Author + information
- Received November 27, 2016
- Revision received January 27, 2017
- Accepted February 9, 2017
- Published online September 18, 2017.
- Mahesh Anantha Narayanan, MDa,∗ (, )
- Kairav Vakil, MDa,b,
- Yogesh N. Reddy, MDc,
- Janani Baskaran, MBBSa,
- Abhishek Deshmukh, MDc,
- David G. Benditt, MDa and
- Selcuk Adabag, MD, MSa,b
- aDivision of Cardiovascular Disease, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
- bDivision of Cardiovascular Disease, Department of Medicine, Veterans Affairs Health Care System, Minneapolis, Minnesota
- cDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- ↵∗Address for correspondence:
Dr. Mahesh Anantha Narayanan, Division of Cardiovascular Diseases, University of Minnesota, Mayo Mail Code 508, 420 Delaware Street SouthEast, Minneapolis, Minnesota 55455.
Objectives This study sought to evaluate the efficacy of implantable cardioverter-defibrillator (ICD) therapy with or without cardiac resynchronization therapy (CRT) in patients with nonischemic cardiomyopathy (NICM).
Background The effect of ICD on mortality of patients with NICM and left ventricular ejection fraction ≤35% has recently been questioned. Prior randomized controlled trials (RCTs) evaluating ICD efficacy in patients with NICM have yielded conflicting results. Furthermore, whether ICD therapy benefits NICM patients with concomitant CRT is unknown.
Methods Relevant RCTs published between 2000 and 2016 were identified. Patients with ischemic cardiomyopathy were excluded. Study sample was stratified into CRT and non-CRT groups. The efficacy of having a defibrillator in each group was compared using random effects meta-analysis techniques.
Results Six RCTs (N = 3,544) were included. Among the 2,347 patients who did not have CRT, ICD use was associated with a 24% reduction in mortality (relative risk [RR]: 0.76; 95% confidence interval [CI]: 0.63 to 0.91; p = 0.003). However, among the 1,197 patients with CRT, having a CRT defibrillator was not associated with a statistically significant reduction in mortality (RR: 0.74; 95% CI: 0.46 to 1.16; p = 0.19) compared to CRT-pacemaker. Subgroup analysis in non-CRT patients showed that ICD use reduced sudden cardiac death by 73% (RR: 0.27; 95% CI: 0.15 to 0.50; p < 0.001) compared to medical therapy.
Conclusions Compared to medical therapy, ICD use significantly improved survival among patients with NICM and ejection fraction ≤35%. Although CRT-defibrillator was not associated with a statistically significant mortality benefit compared to CRT-pacemaker, the apparent lack of power in this analysis warrants further investigation.
- implantable cardioverter-defibrillator
- nonischemic cardiomyopathy
- systematic review
Since the publication of SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) in 2005, prophylactic implantable cardioverter-defibrillator (ICD) therapy has been recommended to prevent sudden cardiac death (SCD) in patients with left ventricular systolic dysfunction (ejection fraction [EF] ≤35%) due to ischemic cardiomyopathy or nonischemic cardiomyopathy (NICM) (1). Whereas the evidence for ICD benefit in ischemic cardiomyopathy has been robust, as endorsed by several randomized controlled trials (RCTs) (2–4), the data supporting prophylactic ICD therapy in patients with NICM has been less conclusive. The difference in the strength of evidence is reflected in the current American College of Cardiology/American Heart Association/Heart Rhythm Society practice guidelines, which recommend ICD therapy for primary prevention of SCD as a Class I indication for ischemic cardiomyopathy but a Class IIa indication for NICM (5,6).
The recently published DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-Ischemic Systolic Heart Failure on Mortality) trial, which randomly assigned NICM patients with left ventricular EF ≤35% to ICD versus no ICD, has raised questions about this recommendation after showing no difference in all-cause mortality with ICD therapy, despite a significant reduction in the incidence of SCD (7). However, it is important to note that 58% of the participants in DANISH underwent cardiac resynchronization therapy (CRT), which might have confounded the results by improving EF in some participants. Indeed, improvement in left ventricular EF alone is associated with a dramatic reduction in all-cause mortality and SCD in patients with ischemic or nonischemic cardiomyopathy (8–10).
Furthermore, whether having a defibrillator offers any survival benefit to patients with CRT remains a matter of controversy. In appropriately selected patients, CRT reduces both sudden and nonsudden deaths when compared to medical therapy (11,12). Patients who qualify for CRT are generally sicker and tend to have more advanced heart failure than those who are eligible for ICD. Therefore, analyses assessing whether ICD therapy offers any survival benefit should be stratified for CRT use. Thus, we performed a systematic review and meta-analysis of published RCTs to assess the efficacy of ICD therapy with or without CRT among patients with NICM.
