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Clinical Review | Clinician's Corner

Cardiac Resynchronization Therapy for Patients With Left Ventricular Systolic Dysfunction:  A Systematic Review FREE

Finlay A. McAlister, MD, MSc; Justin Ezekowitz, MBBCh, MSc; Nicola Hooton, MPH; Ben Vandermeer, MSc; Carol Spooner, BScN, MSc; Donna M. Dryden, PhD; Richard L. Page, MD; Mark A. Hlatky, MD, MPH; Brian H. Rowe, MD, MSc
[+] Author Affiliations

Clinical Review Section Editor: Michael S. Lauer, MD. We encourage authors to submit papers for consideration as a Clinical Review. Please contact Michael S. Lauer, MD, at lauerm@ccf.org.

Author Affiliations: The University of Alberta Evidence-based Practice Center, Edmonton, Alberta (Drs McAlister, Ezekowitz, Dryden, and Rowe, and Mr Vandermeer, and Mss Hooton and Spooner); Division of General Internal Medicine (Dr McAlister), Division of Cardiology (Dr Ezekowitz), and Department of Emergency Medicine (Dr Rowe), University of Alberta, Edmonton; Division of Cardiology, University of Washington School of Medicine, Seattle (Dr Page); and Department of Health Research and Policy, Stanford University, Stanford, Calif (Dr Hlatky).

More Author Information
JAMA. 2007;297(22):2502-2514. doi:10.1001/jama.297.22.2502.
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Published online

Context Left ventricular (LV) systolic dysfunction causes substantial morbidity and mortality, even with optimal pharmacotherapy. Atrial-synchronized biventricular pacemakers (cardiac resynchronization therapy [CRT]) received US Food and Drug Administration (FDA) approval for use in selected patients with LV systolic dysfunction in 2001.

Objective To summarize the current evidence base for the efficacy, effectiveness, and safety of CRT in patients with LV systolic dysfunction.

Evidence Acquisition A search of multiple electronic databases until November 2006 was supplemented by hand searches of reference lists of included studies and review articles, proceedings booklets from meetings, FDA reports, and contact with primary study authors and device manufacturers. A total of 14 randomized trials (4420 patients) were included for the CRT efficacy review, 106 studies (9209 patients) for the CRT effectiveness review, and 89 studies (9677 patients) reported safety outcomes with implantation of a CRT device.

Evidence Synthesis All patients in the CRT studies had LV systolic dysfunction (mean LV ejection fraction [LVEF] range, 21%-30%), prolonged QRS duration (mean range, 155-209 milliseconds), and 91% had New York Heart Association (NYHA) class 3 or 4 heart failure symptoms despite optimal pharmacotherapy. CRT improved LVEF (weighted mean difference, 3.0%; 95% confidence interval [CI], 0.9%-5.1%), quality of life (weighted mean reduction in Minnesota Living With Heart Failure Questionnaire, 8.0 points; 95% CI, 5.6-10.4 points), and functional status (improvements of ≥1 NYHA class were observed in 59% of CRT recipients in the randomized trials). CRT decreased hospitalizations by 37% (95% CI, 7%-57%), and all-cause mortality decreased by 22% (95% CI, 9%-33%). Implant success rate was 93.0% (95% CI, 92.2%-93.7%) and 0.3% of patients died during implantation (95% CI, 0.1%-0.6%). During a median 11-month follow-up, 6.6% (95% CI, 5.6%-7.4%) of CRT devices exhibited lead problems and 5% (95% CI, 4%-7%) malfunctioned.

Conclusions CRT reduces morbidity and mortality in patients with LV systolic dysfunction, prolonged QRS duration, and NYHA class 3 or 4 symptoms when combined with optimal pharmacotherapy. The incremental benefits of combined CRT plus implantable cardioverter-defibrillator devices vs CRT-alone devices in patients with LV systolic dysfunction remain uncertain.

Figures in this Article

Heart failure is the fastest growing cardiovascular diagnosis in the United States, with a community prevalence of 2.5% in adults, and the direct and indirect costs of heart failure exceed $33 billion per year.1Quiz Ref IDDespite many advances in diagnosis and pharmacotherapy for heart failure during the past 2 decades, morbidity and mortality remain high and quality of life is poor for many patients. Thus, there is increasing enthusiasm for the therapeutic potential of atrial-synchronized biventricular pacemakers (cardiac resynchronization therapy [CRT]) in patients with heart failure and left ventricular (LV) systolic dysfunction. CRT is designed to eliminate the delay in activation of the LV free wall found in many patients with LV systolic dysfunction and thereby improves mechanical synchrony, which in turn increases LV filling time, reduces mitral regurgitation, and reduces septal dyskinesis.

Although previous systematic reviews24 have reported morbidity and mortality benefits with CRT therapy in randomized controlled trials (RCTs), there were areas of uncertainty. First, although these earlier systematic reviews focused on randomized efficacy trials, the generalizability of their results to clinical practice were unknown (particularly with respect to response rates, clinical effects, and safety when these devices are used in routine practice outside of clinical trial centers and in less selected patients). Second, none of the earlier reviews was able to clarify the incremental benefits conferred by CRT devices with implantable cardioverter-defibrillator (ICD) capability (combined CRT-ICD devices) over CRT-alone devices, or were these earlier reviews able to define which patient groups would benefit most from these devices. Finally, a number of RCTs have been published since the earlier systematic reviews were performed and their impact on the pooled evidence base was unknown.

