Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials
==================================================================================

* George Wells
* Ratika Parkash
* Jeffrey S. Healey
* Mario Talajic
* J. Malcolm Arnold
* Shannon Sullivan
* Joan Peterson
* Elizabeth Yetisir
* Patricia Theoret-Patrick
* Marilynn Luce
* Anthony S.L. Tang

## Abstract

**Background** Studies of cardiac resynchronization therapy in addition to an implantable cardioverter defibrillator in patients with mild to moderate congestive heart failure had not been shown to reduce mortality until the recent RAFT trial (Resynchronization/Defibrillation for Ambulatory Heart Failure Trial). We performed a meta-analysis including the RAFT trial to determine the effect of cardiac resynchronization therapy with or without an implantable defibrillator on mortality.

**Methods** We searched electronic databases and other sources for reports of randomized trials using a parallel or crossover design. We included studies involving patients with heart failure receiving optimal medical therapy that compared cardiac resynchronization therapy with optimal medical therapy alone, or cardiac resynchronization therapy plus an implantable defibrillator with a standard implantable defibrillator. The primary outcome was mortality. The optimum information size was considered to assess the minimum amount of information required in the literature to reach reliable conclusions about cardiac resynchronization therapy.

**Results** Of 3071 reports identified, 12 studies (*n* = 7538) were included in our meta-analysis. Compared with optimal medical therapy alone, cardiac resynchronization therapy plus optimal medical therapy significantly reduced mortality (relative risk [RR] 0.73, 95% confidence interval [CI] 0.62–0.85). Compared with an implantable defibrillator alone, cardiac resynchronization therapy plus an implantable defibrillator significantly reduced mortality (RR 0.83, 95% CI 0.72–0.96). This last finding remained significant among patients with New York Heart Association (NYHA) class I or II disease (RR 0.80, 95% CI 0.67–0.96) but not among those with class III or IV disease (RR 0.84, 95% CI 0.69–1.07). Analysis of the optimum information size showed that the sequential monitoring boundary was crossed, which suggests no need for further clinical trials.

**Interpretation** The cumulative evidence is now conclusive that the addition of cardiac resynchronization to optimal medical therapy or defibrillator therapy significantly reduces mortality among patients with heart failure.

Congestive heart failure is currently reaching epidemic proportions in Canada, with 500 000 Canadians affected and 50 000 new patients identified each year.1 It accounts for more than 100 000 hospital admissions per year and has a one-year mortality ranging from 15% to 50%, depending on the severity of heart failure.2 By 2050, the number of patients with heart failure is projected to increase threefold.2

Advances in medical therapies have resulted in substantial reductions in mortality associated with congestive heart failure.3–7 The use of devices has recently become an important adjuvant therapy.8 Cardiac resynchronization therapy involves pacing from both the right and left ventricles simultaneously to improve myocardial efficiency (see radiographs in Appendix 1, at [www.cmaj.ca/cgi/content/full/cmaj.101685/DC1](http://www.cmaj.ca/cgi/content/full/cmaj.101685/DC1)). Cardiac resynchronization therapy has been shown to reduce morbidity and, when compared with medical therapy alone, to reduce mortality.9–13 Until recently, it was not shown to reduce mortality among patients who also received an implantable cardioverter defibrillator. Among patients receiving optimal medical therapy, the Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) showed the superiority of cardiac resynchronization therapy in addition to an implantable defibrillator over a standard implantable defibrillator in reducing mortality and the combined outcome of death from any cause or hospital admission related to heart failure.14

We performed a meta-analysis to further assess the effect on mortality of cardiac resynchronization therapy with and without an implantable defibrillator among patients with mildly symptomatic and advanced heart failure.

## Methods

We used the PICO (population, intervention, comparison and outcome) approach to develop the research question for our systematic review. The population of interest included patients with mildly symptomatic or advanced heart failure, with a QRS interval of more than 120 ms. The intervention of interest was cardiac resynchronization therapy with or without an implantable cardioverter defibrillator in patients receiving optimal medical therapy. Comparisons between the following interventions were made: cardiac resynchronization therapy versus optimal medical therapy alone; and cardiac resynchronization therapy with an implantable defibrillator versus a standard implantable defibrillator. Optimal medical therapy was defined as evidence-based use of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II receptor blockers, β-blockers, spironolactone (if indicated) and diuretics at a stable dose for at least one month. The primary outcome was all-cause mortality. Only studies that provided mortality data were included.