Data sources and search strategy
We searched PubMed, EMBASE, Cochrane, CINAHL, and Web of Science databases for RCTs published between January 2000 and September 2016 using the following search terms: “non-ischemic cardiomyopathy,” “heart failure with reduced ejection fraction,” “systolic heart failure,” “implantable cardioverter-defibrillator,” “implantable defibrillator,” “mortality,” “sudden cardiac death,” “prevention,” and their combinations. We limited our search to include studies published in English and those involving humans only. We also searched the ClinicalTrials.gov website and the reference list of relevant articles, and used the Science Citation Index to cross reference any articles that met our selection criteria. The methodology used in this study has been previously published (11,13).
Study and patient selection
To be eligible, studies had to meet the following eligibility criteria: 1) have a RCT design; 2) evaluate adult patients with NICM (EF <40%); 3) assess the effect of ICD therapy (compared to no ICD) on all-cause mortality in patients with or without CRT; and 4) report relative risk (RR) with 95% confidence interval (CI), or other measures of RR such as hazard ratio or odds ratio, or provide data such that RR could be calculated. The final inclusion group consisted of 6 RCTs that met these criteria (1,7,12,14–16). Our search strategy is displayed in Online Figure 1.
We divided the included studies as 1) those comparing ICD to medical therapy without use of CRT; and 2) studies comparing CRT-defibrillator (CRT-D) to CRT-pacemaker (CRT-P). In SCD-HeFT (1), which had 3 treatment groups, we merged patients who were randomized to placebo and amiodarone into a single “no-ICD” control group. This was done by obtaining patient-level data from SCD-HeFT from the National Institutes of Health Biologic Specimen and Data Repository Information Coordinating Center. For the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial (12), which also had 3 treatment groups, we only included the patients assigned to CRT-D and CRT-P, and excluded patients assigned to medical therapy. The mortality rates and hazard ratio (95% CI) among patients with NICM assigned to CRT-D and CRT-P in the COMPANION trial were obtained by personal communication (on January 10, 2017) from the investigators of the trial because such information has not yet been published. Figure 1 illustrates the study design and comparison groups in this analysis.
Two reviewers (M.A.N., Y.R.) independently examined the study titles, abstracts, and full-length articles identified by the described search strategy to determine study inclusion and exclusion. These reviewers also independently abstracted the study characteristics, design, methods, and relevant outcomes. Discrepancies between the 2 reviewers were infrequent and resolved by consensus or by consulting with a third reviewer.
The primary outcome was all-cause mortality. Secondary outcome was SCD, defined as an unexpected death due to a cardiac cause that occurred within 1 hour of symptom onset (1,7). SCD was adjudicated by the events committees of the individual trials.
Categorical data were pooled using the random effects model, with the pooled effect size represented as RR with 95% CI limits. When studies were homogeneous (I2 = 0), we performed both fixed effects and random effects analyses. Analysis was stratified by CRT status. In studies/patients without CRT, the efficacy of ICD was compared with medical therapy. In studies/patients with CRT, the efficacy of CRT-D was compared with CRT-P (Figure 1). Publication bias was assessed using the funnel plot. Cochrane Q statistics were used to determine the heterogeneity of included studies for each outcome. I2 values <25%, 25% to 50%, and 50% to 75% were considered as low, moderate, and high heterogeneity, respectively. An exclusion sensitivity analysis was included for heterogeneity, when necessary. A meta-regression was performed when necessary to analyze the impact of moderator variables on outcomes of interest. A value of p < 0.05 was considered statistically significant. Analyses were performed by M.A.N. using the software Comprehensive Meta-Analysis (version 3.3.07, Michael Borenstein, Englewood, New Jersey). This study was exempt from institutional review board approval at our institution.
Of the 6 RCTs included in the meta-analysis, CAT (Cardiomyopathy Trial) and DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) compared ICD to medical therapy (14,15), whereas AMIOVIRT (Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic non-sustained ventricular tachycardia) compared ICD to amiodarone (16). Two trials (SCD-HeFT and COMPANION) had 3 comparison groups each (1,12). SCD-HeFT compared ICD versus amiodarone versus placebo (we merged the amiodarone and placebo groups into a single “no-ICD” control group in the present analysis), whereas COMPANION compared CRT-D and CRT-P versus medical therapy (we excluded medical therapy group in the present analysis). Finally, DANISH compared ICD (with or without CRT-D) with medical therapy (with or without CRT-P) (7).
Whereas 4 trials only included NICM patients, 2 trials (SCD-HeFT and COMPANION) also included patients with ischemic cardiomyopathy. In this analysis, we excluded the patients with ischemic cardiomyopathy from SCD-HeFT and COMPANION. Table 1 highlights the study characteristics and the patient groups included in the analysis.
