The initial search identified 6481 citations from EMBASE and 4967 from MEDLINE. Of these 3927 were duplicates, leaving 7521 unique citations. Electronic filtering of non-English, followed by non-human, non-randomized controlled trial left 357 studies. These 357 studies were hand searched by two independent investigators to yield two randomized controlled trials. These included the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) trial by Linde et al.12
and the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial by Moss et al.13
Two sub-studies of the REVERSE trial were also identified and were not included in the main analysis.18,19
Details of the study flow are displayed in Figure
. Agreement between the two reviewers was 0.99 and the Cohen–Kappa statistic was 0.875 [95% confidence interval (CI] 0.735, 1.000]. Hand-searching of bibliographies and consultation with experts did not contribute any additional articles that met the pre-specified inclusion criteria.
Characteristics of included studies
Both the REVERSE and MADIT-CRT trials were randomized controlled trials involving patients with poor LV systolic function and a history of symptomatic heart failure (Table ). REVERSE included patients with an LVEF of 40% or less, a QRS duration of at least 120 ms, a left ventricular end diastolic diameter of 55 mm or greater, and NYHA functional Class I or II, irrespective of ischaemic or non-ischaemic heart failure aetiology classification. MADIT-CRT included individuals with an LVEF of 30% or less, a QRS duration of at least 130 ms, and patients with ischaemic cardiomyopathy with NYHA functional Class I or II, or non-ischaemic cardiomyopathy with NYHA functional Class II. Both trials required that patients were treated with optimal medical therapy.
Characteristics of included trials
In the REVERSE trial, all subjects received a CRT device, with or without an implantable cardioverter defibrillator (ICD) in accordance with practice guidelines. The patients were then randomized to have their CRT devices turned on (CRT-ON) or off (CRT-OFF) in a 2:1 fashion. In MADIT-CRT, patients were randomized to receive an ICD with or without CRT in a 3:2 fashion.
The primary outcome in REVERSE was a clinical composite of worsening heart failure, which included mortality, and in MADIT-CRT the primary outcome was a composite endpoint of all-cause mortality and heart failure events.
Both studies were of high quality, with a Jadad Score of 5/5 for REVERSE and 3/5 for MADIT-CRT. Points were lost in MADIT-CRT due to lack of blinding in the patients or physicians, as CRT implantation was only performed in patients randomized to intervention. However, a blinded committee adjudicated events in both of these trials. Follow-up was excellent in both studies with primary endpoint data available for 100% of patients in REVERSE and 95% in MADIT-CRT.
The characteristics of the patients included in both studies are detailed in Table
. The studies included a combined total of 2430 patients (REVERSE n
= 610 and MADIT-CRT n
= 1820). In each study, 55% of the subjects were classified as having ischaemic cardiomyopathy. The median age was 62 years in REVERSE and 65 years in MADIT-CRT. The majority of subjects were male (75–78%). Medical therapy for cardiac dysfunction with angiotensin converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and diuretics was consistent with clinical practice guidelines.1
In the REVERSE trial, 163 (85%) of subjects in the CRT-OFF arm, and 345 (82%) of subjects in the CRT-ON arm, received ICDs. In MADIT-CRT, by protocol all subjects were treated with ICDs.
Baseline characteristics of patients included in the REVERSE and MADIT-CRT studies
Heart failure events and mortality
The definition of heart failure events is based on that used in each of the two clinical trials.12,13
In the REVERSE trial, heart failure events were defined as either hospitalization due to or associated with worsening heart failure, crossover to the CRT therapy arm due to worsening heart failure, and worsened patient global assessment or NYHA functional class. In MADIT-CRT, heart failure events were defined as those signs and symptoms consistent with heart failure and the requirement of decongestive therapy on an outpatient basis, or an augmented decongestive regimen as an inpatient.
In the combined meta-analysis of the REVERSE and MADIT-CRT trials, CRT was associated with a reduction in heart failure events (combined OR 0.57, 95% CI 0.46–0.70, Figure ). In contrast, CRT was not associated with reductions in mortality (combined OR 0.96, 95% CI 0.67–1.36, Figure ). The overall benefit of CRT on the combined endpoint of heart failure events or death (OR 0.63, 95% CI 0.51–0.77, Figure ) was primarily attributable to the effects of CRT on reducing heart failure events. There was no evidence of statistical heterogeneity for each of the analysed outcomes (I2 = 0).
Forest plot demonstrating the effect of CRT on heart failure events, death, or the combined endpoint of heart failure events or death.
