Figure 1 summarises the number of potential citations retrieved and the selection process. Both authors agreed on the selection and methodological assessment. Twelve independent studies met the selection criteria,w1-w12
including one multigroup trialw1
that compared combined cardiac resynchronisation and implantable cardioverter defibrillator therapy, resynchronisation, and medical therapy. Several studies that used univentricular pacing as the comparator for cardiac resynchronisation28 29 30 31 32 33
or as the main experimental group34
did not meet the selection criteria. As per protocol two trials that exclusively recruited patients who had had a recent myocardial infarction35
or undergone recent coronary revascularisation were excluded.36
One unpublished study37
(not identified in the database search) was not included because of potential attrition bias (more than 50% of randomised patients in the control group were not available for follow-up). The potential impact of this study was examined in a post hoc sensitivity analysis.
Fig 1Trial flow diagram of study selection
Figure 2 shows the relation between the network of randomised controlled trials. In total, 1636 events occurred in 8307 patients randomised to cardiac resynchronisation therapy (245/1283), implantable cardioverter defibrillator therapy (367/2429), combined resynchronisation and implantable cardioverter defibrillator therapy (132/1112), amiodarone (247/897), and control (645/2586). Seven studies reported 1013 events in 4319 patients for subgroup analysis of New York Heart Association class III or IV heart failure, including five studies that recruited only patients with class III or IV heart failurew1w2w5w6w9 and two studies that reported subgroup outcomes.w9w11
Fig 2Bayesian network analysis of 12 randomised controlled trials (see table 1 for description of acronyms) comparing treatment strategies for patients with left ventricular dysfunction. Summary odds ratios (95% confidence intervals) are shown (more ...)
Table 1 summarises the design, baseline characteristics, and quality assessment of the included studies. All used the transvenous approach to implantation, whereas one included 11% of patients with leads implanted transthoracically.w4 Most studies were analysed using the intention to treat principle, but concealment of treatment allocation was unclear in most trials. In several studiesw3w5w6w9 blinding of investigators or patients, or both, was possible as only patients with successful device implantations were considered for randomisation.
Table 1 Study characteristics of included randomised controlled trials of combined cardiac resynchronisation therapy and implantable cardioverter defibrillator therapy in left ventricular impairment and symptomatic heart failure
One study was presented in two publications reporting independent results from patients with New York Heart Association class IIw3
and class III or IVw5
heart failure at baseline. The number of deaths reported was identical to a FDA report38
but different from an earlier version39
cited in previous reviews.7 9
In this review published outcomes were abstracted as per two independent studies.w3w5
Mortality data were used from the extension phase of the cardiac resynchronisation heart failure trial.40w2
Four studies accounted for 73% of patients and 88% of observed events.w1w2w6w11 Baseline mortality was comparable in most studies except for five.w3-w6w9 In these five studies duration of follow-up was shorter and patients only with successfully implanted devices were randomised. No major asymmetry was seen in the funnel plots to suggest publication bias (not shown).
Figures 3 and 4 summarise the all cause mortality data for Bayesian network and pairwise comparisons of device therapies compared with medical therapy. Combined resynchronisation and implantable defibrillator therapy significantly reduced mortality compared with medical therapy in one direct comparison studyw1 (odds ratio 0.64, 95% confidence interval 0.46 to 0.90), and in Bayesian network meta-analysis of 12 studies (0.57, 95% credible interval 0.40 to 0.80). Both resynchronisation (0.66, 95% credible interval 0.50 to 0.89) and implantable defibrillator therapy (0.69, 0.55 to 0.87) reduced mortality compared with medical therapy. Amiodarone did not have any apparent effect on mortality compared with medical therapy (0.97, 0.68 to 1.35).
Fig 3Results of Bayesian network meta-analysis of 12 randomised controlled studies of device therapies in 8307 patients with left ventricular dysfunction
Fig 4Results of pairwise meta-analysis and Bayesian network analysis of device therapies compared with medical therapy for patients with left ventricular dysfunction. *95% confidence interval for pairwise comparison, 95% credible interval for (more ...)
The overall mortality for combined resynchronisation and implantable defibrillator therapy was 9.1% compared with 14.0% for medical therapy, corresponding to a 35% relative risk reduction (table 2). The probability determined from the Bayesian analysis that combined resynchronisation and implantable defibrillator therapy was the best option (compared with other devices and optimal medical therapy) was 0.75 in all patients with impaired left ventricular function and 0.62 in the subgroup of patients with New York Heart Association class III or IV heart failure. The corresponding probabilities for resynchronisation therapy were 0.14 and 0.27 and for implantable defibrillator therapy were 0.10 and 0.08.
Table 2 Probability of best treatment for patients with left ventricular dysfunction
Figure 5 shows the results of head to head comparisons of combined resynchronisation and implantable defibrillator therapy with either therapy alone. When combined therapy was compared with implantable defibrillator therapy no evidence was found from pairwise meta-analysis (three studies, odds ratio 0.81, 95% confidence interval 0.48 to 1.37) and Bayesian network meta-analysis (12 studies, odds ratio 0.82, 95% credible interval 0.57 to 1.18; seven studies, New York Heart Association class III or IV subgroup, odds ratio 0.74, credible interval 0.39 to 1.57) to suggest that combined therapy further improved survival (fig 4). Similarly, when combined therapy was compared with resynchronisation therapy no evidence was found from one direct comparison study (odds ratio 0.79, 95% confidence interval 0.60 to 1.06) and Bayesian network meta-analysis (odds ratio 0.85, 95% credible interval 0.60 to 1.22; New York Heart Association class III or IV subgroup, odds ratio 0.89, 95% credible interval 0.45 to 1.76) for an incremental value of combined therapy.
Fig 5Combined cardiac resynchronisation and implantable cardioverter defibrillator therapy compared with either therapy alone. *95% confidence interval for pairwise comparison, 95% credible interval for Bayesian network comparison. See table (more ...)
Estimates of treatment effects were robust for study selection criteria (including a priori and post hoc sensitivity analyses) and for statistical assumption of prior distributions (not shown).