A comparison of anti‐arrhythmic efficacy of carvedilol vs metoprolol succinate in patients with implantable cardioverter‐defibrillators

BACKGROUND The effects of carvedilol and metoprolol succinate on appropriate and inappropriate implantable cardioverter defibrillator (ICD) therapy in patients with heart failure with reduced ejection fraction (HFrEF) are not fully understood. HYPOTHESIS The hypothesis of our study is possible carvedilol superiority over metoprolol in patients with ICD. METHODS All patients with ICD registered to a single device clinic between 1/2012 and 6/2017 (n = 569) were identified. Patients with systolic heart failure (left ventricular ejection fraction ≤40%) treated with carvedilol vs metoprolol succinate were compared. Primary endpoint was difference in survival free of appropriate device therapy (shock or anti‐tachycardia pacing, ATP). Secondary endpoints were freedom from inappropriate therapy (shock or ATP) and all cause death. RESULTS A total of 225 patients were included in the analysis with median follow up of 57 months (IQR 33.7‐90). The 2 groups were comparable in the baseline characteristics. Carvedilol was superior to metoprolol succinate in improving survival free of appropriate ICD therapy (HR 0.42; 95% CI 0.24‐0.72, P = 0.01). This difference was driven by reduction in survival free of appropriate shocks (HR 0.30; 95% CI 0.15‐0.63, P = −0.01) while there was no significant difference in appropriate ATP (HR 0.55; 95% CI 0.28‐1.1, P = 0.12). There was no significant difference in time to inappropriate shocks (HR 1.02; 95% CI 0.19‐5.6, P = 0.97), inappropriate ATP (HR 0.93, OR 0.24‐3.5, p value 0.9) or all cause death (HR 0.8; 95% CI 0.42‐1.5, P = 0.52). CONCLUSIONS This study suggests that carvedilol use was associated with improved survival free of appropriate ICD therapy compared to metoprolol succinate in patients with HFrEF.


| INTRODUCTION
The implantable cardioverter-defibrillator (ICD) is an important tool in the prevention of sudden cardiac death due to arrhythmias in patients with heart failure (HF) with heart failure with reduced ejection fraction (HFrEF). However, appropriate and inappropriate ICD therapies result in pain and subsequent psychological apprehension, anxiety, Abbreviations: ATP, anti-tachycardia pacing; CM, cardiomyopathy; CRT, cardiac resynchronization therapy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; VT, ventricular tachycardia. and impaired quality of life. [1][2][3] Furthermore recurrent inappropriate shocks may lead to worsening HF. 4,5 Medical therapy for HFrEF includes beta adrenergic blockers of which three (carvedilol, metoprolol succinate, and bisoprolol) have been shown to improve mortality. [6][7][8] There have been no direct comparative trials to support the use of one beta-blocker over the other in HFrEF, specifically in reducing cardiac arrhythmias and thus preventing ICD therapies. The aim of the current study was to compare the antiarrhythmic efficacy of carvedilol and metoprolol succinate in the treatment in HFrEF in patients with an ICD. The primary endpoint was survival free of appropriate device therapy (shock or anti-tachycardia pacing [ATP]). Appropriate shock or ATP was defined as therapies administered to treat ventricular arrhythmias. Secondary endpoints included survival free of inappropriate therapy (shock or ATP) and all cause death. Inappropriate ICD therapies were defined as those administered by the device to treat any supraventricular arrhythmias. Events were adjudicated based on record review and correlated with intracardiac electrogram tracings when available. To control for differences in dosage, groups were further stratified based on widely accepted dose equivalency conversion (25 mg carvedilol = 100 mg metoprolol succinate).
Statistical analysis was performed using MedCalc (version 18, Ostend, Belgium). Categorical variables were depicted using percentages and compared using χ 2 test for while continuous variables were described by mean +/− SD and compared using t tests. Kaplan-Meier analysis was performed to compare survival free of primary and secondary endpoints, and the survival curves were compared using log rank test. To control for other risk factors for arrhythmias in this population (chosen based on widely accepted risk and significance on univariate analysis P < 0.1), Cox regression analysis was performed.
A P-value <0.05 was considered statistically significant.

| RESULTS
A total of 225 patients were included in the analysis ( Figure 1).  19.3%, p = NS; 6.25 carvedilol vs 25 mg metoprolol 6.6% vs 15.9%, P = 0.0007). CRT accounted for one third of the devices. Less than 10% of the cohorts were on anti-arrhythmic agents at the time of implantation and use was equally distributed between the two groups.   (Figure 2). This difference was driven by reduction in survival free of appropriate shocks (HR 0.30; 95% CI 0.15-0.63, P = 0.01) ( Figure 3A) while there was no significant difference in appropriate ATP (HR 0.55; 95% CI 0.28-1.1, P = 0.12) ( Figure 3B). There was no significant difference in survival free of inappropriate shocks (HR  Figure 4).

| DISCUSSION
The major finding of this study was that carvedilol was superior in pre-  superior to metoprolol in reducing inappropriate ICD therapies. 20 The present study included patients with both CRT and non-CRT devices and may have been underpowered to detect a significant difference.

| STUDY LIMITATIONS
This was a retrospective, nonrandomized, single center study. We studied beta-blocker type and dose at device implantation (a prespecified intention to treat type of analysis) and about 10% of the cohort switched between the two beta-blockers during the course of follow-up. Compliance with beta-blockers could not be assessed due to the retrospective study design. Programming of ICD therapies was at the discretion of the treating electrophysiologist and may have affected the incidence of the type of therapy administered for ventricular arrhythmias. However, this did not affect the combined endpoint of ICD shocks and ATP. Though the number of patients included was relatively small, this is the first real world, well matched analysis of the efficacy of these drugs in preventing ICD therapies. We limited our analysis to time to event rather than cumulative event rates since patients who receive ICD therapies are often started on other anti-arrhythmic drugs which preclude assessment of the efficacy of the beta-blocker alone. We did not collect data on heart rate which is often used as a surrogate marker for efficacy of beta blockade. However, the superiority of carvedilol over metoprolol at the highest dose equivalents suggests that factors other than rate reduction by beta1 antagonism may be at play.
Finally, residual confounders not included in the analyses may have biased our results.

| CONCLUSION
Carvedilol improves survival free of appropriate ICD therapy compared with metoprolol succinate in patients with HFrEF. Because both these drugs are now available generically, a pragmatic randomized controlled trial to study the efficacy of these drugs in HFrEF (focused on both arrhythmic and nonarrhythmic outcomes) is warranted.