Journal of Cardiac Failure Vol. 17 No.

10 2011

Mortality Reduction of Cardiac Resynchronization and

Implantable Cardioverter-Defibrillator Therapy in Heart
Failure: An Updated Meta-Analysis. Does Recent Evidence
Change the Standard of Care?
EDUARDO GEHLING BERTOLDI, MD, MSc,1,2 CARISI ANNE POLANCZYK, MD, ScD,1,2,3 VIVIAN CUNHA, MS,1
PATRÍCIA KLARMANN ZIEGELMANN, ScD,2 LUIS BECK-DA-SILVA, MD, ScD,3
AND LUIS EDUARDO ROHDE, MD, ScD1,3
Porto Alegre, Brazil

ABSTRACT

Background: The recent publication of the MADIT-CRT and RAFT trials has more than doubled the
number of patients in which a direct comparison of the combination of cardiac resynchronization therapy
(CRT) and implantable cardioverter-defibrillator (ICD) versus ICD alone was carried out. The present
meta-analysis aims to assess the impact of combined CRT and ICD therapy on survival of heart failure
(HF) patients.
Methods and Results: Medline, Embase, and the Cochrane Library databases were searched, and all ran-
domized controlled trials of CRT alone or combined with ICDs in HF resulting from left ventricular sys-
tolic dysfunction were included. Main outcome was all-cause mortality. Summary relative risk (RR) and
95% confidence interval (CI) were calculated employing random-effects models. Twelve studies were in-
cluded, with a total of 8,284 randomized patients. For the comparison of CRT alone versus medical ther-
apy, pooled analysis of 5 available trials demonstrated a significant reduction in all-cause mortality with
CRT (RR 0.76, 95% CI: 0.64e0.9). Pooled analysis of 6 trials that compared the combination of CRT and
ICD therapy to ICD alone also showed a statistically significant reduction in all-cause mortality (RR 0.83,
95% CI: 0.72e0.96). Stratified analysis showed significant mortality reductions in all New York Heart As-
sociation class subgroups, with greater effect in classes IIIeIV (RR 0.70; 95% CI: 0.57e0.88). Pooled
estimates of implant-related risks were 0.6% for death and 8% for implant failure.
Conclusion: Combined CRT and ICD therapy reduces overall mortality in HF patients when compared
with ICD alone. (J Cardiac Fail 2011;17:860e866)
Key Words: Heart failure, cardiac resynchronization therapy, implantable cardioverter-defibrillator, meta-
analysis.

Heart failure (HF) is a leading cause of cardiovascular options. In addition to pharmacologic therapies, device-
morbidity and mortality worldwide.1 Because of its in- based treatmentsdnamely the use of implantable
creased prevalence in the elderly and the progressive aging cardioverter-defibrillators (ICDs) and biventricular cardiac
of the population in many countries, the incidence of HF is pacing devices capable of delivering cardiac resynchroniza-
increasing,1,2 despite modern diagnostic and therapeutic tion therapy (CRT)dare now considered an important part of

From the 1Postgraduate Program in Cardiology and Cardiovascular Funding from the National Council for Scientific and Technological De-
Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil; velopment (CNPq), Brazil. The funder did not contribute to the study de-
2
National Institute for Health Technology Assessment (IATS), National sign, and had no role in the conduct of the study, collection, management,
Council for Scientific and Technological Development (CNPq), Brazil analysis, or interpretation of the data, nor in preparation, review, or ap-
and 3Cardiovascular Division of Hospital de Clınicas de Porto Alegre, proval of the manuscript.
Brazil. See page 865 for disclosure information.
Manuscript received April 4, 2011; revised manuscript received May 24, 1071-9164/$ - see front matter
2011; revised manuscript accepted June 8, 2011. Ó 2011 Elsevier Inc. All rights reserved.
Reprint requests: Luis Eduardo Rohde, MD, ScD, Serviço de Cardiolo- doi:10.1016/j.cardfail.2011.06.372
gia, Hospital de Clınicas de Porto Alegre. Rua Ramiro Barcelos 2350, Sala
2061, Porto Alegre, RS, Brazil 90035-003. E-mail: [email protected]

