythmias, had been established reduced by beta-blockade (34). The use of amiodarone in a (19,30,31). We were able to confirm that carvedilol reduced small proportion of patients might have similarly reduced our ventricular arrhythmias, even in high-risk patients treated with ability to show a difference between carvedilol and placebo. an ACE inhibitor. Indeed, the magnitude of this effect, be it on Furthermore, further analysis of mode of death in those all ventricular arrhythmias or just “malignant” arrhythmias, was experiencing an arrhythmia showed a strong trend to fewer striking; the latter were reduced by 70%. Whether the size of sudden deaths in the carvedilol group. this effect reflects just the beta-blocking action of carvedilol or The present analysis has a number of limitations. First, it an additional antiarrhythmic action of the molecule (for exam- was not prespecified. Second, it is based on an examination of ple, carvedilol has been shown, in vitro, to block HERG AEs and SAEs without electrocardiographic validation of potassium channels) cannot be determined from the current arrhythmias. Spontaneous AE and SAE reporting might be study (32,33). expected to underestimate the true incidence of arrhythmias. Comparison with other recent studies (e.g., the TRACE and DIAMOND studies), however, suggests that this is not the Table 3. Arrhythmia and Mode of Death case for supraventricular arrhythmias (i.e., our rates of arrhyth- mias were similar to the rates reported in those other trials). Placebo Carvedilol (No Arrhythmia (No Arrhythmia, We also believe that under- or overreporting of clinically important ventricular arrhythmias is unlikely. The recent ,924 ؍ n ,867 ؍ n Arrhythmia, Arrhythmia, Eplerenone Post-Acute Myocardial Infarction Heart Failure .Efficacy Survival Study (EPHESUS) is useful for comparison (51 ؍ n (117 ؍ n Death from any cause* Over an average follow-up of 1.33 years, 54 of 3,313 (1.6%) of No arrhythmia 116 (13.4%) 103 (11.1%) placebo-treated patients (75% of whom were treated with a Arrhythmia 35 (29.9%) 13 (25.5%) beta-blocker) were hospitalized for a ventricular arrhythmia. In Sudden death† No arrhythmia (n ϭ 924) 53 (6.1%) 46 (5.0%) the carvedilol group in the CAPRICORN trial, 9 of 975 Arrhythmia (n ϭ 51) 16 (13.7%) 5 (9.8%) (0.9%) of patients experienced a “malignant” ventricular ar- *14 subjects in the placebo group died within 2 days of the arrhythmia report rhythmia over 1.3 years compared with 38 of 984 (3.9%) in the compared with 1 in the carvedilol group; †8 subjects in the placebo group experienced placebo group. sudden death within 2 days of the arrhythmia report compared with 0 in the carvedilol group. However, spontaneous reporting might exaggerate the JACC Vol. 45, No. 4, 2005 McMurray et al. 529 February 15, 2005:525–30 Antiarrhythmic Effect of Carvedilol apparent antiarrhythmic effect of carvedilol because this 13. Morganroth J, Lichstein E, Byington R. Beta-Blocker Heart Attack drug is likely to reduce awareness of an arrhythmia. trial: impact of propranolol therapy on ventricular arrhythmias. Prev Med 1985;14:346–57. 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