### Literature search

We searched the MEDLINE (1980 to Dec. 31, 2010), EMBASE (1980 to Dec. 31, 2010) and Cochrane Library (1980 to Dec. 31, 2010) databases for literature on cardiac resynchronization therapy and implantable defibrillator in patients with heart failure. We also searched various sources of grey literature as well as the US Food and Drug Administration website. Bibliographies of relevant systematic reviews were manually searched. Details of our search strategies are available in Appendix 2 ([www.cmaj.ca/cgi/content/full/cmaj.101685/DC1](http://www.cmaj.ca/cgi/content/full/cmaj.101685/DC1)).

Eligible studies were randomized controlled trials evaluating the effects of cardiac resynchronization therapy compared with control in adults with symptomatic heart failure or arrhythmia. Patients may also have been receiving medical therapy or have an implantable defibrillator.

### Data extraction

Two of us (R.P. and J.H.) independently screened each citation for inclusion. Two reviewers (G.W. and R.P.) independently reviewed the full-text version of relevant articles and extracted the following data from the included studies: baseline characteristics of the study population, interventions and comparison groups, features of the study design, and the outcome of mortality. If necessary, discrepancies between the two reviewers were resolved by discussion involving a third independent reviewer (A.T.) to achieve consensus.

### Assessment of risk of bias

The Cochrane Risk of Bias Tool was used to assess the risk of bias in the included studies.15 With respect to trials evaluating cardiac resynchronization therapy, random allocation of patients after implantation of the device, rather than before implantation, is an important source of bias, because these trials likely overestimate the potential benefits of the intervention.

### Statistical analysis

Data were pooled using the random-effects model, and treatment effect was expressed as a relative risk. Heterogeneity was evaluated using the *I*2 statistic. Subgroup analysis was conducted for New York Heart Association (NYHA) class. The optimum information size was considered for assessing the minimum amount of information required in the literature to reach reliable conclusions about cardiac resynchronization therapy.16–18

## Results

The literature search identified 3071 citations (Figure 1). Of these, the full-text versions of 140 articles were retrieved for further review. (The list of excluded studies is available in Appendix 3, at [www.cmaj.ca/cgi/content/full/cmaj.101685/DC1](http://www.cmaj.ca/cgi/content/full/cmaj.101685/DC1).) If duplicate reports of the same study were found in preliminary abstracts and articles, the data from the most complete dataset were analyzed. In total, 12 trials met the selection criteria for inclusion in our meta-analysis.14,19–29

![Figure 1:](http://www.cmaj.ca/https://www.cmaj.ca/content/cmaj/183/4/421/F1.medium.gif)

[Figure 1:](http://www.cmaj.ca/content/183/4/421/F1)

Figure 1: 
Flow diagram of selection of studies for the meta-analysis.

The characteristics of the 12 trials are summarized in Table 1 (additional details about the studies are available in Appendix 4, at [www.cmaj.ca/cgi/content/full/cmaj.101685/DC1](http://www.cmaj.ca/cgi/content/full/cmaj.101685/DC1)). A total of 7538 patients were enrolled in these trials (4244 in the cardiac resynchronization therapy groups and 3294 in the control groups). Five trials compared cardiac resynchronization therapy plus optimal therapy (*n* = 1342) with optimal medical therapy alone (*n* = 1013).20,21,24,26,27 Seven trials compared cardiac resynchronization therapy and an implantable defibrillator (*n* = 2902) with an implantable defibrillator (*n* = 2281).14,19,22,23,25,28,29 The length of follow-up ranged from 3 to 40 months. Five studies had a follow-up of 12 months or less.19–23 Male patients accounted for 63% to 89% of the study populations. The mean age varied from 62 to 66 years.

View this table:
[Table 1:](http://www.cmaj.ca/content/183/4/421/T1)

Table 1: 
Characteristics of 12 studies included in the meta-analysis of cardiac resynchronization therapy for congestive heart failure

All of the 12 studies included patients with ischemic (38%–70% of patients) and non-ischemic cardiomyopathy. The mean left ventricular ejection fraction was consistent across the studies (21%–25%). The distribution by NYHA class was as follows: four studies enrolled only patients with NYHA class I or II heart failure; four other studies enrolled only patients with NYHA class III or IV disease; in the remaining four studies, 8%–80% of patients had NYHA class I or II disease (20%–92% had NYHA class III or IV disease). Although the minimum duration of QRS interval required for patient enrolment differed between the studies, the mean QRS interval was similar across the studies (153–176 ms).

The risk of bias was often low except for implantation of the cardiac synchronization therapy device after randomization19–23,25,27,28 (Table 2). (For details see Appendix 5, at [www.cmaj.ca/cgi/content/full/cmaj.101685/DC1](http://www.cmaj.ca/cgi/content/full/cmaj.101685/DC1)).