860
 CRT and ICD: An Updated Meta-Analysis  Bertoldi et al 861

HF treatment in selected patients.3 ICDs reduce sudden car- analysis. Disagreements in the selection processes were resolved
diac death4 and CRT has a beneficial impact on HF symp- by adjudication by a third investigator and final consensus.
toms, hospitalization, and survival,5 when added to optimal
Study Quality Assessment
medical therapy. However, whether the combination of
both treatments would bring additional benefit over either Assessment of methodological quality and potential to bias was
treatment alone is still an object of debate. Earlier trials in- performed by gathering information regarding the concealment of
cluded patients with advanced HF (New York Heart Associ- treatment allocation, blinding, and intention to treat analysis on
ation [NYHA] class IIIeIV), whereas later trials each included study.
predominantly included patients with mild to moderate HF
Outcomes
(NYHA class IeII). When previous meta-analyses were per-
formed, few trials had directly compared the combination of Primary outcome was all-cause mortality. For crossover trials,
CRT and ICD to either therapy alone. Previous investigators only results from the first period were considered. Additional out-
had to use strategies such as exploratory meta-regression comes assessed were failure to implant resynchronization devices,
analyses6,7 or Bayesian network meta-analysis8 to combine and major implant-related complications. The authors’ definitions
the results of the available trials, most of which compared for major implant-related complications were implicitly accepted.
the use of either ICD or CRT to medical therapy. Statistical Analysis
Since then, the publication of the MADIT-CRT trial9
and, more recently, the RAFT trial,10 comparing the combi- Because between-study differences to the extent of compromis-
nation of CRT and ICD to ICD alone, has more than dou- ing a fixed-effect analysis were expected, independently of statis-
bled the number of patients subjected to this comparison. tical heterogeneity tests, we used random-effects models for all
comparisons as our main analysis. Fixed-effect models were
This allows an updated combined analysis, adding greater
used for sensitivity analysis in the mortality estimates. For mortal-
reliability to the available information. We have performed ity and hospitalizations, pairwise comparisons were performed
a systematic review, including the latest trials to evaluate separately for the combination of CRT and ICD versus ICD alone,
the effect of the combination of CRT and ICD therapy on and for CRT alone versus medical therapy (MT). Additionally, to
HF mortality, compared with optimal medical therapy alone evaluate the impact of NYHA class on the results of CRT, we per-
and with ICD therapy alone; to explore the impact of formed comparisons for CRT versus no CRT in studies that re-
NYHA class on the benefit of CRT therapy (alone or in stricted inclusion to patients in NYHA Class III or IV, and in
combination); and to assess the pooled estimate of major studies that restricted inclusion to patients in NYHA Class I or II.
implant-related complications with CRT-capable devices Odds ratios from each study were combined, using the inverse
by single-branch meta-analysis. variance method, to provide a pooled risk ratio, using the Review
Manager Software package, version 5.0. For implant failure and
major implant complications, we performed single-branch meta-
Methods analysis with random-effects model, pooling the incidence of
Search Strategy each outcome for patients that received CRT-capable devices
(with or without ICD capability), using the STATA software pack-
We searched Medline, Embase, and the Cochrane Library data- age, version 11. Tests for heterogeneity were performed for all
bases, using a highly sensitive strategy.11 We used keywords and analyses, as well as quantification by the I2 statistic. A P value
MeSH terms such as ‘‘resynchroni?ation therapy’’, ‘‘cardiac pace- #.05 was considered statistically significant both for the overall
maker, artificial’’, ‘‘Defibrillators, Implantable’’, ‘‘((biventricular effect and for the presence of heterogeneity. Funnel plots were
or dual-chamber or single-chamber) adj1 (pacing or pacer or stim- used to investigate the possibility of publication bias.
ulat$))’’, ‘‘heart failure, congestive’’, and several variations. The
detailed search strategy can be found on Supplementary Table A Results
(online only).
Additionally, to address the issue of studies not included in Included studies
these databases, we reviewed the reference lists of the identified
Results of the study search and selection are summarized
studies and previous meta-analyses, and consulted with experts
on the subject. in Figure 1. Twelve randomized controlled trials met the in-
clusion criteria,9,10,12e21 4 of which had a crossover phase
Study Selection (MUSTIC-SR,12 MUSTIC-AF,14 CONTAK CD,15 and
HOBIPACE20). Five trials evaluated combined CRT and
To be considered for inclusion, studies had to be randomized ICD therapy versus ICD only (CONTAK CD,15 MIRACLE
controlled trials, either parallel or crossover, with more than 2 ICD,16 MIRACLE ICD II,17 MADIT-CRT,9 and RAFT10),
weeks of duration, that included patients with HF from left ven-
4 trials compared CRT to medical therapy alone
tricular systolic dysfunction, and evaluated CRT, either alone or
in combination to ICD therapy, versus medical therapy or ICD
(MUSTIC-SR,12 MUSTIC-AF,14 MIRACLE,13 and CARE-
therapy alone. The control group should not receive any sort of HF19), 1 trial had a triple comparison of CRTþICD versus
resynchronization therapy. CRT versus medical therapy (COMPANION18), and 1 trial
Two investigators independently screened titles and abstracts to compared CRT to medical therapy, but 85% of patients in
identify eligible studies, according to the inclusion criteria. Full- both groups also had ICD therapy (REVERSE21). All stud-
text versions of preselected studies were retrieved for detailed ies enrolled only patients with prolonged QRS interval and
862 Journal of Cardiac Failure Vol. 17 No. 10 October 2011