Our systematic review summarizes the current evidence regarding the efficacy (outcomes in randomized trial participants), effectiveness (outcomes in clinical settings), safety (in both randomized trial participants and in clinical settings), and cost-effectiveness of CRT with or without an ICD in patients with LV systolic dysfunction.

Search Strategy

We sought studies that (1) reported mortality, hospitalization, changes in functional outcomes (New York Heart Association [NYHA] class, 6-minute walk test, LV ejection fraction [LVEF], and/or quality of life), or peri-implant/postimplant safety with CRT in (2) patients with LV systolic dysfunction (LVEF ≤35%, whether or not heart failure symptoms were present) that (3) followed participants for at least 2 weeks, (4) had more than 25 participants, (5) reported original research, and (6) represented the primary report from studies with multiple publications. We searched MEDLINE, Ovid MEDLINE In-Process and other non-indexed citations, Cochrane CENTRAL Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database, EMBASE, Science Citation Index Expanded (via Web of Science), International Pharmaceutical Abstracts, PubMed, National Library of Medicine Gateway, OCLC (Online Computer Library Center) Proceedings First and Papers First, CRISP (Computer Retrieval of Information on Scientific Projects), various trial registries (including the National Research Register [UK], Australian Clinical Trials Registry, clinicaltrials.gov, and current controlled trials), and US Food and Drug Administration reports.

In addition, we reviewed all abstracts from the annual Heart Rhythm Society meetings, the reference lists of review articles and included studies, and contacted authors of included studies for additional citations and information. Additional data were also sought from device manufacturers, including Medtronic Inc (Minneapolis, Minn), Boston Scientific (formerly Guidant Corp, Indianapolis, Ind), and St Jude Medical Inc (St Paul, Minn). The search was not limited by language or publication status.

The search terms included biventricular pacing, biventricular pacer, biventricular stimulation, BiV, artificial cardiac pacing, chronic cardiac failure resynchronization therapy, single chamber pacing, dual chamber pacing, cardiac resynchronization, Medtronic, InSync, ELA medical, Guidant, St Jude, congestive heart failure, CHF, chronic heart failure, and heart diseases.

Study Selection

To address the efficacy of CRT in ideal patients and practice settings, we analyzed RCTs that compared CRT or combined CRT-ICD devices with either placebo pacing, right ventricular pacing, or drug therapy alone (or ICD alone for RCTs testing combined CRT-ICD devices). To address the effectiveness of CRT in usual clinical practice, we analyzed observational studies with contemporaneous comparison groups (eg, cohort studies). To address device safety, we included data for CRT recipients from RCTs and observational studies (including those without contemporaneous control groups, such as case series and clinical registry data).

Data Extraction and Analysis

Study selection, quality assessment (using the Jadad scale5 and evaluation of adequacy of allocation concealment for RCTs, and using the Downs and Black checklist6 for observational studies), and data extraction were completed in duplicate and independently. For dichotomous results (congestive heart failure hospitalizations), we calculated relative risks (RRs) and for continuous variables (eg, 6-minute walk test), we calculated weighted mean differences for the pooled estimates. Random-effects models were used for analyses in Review Manager 4.2.5 (The Cochrane Collaboration, Copenhagen, Denmark). All results were reported with 95% confidence intervals (CIs). The I2 statistic was used to describe the percentage of total variation across studies that is due to heterogeneity rather than chance (a value of 0% indicates limited heterogeneity, and larger values demonstrate increasing heterogeneity).7 Device efficacy in different patient subgroups was explored using meta-regression analyses.

Literature Search

From 7110 citations, we identified 14 RCTs821 (4420 patients) for determining CRT efficacy, 106 studies (9209 patients from 2 controlled nonrandomized studies, 91 prospective observational studies, and 13 retrospective observational studies) evaluating CRT effectiveness,2265,6699,100127 and 89 studies (9677 patients from 14 RCTs, 2 controlled nonrandomized studies, 63 prospective observational studies, and 10 retrospective observational studies) reporting success rates and safety outcomes with implantation of a CRT device (Figure 1).821,24,26,30,31,3337,39,40,43,45,46,4850,53,54,56,57,5962,64,67,68,6974,77,80,82,84,86,87,8991,93,9598,101,102,104,106110,112,113,115117,121,122,127136 A full list of search strategies, search results, and quality assessments for each included study are available at http://www.ahrq.gov/clinic/tp/defibtp.htm.

Figure 1. Study Flow
Graphic Jump Location

CRT indicates cardiac resynchronization therapy.

Description of Included Patients in the RCTs

All patients in the CRT RCTs had LV systolic dysfunction (mean LVEF range, 21%-30%), prolonged QRS duration (mean QRS range, 155-209 milliseconds), and heart failure symptoms (91% were NYHA class 3 or 4 at baseline and 9% were NYHA class 2). The RCTs attempted to ensure participants were treated with optimal pharmacotherapy (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, plus β-blockers, and spironolactone in eligible patients) at baseline, and all comparisons were thus of CRT plus pharmacotherapy vs pharmacotherapy alone. The mean (SD) age of trial participants was 65.4 (10.8) years; 72% were male and 5% had atrial fibrillation (data available upon request). Of the patients in the intervention groups, 1310 (47%) received CRT alone and 1474 (53%) received a combined CRT-ICD device. Eleven of the RCTs (n = 2166)814,1618,21 randomized patients after successful CRT implantation; 3 RCTs (n = 2439)15,19,20 randomized patients before attempted CRT implantation. All but 2 of the RCTs14,17 reported industry funding.