Distribution of therapy
Of the 3,544 patients included in this analysis, 2,347 (66%) did not have a CRT. Of these, 962 (41%) received an ICD, whereas 1,385 (59%) were assigned to medical therapy. Among the 1,197 patients (34%) with CRT, 590 (49%) had CRT-D and 607 (51%) had CRT-P.
Non-CRT patients: ICD versus medical therapy
Among patients without a CRT, the risk of all-cause mortality was 24% lower in those assigned to ICD compared to those assigned to medical therapy (RR: 0.76; 95% CI: 0.63 to 0.91; p = 0.003) (Figure 2). Sensitivity analysis after excluding the study with the maximum strength (7) did not alter the results. Funnel plot showed minimal bias (Online Figure 2), and heterogeneity within the included studies was low (I2 = 0). A meta-regression of all-cause death on the follow-up time period was statistically nonsignificant (p = 0.48).
CRT patients: CRT-D versus CRT-P
Among patients with CRT, there was no statistically significant difference in mortality between the CRT-D and CRT-P groups (RR: 0.74; 95%: CI: 0.47 to 1.16; p = 0.19) (Figure 3). Given the smaller number of studies in this group, funnel plot for bias assessment in this subgroup was not constructed.
ICD and SCD
The incidence of SCD was available for only 1,772 patients from 3 studies (AMIOVIRT, DEFINITE, and SCD-HeFT) (1,15,16). None of these trials included patients with CRT. In this subgroup, 678 patients (38%) had an ICD, and 1,094 (62%) were in the control group. Among these patients, the risk of SCD was 73% lower in patients assigned to ICD (RR: 0.27; 95% CI: 0.15 to 0.50; p < 0.001) when compared to medical therapy (Figure 4). Sensitivity analysis after excluding the study with the maximum strength (1) did not alter the results. Heterogeneity within the included studies was low (I2 = 0).
The major finding of this meta-analysis is that among patients with NICM and EF ≤35%, ICD therapy (without CRT) is associated with a 24% reduction in all-cause mortality and a 73% reduction in SCD compared to medical therapy. We also found that although CRT-D use was not associated with a statistically significant reduction in all-cause mortality in comparison to CRT-P, the relatively smaller sample size of this analysis prevents a definitive conclusion. Although these results support the current American College of Cardiology/American Heart Association/Heart Rhythm Society guideline recommendations for ICD implantation for primary prevention of SCD in appropriately selected patients with NICM, they call for further research on the efficacy of defibrillator therapy in patients with CRT.
The principal findings of this study contradict the results of the recent DANISH trial, which randomized patients with NICM (EF ≤35%) to ICD (with or without CRT-D) versus optimal medical therapy (with or without CRT-P) (7). The medical therapy in DANISH consisted of aggressive use of currently available guideline-directed medical therapy, including beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and mineralocorticoid receptor antagonists. In comparison, previously conducted ICD trials enrolled patients in an era when the use of heart failure therapy (particularly the target doses of medications that were achieved) was not as robust as noted in DANISH. To that effect, the event rate in DANISH was lower than that reported in previous landmark ICD trials.
However, several issues, merit discussion when evaluating the findings of DANISH. First, in DANISH, ∼60% of the population had CRT. Subgroup analysis among patients without CRT was underpowered to determine whether ICD therapy alone was better than medical therapy. Second, although aggressive use of heart failure therapy (reaching near-target doses in significant proportion of the patients) was pursued in DANISH, this does not necessarily reflect the practice in the real-world setting. Indeed, in a recent analysis from the National Cardiovascular Data Registry on ∼20,000 patients, use of guideline-directed medical therapy was significantly low at around 50% to 70% and was strongly linked to survival (17). Finally, the median age in DANISH was higher than in DEFINITE and SCD-HEFT. A subgroup analysis of DANISH demonstrated mortality benefit with ICD therapy among patients younger than 68 years. Our meta-analysis confirms this benefit of ICD implantation and SCD prevention, and suggests that the absence of benefit of ICD in DANISH could have been related to selection of an older population with higher noncardiac mortality. Thus, based on the current results, we speculate that ICD therapy is of benefit among appropriately selected patients with NICM, particularly if they are younger.
It is generally accepted that CRT improves EF and significantly reduces both sudden and nonsudden death in a substantial proportion of patients with low EF and left bundle branch block (12). Given that a significant proportion of patients have improved EF >35% after CRT implantation, the benefit of having a primary prevention ICD in such patients is unclear. Thus far, COMPANION has been the only randomized clinical trial to compare patients with CRT-D and CRT-P (12). Although both CRT arms were associated with improved survival compared to medical therapy, the trial was not statistically powered to compare the CRT-D and CRT-P populations per se. Subgroup analysis of COMPANION subsequently showed that in the overall population (which included both ischemic and nonischemic patients), CRT-D failed to show survival benefit over CRT-P (p = 0.12) (18,19). Similar results were noted in DANISH, in which 58% of patients had CRT. However, this subgroup in DANISH also was similarly underpowered to assess a meaningful difference between the CRT-D and CRT-P arms, especially with the relatively low event rates in the trial. Despite combining the NICM groups from both trials in the current meta-analysis, the comparison of CRT-D with CRT-P did not have sufficient power to determine superiority of either modality over the other, suggesting that further research is necessary to answer this question.