ventricular ejection fraction; MT, medical therapy; N, no; NA, not available; NYHA, New York Heart Association; RBBB, right bundle branch block; RCT, randomized controlled trial; RPT, randomized parallel
CA, concealed allocation; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; ITT, intention to treat analysis; MT, medical therapy; LBBB, left bundle branch; LVEF, left
UC/UC/UC
Blinding*

UC/N/Y
N/Y/UC
N/Y/UC

Y/Y/UC
Y/Y/UC

N/Y/UC
Y/Y/UC

Y/Y/UC
Y/Y/Y

Y/Y/Y

N/N/Y
CA/ITT

UC/UC
UC/UC
UC/Y
UC/Y

UC/Y
UC/Y

UC/Y

UC/Y
Y/Y

Y/Y

Y/Y
Y/Y
LBBB/

NA/NA
NA/NA
RBBB

NA/13
NA/17
87/NA

63/NA
(%)

70/11

70/12
44/26

72/9
NA

NA
Mean QRS

65% O 150
Duration
(ms)

N/A
176
209
166

164
165

160

160
174
154

157
Fig. 1. Flow diagram of study selection.

LVEF

21.7

22.6
(%)
23
26

22

25
26
26
24
22
24
24
HF patients were predominantly of ischemic etiology.
Mean age of participants ranged from 62 to 70 years. All
NYHA
Table 1. Characteristics of Included Studies

Class

III-IV

III-IV

III-IV
II-IV
II-IV

II-III
I-IV
I-II
I-II
III
III
but 2 of the studies clearly declared the use of intention-

II
to treat analysis. However, concealment of treatment alloca-
tion was unclear in most studies (Table 1).
Ischemic

Regarding functional class, 1 trial included only NYHA

N/A
(%)
43

54

70
57

55

38
57
55
55
67
69
Class II patients17; 2 trials included only NYHA Class III
patients12,14; 2 trials included NYHA Class II, III, and
IV patients15,18; 3 trials included NYHA Class III and IV
Mean
Age

patients13,16,19; 2 trials included NYHA Class I and II

(y)
63
66
64

67
63

67

67
70
62
65
66
66

patients9,21; 1 trial included patients in NYHA Class II

and III10; and 1 trial included patients in any NYHA class
(Table 1).20
Male

(%)
Sex

86
81
68

68

73
77
78
84
78
89

75
83
All-Cause MortalitydCRT versus MT
RPT/24 months

RPT/29 months

RPT/12 months
RPT/28 months
RPT/40 months
RCT/6 months
RCT/6 months

RCT/9 months
RCT/6 months
RPT/6 months

RPT/6 months
RPT/6 months
Follow-up

For the comparison of CRT alone versus medical therapy,

Design/

pooled analysis of 5 available trials demonstrated a signifi-

cant reduction in all-cause mortality with CRT (RR 0.76,
95% CI: 0.64e0.9) (Fig. 2A). No statistically significant 15% of patients in both groups did not receive ICD therapy.
heterogeneity was found (P 5 .71; I2 5 0%). Results
CRTþICD vs. ICDy
CRT on vs. CRT off
CRT on vs. CRT off