A sub-study from the REVERSE trial reported 24-month clinical and left ventricular remodelling outcomes in the European arm of the trial.19
The European arm was randomized throughout the 24-month period as opposed to the North American arm, which was randomized only to 12 months. CRT-ON was associated with a reduction in the odds of heart failure events or death relative to those in the CRT-OFF group (OR = 0.45, 95% CI 0.25–0.81). Notably, when compared with those patients in the North American arm of the study, patients in the European arm were younger (61 ± 10 vs. 63 ± 11 years, P
= 0.02), less likely to have ischaemic cardiomyopathy (44 vs. 63%, P
< 0.001), had a longer QRS duration (156 ± 23 vs. 151 ± 21 ms, P
= 0.008), and had fewer comorbidities. Patients in the European arm were also less likely to have received ICDs (68 vs. 95%, P
< 0.001). Due to the smaller study sample, we used the 12-month outcomes reported for both the North American and European arms in our meta-analysis.
Reverse left ventricular remodelling
Both trials evaluated the impact of CRT therapy on left ventricular remodelling as assessed by baseline and 12-month echocardiographic parameters. The two trials differed in their approach to CRT programming status during follow-up echocardiography. In REVERSE, echocardiographic measurements were made with CRT turned off, irrespective of treatment assignment. For CRT-ON subjects these measurements were recorded after waiting for a 10 min period. In MADIT-CRT, echocardiography was initially performed with CRT turned off for subjects who received CRT–ICD, as required by the Food and Drug Administration; however, this requirement was later reversed, and the 1-year echocardiograms were subsequently performed with CRT turned on for the duration of the study. The initial 201 CRT–ICD subjects in whom CRT was turned off were excluded from the final analysis of LV remodelling parameters reported in MADIT-CRT.
CRT significantly improved LV remodelling parameters in both studies (Table ). In REVERSE, CRT-ON subjects experienced a significantly greater reduction in LV end systolic volume index when compared with CRT-OFF subjects (−18.4 ± 29.5 vs. −1.3 ± 23.4 mL/m2, respectively, P = <0.001). The difference in left ventricular end systolic volume index significantly favoured CRT-ON for all subgroups assessed. A similar improvement in LV end systolic volume was observed with CRT in MADIT-CRT (−57 and −18 mL, respectively, P < 0.001). Significant improvement in LVEF was observed with CRT in both studies, with a greater benefit demonstrated in MADIT-CRT (Table ). Superior improvements in left ventricular end diastolic volume index, left ventricular end systolic and diastolic diameter, and interventricular conduction delay were also demonstrated with CRT in REVERSE, and in left ventricular end diastolic volume in MADIT-CRT (Table ).
Assessment of left ventricular remodelling after 1-year follow-up in REVERSE and MADIT-CRT
Two sub-studies of REVERSE also reported on the left ventricular remodelling parameters.18,19
In a sub-study analysis including 487 of the 610 patients in the trial, improvements in left ventricular remodelling parameters with CRT immediately after implantation did not correlate with long-term improvement in parameters (left ventricular end systolic volume index r
= 0.11, P
= 0.31, left ventricular end diastolic volume index r
= 0.10 P
= 0.38, LVEF r
= 0.07, P
= 0.72). Favourable effects of CRT on remodelling were greatest in subjects with more prolonged interventricular mechanical delay (>40 ms), longer QRS duration (>160 ms), and for those with a non-ischaemic HF aetiology.18
Additionally, no differences in changes of diastolic function measurements were noted between CRT-ON and CRT-OFF groups. In a separate sub-study of the 262 patients in the European arm of the REVERSE study, improvement in left ventricular remodelling parameters was also greater for patients in the CRT-ON rather than CRT-OFF arm at the 24-month follow-up period.19
Detailed results of left ventricular remodelling according to subgroup in MADIT-CRT have not yet been released.
The success rate of CRT implantation was 97% in the REVERSE trial and 99% in MADIT-CRT. One death was reported during the peri-implantation period in a patient receiving CRT in the MADIT-CRT trial as a result of a pulmonary embolism. Peri-implantation mechanical complications, including pneumothorax, coronary dissection, and pericardial tamponade occurred with a 1% frequency in the REVERSE trial, and 2% frequency in MADIT-CRT. Left ventricular lead problems following implantation were reported in ~7% of participants in the REVERSE trial during the 12-month follow-up period, and 4% in MADIT-CRT during a reported 30-day period. Device related infections occurred in 1% of subjects with CRT in the MADIT-CRT trial within 30 days of implantation.
No significant difference in the rate of complications was detected during the 12 months of follow-up between the CRT-ON and CRT-OFF groups in the REVERSE trial. During follow-up in the REVERSE trial, one case of heart failure occurred that resolved after turning CRT off. During follow-up beyond 30 days in the MADIT-CRT trial, adverse events defined as serious device-related events were reported with an incidence of 4.5 per 100 device-months in the CRT–ICD group, when compared with 5.2 per 100 device-months in the ICD-only group.