- Email: [email protected]
Efficacy of Implantable Cardioverter-Defibrillator Therapy in Patients With Nonischemic Cardiomyopathy
JACC: CLINICAL ELECTROPHYSIOLOGY
VOL.
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. PUBLISHED BY ELSEVIER. ALL RIGHTS RESERVED.
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ISSN 2405-500X/$36.00 http://dx.doi.org/10.1016/j.jacep.2017.02.006
Efficacy of Implantable Cardioverter-Defibrillator Therapy in Patients With Nonischemic Cardiomyopathy A Systematic Review and Meta-Analysis of Randomized Controlled Trials Mahesh Anantha Narayanan, MD,a Kairav Vakil, MD,a,b Yogesh N. Reddy, MD,c Janani Baskaran, MBBS,a Abhishek Deshmukh, MD,c David G. Benditt, MD,a Selcuk Adabag, MD, MSa,b
ABSTRACT 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 ¼ 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 ¼ 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 ¼ 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. (J Am Coll Cardiol EP 2017;-:-–-) © 2017 by the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.
From the aDivision of Cardiovascular Disease, Department of Medicine, University of Minnesota, Minneapolis, Minnesota; b
Division of Cardiovascular Disease, Department of Medicine, Veterans Affairs Health Care System, Minneapolis, Minnesota; and
the cDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Dr. Vakil has 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 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. Manuscript received November 27, 2016; revised manuscript received January 27, 2017, accepted February 9, 2017.
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ABBREVIATIONS AND ACRONYMS CI = confidence interval
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ICD Efficacy in Nonischemic Cardiomyopathy
ince the publication of SCD-HeFT
METHODS
(Sudden Cardiac Death in Heart Failure Trial) in 2005, prophylactic implant-
DATA
SOURCES
AND
SEARCH
STRATEGY. We
able cardioverter-defibrillator (ICD) therapy
searched PubMed, EMBASE, Cochrane, CINAHL, and
has been recommended to prevent sudden
Web of Science databases for RCTs published between
cardiac death (SCD) in patients with left
January 2000 and September 2016 using the following
resynchronization therapy–
ventricular systolic dysfunction (ejection
search terms: “non-ischemic cardiomyopathy,” “heart
defibrillator
fraction [EF] #35%) due to ischemic cardio-
failure with reduced ejection fraction,” “systolic heart
CRT-P = cardiac
myopathy or nonischemic cardiomyopathy
failure,”
resynchronization therapy–
(NICM) (1). Whereas the evidence for ICD
“implantable
benefit in ischemic cardiomyopathy has
cardiac death,” “prevention,” and their combinations.
been robust, as endorsed by several random-
We limited our search to include studies published in
ized controlled trials (RCTs) (2–4), the data
English and those involving humans only. We also
supporting prophylactic ICD therapy in pa-
searched the ClinicalTrials.gov website and the refer-
tients with NICM has been less conclusive.
ence list of relevant articles, and used the Science
The difference in the strength of evidence is
Citation Index to cross reference any articles that met
trial
reflected in the current American College of
our selection criteria. The methodology used in this
RR = risk ratio
Cardiology/American
study has been previously published (11,13).
CRT = cardiac resynchronization therapy
CRT-D = cardiac
pacemaker
EF = ejection fraction ICD = implantable cardioverter-defibrillator
NICM = nonischemic cardiomyopathy
RCT = randomized controlled
Heart
Association/
“implantable
cardioverter-defibrillator,”
defibrillator,”
“mortality,”
“sudden
Heart Rhythm Society practice guidelines,
SCD = sudden cardiac death
which recommend ICD therapy for primary
STUDY AND PATIENT SELECTION. To be eligible,
prevention of SCD as a class I indication for ischemic
studies had to meet the following eligibility criteria:
cardiomyopathy
1) have a RCT design; 2) evaluate adult patients with
but
a
class
IIa
indication
for
NICM (EF <40%); 3) assess the effect of ICD therapy
NICM (5,6). The recently published DANISH (Danish Study to
(compared to no ICD) on all-cause mortality in pa-
Assess the Efficacy of ICDs in Patients with Non-
tients with or without CRT; and 4) report relative risk
Ischemic Systolic Heart Failure on Mortality) trial,
(RR) with 95% confidence interval (CI), or other
which randomly assigned NICM patients with left
measures of RR such as hazard ratio or odds ratio, or
ventricular EF #35% to ICD versus no ICD, has raised
provide data such that RR could be calculated. The
questions about this recommendation after showing
final inclusion group consisted of 6 RCTs that met
no difference in all-cause mortality with ICD therapy,
these criteria (1,7,12,14–16). Our search strategy is
despite a significant reduction in the incidence of SCD
displayed in Online Figure 1.