were not altered by removal of trials with less than 10

CRTþICD vs. ICD
CRTþICD vs. ICD
CRTþICD vs. ICD

CRTþICD vs. ICD

CRTþICD vs. ICD
CRTþMT vs. MT

CRTþMT vs. MT

*Blinding of patient/caregiver/endpoint assessment.

Intervention

events (RR 0.76, 95% CI: 0.60e0.95), or by fixed-effect

CRT vs. MT
CRTþICD vs.

analysis (RR 0.76, 95% CI: 0.64e0.9).12e14,20

CRT vs. MT

All-Cause MortalitydCRT D ICD versus ICD alone

Pooled analysis from 5 trials that compared the combina-

1520

1820
1798
453
581
369
186

813

610
58
43

33
N

tion of CRT and ICD therapy to ICD therapy alone showed

a statistically significant reduction in all-cause mortality
trial; UC, unclear; Y, yes.

(risk ratio [RR] 0.83, 95% confidence interval [CI]:

MIRACLE ICD, 200316

COMPANION, 200418
CONTAK CD, 200315
MUSTIC SR, 200112

0.72e0.96) (Fig. 2B). There was no statistically significant

MADIT-CRT, 20099
HOBIPACE, 200620
MUSTIC A, 200214

REVERSE, 200821
MIRACLE ICD II,

CARE HF, 200519

heterogeneity among trials (P 5 .91; I2 5 0%). Results re-

MIRACL, 200213
Acronym, Year

RAFT, 201010

mained similar after excluding the trial in which 15% of pa-

tients in both groups did not receive ICD therapy (RR 0.82,
200417

95% CI: 0.71e0.95),21 with fixed-effect analysis (RR 0.83,

y

95% CI: 0.72e0.96), and after restricting analysis to studies

 CRT and ICD: An Updated Meta-Analysis  Bertoldi et al 863

Fig. 2-A. All-cause mortalityeCRT versus MT. CRT, cardiac resynchronization therapy; IV, inverse variance method; MT, medical therapy.

with more than 6 months of follow-up (RR 0.83, 95% CI absolute risk of 0.6% (95% CI: 0.2%e2.2%) (Table 2).
0.71e0.96).9,10,21 Rate of peri-implant complications related to the left ventric-
Figure 3 represents the results of cumulative meta- ular lead was reported by 5 trials.9,16e19 Pooled analysis
analysis, adding studies 1 at a time in chronological order, showed a combined risk of 3% (95% CI: 1e8.7).
demonstrating that the point estimate suggested a reduction The rate of all types of implant-related complication
in mortality since the earlier trials. However, statistical sig- showed a progressive decline from earlier to more recent
nificance is evident only after adding the results of the studies. Restricting analysis to trials published after 2004
RAFT trial. reduced the pooled risks of implant failure to 6.3% (95%
CI: 4.3e9.2), any peri-implant complication to 9.8%
All-Cause MortalitydImpact of NYHA Class (95% CI: 6.3e15.4), complications related to left ventricu-
Stratified analyses showed that the lowest risk-ratio for lar lead to 1.8% (95% CI: 0.7e4.5), and implant-related
all-cause mortality was found in clinical trials that re- mortality to 0.2% (95% CI: 0.1e0.9).
stricted inclusion to patients in NYHA Class III and IV.
However, a significant mortality reduction was also present Discussion
in studies that did not make such restriction, and in those
that included only patients in NYHA Class I or II (Fig. 4). Since the publication of the CARE-HF trial19 and of pre-
vious meta-analyses,6e8 the effectiveness of CRT in reduc-
Implant Failure and ComplicationsdCRT-Capable
ing mortality of HF patients is well established, when
Devices
compared to medical therapy alone. However, because cur-
Implant failure rate for CRT devices was reported by all rent guidelines indicate the use of ICD therapy for most HF
but one20 of the included trials. Pooled analysis showed an patients with reduced left ventricular ejection fraction,3 the
8% risk of implant failure (95% CI: 6e11). Results were sim- consideration of adding CRT to patients already eligible to
ilar with fixed effect analysis. The rate of any major peri- receive ICD therapy is a clinically relevant dilemma in ev-
implant complications was reported by 7 trials.9,10,16e19,21 eryday practice, because patients with HF frequently fulfill
Pooled analysis resulted in a risk of major complication of the indication criteria for both devices.
13.2% (95% CI: 7.3e23.9). Implant-related mortality was In this scenario, one must consider that the addition of
reported by 5 trials,10,14,15,18,19 with a pooled estimation of CRT to ICD therapy is an expensive strategy, and device

