© 2006 European Society of Cardiology
Cardiac resynchronisation for patients with heart failure due to left ventricular systolic dysfunction — a systematic review and meta-analysis
a Clinical Epidemiology and Biostatistics, Department of Primary Care and General Practice, Primary Care Clinical Sciences Building, University of Birmingham Edgbaston, Birmingham B15 2TT, UK
b Ohio State University Heart Center Columbus, USA
c Department of Academic Cardiology, University of Hull UK
* Corresponding author. Tel.: +44 121 414 7943; fax: +44 121 414 3353. E-mail address: N.Freemantle{at}bham.ac.uk
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Background: Randomised controlled trials generally suggest that cardiac resynchronisation improves outcomes in patients with heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony. Our objective was to provide a valid synthesis of the effects of CRT on mortality, major morbidity, quality of life and implantation success rates.
Methods: Systematic overview and meta-analysis of randomised trials, both blinded and open, comparing cardiac resynchronisation with control. The primary outcome was all-cause mortality, and secondary outcomes included hospitalisation for worsening heart failure, quality of life and implantation success rates.
Results: We identified 8 randomised trials which included 3380 patients and observed a total of 524 deaths. Follow-up ranged from 1 month to a mean of 29.4 months. Most trials were of high quality, with centrally administered randomisation and few patients lost to follow-up. CRT reduced mortality in these trials (odds ratio 0.72, 95% CI 0.59 to 0.88). In addition CRT reduced hospitalisation for worsening heart failure (odds ratio 0.55, 95% CI 0.44 to 0.68) and improved quality of life as measured by the Minnesota Living with Heart Failure Questionnaire (weighted mean difference –7.1, 95% CI –2.9 to –11.4). Implantation success rates in the trials were 87% or greater.
Conclusion: Cardiac resynchronisation in patients with heart failure characterised by dyssynchrony substantially reduces all-cause mortality, major morbidity and improves quality of life.
Key Words: Heart failure • Cardiac resynchronisation therapy • Meta-analysis
Received July 20, 2005; Revised September 8, 2005; Accepted November 24, 2005
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Despite the additive benefits of several pharmacological interventions, patients with heart failure due to left ventricular systolic dysfunction and dyssynchrony often remain highly symptomatic and have a poor prognosis [1,2]. A series of randomised controlled trials have shown that cardiac resynchronisation therapy (CRT) can improve cardiac function leading to an improvement in symptoms and well-being and reduce the rate of hospitalisation [3]. Recently, the CARE-HF trial demonstrated a positive effect of CRT on all these outcomes and, for the first time, showed that CRT could reduce all-cause mortality [4].
An important function of meta-analysis is to assess whether the results of a study of particular interest, whatever its outcome, are consistent with the rest of the available data. Meta-analysis also allows the effect of study inclusion criteria and potentially confounding factors to be assessed. This is particularly relevant in the context of CRT where trials have been conducted comparing the effects of CRT to control in the absence and presence of an implantable defibrillator [5,6].
Previous meta-analyses have suggested that CRT reduces hospitalisation for heart failure but the effect on other outcomes, including mortality, was uncertain [3,7,8,9]. These meta-analyses were completed before the availability of data from the CARE-HF trial [4] which adds substantially to the available evidence.
We report a meta-analysis of all randomised controlled trials comparing cardiac resynchronisation therapy with control in patients with heart failure and left ventricular systolic dysfunction who had QRS prolongation indicating an increased risk of cardiac dyssynchrony.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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2.1. Intervention
The technology being evaluated in this review is CRT, including atrial synchronised biventricular pacing for patients in sinus rhythm or biventricular for patients in atrial fibrillation (no atrial pacing). Comparison was between CRT and control. We included trials where all patients received medical therapy with cardiac resynchronisation allocated on a random basis, and in addition where CRT was evaluated in the context of implantable cardiac defibrillator use in all patients.
2.2. Outcome measures
We assessed all-cause mortality, quality of life (Minnesota Living with Heart Failure Questionnaire) and hospitalisation for worsening heart failure. In addition we summarised the rate of implant success in trials of CRT.