(7). However, it is important to note that 58% of the
We divided the included studies as 1) those
participants in DANISH underwent cardiac resynch-
comparing ICD to medical therapy without use of
ronization
have
CRT; and 2) studies comparing CRT-defibrillator
confounded the results by improving EF in some par-
therapy
(CRT),
which
might
(CRT-D) to CRT-pacemaker (CRT-P). In SCD-HeFT
ticipants. Indeed, improvement in left ventricular EF
(1), which had 3 treatment groups, we merged pa-
alone is associated with a dramatic reduction in all-
tients who were randomized to placebo and amio-
cause mortality and SCD in patients with ischemic or
darone into a single “no-ICD” control group. This was
nonischemic cardiomyopathy (8–10).
done by obtaining patient-level data from SCD-HeFT
Furthermore, whether having a defibrillator offers
from the National Institutes of Health Biologic Spec-
any survival benefit to patients with CRT remains a
imen and Data Repository Information Coordinating
matter of controversy. In appropriately selected pa-
Center. For the COMPANION (Comparison of Medical
tients, CRT reduces both sudden and nonsudden
Therapy, Pacing, and Defibrillation in Heart Failure)
deaths when compared to medical therapy (11,12).
trial (12), which also had 3 treatment groups, we only
Patients who qualify for CRT are generally sicker
included the patients assigned to CRT-D and CRT-P,
and tend to have more advanced heart failure
and excluded patients assigned to medical therapy.
than those who are eligible for ICD. Therefore, ana-
The mortality rates and hazard ratio (95% CI) among
lyses assessing whether ICD therapy offers any sur-
patients with NICM assigned to CRT-D and CRT-P in
vival benefit should be stratified for CRT use. Thus,
the COMPANION trial were obtained by personal
we performed a systematic review and meta-analysis
communication (on January 10, 2017) from the in-
of published RCTs to assess the efficacy of ICD
vestigators of the trial because such information has
therapy with or without CRT among patients with
not yet been published. Figure 1 illustrates the study
NICM.
design and comparison groups in this analysis.
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ICD Efficacy in Nonischemic Cardiomyopathy
F I G U R E 1 Design of the Analysis and the Comparison Groups
*No-ICD group in SCD-HeFT consists of both amiodarone and placebo arms. AMIOVIRT ¼ Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic non-sustained ventricular tachycardia; CAT ¼ Cardiomyopathy Trial; COMPANION ¼ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; CRT ¼ cardiac resynchronization therapy; CRT-D ¼ cardiac resynchronization therapy–defibrillator; CRT-P ¼ cardiac resynchronization therapy–pacemaker; DANISH ¼ Danish Study to Assess the Efficacy of ICDs in Patients with Non-Ischemic Systolic Heart Failure on Mortality; DEFINITE ¼ Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; ICD ¼ implantable cardioverter-defibrillator; SCD-HeFT ¼ Sudden Cardiac Death in Heart Failure Trial.
DATA EXTRACTION. Two reviewers (M.A.N., Y.R.)
to 75% were considered as low, moderate, and high
independently examined the study titles, abstracts,
heterogeneity, respectively. An exclusion sensitivity
and full-length articles identified by the described
analysis was included for heterogeneity, when neces-
search strategy to determine study inclusion and
sary. A meta-regression was performed when neces-
exclusion.
independently
sary to analyze the impact of moderator variables on
abstracted the study characteristics, design, methods,
outcomes of interest. A value of p < 0.05 was consid-
and relevant outcomes. Discrepancies between the 2
ered statistically significant. Analyses were per-
reviewers were infrequent and resolved by consensus
formed by M.A.N. using the software Comprehensive
or by consulting with a third reviewer.
Meta-Analysis (version 3.3.07, Michael Borenstein,
These
reviewers
also
OUTCOMES. 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. STATISTICAL
Englewood, New Jersey). This study was exempt from institutional review board approval at our institution.
RESULTS STUDY CHARACTERISTICS. Of the 6 RCTs included in
the meta-analysis, CAT (Cardiomyopathy Trial) and ANALYSIS. Categorical
were
DEFINITE (Defibrillators in Non-Ischemic Cardiomy-
pooled using the random effects model, with the
data
opathy Treatment Evaluation) compared ICD to med-
pooled effect size represented as RR with 95% CI
ical therapy (14,15), whereas AMIOVIRT (Amiodarone
limits. When studies were homogeneous (I 2 ¼ 0), we
versus implantable cardioverter-defibrillator: ran-
performed both fixed effects and random effects
domized trial in patients with nonischemic dilated
analyses. Analysis was stratified by CRT status. In
cardiomyopathy and asymptomatic non-sustained
studies/patients without CRT, the efficacy of ICD was
ventricular tachycardia) compared ICD to amiodar-
compared with medical therapy. In studies/patients
one (16). Two trials (SCD-HeFT and COMPANION) had
with CRT, the efficacy of CRT-D was compared with
3 comparison groups each (1,12). SCD-HeFT compared
CRT-P (Figure 1). Publication bias was assessed using
ICD versus amiodarone versus placebo (we merged the
the funnel plot. Cochrane Q statistics were used to
amiodarone and placebo groups into a single “no-ICD”