Observational Studies

All patients in the CRT observational studies had LV systolic dysfunction (mean LVEF range, 17%-35%) and prolonged QRS duration (mean QRS range, 140-206 milliseconds). Patient demographics were similar to the participants in the CRT RCTs (mean [SD] age, 66 [10] years; 77% were male and virtually all had heart failure symptoms at baseline [8% NYHA class 2 and 91% NYHA class 3 or 4]).

Efficacy of CRT

Quiz Ref IDIn the RCTs, 59% of CRT recipients improved by at least 1 NYHA class between baseline and 6 months vs 37% of controls (RR, 1.55; 95% CI, 1.25-1.92 for improving at least 1 NYHA class with CRT). Compared with controls, patients assigned to CRT demonstrated improvements in LVEF (weighted mean difference, 3.0%; 95% CI, 0.9%-5.1%), 6-minute walk test distance (weighted mean difference, 24 m; 95% CI, 13-35 m), and quality of life (weighted mean difference in Minnesota Living With Heart Failure Questionnaire, 8.0 points; 95% CI, 5.6-10.4 points).

The percentage of patients hospitalized for heart failure was 27% in controls and 19% in patients assigned to CRT (RR, 0.63; 95% CI, 0.43-0.93) (Figure 2), and all-cause mortality was 13.2% in patients assigned to CRT vs 15.5% in controls (RR, 0.78; 95% CI, 0.67-0.91) (Figure 3). Quiz Ref IDThe survival benefit was driven largely by reductions in progressive heart failure deaths (RR, 0.64; 95% CI, 0.49-0.84). Although the mortality reduction with CRT was evident by 6 months in these trials, the mortality reduction was larger in those RCTs with the longest follow-up. For example, a long-term extension of the CARE-HF trial137 confirmed that the relative survival benefits of CRT were stable (constant hazard ratio), and as such the absolute magnitude of benefit increased substantially over time. Consequently, although our meta-analysis demonstrated a number needed to treat to prevent 1 death of 29 patients at 6 months, the CARE-HF trial follow-up data demonstrated the numbers needed to treat to prevent 1 death of 13 patients at 2 years and 9 patients at 3 years.137 The long-term impact of CRT on hospitalizations and functional outcomes is uncertain due to a paucity of data at this time.

Figure 2. Effect of CRT on Proportion of Patients Hospitalized for Heart Failure (Randomized Trial Data)
Graphic Jump Location

CRT indicates cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator. Size of data markers indicates the weight of the study.

Figure 3. Effect of CRT on All-Cause Mortality (Randomized Trial Data)
Graphic Jump Location

CRT indicates cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator. Size of data markers indicates the weight of the study.

No definitive subgroup effects were apparent in the CRT RCTs, although it should be recognized that these RCTs were not powered to detect subgroup effects of small to moderate magnitude. For example, although the PATH CHF II Investigators16 reported significantly greater improvements in exercise capacity in their 16 patients with QRS duration of more than 150 milliseconds at baseline than in those with shorter QRS width, the 5 other RCTs8,10,13,15,19 that evaluated this subgroup did not find such a relationship. Furthermore, although a post hoc analysis of the MIRACLE trial138 suggested that patients with an ischemic etiology demonstrated less improvements in LVEF and LV volumes with CRT than those patients with nonischemic disease, the effect of CRT on mortality did not differ between patients with and without ischemia in the CONTAK CD,13 COMPANION,15 or CARE-HF19 studies (3 RCTs that specifically tested for this interaction in a priori specified subgroup analyses).

Univariate meta-regressions found no significant modification of the effect of CRT on all-cause mortality by presence or absence of ICD, ischemic etiology, duration of follow-up, whether randomization was predevice or postdevice implantation, whether the RCT was industry funded, the Jadad score for the RCT, or various patient characteristics (including NYHA class, age, or LVEF, within the narrow range enrolled in these RCTs). However, these meta-regression analyses were based on aggregate data from a small number of relatively homogenous trials and thus were underpowered to detect subgroup effects. In contrast, several factors were found to be associated with a reduced benefit from CRT on heart failure hospitalizations (presence of an ICD in both controls and patients assigned to CRT [P<.001], NYHA class 2 at baseline [P = .003], and higher LVEF [P = .004]). Although CRT markedly reduced the proportion of patients hospitalized with heart failure when compared with medical therapy alone (RR, 0.51; 95% CI, 0.41-0.64; in the 5 RCTs reporting this outcome [280 of 1411 patients hospitalized]), CRT had no effect on heart failure hospitalizations in those trials in which combined CRT-ICD devices were compared with ICD-alone devices (RR, 1.00; 95% CI, 0.80-1.24; in 2 trials [234 of 859 patients hospitalized]).