Fig. 2-B. All-cause mortalityeCRT þ ICD versus ICD alone. CRT, cardiac resynchronization therapy; ICD, implantable cardioverter de-
fibrillator therapy; IV, inverse variance method.
864 Journal of Cardiac Failure Vol. 17 No. 10 October 2011

Fig. 3. Cumulative meta-analysis of all-cause mortality with CRTþICD versus ICD alone. CRT, cardiac resynchronization therapy; ICD,
implantable cardioverter defibrillator therapy; IV, inverse variance method. Note that the point estimate suggests a reduction in mortality
since the earlier trials, but statistical significance only appears after addition of the RAFT trial.

implantation is technically more difficult and risky. Com- assessment of the 2 strategies were scarce. Since then, the
mon sense and rationalization of resource use indicate publication of REVERSE,21 MADIT-CRT,9 and the re-
that hard clinical evidence demonstrating the additional cently published RAFT trial10 have added a great number
benefit should be available before broad implementation of HF patients that were allocated to combined device ther-
of combined therapy (CRT þ ICD). Earlier trials had apy. RAFT trial was the first individual study to show a sig-
used surrogate endpoints such as exercise capacity, and nificant reduction in mortality with the addition of CRT to
larger trials focused on combined endpoints such as HF ICD therapy, whereas the MADIT-CRT trial failed to dem-
or death. In this context, meta-analysis is a useful statistic onstrate such benefit. The absence of survival benefit in ear-
tool, making it possible to combine the results from all lier trials, including MADIT-CRT, may be due, in part, to
available trials to produce more robust evidence of reduc- the fact that previous studies comparing CRT þ ICD to
tion of hard endpoints. ICD alone have included patients in less advanced stages
Previously published meta-analysis seeking to answer of HF, and follow-up periods were relatively short (most of-
this question yielded conflicting results,6e8 but they were ten less than 1 year). The RAFT trial, in contrast, was the
limited to indirect comparisons (such as meta-regression study with the longest follow-up period among all CRT tri-
or Bayesian meta-analysis), because data on direct als. Our data indicate that all available studies were

Fig. 4. Stratified analysis of all-cause mortality according to NYHA class and inclusion of ICD therapy. CI, confidence interval; ICD, im-
plantable cardioverter-defibrillator; NYHA, New York Heart Association; RR, relative risk.
 CRT and ICD: An Updated Meta-Analysis  Bertoldi et al 865

Table 2. Pooled Incidence of Implant-Related Complications

Complication Rate (Absolute) 95% CI Studies with Available Data
Implant failure 8% 6%e11% 9, 10, 12, 14-17, 19, 21
Any major complication 13.2% 7.3%e23.9% 9, 10, 16-19, 21
LV lead complication 3% 1%e8.7% 9, 16-19
Implant-related mortality 0.6% 0.2%e2.2% 10, 14, 15, 18, 19

LV, left ventricular.