determine the heterogeneity of included studies for
control group in the present analysis), whereas
each outcome. I2 values <25%, 25% to 50%, and 50%
COMPANION compared CRT-D and CRT-P versus
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ICD Efficacy in Nonischemic Cardiomyopathy
T A B L E 1 Randomized Controlled Clinical Trials Included in the Analysis
Study Name (Ref. #)
Enrollment Years
Publication Year
Comparison Groups
Mean Follow-Up (months)
CAT (14)
1991–1997
2002
EF #30% NYHA II–III
ICD vs. medical therapy
w23
AMIOVIRT (16)
1996–2000
ICM: No NICM: Yes CRT: No
EF #35% NSVT NYHA I–III
ICD vs. amiodarone
w24
DEFINITE (15)
458
ICM: No NICM: Yes CRT: No
EF #35% PVCs or NSVT
ICD vs. medical therapy
w29
SCD-HEFT (1)
2,521
1,211*
ICM: Yes NICM: Yes CRT: No
EF #35% NYHA II–III
ICD vs. amiodarone vs. medical therapy
w46
2004
1,520
552*
ICM: Yes NICM: Yes CRT: Yes
EF #35% NYHA III–IV QRS >120 ms
CRT-D vs. CRT-P vs. medical therapy
w16
2016
1,116
ICM: No NICM: Yes CRT: Yes
EF #35% NYHA II–IV Optimal medical therapy†
ICD with or without CRT-D vs. optimal medical therapy with or without CRT-P
w68
No. Overall
No. Included
Participants
104
104
ICM: No NICM: Yes CRT: No
2003
103
103
1998–2002
2004
458
1997–2001
2005
COMPANION (12)
2000–2002
DANISH (7)
2008–2014
1,116
Patient Characteristics
*Patients with ischemic cardiomyopathy were excluded from SCD-HeFT, and patients with ischemic cardiomyopathy and those randomized to medical therapy arm in COMPANION were excluded. †Patients in NYHA functional class IV only if cardiac resynchronization therapy was planned. Trial was specifically designed to be conducted on patients receiving maximally tolerated guideline-directed medical therapy. AMIOVIRT ¼ Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic non-sustained ventricular tachycardia; CAT ¼ Cardiomyopathy Trial; COMPANION ¼ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; CRT-D ¼ cardiac resynchronization therapy–defibrillator; CRT-P ¼ cardiac resynchronization therapy–pacemaker; DANISH ¼ Danish Study to Assess the Efficacy of ICDs in Patients with Non-Ischemic Systolic Heart Failure on Mortality; DEFINITE ¼ Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; EF ¼ ejection fraction; ICD ¼ implantable cardioverter-defibrillator; ICM ¼ ischemic cardiomyopathy; NICM ¼ nonischemic cardiomyopathy; NSVT ¼ nonsustained ventricular tachycardia; NYHA ¼ New York Heart Association functional class; PVC ¼ premature ventricular contraction; SCD-HeFT ¼ Sudden Cardiac Death in Heart Failure Trial.
medical therapy (we excluded medical therapy group
Funnel plot showed minimal bias (Online Figure 2),
in the present analysis). Finally, DANISH compared
and heterogeneity within the included studies was
ICD (with or without CRT-D) with medical therapy
low (I 2 ¼ 0). A meta-regression of all-cause death on
(with or without CRT-P) (7).
the follow-up time period was statistically nonsig-
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.
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. PATIENTS:
ICD
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 ¼ 0.19) (Figure 3). Given the smaller number of studies in this group, funnel plot for bias assessment
DISTRIBUTION OF THERAPY. Of the 3,544 patients
NON-CRT
nificant (p ¼ 0.48).
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
VERSUS
MEDICAL
in the control group. Among these patients, the risk of
THERAPY. Among patients without a CRT, the risk of
SCD was 73% lower in patients assigned to ICD (RR:
all-cause mortality was 24% lower in those assigned
0.27; 95% CI: 0.15 to 0.50; p < 0.001) when compared
to ICD compared to those assigned to medical therapy
to medical therapy (Figure 4). Sensitivity analysis af-
(RR: 0.76; 95% CI: 0.63 to 0.91; p ¼ 0.003) (Figure 2).
ter excluding the study with the maximum strength
Sensitivity analysis after excluding the study with the
(1) did not alter the results. Heterogeneity within the
maximum strength (7) did not alter the results.
included studies was low (I2 ¼ 0).
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DISCUSSION The major finding of this meta-analysis is that among
ICD Efficacy in Nonischemic Cardiomyopathy
F I G U R E 2 Forest Plot and Pooled Analysis for All-Cause Mortality (n ¼ 2,347) in NICM
Patients Without CRT (ICD vs. Medical Therapy Alone)
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
CI ¼ confidence interval; NICM ¼ nonischemic cardiomyopathy; RR ¼ relative risk; other abbreviations as in Figure 1.
without CRT-P) (7). The medical therapy in DANISH consisted of aggressive use of currently available guideline-directed medical therapy, including beta-
and SCD prevention, and suggests that the absence of
blockers, angiotensin-converting enzyme inhibitors
benefit of ICD in DANISH could have been related to
or angiotensin receptor blockers, and mineralocorti-
selection of an older population with higher noncar-
coid receptor antagonists. In comparison, previously
diac mortality. Thus, based on the current results, we
conducted ICD trials enrolled patients in an era when
speculate that ICD therapy is of benefit among
the use of heart failure therapy (particularly the
appropriately selected patients with NICM, particu-
target doses of medications that were achieved) was
larly if they are younger.