The COMPANION trial15 performed the only direct comparison between combined CRT-ICD devices and medical therapy alone, and confirmed that combined CRT-ICD devices reduced all-cause mortality (hazard ratio, 0.64; 95% CI, 0.48-0.86) and improved 6-minute walk test distance (weighted mean difference, 45 m; 95% CI, 27-63 m), NYHA class (RR, 1.49; 95% CI, 1.23-1.81; for improving at least 1 NYHA class), and quality of life (weighted mean difference in Minnesota Living With Heart Failure Questionnaire, 14 points; 95% CI, 10-18 points) compared with medical therapy alone.

The COMPANION trial15 also permits a secondary comparison of combined CRT-ICD devices vs CRT-alone devices within the same trial. Although this latter comparison is underpowered and was not prespecified in the protocol, there was a statistically nonsignificant reduction in all-cause mortality (P = .13) and in time to death or heart failure hospitalization in those patients receiving the combined CRT-ICD device compared with those receiving the CRT-alone device.15 This is consistent with our meta-regression of aggregate trial data, which suggested that combined CRT-ICD devices and CRT-alone devices demonstrated similar effects, but is also not definitive.

Effectiveness of CRT

Survival over time in recipients of CRT or combined CRT-ICD devices was similar in the 95 observational studies that reported this outcome as in the 14 RCTs. Only 1 observational study43 compared outcomes in patients with CRT with outcomes in contemporaneous controls without CRT; their findings of improved LVEF (weighted mean difference, 4.6%; 95% CI, 2.9%-6.3%) and lower mortality rates (RR, 0.64; 95% CI, 0.26-1.56) in the CRT group were consistent in magnitude to the findings from our meta-analysis of the CRT trials.

The pooled effectiveness estimates from the observational studies for functional outcomes were consistent with those estimates from the efficacy RCTs. For example, in the RCTs, 59% of patients implanted with a CRT device improved by at least 1 NYHA class, and in the observational studies between 63% and 82% of patients improved by at least 1 NYHA class (Table 1). Determining the true response rate with CRT is hampered by the lack of a universally accepted definition for response139 and the fact that patients may demonstrate a response clinically but not echocardiographically or vice versa (with only 76% agreement in the classification of responder/nonresponder between definitions).140 No covariates were consistently shown across studies to predict CRT response.

Table Graphic Jump LocationTable 1. Response Rates Reported in Observational Studies: CRT Alone or Combined CRT-ICD Devices
Safety of CRT

Quiz Ref IDIn 54 studies (6123 patients) of CRT-alone devices, implant success rate was 93.0% (95% CI, 92.2%-93.7%), peri-implantation mechanical complications occurred in 4.3% (95% CI, 3.6%-5.1%) of procedures, and peri-implant deaths occurred in 0.3% of patients (95% CI, 0.1%-0.6%). During a median 6-month follow-up, 5% (95% CI, 4%-7%) of CRT devices malfunctioned and 1.8% (95% CI, 1.3%-2.5%) of patients were hospitalized for infections in the implant site; and during a median 11-month follow-up, lead problems occurred in 6.6% (95% CI, 5.6%-7.4%) of CRT devices. Although earlier studies raised concerns about a potentially higher risk of non–heart failure outcomes in patients with CRT (particularly an excess of ventricular arrhythmias),141 pooling the data from all of the RCTs did not reveal any excess risk of sudden death (RR, 1.07; 95% CI, 0.79-1.46) or noncardiac death (RR, 0.81; 95% CI, 0.43-1.52) in recipients of a CRT device.

In 36 studies (5199 patients) of combined CRT-ICD devices, safety outcomes were similar to CRT-alone devices (implant success rate was 93.7% [95% CI, 92.9%-94.4%]; peri-implantation mechanical complications occurred in 4.6% [95% CI, 3.7%-5.6%] of procedures; peri-implant deaths occurred in 0.5% [95% CI, 0.2%-0.8%] of patients; and during a median 12-month follow-up, 5% [95% CI, 4.0%-6.3%] of combined CRT-ICD devices malfunctioned, 1.1% [95% CI, 0.7%-1.7%] of patients developed site infection, and lead problems were detected in 7.2% [95% CI, 6.3%-8.1%] of patients). There were no appreciable differences between implant success rates or frequency of adverse events in the RCTs or the observational studies for CRT-alone or combined CRT-ICD devices.

Cost-effectiveness of CRT

Five published decision analyses142146 have explored the cost-effectiveness of CRT therapy. Although 1 study142 estimated the median incremental cost of CRT plus medical therapy over medical therapy alone to be as high as $107 800 per quality-adjusted life-year, this was based on outcome data from the early CRT RCTs (most of which reported outcome data only within the first 3 months after CRT activation). Four subsequent cost-effectiveness analyses,143146 which incorporated more recently published trials with substantially longer follow-up durations, reported lower incremental costs per quality-adjusted life-year gained with CRT devices: $19 600 in an analysis of the COMPANION trial data,143 £19 319 (US $38 202) in an analysis of the CARE-HF trial data,144 €7538 (US $10 192) in an analysis using data from the COMPANION trial and long-term follow-up data from the CARE-HF database,145 and £16 598 (US $32 822) in an analysis based on data from the 5 longest CRT RCTs.146 An analysis using long-term individual patient data from the CARE-HF trial confirmed that CRT alone was cost-effective in all age groups (ranging from €7139 [US $9653] per quality-adjusted life-year in 55-year-old patients to €7982 [US $10 792] in 75-year-old patients).145 Combined CRT-ICD devices were also found to be cost-effective when compared against medical therapy (€18 017 [US $24 360] per quality-adjusted life-year gained), but the cost-effectiveness ratios were less favorable in older patients (€15 805 [US $21 370] in 55-year-old patients vs €22 490 [US $30 408] in 75-year-old patients).145 The incremental cost-effectiveness of combined CRT-ICD devices vs CRT-alone devices, however, was markedly higher in all of these analyses ($171 538 per quality-adjusted life-year in the United States, £34 664 [US $68 547] in the United Kingdom, and €47 909 [US $64 777] in Europe). Thus, although CRT-alone devices are clearly cost-effective compared with medical therapy alone in trial eligible patients, the cost-effectiveness ratios when these devices are used in clinical practice are uncertain, as is the incremental cost-effectiveness of combined CRT-ICD devices vs CRT-alone devices remains uncertain pending further research.

