Systematic Review: Cardiac Resynchronization in Patients with Symptomatic Heart Failure

Context A biventricular pacemaker to resynchronize ventricular contraction is a new therapy for heart failure. A 2003 meta-analysis included only 2 published and 2 unpublished trials, but 5 additional studies have since become available. Contribution Data from 3216 patients who participated in 9 trials demonstrate that cardiac resynchronization improves many outcomes, including mortality. Data from 3701 patients participating in 18 studies showed that leads dislodged in 9% of patients during 6 months of follow-up and that the device malfunctioned in 7%. Implications In select patients, cardiac resynchronization is an effective therapy for heart failure. The Editors Heart failure is the fastest-growing cardiovascular diagnosis in North America, and the lifetime risk is now estimated at nearly 20% (1, 2). Despite many diagnostic and pharmacotherapeutic advances over the past 2 decades, symptomatic heart failure still carries a poor prognosis (1, 3). Thus, novel therapies for heart failure are still needed. To improve survival, these therapies must reduce either sudden cardiac death (the most common cause of death in patients with New York Heart Association [NYHA] class I or II symptoms) or progressive heart failure (the predominant cause of death in those with NYHA class III or IV symptoms) (4, 5). Intraventricular conduction disturbances are common in heart failure and are associated with increased mortality (6-8). As such, electrophysiologic therapies may help improve outcomes in heart failure. Indeed, studies have recently evaluated atrial-synchronized biventricular pacing (cardiac resynchronization therapy) and implantable cardioverter-defibrillators (ICDs) for their effects in heart failure. While ICDs do not improve functional outcomes, they do provide substantial mortality benefits by preventing sudden cardiac death in patients with heart failure who have an ischemic substrate, poor ejection fraction, and history of ventricular arrhythmias (9). On the other hand, cardiac resynchronization therapy improves many of the pathophysiologic changes seen in patients with wide QRS complexes: less mechanical dyssynchrony leading to increased left ventricular filling time, reduced mitral regurgitation, and reduced septal dyskinesis (10). Several trials have shown that cardiac resynchronization therapy improves quality of life, NYHA class, and 6-minute walk distances in patients with advanced heart failure; however, they have not yet shown this therapy to confer a conclusive mortality benefit because of the small number of deaths in each trial. This distinction is important, since not all therapies that improve functional outcomes in patients with heart failure reduce mortality (11). A meta-analysis of the efficacy of cardiac resynchronization therapy has been published (10); however, it combined data from only 2 published trials and 2 U.S. Food and Drug Administration (FDA) reports (both of which have subsequently been published) (12-15). We conducted this systematic review as an update: Five additional trials have now been reported, and we obtained further details on 3 of the 4 studies included in the earlier meta-analysis through contact with the trial investigators (12-14). Moreover, while the earlier meta-analysis focused on efficacy data, we systematically examined the success rate and safety of biventricular pacemaker implantation as well as the efficacy data. Methods Search Strategy We developed detailed search strategies (see the Appendix and Appendix Tables 1 to 16) for the following electronic resources: CochraneCentral Register of Controlled Trials, Cochrane Database of Abstracts of Reviews of Effectiveness (DARE), Cochrane Database of Systematic Reviews, EMBASE, International Pharmaceutical Abstracts, MEDLINE, PubMed, Web of Science, and several trial registries (www2.umdnj.edu/~shindler/trials/trials_a.html, www.nhlbi.nih.gov/index.htm, www.controlled-trials.com/, clinicaltrials.gov, www.update-software.com/National/, www.centerwatch.com/search.asp, and www.cardiosource.com). In addition, we contacted the primary authors of included studies, sought FDA reports, and reviewed the reference lists of all included articles. We also sought additional data from the companies that produce biventricular devices: Medtronic Inc. (Minneapolis, Minnesota), Guidant Corporation (Indianapolis, Indiana), and ELA Medical (Le Plessis-Robinson, France). The search was not limited by language or publication status and is considered up to date as of 4 May 2004. Study Selection Two investigators independently screened all titles and abstracts to determine whether an article met the general inclusion criteria (that is, a study that investigated cardiac resynchronization therapy; was done in humans; and included patients with symptomatic heart failure). For the efficacy substudy, we selected only randomized, controlled trials; for the safety