not as robust as noted in DANISH. To that effect, the
It is generally accepted that CRT improves EF and
event rate in DANISH was lower than that reported in
significantly reduces both sudden and nonsudden
previous landmark ICD trials.
death in a substantial proportion of patients with
However, several issues, merit discussion when
low EF and left bundle branch block (12). Given that
evaluating the findings of DANISH. First, in DANISH,
a significant proportion of patients have improved
w60% of the population had CRT. Subgroup analysis
EF >35% after CRT implantation, the benefit of having
among patients without CRT was underpowered to
a primary prevention ICD in such patients is unclear.
determine whether ICD therapy alone was better than
Thus far, COMPANION has been the only randomized
medical therapy. Second, although aggressive use of
clinical trial to compare patients with CRT-D and
heart failure therapy (reaching near-target doses in
CRT-P (12). Although both CRT arms were associated
significant proportion of the patients) was pursued in
with improved survival compared to medical therapy,
DANISH, this does not necessarily reflect the practice
the trial was not statistically powered to compare the
in the real-world setting. Indeed, in a recent analysis
CRT-D and CRT-P populations per se. Subgroup anal-
from the National Cardiovascular Data Registry on
ysis of COMPANION subsequently showed that in the
w20,000 patients, use of guideline-directed medical
overall population (which included both ischemic and
therapy was significantly low at around 50% to 70%
nonischemic patients), CRT-D failed to show survival
and was strongly linked to survival (17). Finally, the
benefit over CRT-P (p ¼ 0.12) (18,19). Similar results
median age in DANISH was higher than in DEFINITE
were noted in DANISH, in which 58% of patients had
and SCD-HEFT. A subgroup analysis of DANISH
CRT. However, this subgroup in DANISH also was
demonstrated mortality benefit with ICD therapy
similarly underpowered to assess a meaningful dif-
among patients younger than 68 years. Our meta-
ference between the CRT-D and CRT-P arms, especially
analysis confirms this benefit of ICD implantation
with the relatively low event rates in the trial.
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ICD Efficacy in Nonischemic Cardiomyopathy
F I G U R E 3 Forest Plot and Pooled Analysis for All-Cause Mortality (n ¼ 1,197) in NICM Patients With CRT (CRT-D vs. CRT-P)
Abbreviations as in Figures 1 and 2.
Despite combining the NICM groups from both trials in
of SCD compared to ischemic cardiomyopathy (1). One
the current meta-analysis, the comparison of CRT-D
possible explanation for the lower risk of SCD is the
with CRT-P did not have sufficient power to deter-
higher likelihood of improvement of EF in patients
mine superiority of either modality over the other,
with NICM compared to ischemic cardiomyopathy
suggesting that further research is necessary to answer
(20). Indeed, improvement in EF can be seen in 40%
this question.
to 50% of patients with NICM, which is associated
Except for some rare specific conditions such as
with a dramatic reduction in mortality and SCD risk
end-stage hypertrophic cardiomyopathy or cardiac
(21–23). However, recent data shows that the relative
sarcoidosis, which may have a high burden of ven-
benefit of ICD therapy is maintained among these
tricular arrhythmias, NICM in general has a lower risk
patients even after EF improvement (10).
F I G U R E 4 Forest Plot and Pooled Analysis for Sudden Cardiac Death (n ¼ 1,772)
Data available from only 3 studies (AMIOVIRT, DEFINITE, and SCD-HeFT), which included only non-CRT patients. Abbreviations as in Figures 1 and 2.
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STUDY
ICD Efficacy in Nonischemic Cardiomyopathy
LIMITATIONS. 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.
PERSPECTIVES 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.
CONCLUSIONS 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. ADDRESS
Anantha
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
FOR
CORRESPONDENCE:
Narayanan,
Division
of
Dr. Mahesh
Cardiovascular
Diseases, University of Minnesota, Mayo Mail Code 508, 420 Delaware Street SouthEast, Minneapolis,
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.
Minnesota 55455. E-mail: [email protected].
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12. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–50. 13. Vakil K, Kazmirczak F, Sathnur N, et al. Implantable cardioverter-defibrillator use in patients with left ventricular assist devices: a systematic review and meta-analysis. J Am Coll Cardiol HF 2016;4:772–9. 14. Bansch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation 2002;105:1453–8. 15. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151–8. 16. Strickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular
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tachycardia—AMIOVIRT. J Am Coll Cardiol 2003; 41:1707–12. 17. Roth GA, Poole JE, Zaha R, Zhou W, Skinner J, Morden NE. Use of guideline-directed medications for heart failure before cardioverter-defibrillator implantation. J Am Coll Cardiol 2016;67:1062–9. 18. Colquitt JL, Mendes D, Clegg AJ, et al. Implantable cardioverter defibrillators for the treatment of arrhythmias and cardiac resynchronisation therapy for the treatment of heart failure: systematic review and economic evaluation. Health Technol Assess 2014;18:1–560. 19. Lam SK, Owen A. Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction: Bayesian network metaanalysis of randomised controlled trials. BMJ 2007;335:925. 20. Stevenson LW. Heart failure with better ejection fraction: a modern diagnosis. Circulation 2014;129:2364–7. 21. Naksuk N, Saab A, Li JM, et al. Incidence of appropriate shock in implantable
cardioverter-defibrillator patients with improved ejection fraction. J Card Fail 2013; 19:426–30. 22. Madhavan M, Waks JW, Friedman PA, et al. Outcomes after implantable cardioverterdefibrillator generator replacement for primary prevention of sudden cardiac death. Circ Arrhythm Electrophysiol 2016;9:e003283. 23. Kini V, Soufi MK, Deo R, et al. Appropriateness of primary prevention implantable cardioverterdefibrillators at the time of generator replacement: are indications still met? J Am Coll Cardiol 2014;63:2388–94.
