Author + information
- Received January 22, 2013
- Revision received March 6, 2013
- Accepted March 26, 2013
- Published online October 8, 2013.
- Martin H. Ruwald, MD, PhD∗,†∗ (, )
- Abeer Abu-Zeitone, BPharm, MS∗,
- Christian Jons, MD, PhD†,
- Anne-Christine Ruwald, MD∗,†,
- Scott McNitt, MS∗,
- Valentina Kutyifa, MD, PhD, MSc∗,
- Wojciech Zareba, MD, PhD∗ and
- Arthur J. Moss, MD∗
- ∗Heart Research Follow-up Program, Cardiology Division, University of Rochester Medical Center, Rochester, New York
- †Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark
- ↵∗Reprint requests and correspondence:
Dr. Martin H. Ruwald, Heart Research Follow-up Program, Cardiology Division, University of Rochester Medical Center, 265 Crittenden Boulevard, Box 653, Rochester, New York 14642.
Objectives The goal of this study was to evaluate the effects of carvedilol and metoprolol on the endpoint of inappropriate implantable cardioverter-defibrillator therapy in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy) study.
Background The impact of carvedilol and metoprolol on inappropriate therapy in heart failure patients with devices has not yet been investigated.
Methods All patients in the MADIT-CRT study who received a device (N = 1,790) were identified. Using time-dependent Cox regression analysis, we compared patients treated with different types of beta-blockers or no beta-blockers on the primary endpoint of inappropriate therapy, delivered as antitachycardia pacing (ATP) or shock therapy. Secondary endpoints were inappropriate therapy due to atrial fibrillation and atrial tachyarrhythmias, also evaluated as ATP or shock therapy.
Results Inappropriate therapy occurred in 253 (14%) of 1,790 patients during a follow-up period of 3.4 ± 1.1 years. Treatment with carvedilol was associated with a significantly decreased risk of inappropriate therapy compared with metoprolol (hazard ratio [HR]: 0.64 [95% confidence interval (CI): 0.48 to 0.85]; p = 0.002). The reduction in risk was consistent for inappropriate ATP (HR: 0.66 [95% CI: 0.48 to 0.90]; p = 0.009) and inappropriate shock therapy (HR: 0.54 [95% CI: 0.36 to 0.80]; p = 0.002). The risk of inappropriate therapy caused by atrial fibrillation was also reduced in patients receiving carvedilol compared with metoprolol (HR: 0.50 [95% CI: 0.32 to 0.81]; p = 0.004). General use of beta-blockers (93%) and adherence in this study was high.
Conclusions In heart failure patients undergoing either cardiac resynchronization therapy with a defibrillator or with an implantable cardioverter-defibrillator device, carvedilol was associated with a 36% lower rate of inappropriate ATP and shock therapy compared with metoprolol. Inappropriate therapy due to atrial fibrillation was associated with a 50% lower rate in patients receiving carvedilol compared with those receiving metoprolol. (MADIT-CRT: Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy; NCT00180271)
Inappropriate implantable cardioverter-defibrillator (ICD) therapy remains a devastating problem for patients treated with ICDs and cardiac resynchronization therapy with defibrillators (CRT-Ds), leading to pain and impaired quality of life (1–5). Multiple inappropriate shocks may lead to progression of heart failure (HF) (3,6). Strategies to prevent or reduce inappropriate therapy are warranted, and clinical trials have been undertaken in attempts to reduce this burden (7). Carvedilol and metoprolol are the beta-blockers most commonly used in patients with HF. Carvedilol improves cardiac performance to a greater extent than metoprolol, and the differences may be related to carvedilol's greater antiadrenergic activity (8). It has previously been shown that carvedilol, compared with metoprolol, led to an overall significant reduction in hospitalizations for HF, ventricular arrhythmias (9), and cardiovascular deaths (10,11). Current guidelines, however, do not specifically comment on issues related to inappropriate therapy. To our knowledge, the general and individual impact of beta-blockers on the risk of inappropriate ICD therapy has not yet been investigated.
The goal of the current study was to evaluate the effects of carvedilol and metoprolol on the endpoint of inappropriate ICD therapy in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy) study.
We hypothesized that carvedilol would be associated with a decreased risk of inappropriate therapy due to its greater antiadrenergic effect.