Proportion of Patients With Heart Failure Likely to Be Eligible for CRT

Approximately 1% to 3% of all patients discharged alive after their index hospitalization for heart failure and 15% to 20% of patients observed in specialized heart failure clinics met CRT trial eligibility criteria (LVEF ≤35%, QRS ≥120 milliseconds, sinus rhythm, and NYHA class 3 or 4 symptoms despite optimal medical management).147 Of these patients, approximately 50% also met trial eligibility criteria for an ICD.148

Controversies and Areas for Future Research

Despite consistent evidence across published studies, a number of areas of uncertainty remain. Some of these gray areas result from the underrepresentation of patients with particular characteristics, such as bradyarrhythmias, atrial fibrillation, less severe heart failure symptoms, chronic kidney disease, or right-bundle branch blocks, in the RCTs conducted thus far and should be resolved by ongoing trials (Table 2). However, a number of other caveats should be raised when considering the CRT data presented herein.

Table Graphic Jump LocationTable 2. Summary of Evidence for CRT Alone or Combined CRT-ICD Devices in Patients With Left Ventricular Systolic Dysfunction (LVEF ≤35%)*

First, an important question about CRT, as with any new therapy, is whether the efficacy demonstrated in RCTs translates into effectiveness when applied in clinical practice. This is of particular concern for device therapies such as CRT that have been tested in a selected spectrum of patients and depend on specialized technical expertise. Thus, although the trials proving the efficacy of CRT enrolled relatively young patients and a high proportion of men, population-based cohort data147 demonstrate that patients with heart failure in clinical practice are almost a decade older than trial participants and have a substantially greater burden of comorbid illnesses. Recent analyses of Medicare ICD recipients confirmed that these devices are being implanted in older patients with more comorbidities152 than trial participants, and are being implanted by less experienced health care practitioners working in lower volume hospitals153 than those health care practitioners and hospitals that participated in the RCTs. It seems likely that such trends exist in CRT implants as well.

Second, approximately half of the patients in our efficacy analysis were participants in RCTs that randomized patients only after successful device implantation; as a result, patients who could not tolerate the procedure or in whom implantation was unsuccessful were not included in the final trial data. Although our meta-regression did not demonstrate this factor to be statistically significantly related to magnitude of demonstrated benefits, this analysis was underpowered due to the small number of studies, and it is still possible that these RCTs may overestimate the potential benefits from CRT and underestimate the risks.

And third, our estimates of implant success and peri-implant vs postimplant safety are based on only a few thousand patients and thus should not be considered definitive (particularly in light of the recent experiences with ICD device recalls).

These points serve to emphasize the importance of establishing a prospective CRT registry—akin to the Heart Rhythm Society and American College of Cardiology National Cardiovascular Data Registry for ICD devices—to provide real world estimates of benefits and risks with CRT or combined CRT-ICD devices. Such a registry would also provide much needed data on the long-term functional and morbidity outcomes with CRT and combined CRT-ICD devices, and would permit the tracking of complication rates as device implanters, the tools for implantation, and the sophistication of the devices change over time.

Second, although we were unable to detect any differential subgroup effects in the efficacy of CRT, the RCT subgroup analyses and our meta-regressions were post hoc and underpowered. Individual patient data from the RCTs conducted thus far would be needed to appropriately examine this issue, and we believe the compilation and analysis of this data should be an urgent research priority in this field. Indeed, relying on RCT eligibility criteria to define those patients most likely to benefit is imperfect, particularly since more than one third of CRT recipients do not exhibit any functional or echocardiographic improvements after activation of their CRT.