KEY WORDS implantable cardioverterdefibrillator, meta-analysis, mortality, nonischemic cardiomyopathy, systematic review
A PPE NDI X For supplemental figures, please see the online version of this paper.
VOL.
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. PUBLISHED BY ELSEVIER. ALL RIGHTS RESERVED.
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ISSN 2405-500X/$36.00 http://dx.doi.org/10.1016/j.jacep.2017.02.006
Efficacy of Implantable Cardioverter-Defibrillator Therapy in Patients With Nonischemic Cardiomyopathy A Systematic Review and Meta-Analysis of Randomized Controlled Trials Mahesh Anantha Narayanan, MD,a Kairav Vakil, MD,a,b Yogesh N. Reddy, MD,c Janani Baskaran, MBBS,a Abhishek Deshmukh, MD,c David G. Benditt, MD,a Selcuk Adabag, MD, MSa,b
ABSTRACT 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 ¼ 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 ¼ 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 ¼ 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. (J Am Coll Cardiol EP 2017;-:-–-) © 2017 by the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.
From the aDivision of Cardiovascular Disease, Department of Medicine, University of Minnesota, Minneapolis, Minnesota; b
Division of Cardiovascular Disease, Department of Medicine, Veterans Affairs Health Care System, Minneapolis, Minnesota; and
the cDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Dr. Vakil has 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 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. Manuscript received November 27, 2016; revised manuscript received January 27, 2017, accepted February 9, 2017.
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S
ABBREVIATIONS AND ACRONYMS CI = confidence interval
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ICD Efficacy in Nonischemic Cardiomyopathy
ince the publication of SCD-HeFT
METHODS
(Sudden Cardiac Death in Heart Failure Trial) in 2005, prophylactic implant-
DATA
SOURCES
AND
SEARCH
STRATEGY. We
able cardioverter-defibrillator (ICD) therapy
searched PubMed, EMBASE, Cochrane, CINAHL, and
has been recommended to prevent sudden
Web of Science databases for RCTs published between
cardiac death (SCD) in patients with left
January 2000 and September 2016 using the following
resynchronization therapy–
ventricular systolic dysfunction (ejection
search terms: “non-ischemic cardiomyopathy,” “heart
defibrillator
fraction [EF] #35%) due to ischemic cardio-
failure with reduced ejection fraction,” “systolic heart
CRT-P = cardiac
myopathy or nonischemic cardiomyopathy
failure,”
resynchronization therapy–
(NICM) (1). Whereas the evidence for ICD
“implantable
benefit in ischemic cardiomyopathy has
cardiac death,” “prevention,” and their combinations.
been robust, as endorsed by several random-
We limited our search to include studies published in
ized controlled trials (RCTs) (2–4), the data
English and those involving humans only. We also
supporting prophylactic ICD therapy in pa-
searched the ClinicalTrials.gov website and the refer-
tients with NICM has been less conclusive.
ence list of relevant articles, and used the Science
The difference in the strength of evidence is
Citation Index to cross reference any articles that met
trial
reflected in the current American College of
our selection criteria. The methodology used in this
RR = risk ratio
Cardiology/American
study has been previously published (11,13).
CRT = cardiac resynchronization therapy
CRT-D = cardiac
pacemaker
EF = ejection fraction ICD = implantable cardioverter-defibrillator
NICM = nonischemic cardiomyopathy
RCT = randomized controlled
Heart
Association/
“implantable
cardioverter-defibrillator,”
defibrillator,”
“mortality,”
“sudden
Heart Rhythm Society practice guidelines,
SCD = sudden cardiac death
which recommend ICD therapy for primary
STUDY AND PATIENT SELECTION. To be eligible,
prevention of SCD as a class I indication for ischemic
studies had to meet the following eligibility criteria:
cardiomyopathy
1) have a RCT design; 2) evaluate adult patients with
but
a
class
IIa
indication
for
NICM (EF <40%); 3) assess the effect of ICD therapy
NICM (5,6). The recently published DANISH (Danish Study to
(compared to no ICD) on all-cause mortality in pa-
Assess the Efficacy of ICDs in Patients with Non-
tients with or without CRT; and 4) report relative risk
Ischemic Systolic Heart Failure on Mortality) trial,
(RR) with 95% confidence interval (CI), or other
which randomly assigned NICM patients with left
measures of RR such as hazard ratio or odds ratio, or
ventricular EF #35% to ICD versus no ICD, has raised
provide data such that RR could be calculated. The
questions about this recommendation after showing
final inclusion group consisted of 6 RCTs that met
no difference in all-cause mortality with ICD therapy,
these criteria (1,7,12,14–16). Our search strategy is
despite a significant reduction in the incidence of SCD
displayed in Online Figure 1.