2.3. Search method
The search strategy employed in this review is based on the search methods used in a recently published systematic review [3]. We decided to use this strategy in our attempt to update the evidence-base on CRT in patients with symptomatic heart failure, as it was sufficiently current and comprehensive. All studies included in the previous review were assessed for inclusion here. Electronic resources were searched for citations from January 2003 onwards, ensuring adequate overlap with the previous searches. As in the previous review, primary authors were contacted or additional data from commercial entities sourced where necessary. Our search may be considered up to date as of 11 March 2005.
2.4. Study selection and data extraction
Studies were selected on the basis of evaluation of the output of searches conducted by one of us (PT) and inclusion was evaluated and confirmed by the research group. Data were extracted by PT, and checked by a second researcher. Descriptors of each study were extracted and the quality of the study described using a standard format which included design, length of follow-up and loss to follow-up, and blinding of patients and investigators. Only events in the first (unconfounded) treatment period were included for crossover trials.
2.5. Statistical methods
In the principal analyses studies were summarised using theoretically exact methods and full random effects analyses. Tests for heterogeneity were also described. Potential publication bias was assessed using a regression-based assessment of asymmetry of funnel plots, as suggested by Egger et al. [10].
The potential influence on treatment of the presence or absence of an implantable cardiac defibrillator was assessed using meta-regression. Analyses were performed in StatsDirect Software version 2.4.3 [11] for fixed effects analyses, and the BUGS statistical program version 1.4.1 for odds random effects and meta-regression analyses [12]. Continuous data were analysed using StatsDirect.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1. Included trials
Overall we identified 8 randomised trials which included 3380 patients and observed a total of 524 deaths. Follow-up ranged from 1 month to a mean of 29.4 months. The characteristics of the trials are described in Table 1 [4-6,13-17]. Most trials were of high quality, with centrally administered randomisation and few patients lost to follow-up, although one longer term trial had substantial loss to follow-up [17]. Several short-term trials were blinded to some degree (see Table 1). In the blinded trials all patients received CRT prior to randomisation, which was used to select patients in whom CRT was activated. The two large long-term evaluations [4,17] compared the intention to treat with CRT (thus incorporating the risks of implantation and implantation failure in the evaluation). Patients were recruited from large numbers of sites, with COMPANION [17] recruiting patients from 128 US treatment centres, and CARE-HF [4] recruiting patients from 82 centres in Europe.
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3.2. Implantation success rates
Implantation success rate ranged from 86% to 95% of subjects included in the trials (Table 2).
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3.3. Cardiac resynchronisation therapy in control patients
Data were poorly reported regarding the rates of ‘drop in’ CRT therapy for the control groups in the included trials, particularly in the crossover designed trials. In COMPANION trial a ‘substantial number of patients withdrew from the pharmacologic-therapy group to receive commercially available implants because of arrhythmia or heart failure’ although the rate of implants in the control group of the trial is not reported [17]. In the CARE-HF control group 50 patients received CRT (12%) [4].
3.4. Effects of CRT on all-cause mortality
Overall CRT had a marked effect in reducing mortality across the trials, with no evidence of heterogeneity. Both the theoretically exact fixed effects method and the full random effects meta-analysis provided consistent evidence of an effect (fixed effects odds ratio 0.72, 95% CI 0.59 to 0.88). These effects are described in Fig. 1.
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3.5. Influence of ICD therapy on effect of CRT
In two trials [5,6] all patients received an ICD, and were then randomised to receive CRT or no CRT. Meta-regression analysis provided no evidence on the potential interaction effects between ICD and CRT therapy, odds ratio 1.14 (95% CI 0.56 to 2.25), where a value for the odds ratio greater than unity indicates smaller benefits in patients with both ICD and CRT compared to those with CRT alone.