In particular, QRS duration has been used to select patients for CRT in the RCTs conducted thus far and it is uncertain whether, and to what extent, the use of newer techniques to detect electromechanical dyssynchrony, such as tissue doppler imaging, or to detect those patients at increased risk for ventricular arrhythmias, such as the microvolt T-wave alternans test, will impact the effectiveness and safety of these devices.154

Quiz Ref IDAlthough the incremental benefit of combined CRT-ICD devices vs ICD alone is uncertain, this issue should be resolved after the ongoing RAFT (Resynchronization/Defibrillation for Advanced Heart Failure Trial; http://www.clinicaltrial.gov: NCT00251251) and DECREASE-HF150 trials are completed. However, we are not aware of any ongoing randomized trials exploring the incremental benefit of combined CRT-ICD devices vs CRT alone, which we believe is a key area of residual uncertainty for patients with LV systolic dysfunction. Because CRT alone appears to reduce the frequency of ventricular arrhythmias155 and the long-term risk of sudden death,137 the incremental benefits of a combined CRT-ICD device in patients who are CRT eligible may be less than anticipated by those clinicians extrapolating from RCTs comparing ICD with drug therapy. Although we believe that combined CRT-ICD devices should be considered in patients who are CRT eligible who would otherwise be candidates for ICD (those patients with a history of, or at increased risk for, sudden cardiac death who do not have significant comorbidities), this should not be extrapolated to endorse the implantation of combined CRT-ICD devices in all patients who are CRT eligible or all patients who are ICD eligible. We believe there is a need for device manufacturers and trialists to design studies that compare the effect of combined CRT-ICD devices with CRT-alone devices.

CRT is an efficacious and cost-effective therapy for patients with NYHA class 3 or 4 heart failure despite optimal medical management, an LVEF of 35% or less, sinus rhythm, and ventricular dyssynchrony (currently identified by prolonged QRS duration). CRT improves ventricular function and remodelling, symptoms, and exercise capacity, while also reducing frequency of heart failure hospitalizations by 37% and death by 22%. The magnitude of these benefits are similar to those reported for angiotensin-converting enzyme inhibitors or β-blockers and are additive to the benefit of such medical therapy. Although the periprocedural risks of CRT appear modest and are similar to the frequency reported for patients undergoing implantation of conventional dual-chamber pacemakers,156 there is a 5% risk of device or lead failure and a 2% risk of infection in the first 6 months after CRT implantation, and these risks should be factored into clinical decisions about whether to refer a patient for device implantation.

However, implantation of a CRT pacemaker (in particular the LV lead) can be technically challenging, and device malfunctions or lead problems (most frequently with the LV lead) are not infrequent. Even when lead placement is thought to be successful, CRT does not always restore mechanical synchrony. Studies to define which patients are most likely to benefit from CRT, such as the ongoing Predictors of Response to Cardiac Resynchronization Therapy Study,157 and which positions in the ventricular wall are most appropriate for implantation of the pacing leads are clear research priorities,154 as are studies to better define which patients who are CRT eligible are at highest risk for ventricular arrhythmias and thus most likely to benefit from a combined CRT-ICD device.

Corresponding Author: Finlay A. McAlister, MD, MSc, 2E3.24 WMC, University of Alberta Hospital, 8440 112th St, Edmonton, Alberta, Canada T6G 2R7 (finlay.mcalister@ualberta.ca).

Author Contributions: Dr McAlister had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: McAlister, Ezekowitz, Page, Rowe.

Acquisition of data: McAlister, Ezekowitz, Hooton, Spooner, Dryden.

Analysis and interpretation of data: McAlister, Ezekowitz, Vandermeer, Page, Hltaky, Rowe.

Drafting of the manuscript: McAlister, Ezekowitz, Vandermeer.

Critical revision of the manuscript for important intellectual content: McAlister, Ezekowitz, Hooton, Vandermeer, Spooner, Dryden, Page, Hltaky, Rowe.

Statistical analysis: Vandermeer.

Obtained funding: Rowe.

Administrative, technical, or material support: Hooton, Spooner, Dryden.

Study supervision: McAlister, Ezekowitz, Hooton, Dryden.

Financial Disclosures: Dr Page is an officer of the Heart Rhythm Society and a member of the Circulatory System Device Panel of the Medical Devices Advisory Committee, Center for Devices and Radiological Health, Food and Drug Administration. He reports serving within the past 5 years as a consultant for Procter & Gamble Pharmaceuticals, GlaxoSmithKline, AstraZeneca, Forrest Research, Cardiome, Pharma Corp, Alza Corp, Berlex Labs, Hewlett Packard Co, Reliant Pharmaceuticals Inc, Sanofi-Aventis, and Pfizer Inc. No other authors reported financial disclosures.

Funding/Support: This work was based on an evidence report produced by the University of Alberta Evidence-based Practice Center under contract 290-02-0023 from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, Rockville, Md. The authors of this article are responsible for its content. Dr McAlister is a Population Health Scholar supported by the Alberta Heritage Foundation for Medical Research, a New Investigator of the Canadian Institutes of Health Research (CIHR), and holds the Merck Frosst/Aventis Chair in Patient Health Management at the University of Alberta, Edmonton. Dr Ezekowitz is supported by CIHR. Dr Rowe is supported by the 21st Century Canada Research Chairs program through the Government of Canada. He is also supported by the Faculty of Medicine and Dentistry, University of Alberta, Edmonton, and the Capital Health Authority, Edmonton.

Role of the Sponsor: The funding source had no role in the collection, analysis, or interpretation of the data, or in the preparation of the manuscript, or in the decision to submit the paper for publication.

Disclaimer: Statements in this article should not be construed as endorsement by the AHRQ or the US Department of Health and Human Services.