(7). However, it is important to note that 58% of the
We divided the included studies as 1) those
participants in DANISH underwent cardiac resynch-
comparing ICD to medical therapy without use of
ronization
have
CRT; and 2) studies comparing CRT-defibrillator
confounded the results by improving EF in some par-
therapy
(CRT),
which
might
(CRT-D) to CRT-pacemaker (CRT-P). In SCD-HeFT
ticipants. Indeed, improvement in left ventricular EF
(1), which had 3 treatment groups, we merged pa-
alone is associated with a dramatic reduction in all-
tients who were randomized to placebo and amio-
cause mortality and SCD in patients with ischemic or
darone into a single “no-ICD” control group. This was
nonischemic cardiomyopathy (8–10).
done by obtaining patient-level data from SCD-HeFT
Furthermore, whether having a defibrillator offers
from the National Institutes of Health Biologic Spec-
any survival benefit to patients with CRT remains a
imen and Data Repository Information Coordinating
matter of controversy. In appropriately selected pa-
Center. For the COMPANION (Comparison of Medical
tients, CRT reduces both sudden and nonsudden
Therapy, Pacing, and Defibrillation in Heart Failure)
deaths when compared to medical therapy (11,12).
trial (12), which also had 3 treatment groups, we only
Patients who qualify for CRT are generally sicker
included the patients assigned to CRT-D and CRT-P,
and tend to have more advanced heart failure
and excluded patients assigned to medical therapy.
than those who are eligible for ICD. Therefore, ana-
The mortality rates and hazard ratio (95% CI) among
lyses assessing whether ICD therapy offers any sur-
patients with NICM assigned to CRT-D and CRT-P in
vival benefit should be stratified for CRT use. Thus,
the COMPANION trial were obtained by personal
we performed a systematic review and meta-analysis
communication (on January 10, 2017) from the in-
of published RCTs to assess the efficacy of ICD
vestigators of the trial because such information has
therapy with or without CRT among patients with
not yet been published. Figure 1 illustrates the study
NICM.
design and comparison groups in this analysis.
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F I G U R E 1 Design of the Analysis and the Comparison Groups
*No-ICD group in SCD-HeFT consists of both amiodarone and placebo arms. AMIOVIRT ¼ Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic non-sustained ventricular tachycardia; CAT ¼ Cardiomyopathy Trial; COMPANION ¼ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; CRT ¼ cardiac resynchronization therapy; CRT-D ¼ cardiac resynchronization therapy–defibrillator; CRT-P ¼ cardiac resynchronization therapy–pacemaker; DANISH ¼ Danish Study to Assess the Efficacy of ICDs in Patients with Non-Ischemic Systolic Heart Failure on Mortality; DEFINITE ¼ Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; ICD ¼ implantable cardioverter-defibrillator; SCD-HeFT ¼ Sudden Cardiac Death in Heart Failure Trial.
DATA EXTRACTION. Two reviewers (M.A.N., Y.R.)
to 75% were considered as low, moderate, and high
independently examined the study titles, abstracts,
heterogeneity, respectively. An exclusion sensitivity
and full-length articles identified by the described
analysis was included for heterogeneity, when neces-
search strategy to determine study inclusion and
sary. A meta-regression was performed when neces-
exclusion.
independently
sary to analyze the impact of moderator variables on
abstracted the study characteristics, design, methods,
outcomes of interest. A value of p < 0.05 was consid-
and relevant outcomes. Discrepancies between the 2
ered statistically significant. Analyses were per-
reviewers were infrequent and resolved by consensus
formed by M.A.N. using the software Comprehensive
or by consulting with a third reviewer.
Meta-Analysis (version 3.3.07, Michael Borenstein,
These
reviewers
also
OUTCOMES. 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. STATISTICAL
Englewood, New Jersey). This study was exempt from institutional review board approval at our institution.