homogeneous and that there is a significant beneficial effect This information may be useful for selection of patients that
in adding CRT to most HF patients that are eligible for ICD benefit the most from CRT, in budget-constrained scenar-
therapy. It is noteworthy that the pooled model that showed ios. Cost-effectiveness studies of CRT that incorporate
that sequentially adding trials did not lead to statistical sig- these latest findings may provide additional information
nificance until the RAFT trial was added. This major effect in the future.
of 1 trial can be explained because the number of events Our study design deserves several considerations. Firstly,
was tripled after the RAFT trial was published. Moreover, the unavailability of raw data of HF hospitalization did not
data from cumulative meta-analysis demonstrates consis- allow us to produce a reliable pooled estimate of the impact
tency of effect size over time (Fig. 3), and make a strong of CRT in HF symptoms. In addition, the follow-up period
case for a significant mortality reduction with the addition for earlier trials that compared CRT þ ICD to ICD alone
of CRT to ICD. was 12 months or less, which limits their ability to detect
Another potential benefit of the addition of CRT to ICD long-term effects on mortality. The Kaplan-Meier estimates
therapy is the reduction of HF-related symptoms. Trials that of death from any cause in the RAFT trial show a slight in-
evaluated combined device therapy have demonstrated im- crease in the benefit of CRT over time, which suggests that
provement in exercise capacity,15e17 improvement in longer follow-up in the earlier trials might have yielded
NYHA class,16,17 or composite clinical endpoints including a mortality reduction of greater magnitude. It is worth not-
symptoms requiring augmentation of decongestive medica- ing, however, that restricting the analysis to trials with
tions.9 Reduction of HF hospitalizations is a more robust follow-up longer than 6 months did not significantly alter
evidence of symptomatic benefit, especially considering our results.
the partially unblinded nature of many of the trials. Our ini- Publication bias should always be considered a potential
tial intention was to pool hospitalization data from trials limitation in meta-analysis. In the case of our results, funnel
that compared CRT þ ICD to ICD alone. However, three plots showed some asymmetry, but their results would sug-
trials reported only the number of hospitalized pa- gest that studies favoring CRT were less likely to be pub-
tients,10,15,16 1 trial reported the total number of hospitali- lished (Supplementary Figures A and B [online only]).
zations,21 and 1 of the 2 largest trials, MADIT-CRT,9 did Consequently, if publication bias did exist, the true relative
not report hospitalization rates. We considered that pooling risk reduction with CRT would be even greater than ob-
these data would not properly represent true effects. Unfor- served in our results.
tunately, we were unable to obtain raw patient data directly
from authors, which would allow us to pool incidence of Conclusion
a single outcome in all trials.
Our study also provided a pooled estimate of the risk of The current meta-analysis included new data from the
peri-implant complications. These risks should not be REVERSE, MADIT-CRT, and RAFT trial, adding a total
underestimated in the process of defining CRT indication of 4228 HF patients to previous evaluations. Our findings
to a broad population of HF patients. Possibly related to support a profound reduction in all-cause mortality with
progress in device design and greater operator experience, CRT when compared to optimal medical therapy in selected
the incidences of all complications have declined in more patients with systolic HF and prolonged QRS duration. Ad-
recent studies, as clearly demonstrated in the decrease in ditionally, our results show compelling evidence that the
peri-implant mortality over time. combination of CRT and ICD therapy also reduces overall
Finally, HF severity seems to be an important aspect that mortality, when compared to ICD alone, an effect that is
influences the magnitude of benefit in the response to CRT. greater in patients in NYHA Class III or IV. Finally, our
Individual trials that included patients in NYHA functional data suggest that morbidity and mortality associated to im-
Class I have not showed a significant mortality reduction. plant procedure is not negligible, but has decreased over
When we performed stratified meta-analysis of the studies time.
according to NYHA class, we found that trials that limited
inclusion to patients in NYHA Class III and IV had the Disclosures
greatest mortality reduction, although studies with other
combinations of NYHA class also had a significant benefit. None.
866 Journal of Cardiac Failure Vol. 17 No. 10 October 2011

Supplementary Data 11. Higgins JPT, Green S, Cochrane Collaboration. Cochrane handbook
for systematic reviews of interventions. Chichester, UK: Wiley-Black-
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online at doi:10.1016/j.cardfail.2011.06.372 12. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al.
Effects of multisite biventricular pacing in patients with heart failure
and intraventricular conduction delay. N Engl J Med 2001;344:
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