3.6. Heart failure hospitalisation
Seven trials provided data on patients experiencing heart failure related hospitalisation (see Fig. 2). Since heart failure hospitalisation could be defined differently between trials, but published reports and available information did not provide adequate detail to assess this potential bias, we examined the effects of observed heterogeneity in observed treatment effects between trials using random effects meta-analysis. Both the theoretically exact fixed effects method and the full random effects meta-analysis provided consistent evidence of an effect (fixed effects odds ratio 0.55, 95% CI 0.44 to 0.68; random effects odds ratio 0.52, 95% CI 0.32 to 0.75).
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3.7. Effect of CRT on quality of life
Eight trials provided quality of life data derived from the Minnesota Living with Heart Failure Questionnaire. Where available, we included analysis of quality of life at three months. Where this was not available we included the nearest treatment period measurement to that time period. Individual patient data were accessed by the authors for analysis of two trials [5,16]. For MIRACLE-ICD [5] data from the 3 month evaluation, rather than previously published 6 month evaluation, were available. For MIRACLE [16] only 6 month data were available.
Overall CRT was associated with a substantial improvement in quality of life across the trials (Fig. 3). There was considerable heterogeneity in treatment effect across the trials (
2 41.7; df=7; P<0.0001). Incorporation of this heterogeneity in the analysis (random effects analysis) did not qualitatively affect the magnitude of the results (Fig. 3).
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Analysis of the effects of cardiac resynchronisation therapy by the presence or absence of an implantable cardiac defibrillator provided strong evidence of a systematic difference between subgroups (difference=–9.3; 95% CI –6.0 to –12.6; P<.0001). As the baseline quality of life assessment was undertaken in these trials after implantation this difference appears to be an artefact and will be considered further below.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Trials prior to CARE-HF, individually or combined, did not demonstrate a convincing effect of CRT on mortality. This meta-analysis provides further support for the reduction in mortality observed with CRT in the CARE-HF trial [4], showing that the non-significant trends observed in other studies reflected a lack of adequate power rather than the absence of an effect. In these trials, treating 11 patients with CRT for 2.5 years will avoid a death (95% CI 7 to 32) based upon the inverse of the annualised risk difference. If we extrapolate this finding to a period of 6 years (the expected life of a CRT device) assuming a constant relative risk then the number of patients needed to treat to avoid a death is reduced to 5 (95% CI 3 to 13). The analysis also demonstrates the effect of CRT on non-fatal outcomes including symptoms, quality of life and hospitalisation. These data reinforce the view that implantation of CRT should be considered routinely as part of the management of patients with major left ventricular systolic dysfunction and evidence of cardiac dyssynchrony who remain symptomatic despite standard pharmacological therapy.
The fixed effects analyses weighted the studies in relation to the size and the event rate. However, in the presence of heterogeneity the random effects model gave the studies more uniform weight. Thus, in the presence of heterogeneity the CARE-HF study, which is the largest, had relatively less impact in the random effects model on the pooled estimates than the fixed effects model. The consistency of the pooled estimates in the different models is good, which is reassuring.
Implantation success in the trials included in this review was surprisingly high, with rates exceeding 87% reported (see Table 2). These rates may improve with increased volumes of activity and developments in lead technology.
Hospitalisation events, symptoms or quality of life may be prone to observer bias in unblinded clinical trials. However, all-cause mortality is a robust outcome even in an unblinded trial. The observed effect was large, additional to that of a high standard of pharmacological therapy and the incremental effect was as large as that of β-blockers compared to placebo in a similar population [18].
Our analysis suggests that CRT might have less favourable effects on quality of life in patients who also receive an ICD. This could reflect the selection of different populations in trials including or excluding an ICD, an artefact (such as the timing) of the estimation of quality of life, or a less than additive benefit of these therapies. The COMPANION trial [17] described similar (positive) results in the CRT and CRT-ICD groups on quality of life.
The COMPANION trial [17] allocated twice as many patients to each of CRT and CRT-D as to the control group but allocated no power in its statistical analysis plan to the comparison of CRT with CRT-D. This trial design means that for a given difference in event rates, the power to compare the effect of one intervention versus the other is greater than for the difference between either intervention and control. It is now clear that CRT reduces mortality, major morbidity, and improves quality of life in patients with heart failure due to left ventricular systolic dysfunction complicated by dyssynchrony.
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