RESULTS STUDY CHARACTERISTICS. Of the 6 RCTs included in
the meta-analysis, CAT (Cardiomyopathy Trial) and ANALYSIS. Categorical
were
DEFINITE (Defibrillators in Non-Ischemic Cardiomy-
pooled using the random effects model, with the
data
opathy Treatment Evaluation) compared ICD to med-
pooled effect size represented as RR with 95% CI
ical therapy (14,15), whereas AMIOVIRT (Amiodarone
limits. When studies were homogeneous (I 2 ¼ 0), we
versus implantable cardioverter-defibrillator: ran-
performed both fixed effects and random effects
domized trial in patients with nonischemic dilated
analyses. Analysis was stratified by CRT status. In
cardiomyopathy and asymptomatic non-sustained
studies/patients without CRT, the efficacy of ICD was
ventricular tachycardia) compared ICD to amiodar-
compared with medical therapy. In studies/patients
one (16). Two trials (SCD-HeFT and COMPANION) had
with CRT, the efficacy of CRT-D was compared with
3 comparison groups each (1,12). SCD-HeFT compared
CRT-P (Figure 1). Publication bias was assessed using
ICD versus amiodarone versus placebo (we merged the
the funnel plot. Cochrane Q statistics were used to
amiodarone and placebo groups into a single “no-ICD”
determine the heterogeneity of included studies for
control group in the present analysis), whereas
each outcome. I2 values <25%, 25% to 50%, and 50%
COMPANION compared CRT-D and CRT-P versus
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Anantha Narayanan et al.
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T A B L E 1 Randomized Controlled Clinical Trials Included in the Analysis
Study Name (Ref. #)
Enrollment Years
Publication Year
Comparison Groups
Mean Follow-Up (months)
CAT (14)
1991–1997
2002
EF #30% NYHA II–III
ICD vs. medical therapy
w23
AMIOVIRT (16)
1996–2000
ICM: No NICM: Yes CRT: No
EF #35% NSVT NYHA I–III
ICD vs. amiodarone
w24
DEFINITE (15)
458
ICM: No NICM: Yes CRT: No
EF #35% PVCs or NSVT
ICD vs. medical therapy
w29
SCD-HEFT (1)
2,521
1,211*
ICM: Yes NICM: Yes CRT: No
EF #35% NYHA II–III
ICD vs. amiodarone vs. medical therapy
w46
2004
1,520
552*
ICM: Yes NICM: Yes CRT: Yes
EF #35% NYHA III–IV QRS >120 ms
CRT-D vs. CRT-P vs. medical therapy
w16
2016
1,116
ICM: No NICM: Yes CRT: Yes
EF #35% NYHA II–IV Optimal medical therapy†
ICD with or without CRT-D vs. optimal medical therapy with or without CRT-P
w68
No. Overall
No. Included
Participants
104
104
ICM: No NICM: Yes CRT: No
2003
103
103
1998–2002
2004
458
1997–2001
2005
COMPANION (12)
2000–2002
DANISH (7)
2008–2014
1,116
Patient Characteristics
*Patients with ischemic cardiomyopathy were excluded from SCD-HeFT, and patients with ischemic cardiomyopathy and those randomized to medical therapy arm in COMPANION were excluded. †Patients in NYHA functional class IV only if cardiac resynchronization therapy was planned. Trial was specifically designed to be conducted on patients receiving maximally tolerated guideline-directed medical therapy. AMIOVIRT ¼ Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic non-sustained ventricular tachycardia; CAT ¼ Cardiomyopathy Trial; COMPANION ¼ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; CRT-D ¼ cardiac resynchronization therapy–defibrillator; CRT-P ¼ cardiac resynchronization therapy–pacemaker; DANISH ¼ Danish Study to Assess the Efficacy of ICDs in Patients with Non-Ischemic Systolic Heart Failure on Mortality; DEFINITE ¼ Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; EF ¼ ejection fraction; ICD ¼ implantable cardioverter-defibrillator; ICM ¼ ischemic cardiomyopathy; NICM ¼ nonischemic cardiomyopathy; NSVT ¼ nonsustained ventricular tachycardia; NYHA ¼ New York Heart Association functional class; PVC ¼ premature ventricular contraction; SCD-HeFT ¼ Sudden Cardiac Death in Heart Failure Trial.
medical therapy (we excluded medical therapy group
Funnel plot showed minimal bias (Online Figure 2),
in the present analysis). Finally, DANISH compared
and heterogeneity within the included studies was
ICD (with or without CRT-D) with medical therapy
low (I 2 ¼ 0). A meta-regression of all-cause death on
(with or without CRT-P) (7).
the follow-up time period was statistically nonsig-
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.
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. PATIENTS:
ICD
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 ¼ 0.19) (Figure 3). Given the smaller number of studies in this group, funnel plot for bias assessment
DISTRIBUTION OF THERAPY. Of the 3,544 patients
NON-CRT
nificant (p ¼ 0.48).
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
VERSUS
MEDICAL
in the control group. Among these patients, the risk of
THERAPY. Among patients without a CRT, the risk of
SCD was 73% lower in patients assigned to ICD (RR:
all-cause mortality was 24% lower in those assigned
0.27; 95% CI: 0.15 to 0.50; p < 0.001) when compared
to ICD compared to those assigned to medical therapy
to medical therapy (Figure 4). Sensitivity analysis af-
(RR: 0.76; 95% CI: 0.63 to 0.91; p ¼ 0.003) (Figure 2).
ter excluding the study with the maximum strength
Sensitivity analysis after excluding the study with the
(1) did not alter the results. Heterogeneity within the
maximum strength (7) did not alter the results.
included studies was low (I2 ¼ 0).