Acknowledgment: We thank the members of the technical expert panel for this AHRQ article: Gillian D. Sanders, PhD, Department of Medicine, Duke University Medical Center, Durham, NC, William T. Abraham, MD, Division of Cardiovascular Medicine, The Ohio State University, Columbus, and Mary Nix, MS, MT(ASCP), AHRQ, who provided direction for the scope and content of the review. We also thank our librarians, Carol Friesen, MA, MLIS, and Tamara Durec, BSc, MLIS, University of Alberta Evidence-based Practice Center, Edmonton, Alberta, and the external reviewers who submitted written comments on earlier drafts of the manuscript: David Atkins, MD, MPH, AHRQ, Eric Fain, MD, St Jude Medical, Sunnyvale, Calif, Martin Fromer, MD, Centre Hospitalier Universtaire Vaudois, Lausanne, Switzerland, Gordon Moe, MS, MD, FRCPC, Heart Failure Program and Biomarker Laboratory, St Michael's Hospital, University of Toronto, Toronto, Ontario, Robert F. Rea, MD, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minn, John Spertus, MD, MPH, Cardiovascular Education and Outcomes Research, University of Missouri, Kansas City, Mo, Bob Thompson, MS, MA, Medtronic Inc, Minneapolis, Minn, and Clyde W. Yancy, MD, Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Tex. No persons mentioned received any financial compensation outside of the baseline salary paid to employees of the University of Alberta Evidence-based Practice Center, which is supported by the AHRQ. Finally, we also thank William T. Abraham, MD, C. Leclerq, MD, and S. Cazeau, MD, for providing further information about their studies.