View this table:
[Table 2:](http://www.cmaj.ca/content/183/4/421/T2)

Table 2: 
Methodologic quality of the 12 studies of cardiac resynchronization therapy included in the meta-analysis

### Overall effect of cardiac resynchronization therapy

A summary of the overall effect of cardiac resynchronization therapy on mortality is provided in Figure 2. In general, a relative risk reduction of 22% in mortality was found when cardiac resynchronization therapy was added to treatment (relative risk [RR] 0.78, 95% confidence interval [CI] 0.70–0.87); there was no significant heterogeneity across the trials (*I*2 = 0).

![Figure 2:](http://www.cmaj.ca/https://www.cmaj.ca/content/cmaj/183/4/421/F2.medium.gif)

[Figure 2:](http://www.cmaj.ca/content/183/4/421/F2)

Figure 2: 
Results of random-effects meta-analysis of overall mortality among patients with heart failure given cardiac resynchronization therapy (CRT) in addition to optimal medical therapy (OMT) or implantable cardioverter defibrillator (ICD). Values less than 1.0 indicate a decreased risk of death with cardiac resynchronization therapy. Note CI = confidence interval, RR = relative risk. For complete study names, see Box 1. *All patients received optimal medical therapy.

### Cardiac resynchronization therapy versus optimal medical therapy alone

Five studies evaluated the effect on mortality of cardiac resynchronization therapy plus optimal medical therapy versus optimal medical therapy alone.20,21,24,26,27 All of these studies involved patients with NYHA class III or IV heart failure. A significant relative risk reduction of 27% in mortality was found (RR 0.73, 95% CI 0.62–0.85) (Figure 2). There was no significant heterogeneity across the studies (*I*2 = 0); all studies indicated a relative risk reduction in mortality, but only the largest study (CARE-HF [Cardiac Resynchronization in Heart Failure]) reported a significant reduction (RR 0.65, 95% CI 0.53–0.80).26 Without the CARE-HF study, the reduction in mortality in the treatment group was not significant compared with optimal medical therapy alone. The CARE-HF study and the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) study,24 were the principal studies that led to the change in guidelines recommending that cardiac resynchronization therapy be used in addition to optimal medical therapy in patients with NYHA class III heart failure and ambulatory patients with NYHA class IV disease.

### Cardiac resynchronization therapy and implantable defibrillator versus implantable defibrillator

The intervention of cardiac resynchronization therapy and an implantable defibrillator, in addition to optimal medical therapy, was considered in seven studies that reported mortality.14,19,22,23,25,28,29 Patients with a spectrum of heart failure ranging from NYHA class I to IV were enrolled in these studies. A significant relative risk reduction of 17% was found (RR 0.83, 95% CI 0.72–0.96) (Figure 2). Although there was no significant heterogeneity across the studies (*I*2 = 0), before the RAFT study, three studies indicated a relative risk reduction in mortality and three studies indicated a relative risk increase; none of these relative risks was significant. RAFT was the largest study, with a significant relative risk reduction of 20% (RR 0.80, 95% CI 0.67–0.94).14 Without the RAFT study, the reduction in mortality with the intervention of cardiac resynchronization therapy and an implantable defibrillator was not significant (RR 0.93, 95% CI 0.70–1.23).

#### Patients with NYHA class I or II disease

The intervention of cardiac resynchronization therapy and an implantable defibrillator versus an implantable defibrillator in patients with NYHA class I or II heart failure was considered in four studies that reported mortality. A significant relative risk reduction of 20% in mortality was found (RR 0.80, 95% CI 0.67–0.96)14,23,28,29 (Figure 3). There was no significant heterogeneity across the studies (*I*2 = 0), with three studies having a non-significant reduction or increase in relative risk23,28,29 and only the RAFT study having a significant relative risk reduction of 26% (RR 0.74, 95% CI 0.59–0.92).14 Without the RAFT study, the reduction in mortality with cardiac resynchronization therapy and an implantable defibrillator was not significant (RR 0.97, 95% CI 0.70–1.34). The MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy) study was larger, but it reported a nonsignificant relative risk reduction of only 6% (RR 0.94, 95% CI 0.67–1.32).29

![Figure 3:](http://www.cmaj.ca/https://www.cmaj.ca/content/cmaj/183/4/421/F3.medium.gif)

[Figure 3:](http://www.cmaj.ca/content/183/4/421/F3)

Figure 3: 
Results of random-effects meta-analysis of overall mortality among patients with heart failure given cardiac resynchronization therapy plus an implantable cardioverter defibrillator (CRT-ICD) versus an implantable defibrillator (ICD), by New York Heart Association (NYHA) class. Values less than 1.0 indicate a decreased risk of death with cardiac resynchronization therapy. Note CI = confidence interval, RR = relative risk. For complete study names, see Box 1. *All patients received optimal medical therapy.