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DISCUSSION The major finding of this meta-analysis is that among
ICD Efficacy in Nonischemic Cardiomyopathy
F I G U R E 2 Forest Plot and Pooled Analysis for All-Cause Mortality (n ¼ 2,347) in NICM
Patients Without CRT (ICD vs. Medical Therapy Alone)
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
CI ¼ confidence interval; NICM ¼ nonischemic cardiomyopathy; RR ¼ relative risk; other abbreviations as in Figure 1.
without CRT-P) (7). The medical therapy in DANISH consisted of aggressive use of currently available guideline-directed medical therapy, including beta-
and SCD prevention, and suggests that the absence of
blockers, angiotensin-converting enzyme inhibitors
benefit of ICD in DANISH could have been related to
or angiotensin receptor blockers, and mineralocorti-
selection of an older population with higher noncar-
coid receptor antagonists. In comparison, previously
diac mortality. Thus, based on the current results, we
conducted ICD trials enrolled patients in an era when
speculate that ICD therapy is of benefit among
the use of heart failure therapy (particularly the
appropriately selected patients with NICM, particu-
target doses of medications that were achieved) was
larly if they are younger.
not as robust as noted in DANISH. To that effect, the
It is generally accepted that CRT improves EF and
event rate in DANISH was lower than that reported in
significantly reduces both sudden and nonsudden
previous landmark ICD trials.
death in a substantial proportion of patients with
However, several issues, merit discussion when
low EF and left bundle branch block (12). Given that
evaluating the findings of DANISH. First, in DANISH,
a significant proportion of patients have improved
w60% of the population had CRT. Subgroup analysis
EF >35% after CRT implantation, the benefit of having
among patients without CRT was underpowered to
a primary prevention ICD in such patients is unclear.
determine whether ICD therapy alone was better than
Thus far, COMPANION has been the only randomized
medical therapy. Second, although aggressive use of
clinical trial to compare patients with CRT-D and
heart failure therapy (reaching near-target doses in
CRT-P (12). Although both CRT arms were associated
significant proportion of the patients) was pursued in
with improved survival compared to medical therapy,
DANISH, this does not necessarily reflect the practice
the trial was not statistically powered to compare the
in the real-world setting. Indeed, in a recent analysis
CRT-D and CRT-P populations per se. Subgroup anal-
from the National Cardiovascular Data Registry on
ysis of COMPANION subsequently showed that in the
w20,000 patients, use of guideline-directed medical
overall population (which included both ischemic and
therapy was significantly low at around 50% to 70%
nonischemic patients), CRT-D failed to show survival
and was strongly linked to survival (17). Finally, the
benefit over CRT-P (p ¼ 0.12) (18,19). Similar results
median age in DANISH was higher than in DEFINITE
were noted in DANISH, in which 58% of patients had
and SCD-HEFT. A subgroup analysis of DANISH
CRT. However, this subgroup in DANISH also was
demonstrated mortality benefit with ICD therapy
similarly underpowered to assess a meaningful dif-
among patients younger than 68 years. Our meta-
ference between the CRT-D and CRT-P arms, especially
analysis confirms this benefit of ICD implantation
with the relatively low event rates in the trial.
5
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F I G U R E 3 Forest Plot and Pooled Analysis for All-Cause Mortality (n ¼ 1,197) in NICM Patients With CRT (CRT-D vs. CRT-P)
Abbreviations as in Figures 1 and 2.
Despite combining the NICM groups from both trials in
of SCD compared to ischemic cardiomyopathy (1). One
the current meta-analysis, the comparison of CRT-D
possible explanation for the lower risk of SCD is the
with CRT-P did not have sufficient power to deter-
higher likelihood of improvement of EF in patients
mine superiority of either modality over the other,
with NICM compared to ischemic cardiomyopathy
suggesting that further research is necessary to answer
(20). Indeed, improvement in EF can be seen in 40%
this question.
to 50% of patients with NICM, which is associated
Except for some rare specific conditions such as
with a dramatic reduction in mortality and SCD risk
end-stage hypertrophic cardiomyopathy or cardiac
(21–23). However, recent data shows that the relative
sarcoidosis, which may have a high burden of ven-
benefit of ICD therapy is maintained among these
tricular arrhythmias, NICM in general has a lower risk
patients even after EF improvement (10).
F I G U R E 4 Forest Plot and Pooled Analysis for Sudden Cardiac Death (n ¼ 1,772)
Data available from only 3 studies (AMIOVIRT, DEFINITE, and SCD-HeFT), which included only non-CRT patients. Abbreviations as in Figures 1 and 2.
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STUDY
ICD Efficacy in Nonischemic Cardiomyopathy
LIMITATIONS. 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.
PERSPECTIVES 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.
CONCLUSIONS 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. ADDRESS
Anantha
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
FOR
CORRESPONDENCE:
Narayanan,
Division
of
Dr. Mahesh
Cardiovascular
Diseases, University of Minnesota, Mayo Mail Code 508, 420 Delaware Street SouthEast, Minneapolis,
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.
Minnesota 55455. E-mail: [email protected].
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KEY WORDS implantable cardioverterdefibrillator, meta-analysis, mortality, nonischemic cardiomyopathy, systematic review
A PPE NDI X For supplemental figures, please see the online version of this paper.