The protocol and primary report of the MADIT-CRT study have previously been published (12,13). The study included 1,820 patients with ischemic cardiomyopathy New York Heart Association class I or II, nonischemic cardiomyopathy New York Heart Association class II, a left ventricular ejection fraction ≤30%, and a QRS duration ≥130 ms. Patients were enrolled from 110 centers in the United States, Europe, and Canada and randomized (3:2) to receive CRT-D and ICD devices.
Patients were excluded if they had atrial fibrillation at enrollment; a history of atrial fibrillation was not an exclusion criterion. Of the 1,820 patients included in the MADIT-CRT study, 30 patients (2%) never received a device, leaving a study population of 1,790 patients.
Patients had to be on optimal pharmacotherapy in accordance with HF guidelines (14). However, the choice of beta-blockers and other HF therapy was left to the discretion of the physician performing the implantation. All medication, including type of beta-blocker, and the doses were recorded at baseline and during clinical follow-up at 1 month and then at 3-month intervals until termination of the trial.
Device Programming and Interrogation
All devices were programmed according to the prespecified protocol (13). The ventricular tachycardia zone was programmed from 180 beats/min up to 250 beats/min, and ventricular fibrillation was defined as a ventricular rate faster than 250 beats/min with disorganized ventricular electrograms.
All devices were interrogated 1 month after enrollment and thereafter every 3 months and adjudicated by an independent core laboratory for predefined categories of appropriate or inappropriate therapy.
The primary endpoint of the current study was defined as occurrence of inappropriate therapy, delivered as antitachycardia pacing (ATP) or shock therapy, without the presence of ventricular tachycardia or ventricular fibrillation. The secondary endpoints were inappropriate therapy for atrial tachyarrhythmia and inappropriate therapy for atrial fibrillation and/or atrial flutter. All endpoints of inappropriate therapy were secondarily subdivided into inappropriate ATP or shock therapy. Last, inappropriate therapy caused by nonarrhythmic events and other inappropriate arrhythmic events were investigated (the Online Appendix provides specific definitions).
Continuous variables are expressed as mean ± SD. Categorical data are summarized as frequencies and percentages. As shown in Table 1, patients were divided into 4 groups based on their beta-blocker use: metoprolol, carvedilol, other beta-blockers (bisoprolol, atenolol, and others), or no beta-blockers. Baseline characteristics were compared between patients by using the chi-square test for binary variables and the Kruskal-Wallis test for continuous variables.
Beta-blocker therapy was assessed in the multivariate model in a time-dependent manner (i.e., by incorporating into the Cox model, data for each patient that identifies the effect of each follow-up time “on” and “off” beta-blocker therapy during the trial). The effects of time-dependent beta-blocker therapy on the endpoints were assessed with interaction-term analysis.
Univariate and multivariate time-dependent Cox proportional hazards regression analysis were performed on the primary and secondary endpoints of inappropriate therapy and also divided into ATP or shock therapy. In the multivariate model, we adjusted for relevant variables for the outcome of inappropriate therapy found by stepwise selection, setting the limits for entry into the model at 0.05. Five variables were found to have a significant impact on the results (p < 0.05) in the main model on inappropriate therapy: previous ventricular arrhythmias, female sex, QRS duration, use of statins, and diastolic blood pressure. Results are reported as hazard ratios (HRs) with their 95% confidence intervals (CIs) and 2-sided p values. The cumulative probability of inappropriate therapy, ATP, and shocks were displayed by the Kaplan-Meier method using the log-rank test to compare cumulative events. A 2-tailed p value ≤0.05 was considered statistically significant.
Analyses were performed by using SAS version 9.3 (SAS Institute, Inc., Cary, North Carolina).
A total of 1,790 patients received either ICD or CRT-D; of these, 1,077 (61%), 438 (24%), 94 (5%), and 40 (2%) received carvedilol, metoprolol, bisoprolol, and atenolol, respectively. Only 12 patients received other beta-blockers, and a combination of beta-blockers was used in 9 patients. A total of 120 (7%) patients were not receiving beta-blockers due to intolerance, asthma, and other causes.
Compared with patients taking carvedilol, metoprolol was more frequently used in patients of older age, patients with ischemic cardiomyopathy and hypertension, and in those who had previously undergone revascularization (Table 1). Notably, the highest proportion of patients taking carvedilol were from U.S. centers; the highest users of bisoprolol (94%) were from non-U.S. centers (data not shown).
Inappropriate therapy occurred in 253 (14%) of 1,790 patients during the follow-up period of 3.4 ± 1.1 years. There was no difference between patients receiving an ICD and those who received a CRT-D (p = 0.944).