#### Patients with NYHA class III or IV disease

Four studies considered the effect on mortality among patients with NYHA class III or IV heart failure when cardiac resynchronization therapy was combined with an implantable defibrillator.14,19,22,25 A nonsignificant relative risk reduction of 14% was found (RR 0.86, 95% CI 0.69–1.07) (Figure 3); there was no significant heterogeneity across the studies (*I*2 = 0). Without the inclusion of the RAFT study, the other three studies combined had a relative risk reduction of 17% (RR 0.83, 95% CI 0.48–1.43) with a wide confidence interval.

### Optimal information size

With the recent addition of the RAFT study to the body of evidence on cardiac resynchronization therapy in patients with mildly symptomatic or advanced heart failure, the Lan–DeMets sequential monitoring boundary17 has now been crossed (Figure 4). The cumulative evidence is now conclusive that the addition of cardiac resynchronization therapy to optimal medical therapy or to implantable defibrillator significantly reduces mortality (for details see Appendix 6, available at [www.cmaj.ca/cgi/content/full/cmaj.101685/DC1](http://www.cmaj.ca/cgi/content/full/cmaj.101685/DC1)).

![Figure 4:](http://www.cmaj.ca/https://www.cmaj.ca/content/cmaj/183/4/421/F4.medium.gif)

[Figure 4:](http://www.cmaj.ca/content/183/4/421/F4)

Figure 4: 
Cumulative meta-analysis of the effect on overall mortality of cardiac resynchronization therapy in addition to optimal medical therapy or implantable defibrillator therapy among patients with mildly symptomatic or advanced heart failure. With the addition of the RAFT study, the cumulative Z score crosses the Lan–DeMets sequential monitoring boundary,17 which indicates that the cumulative evidence supporting cardiac resynchronization therapy in addition to optimal medical therapy or defibrillator therapy is now conclusive. For complete study names, see Box 1.

## Interpretation

Our findings indicate an unequivocal benefit of cardiac resynchronization therapy in addition to optimal medical therapy or an implantable cardioverter defibrillator in reducing all-cause mortality. This effect was particularly evident among patients with NYHA class II heart failure, a group in which a significant reduction in mortality had not been shown before the RAFT study, even in the presence of an implantable defibrillator.

The overall beneficial incremental effect of cardiac resynchronization therapy is supported by findings from the analysis of optimal information size. With the recently reported RAFT study, the sequential monitoring boundary has now been crossed, which indicates that the cumulative evidence now conclusively shows that the addition of cardiac resynchronization therapy to optimal medical therapy or to implantable defibrillator significantly reduces mortality among patients with mildly symptomatic or advanced heart failure. This sequential monitoring boundary is designed to be restrictive so that, when crossed, there is clear evidence of benefit. The cumulative evidence available from the previous 11 studies was not sufficient for the boundary to be crossed.

Our findings add to those of prior meta-analyses examining the effects of cardiac resynchronization therapy among patients with heart failure.13,30–32 Previous meta-analyses showed observations similar to ours when comparing cardiac resynchronization therapy with optimal medical therapy alone,13,32 but they did not show a mortality benefit when comparing cardiac resynchronization therapy plus an implantable defibrillator with an implantable defibrillator. The addition of the data from the RAFT study in our review substantially changed these findings, supporting cardiac resynchronization therapy over and above an implantable defibrillator in eligible patients with heart failure.

The lack of a significant relative risk reduction in mortality among patients with NYHA class III heart failure may be explained by several factors. Many studies had short follow-up, with a range of 3–12 months.19–23 In addition, the number of patients with NYHA class III disease (*n* = 1330) was significantly smaller than the group with NYHA class II disease (*n* = 3947). This difference is predominantly due to the publication of the CARE-HF study, which showed a significant reduction in mortality with cardiac resynchronization therapy over optimal medical therapy alone. That study’s findings resulted in the American College of Cardiology/American Heart Association Task Force on Practice Guidelines to issue a class I recommendation in 2008 for cardiac resynchronization therapy in patients with NYHA class III heart failure, a left ventricular ejection fraction of less than 35% and a QRS interval of more than 130 ms.33 The RAFT study, which originally enrolled patients with either NYHA class II or III heart failure, changed its inclusion criteria in 2006 to include only those with NYHA class II disease, thereby limiting the number of patients with NYHA class III disease available for analysis. No further studies have been done involving patients with NYHA class III heart failure to examine the effect of cardiac resynchronization therapy over a standard implantable defibrillator.