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Saxon LA, Greenfield RA, Crandall BG, Nydegger CC, Orlov M, Van Genderen R. Results of the multicenter RENEWAL 3 AVT clinical study of cardiac resynchronization defibrillator therapy in patients with paroxysmal atrial fibrillation.  J Cardiovasc Electrophysiol. 2006;17:520-525
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Ståhlberg M, Braunschweig F, Gadler F, Karlson H, Linde C. Three year outcome of cardiac resynchronization therapy: a single center evaluation.  Pacing Clin Electrophysiol. 2005;28:1013-1017
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Teo WS, Kam R, Hsu LF. Treatment of heart failure: role of biventricular pacing for heart failure not responding well to drug therapy.  Singapore Med J. 2003;44:114-122
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Theuns DA, Thornton AS, Klootwijk AP.  et al.  Outcome in patients with an ICD incorporating cardiac resynchronisation therapy: differences between primary and secondary prophylaxis.  Eur J Heart Fail. 2005;7:1027-1032
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Toussaint JF, Lavergne T, Kerrou K.  et al.  Basal asynchrony and resynchronization with biventricular pacing predict long-term improvement of LV function in heart failure patients.  Pacing Clin Electrophysiol. 2003;26:1815-1823
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Waggoner AD, Rovner A, de las Fuentes L.  et al.  Clinical outcomes after cardiac resynchronization therapy: importance of left ventricular diastolic function and origin of heart failure.  J Am Soc Echocardiogr. 2006;19:307-313
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Witte KKA, Pipes RR, Nanthakumar K, Parker JD. Biventricular pacemaker upgrade in previously paced heart failure patients: improvements in ventricular dyssynchrony.  J Card Fail. 2006;12:199-204
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Yu CM, Fung WH, Lin H, Zhang Q, Sanderson JF, Lau CP. Predictors of left ventricular reverse remodeling after cardiac resynchronization therapy for heart failure secondary to idiopathic dilated or ischemic cardiomyopathy.  Am J Cardiol. 2003;91:684-688
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Yu CM, Fung JW, Chan CK.  et al.  Comparison of efficacy of reverse remodeling and clinical improvement for relatively narrow and wide QRS complexes after cardiac resynchronization therapy for heart failure.  J Cardiovasc Electrophysiol. 2004;15:1058-1065
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Yu CM, Bleeker GB, Fung JW.  et al.  Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy.  Circulation. 2005;112:1580-1586
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Kautzner J, Riedlbauchova L, Cihak R, Bytesnik J, Vancura V. Technical aspects of implantation of LV lead for cardiac resynchronization therapy in chronic heart failure.  Pacing Clin Electrophysiol. 2004;27:783-790
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Lewicka-Nowak E, Sterlinski M, Dabrowska-Kugacka A.  et al.  Problemy i niepowodzenia zwiazane ze stosowzniem stymulacji dwukomorowej u pacjentow z zaawansowana niewydolnoscia serca [Complications of permanent biventricular pacing in patients with advanced heart failure].  Folia Cardiol. 2005;12:343-353
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Romeyer-Bouchard C, Da Costa A, Abdellaoui L.  et al.  Simplified cardiac resynchronization implantation technique involving right access and a triple-guide/single introducer approach.  Heart Rhythm. 2005;2:714-719
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Schuchert A, Seidl K, Pfeiffer D.  et al.  Two-year performance of a preshaped lead for left ventricular stimulation.  Pacing Clin Electrophysiol. 2004;27:1610-1614
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Cleland JGF, Daubert JC, Erdmann E.  et al.  Longer-term effects of cardiac resynchronization therapy on mortality in heart failure (the CArdiac REsynchronization-Heart Failure [CARE-HF] trial extension phase).  Eur Heart J. 2006;27:1928-1932
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Woo GW, Petersen-Stejskal S, Johnson JW, Conti JB, Aranda JA Jr, Curtis AB. Ventricular reverse remodeling and 6-month outcomes in patients receiving cardiac resynchronization therapy: analysis of the MIRACLE study.  J Interv Card Electrophysiol. 2005;12:107-113
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Birnie DH, Tang AS. The problem of non-response to cardiac resynchronization therapy.  Curr Opin Cardiol. 2006;21:20-26
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Bleeker GB, Bax JJ, Fung JW.  et al.  Clinical versus echocardiographic parameters to assess response to cardiac resynchronization therapy.  Am J Cardiol. 2006;97:260-263
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Medina-Ravell VA, Lankipalli RS, Yan GX.  et al.  Effect of epicardial or biventricular pacing to prolong QT interval and increase transmural dispersion of repolarization: does resynchronization therapy pose a risk for patients predisposed to long QT or torsade de pointes?  Circulation. 2003;107:740-746
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Nichol G, Kaul P, Huszti E, Bridges JF. Cost-effectiveness of cardiac resynchronization therapy in patients with symptomatic heart failure.  Ann Intern Med. 2004;141:343-351
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Feldman AM, de Lissovoy G, Bristow MR.  et al.  Cost effectiveness of cardiac resynchronization therapy in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial.  J Am Coll Cardiol. 2005;46:2311-2321
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Calvert MJ, Freemantle N, Yao G.  et al.  Cost-effectiveness of cardiac resynchronization therapy: results from the CARE-HF trial.  Eur Heart J. 2005;26:2681-2688
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Yao G, Freemantle N, Calvert MJ, Bryan S, Daubert JC, Cleland JG. The long-term cost-effectiveness of cardiac resynchronization therapy with or without an implantable cardioverter-defibrillator.  Eur Heart J. 2007;28:42-51
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Fox M, Mealing S, Anderson R.  et al.  The effectiveness and cost-effectiveness of cardiac resynchronization (biventricular pacing) for heart failure: a systematic review and economic model. Southampton, England: Peninsula Technology Assessment Group; 2006. http://www.nice.org.uk/page.aspx?o=388638. Accessed September 28, 2006
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Toma M, McAlister F, Ezekowitz J.  et al.  Proportion of patients followed in a specialized heart failure clinic needing an implantable cardioverter defibrillator as determined by applying different trial eligibility criteria.  Am J Cardiol. 2006;97:882-885
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Linde C, Gold M, Abraham WT, Daubert JC.REVERSE Study Group.  Rationale and design of a randomized controlled trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with asymptomatic left ventricular dysfunction with previous symptoms or mild heart failure—the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study.  Am Heart J. 2006;151:288-294
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De Lurgio DB, Foster E, Higginbotham MB, Larntz K, Saxon LA. A comparison of cardiac resynchronization by sequential biventricular pacing and left ventricular pacing to simultaneous biventricular pacing: rationale and design of the DECREASE-HF clinical trial.  J Card Fail. 2005;11:233-239
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Moss AJ, Brown MW, Cannom DS.  et al.  Multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT): design and clinical protocol.  Ann Noninvasive Electrocardiol. 2005;10:(suppl)  34-43
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Reynolds MR, Cohen DJ, Kugelmass AD.  et al.  The frequency and incremental cost of major complications among medicare beneficiaries receiving implantable cardioverter-defibrillators.  J Am Coll Cardiol. 2006;47:2493-2497
PubMed   |  Link to Article
Al-Khatib SM, Lucas FL, Jollis JG, Mallenka DJ, Wennberg DE. The relation between patients' outcomes and the volume of cardioverter-defibrillator implantation procedures performed by physicians treating Medicare beneficiaries.  J Am Coll Cardiol. 2005;46:1536-1550
PubMed   |  Link to Article
Mehra MR, Greenberg BH. Cardiac resynchronization therapy: caveat medicus!  J Am Coll Cardiol. 2004;43:1145-1148
PubMed   |  Link to Article
Ermis C, Seutter R, Zhu AX.  et al.  Impact of upgrade to cardiac resynchronization therapy on ventricular arrhythmia frequency in patients with implantable cardioverter-defibrillators.  J Am Coll Cardiol. 2005;46:2258-2263
PubMed   |  Link to Article
Ellenbogen KA, Hellkamp AS, Wilkoff BL.  et al.  Complications arising after implantation of DDD pacemakers: the MOST experience.  Am J Cardiol. 2003;92:740-741
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Yu CM, Abraham WT, Bax J.  et al.  Predictors of response to cardiac resynchronization therapy (PROSPECT)—study design.  Am Heart J. 2005;149:600-605
PubMed   |  Link to Article

Figures

Figure 1. Study Flow
Graphic Jump Location

CRT indicates cardiac resynchronization therapy.

Figure 2. Effect of CRT on Proportion of Patients Hospitalized for Heart Failure (Randomized Trial Data)
Graphic Jump Location

CRT indicates cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator. Size of data markers indicates the weight of the study.

Figure 3. Effect of CRT on All-Cause Mortality (Randomized Trial Data)
Graphic Jump Location

CRT indicates cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator. Size of data markers indicates the weight of the study.

Tables

Table Graphic Jump LocationTable 1. Response Rates Reported in Observational Studies: CRT Alone or Combined CRT-ICD Devices
Table Graphic Jump LocationTable 2. Summary of Evidence for CRT Alone or Combined CRT-ICD Devices in Patients With Left Ventricular Systolic Dysfunction (LVEF ≤35%)*

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