A univariate comparison of the 4 groups is presented in Figure 1 showing an overall significant difference. Carvedilol and “other beta-blockers” (composed of bisoprolol and atenolol) are markedly separated from patients taking metoprolol. Figures 2 and 3 present the head-to-head comparison of carvedilol and metoprolol on overall cumulative probability of inappropriate ATP and inappropriate shock therapy, with significant differences between them. The multivariate time-dependent Cox regression analysis in Table 2 displays a significant relative risk reduction in all inappropriate therapies associated with the use of carvedilol compared with metoprolol (HR: 0.64 [95% CI: 0.48 to 0.85]; p = 0.002). This finding was consistent and also evident for inappropriate ATP (HR: 0.66 [95% CI: 0.48 to 0.90]; p = 0.009) and for inappropriate shocks (HR: 0.54 [95% CI: 0.36 to 0.80]; p = 0.002).
Inappropriate therapy caused by atrial fibrillation occurred in 86 (5%) of 1,790 patients; 16 (19%) of these patients had a history of atrial arrhythmias requiring treatment.
Table 3 displays the multivariate analysis comparing beta-blockers. There was a reduction in risk of inappropriate therapy due to atrial fibrillation in patients treated with carvedilol compared with metoprolol (HR: 0.50 [95% CI: 0.32 to 0.81]; p = 0.004). This reduction in risk, however, was driven primarily by the use of ATP (HR: 0.44 [95% CI: 0.25 to 0.78]; p = 0.005), whereas there was no significant reduction in risk of inappropriate shock therapy for atrial fibrillation associated with the use of carvedilol. For inappropriate therapy for all atrial tachyarrhythmias, a significant risk reduction was associated with the use of carvedilol regarding both inappropriate ATP and inappropriate shock therapy compared with metoprolol (Table 4).
Finally, no differences were found in inappropriate therapy for nonatrial tachyarrhythmias in a comparison of the beta-blockers, and no differences were found for nonarrhythmic causes of inappropriate therapy (total of 29 and 22 events, respectively [data not shown]).
The mean doses of beta-blockers at baseline and after first change are shown in Table 5; only minor changes in dose occurred after the first change. Few patients switched from 1 type of beta-blocker to the other, and these changes were taken into account in the time-dependent analyses. The mean dose increase for carvedilol was higher than for metoprolol throughout the course of the study, but when exploring baseline dose-dependent relationships on the endpoints, we found no clear association. In addition, when adjusting for baseline and first change doses of carvedilol dose-equivalents in the Cox regression models, the results were not altered.
The major and novel finding of the current study was the significant difference in all measured outcomes between carvedilol and metoprolol. Carvedilol was associated with a significant reduction in risk of inappropriate therapy and remained independently significant throughout the study regarding inappropriate ATP and shock therapy, enforcing these results. The analysis also found that carvedilol was significantly associated with a reduced risk of inappropriate therapy for atrial tachyarrhythmias, which was also consistent when subdivided into ATP and shock therapy. The subdivision of inappropriate therapy is important to establish that the reduction in risk is not driven by ATP alone but rather by inappropriate shock therapy and thus is clinically very important. Furthermore, the subdivision into atrial tachyarrhythmias and atrial fibrillation is clinically important and implies that the reduction in risk associated with the use of carvedilol is not driven by other nonarrhythmic inappropriate causes.
Although there were significant differences at baseline between the allocated beta-blocker groups, factors clinically relevant for development of inappropriate therapy were taken into account when adjusting for factors in the multivariate analysis. This point is very important, and factors associated with increased risk of death or hospitalizations as a whole are not necessarily the same as the factors associated with inappropriate therapy. Previous studies have shown similar clinically relevant covariates as our model selected, in which primarily the nonuse of statins, previous ventricular or atrial arrhythmias, younger age, and male sex are considered risk factors for development of inappropriate therapy (3,6,15–17).
In the current study, carvedilol, in doses comparable to metoprolol as well as in real-life doses, was associated with a significant reduction in inappropriate therapy. One previous study was underpowered to show a significant effect of beta-blockers on inappropriate therapy (18), and other studies have generally only compared beta-blockers versus other antiarrhythmic agents. Thus, no previous comparison of different beta-blockers has been undertaken on this clinically important endpoint. Amiodarone and sotalol are drugs associated with wide adverse effects, and preferably any beta-blocker with an optimal impact on appropriate and inappropriate therapy should be the first choice for treatment, particularly because beta-blockers are standard therapy for HF. This, along with previous results (9), suggests that carvedilol may be the drug of choice in HF patients with implanted devices.