Except for some rare specific conditions such as end-stage hypertrophic cardiomyopathy or cardiac sarcoidosis, which may have a high burden of ventricular arrhythmias, NICM in general has a lower risk of SCD compared to ischemic cardiomyopathy (1). One possible explanation for the lower risk of SCD is the higher likelihood of improvement of EF in patients with NICM compared to ischemic cardiomyopathy (20). Indeed, improvement in EF can be seen in 40% to 50% of patients with NICM, which is associated with a dramatic reduction in mortality and SCD risk (21–23). However, recent data shows that the relative benefit of ICD therapy is maintained among these patients even after EF improvement (10).
The strength of this meta-analysis is the inclusion of only RCTs to avoid patient selection bias. Another important strength of this study is that analyses were stratified for CRT status, which has not been previously done in randomized studies. However, we did not have patient-level data (except from SCD-HeFT), which limited our ability to assess ICD efficacy in certain subgroups (e.g., young vs. old or male vs. female). Also, we were not able to analyze SCD among all included patients with NICM unless SCD was reported in the original article, except in the case of SCD-HeFT, for which we had access to patient-level data. Studies reporting outcomes with CRT were limited in number and sample size, which reduced the power of the analysis and our ability to make definitive conclusions in the CRT subgroup. Finally, publication bias is an inherent limitation of meta-analysis.
This systematic review and meta-analysis of published RCTs supports the use of ICD in appropriately selected patients with NICM who are not eligible for CRT. Further research, perhaps an adequately powered trial, of NICM patients with CRT is essential to assess the efficacy of CRT-D in comparison to CRT-P in NICM.
COMPETENCY IN MEDICAL KNOWLEDGE: The benefit of ICD use in patients with NICM and reduced EF has been largely questioned after the findings of the recently published DANISH trial, which showed lack of ICD benefit in NICM patients who were receiving excellent medical therapy for heart failure. However, 58% of patients in the trial had concomitant CRT. Patients who qualify for CRT are significantly different and perhaps “sicker” (i.e., had advanced heart failure symptoms, left bundle branch block) than those who meet traditional indications for only an ICD. Given that CRT leads to significant reverse remodeling, improves EF, and mitigates sudden and nonsudden death risk, one may speculate that ICDs may not be effective in such a population. As such, any conclusive ICD study should account for the presence of CRT. Indeed “CRT-D versus CRT-P” has remained a matter of academic controversy for the last decade. Results from this meta-analysis of 6 RCTs are the largest to date highlighting the importance of ICD use in patients with NICM stratified by the presence of CRT.
TRANSLATIONAL OUTLOOK: There is currently a lack of robust RCT data addressing the effectiveness of CRT-D use over CRT-P. Despite that, vast majority of the CRT implantations across the United States are CRT-D, perhaps due to the assumption that because most patients meeting CRT indications also meet indications for ICD, having a defibrillator would improve survival in CRT patients. This “assumption” could have significant medical (e.g., higher complications, inappropriate shocks with CRT-D) and economic implications. Despite meta-analysis of the 2 large trials with this comparison, the analysis lacked sufficient power to make a definitive conclusion about the CRT-D versus CRT-P comparison. Further research is warranted to answer this question.
Dr. Vakil has received an investigator initiated research grant from Medtronic Inc. Dr. Benditt is a consultant for, and holds equity in, Medtronic Inc. and St. Jude Medical Inc.; and is supported in part by a grant from the Dr. Earl E. Bakken Family in support of heart-brain research. Dr. Adabag has received an investigator initiated research grant from Medtronic Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. This manuscript was prepared using SCD-HeFT Research Materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of the SCD-HeFT or the NHLBI. This material is the result of work supported with resources and the use of facilities at the Minneapolis Veterans Affairs Health Care System. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. Drs. Anantha Narayanan and Vakil contributed equally to this work and share first authorship.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- confidence interval
- cardiac resynchronization therapy
- cardiac resynchronization therapy–defibrillator
- cardiac resynchronization therapy–pacemaker
- ejection fraction
- implantable cardioverter-defibrillator
- nonischemic cardiomyopathy
- randomized controlled trial
- risk ratio
- sudden cardiac death
- Received November 27, 2016.
- Revision received January 27, 2017.
- Accepted February 9, 2017.
- 2017 American College of Cardiology Foundation
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