substudy, we selected controlled trials or prospective cohort studies. Then, another 2 investigators independently assessed the full text of potentially relevant studies using specific inclusion criteria (study duration 2 weeks, primary outcomes of interest [all-cause mortality or heart failure hospitalization or both] reported according to randomized treatment, confirmation that general inclusion criteria were met) for final inclusion. Two of the investigators independently abstracted data. Discrepancies were resolved through third-party adjudication and consensus. Statistical Analysis We did intention-to-treat analyses by using the same standardized end point definitions as in the primary studies. We used Stata 7.0 (Stata Corp., version 7.0, 2003) to pool data and calculate summary relative risks (RRs) for dichotomous results and weighted mean differences for continuous variables. Because of the differences expected between studies (particularly in control group therapies), a priori we decided to combine results primarily by using a random-effects model; fixed-effects models were considered in sensitivity analyses. Statistical heterogeneity was assessed by using the chi-square test and was quantified using the I2 statistic (16). Time-to-event data were summarized by the log hazards ratio. An individual-patient data set for this analysis was constructed by using summary monthly mortality tables in the trial manuscripts. A priori sensitivity analyses included the effects of cardiac resynchronization therapy on patients with NYHA class III or IV symptoms. We planned to examine the effect of ICDs, -blockers, and digoxin in indirect subgroup comparisons using meta-regression. Estimates of carryover effect were extracted from crossover designs. Only period 1 data were used for irreversible outcomes (that is, death and heart failure hospitalizations). Standard errors for crossover weighted mean differences were calculated (17). Simple pooling and exact 95% CIs were used for the safety analyses. Role of the Funding Source The Agency for Healthcare Research and Quality had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Data Synthesis Figure 1 shows the results of the search and study selection. Nine randomized trials (Table) met the inclusion criteria for the efficacy review (12-15, 18-22). Eight of these and an additional 10 studies9 of which were published (23-31) and 1 of which remains unpublished (Leclercq C, Alonso F, d'Allones FR, et al. Effets moyen terme de la stimulation multisite biventriculaire dans l'insuffisance cardiaque svre. Personal communication. May 2003)met the inclusion criteria for the safety review. Data in addition to those reported in the journal publications or conference presentations were provided by the investigators from 6 trials and are included in these analyses (12-14, 20-22). Although most of the trials reported secondary outcomes in multiple publications, we include only the reference to the primary publication for each trial in this manuscript (for a listing of all publications from each trial, please see the full Agency for Healthcare Research and Quality (AHRQ) report at www.ahrq. gov/clinic/epc/index.html#Reports). Figure 1. Flow diagram of study selection. Table. Description of Randomized Trials Included in the Efficacy Review and Baseline Characteristics of Patients Appendix Table 1. MEDLINE Search: Cardiac Resynchronization for Heart Failure (Basic Search) Appendix Table 2. EMBASE Search: Cardiac Resynchronization for Heart Failure (Basic Search) Appendix Table 3. Search of International Pharmaceutical Abstracts: Cardiac Resynchronization for Heart Failure (Basic Search) Appendix Table 4. PubMed Search: Cardiac Resynchronization for Heart Failure (Basic Search) Appendix Table 5. Search of Web of Science: Cardiac Resynchronization for Heart Failure (Basic Search) Appendix Table 6. MEDLINE Search: Cardiac Resynchronization for Heart Failure (Safety Search) Appendix Table 7. EMBASE Search: Cardiac Resynchronization for Heart Failure (Safety Search) Appendix Table 8. PubMed Search: Cardiac Resynchronization for Heart Failure (Safety Search) Appendix Table 9. Search of Web of Science: Cardiac Resynchronization for Heart Failure (Safety Search) Appendix Table 10. MEDLINE Search: Cardiac Resynchronization for Heart Failure (Efficacy Search) Appendix Table 11. EMBASE Search: Cardiac Resynchronization for Heart Failure (Efficacy Search) Appendix Table 12. Search of Cochrane Controlled Trials Register: Cardiac Resynchronization for Heart Failure (Efficacy Search) Appendix Table 13. Search of DARE (Database of Abstracts of Reviews of Effectiveness): Cardiac Resynchronization for Heart Failure (Efficacy Search) Appendix Table 14. Search of Cochrane Database of Systematic Reviews: Cardiac Resynchronization for Heart Failure (Efficacy Search) Appendix Table 15. PubMed Search: Cardiac Resynchronization for Heart Failure (Efficacy Search) Appendix Table 16. Search of Web of Science: Cardiac R