We found that the relative doses of beta-blockers used in the MADIT-CRT study were comparable to those used in real-life scenarios of HF patients, supported by numerous previous nonrandomized or observational studies reporting the mean doses of beta-blockers (19–21). Hypothesized factors associated with reduced risk of inappropriate therapy in patients treated with carvedilol may be differences in the adrenergic receptor selectivity and ancillary properties. Metoprolol acts selectively on beta1-receptors, and carvedilol blocks all 3 adrenergic receptors (alpha1, beta1, and beta2) implicated in facilitating harmful effects of catecholamines on the heart. Carvedilol decreases levels of cardiac norepinephrine and suppresses beta-receptors, whereas metoprolol increases catecholamines and enhances the sensitivity of the heart to beta-receptor stimulation. These actions may help explain, in part, the electrophysiological differences between carvedilol and metoprolol in the current study and may be due to different effects at the cellular level (8,22,23). Furthermore, a meta-analysis has indicated a greater increase in left ventricular ejection fraction in patients with HF treated with carvedilol (24).
This was a retrospective, nonrandomized post hoc study. Although multivariate analysis showed that carvedilol was superior to metoprolol when taking many confounders into consideration, it was not a prospective randomized trial comparing these drugs, and other confounders not included in the analyses may have biased our results. An adjusted multivariate analysis was performed, taking into account many confounders associated with inappropriate therapy and those that played a significant role on this outcome in our population. Our study patients were, on average, not receiving recommended doses of beta-blocker therapy and thus were not ideal for generalizing. However, we find our results reflect real-life scenarios of patients with HF.
In patients with mildly symptomatic HF with either a CRT-D or ICD device, carvedilol was associated with a 36% reduction in inappropriate ATP and shock therapy compared with patients taking metoprolol. Inappropriate therapy due to atrial fibrillation was reduced by 50% in patients taking carvedilol compared with metoprolol. Further prospective studies are needed to confirm these results.
For supplementary study definitions, please see the online version of this article.
The MADIT-CRT study was supported by a research grant from Boston Scientific to the University of Rochester, with funds distributed to the coordination and data center, enrolling centers, core laboratories, committees, and boards under subcontracts from the University of Rochester. The current study was not funded by Boston Scientific. Dr. M. Ruwald has received unrestricted funding grants from the Danish Heart Association (12-04-R90-A3806-22701), the Lundbeck Foundation (R108-A104415), Helsefonden (2012B018), Arvid Nilssons Fond, and Knud Hoejgaard Fonden. Mr. Abu-Zeitone was supported in part by the University of Rochester CTSA award number TL1 RR024135 from the National Center for Research Resources and the National Center for Advancing Translational Sciences. Dr. Moss has received grant support from Boston Scientific; and lecture fees from Boston Scientific, Medtronic, and St. Jude Medical. Dr. Kutyifa has received research support from Boston Scientific; and honoraria from Biotronik and Servier. Dr. Zareba has received lecture fees and research grants from Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- antitachycardia pacing
- confidence interval
- cardiac resynchronization therapy with defibrillator
- hazard ratio
- implantable cardioverter-defibrillator
- Received January 22, 2013.
- Revision received March 6, 2013.
- Accepted March 26, 2013.
- American College of Cardiology Foundation
- Schron E.B.,
- Exner D.V.,
- Yao Q.,
- et al.
- Daubert J.P.,
- Zareba W.,
- Cannom D.S.,
- et al.
- Ellenbogen K.A.,
- Levine J.H.,
- Berger R.D.,
- et al.
- van Rees J.B.,
- Borleffs C.J.,
- de Bie M.K.,
- et al.
- Metra M.,
- Giubbini R.,
- Nodari S.,
- et al.
- Ruwald M.H.,
- Ruwald A.C.,
- Jons C.,
- et al.
- Epstein A.E.,
- Dimarco J.P.,
- Ellenbogen K.A.,
- et al.
- Bhavnani S.P.,
- Coleman C.I.,
- White C.M.,
- et al.
- Gilbert E.M.,
- Abraham W.T.,
- Olsen S.,
- et al.
- Sanderson J.E.,
- Chan S.K.,
- Yip G.,
- et al.