### Limitations

There are some limitations to our meta-analysis that are inherent to the studies we included. First, the timing of randomization to cardiac resynchronization therapy was not uniform across the studies. In many studies, randomization was done after a successful implantation, instead of at study entry. Deaths that may have occurred before or during implantation were not counted in these instances.

Second, optimization of medical therapy was not accurately specified at baseline in the studies. This issue is of importance when examining the data by NYHA class.

Third, many studies did not report outcomes by NYHA class; therefore, the data used in the NYHA II and III classification may not be completely accurate, because the raw data by NYHA class were not uniformly available.

Fourth, follow-up varied greatly, with a large number of studies not reporting follow-up beyond 6 months.

Box 1: 
### Full names of trials included in the meta-analysis

*   CARE-HF = Cardiac Resynchronization in Heart Failure Trial

*   COMPANION = Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure

*   MADIT-CRT = Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy

*   MIRACLE = Multicenter Insync Randomized Clinical Evaluation

*   MUSTIC = Multisite Stimulation in Cardiomyopathies Study

*   RAFT = Resynchronization/Defibrillation for Ambulatory Heart Failure Trial

*   REVERSE = Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction

*   RHYTHM = Resynchronization for Hemodynamic Treatment for Heart Failure Management

*   VECTOR = Ventricular Resynchronization Therapy Randomized Trial

These limitations may significantly underestimate the true effect of cardiac resynchronization therapy among patients with heart failure, particularly when results of studies with prolonged follow-up are compared with those of shorter duration. Finally, the mechanism by which cardiac resynchronization therapy prevents mortality in this patient population remains to be elucidated.

### Conclusion

Our meta-analysis showed a significant reduction in mortality with cardiac resynchronization therapy in addition to either optimal medical therapy or an implantable cardioverter defibrillator. Although this benefit was evident across the spectrum of symptomatic heart failure, it was particularly evident among patients with mildly symptomatic heart failure (NYHA class II disease) who had a QRS interval of more than 120 ms, a finding not previously shown, even in the presence of an implantable defibrillator. The added risk of performing cardiac resynchronization in this patient population must be weighed against the benefit. Cardiac resynchronization therapy may now be extended to a much wider proportion of patients with heart failure, improving long-term outcomes in this growing population.

## Footnotes

*   **Competing interests:** George Wells, Jeffrey Healey, Mario Talajic, Malcolm Arnold and Anthony Tang were also authors of the RAFT study. Ratika Parkash has received a research grant from Medtronic Canada for research into outcomes with implantable defibrillators. George Wells has received speaker fees from Medtronic Canada. Jeffrey Healey has received research grants from St. Jude Medical and Boston Scientific for research into the role of defibrillation testing at the time of implantation and the significance of pacemaker-detected atrial tachyarrhythmias; he has received consulting fees from St. Jude Medical. Mario Talajic has served on an advisory board for Medtronic and has received speaker fees from Medtronic. Malcolm Arnold has served on ad hoc advisory boards for Medtronic and Biotronic and has received speaker fees from Medtronic for CME talks about device therapies. No competing interests declared by Shannon Sullivan, Joan Peterson, Elizabeth Yetisir, Patricia Theoret-Patrick or Marilynn Luce.

*   This article has been peer reviewed.

*   **Disclaimer:** George Wells is a biostatistical consultant for *CMAJ* and was not involved in the editorial decision-making process for this article.

*   **Contributors:** George Wells, Ratika Parkash, Jeffrey Healey, Mario Talajic, Malcolm Arnold and Anthony Tang participated in the development of the study concept. George Wells, Ratika Parkash, Jeffrey Healey, Shannon Sullivan, Joan Peterson, Elizabeth Yetisir and Anthony Tang contributed to the collection, analysis and interpretation of the data. Mario Talajic, Malcolm Arnold, Patricia Theoret-Patrick and Marilynn Luce participated in data collection and interpretation of the data. George Wells, Ratika Parkash, Jeffrey Healey, Shannon Sullivan, Joan Peterson, Elizabeth Yetisir and Anthony Tang participated in the drafting of the manuscript. All of the authors revised the manuscript for important intellectual content and approved the final version submitted for publication.

*   **Funding:** This paper was supported by funding from the Canadian Institutes of Health Research as a University/Industry grant, with Medtronic Canada as the industrial partner.

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