European Heart Journal

European Heart Journal Advance Access originally published online on September 11, 2006
European Heart Journal 2006 27(22):2682-2688; doi:10.1093/eurheartj/ehl203

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Effects of cardiac resynchronization therapy on overall mortality and mode of death: a meta-analysis of randomized controlled trials

Máximo Rivero-Ayerza^*, Dominic A.M.J. Theuns, Hector M. Garcia-Garcia, Eric Boersma, Maarten Simoons and Luc J. Jordaens

Department of Cardiology, Thoraxcenter, Erasmu MC, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands

Received 27 March 2006; revised 6 July 2006; accepted 4 August 2006; online publish-ahead-of-print 11 September 2006.

^* Corresponding author. Tel: +31 10 463 3991; fax: +31 10 463 4420. E-mail address: m.riveroayerza{at}erasmusmc.nl

See page 2617 for the editorial comment on this article (doi:10.1093/eurheartj/ehl310)

	Abstract

Top Abstract Introduction Methods Results Discussion Conclusion References

 
Aims Cardiac resynchronization therapy (CRT) has been shown to improve symptoms and exercise tolerance in patients with advanced heart failure (HF). However, studies were underpowered to address its effect on overall mortality. To evaluate whether CRT alone (without a combined defibrillator function) reduces overall mortality as compared with optimal pharmacological therapy, and how it affects the mode of death in patients with advanced HF.

Methods and results Public domain databases were systematically searched. Randomized controlled studies that evaluated the effects of CRT alone in patients with advanced HF and a depressed left ventricular systolic performance were selected for this analysis. Trials, which did not independently report data on CRT alone or had a follow-up period of less than 3 months, were excluded. Five studies were identified and analyzed. They included a total of 2371 patients, 1028 controls and 1343 CRT-treated patients. Pooled analysis demonstrated that CRT alone, as compared with optimal medical therapy, significantly reduced all-cause mortality by 29% [16.9 vs. 20.7%; odds ratio (OR), 0.71; 95% confidence interval (CI), 0.57–0.88] and mortality due to progressive HF by 38% (6.7 vs. 9.7%; OR, 0.62; 95% CI, 0.45–0.84). No effect on sudden cardiac death (SCD) was observed with CRT (6.4 vs. 5.9%; OR, 1.04; 95% CI, 0.73–1.22).

Conclusions CRT alone as compared with optimal medical therapy reduces all-cause mortality in patients with advanced HF. It predominantly reduces worsening HF mortality, not affecting SCD.

Key Words: Cardiac resynchronization therapy • Heart failure • Mortality • Mode of death

	Introduction

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Heart failure (HF) is a growing public health problem in the western world. For instance only in the USA, more than 5 million patients suffer from this disease, and about 500 000 patients are diagnosed with HF yearly.¹ Despite the latest achievements of medical therapy,^2–8 in patients with advanced stages of the disease, mortality remains high and quality-of-life (QOL) severely impaired.⁹

Cardiac resynchronization therapy (CRT) has consistently proven to improve symptoms, QOL, and exercise tolerance in patients with a severely depressed left ventricular ejection fraction (35%) who remain symptomatic (NYHA class III and IV) despite optimal medical therapy.^10–16 Early published studies were specifically designed to evaluate the effects of CRT upon these functional endpoints and were underpowered to evaluate its effect on mortality.^10,12,14,15 The recently published Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure study¹¹ has shown a survival benefit only in those patients randomized to CRT with a combined defibrillator function (CRT-D). In the CARE-HF trial,¹³ patients who received CRT alone (without a CRT-D function) had a significant reduction in overall mortality compared with those under optimal pharmacological therapy.

Previously published meta-analyses have corroborated the effects of CRT upon symptoms, QOL, and exercise tolerance.^17–19 However, an overall survival benefit of CRT alone has not been addressed. This is true, mainly because in their analysis, trials that also evaluated the effects of CRT-D were included. In this way, the effects of CRT were confounded by the proven life-saving effect of the ICD. Performing a meta-analysis increases the power to see a difference in mortality that was not evident in the majority of individual trials performed. It also allows having a more precise estimation of this effect.²⁰ We designed a meta-analysis with the purpose of establishing whether CRT alone, compared with optimal medical therapy, reduces overall mortality and in which way it affects the different modes of death in patients with advanced HF.

	Methods

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Search strategy
A comprehensive search of public domain databases was carried out with the purpose of identifying reports of randomized trials comparing CRT alone vs. optimal pharmacological therapy (control) in patients with advanced symptoms of HF due to left ventricular systolic dysfunction. Using the terms HF, pacemaker, pacing, biventricular, biventricular pacing, left ventricular pacing, left ventricular pre-excitation, multi-site pacing, cardiac resynchronization, and cardiac resynchronisation MEDLINE (1985–2005) and the Cochrane Central Register of Controlled Trials (third quarter 2005) were searched. The search was limited to English language publications. In addition, the website of the US Food and Drug Administration (www.fda.gov) was searched, and the reference lists of identified papers were examined. Reports presented during the last 5 years at the scientific sessions of the American College of Cardiology, the American Heart Association, the North American Society of Pacing and Electrophysiology later the Heart Rhythm Society, and the European Society of Cardiology were manually or electronically sought. The latest search was carried out in November 2005.

Study selection
Randomized trials performed in patients with advanced symptoms of HF due to left ventricular systolic dysfunction that evaluated the effects of CRT alone vs. optimal pharmacological therapy (control) were included in this analysis. Studies were excluded if they evaluated the effects of CRT-D and did not separately report data on CRT alone. Because we were mainly interested in the chronic effects of CRT, studies with a follow-up of less than 3 months were excluded. To be included, the duration of the first follow-up phase of the randomized cross-over trials had to be at least 3 months. To avoid a carry-over effect, only the first randomized cross-over period was considered for analysis.

Two investigators (M.R.A., D.A.M.J.T.) independently screened all titles and abstracts to determine which studies met the inclusion criteria. Publications for this review were selected if they fulfilled the following criteria: (i) randomized trials performed in humans; (ii) comparing the effects of CRT alone with optimal pharmacological therapy in patients with advanced HF due to left ventricular systolic dysfunction; and (iii) reported mortality and mode of death during the randomized period. Discrepancies between investigators were resolved by consensus.

Data analysis
Two investigators using a standardized form independently abstracted data. A meta-analysis of summary statistics from individual trials was performed. ORs from each included trial were pooled using both fixed and random effects model that used weighting based on inverse variance calculated according to DerSimonian and Laird.²¹ To check for statistical evidence of heterogeneity among trial-specific ORs, a ² test was used and it was quantified using the I² statistic.²² When pooled analysis resulted in a significant heterogeneity, the random effects model was used.

Quantitative analyses were performed on an intention-to-treat basis using the same standardized endpoint definitions [overall mortality, worsening HF mortality, and sudden cardiac death (SCD)] as in the primary studies. For non-worsening HF mortality, all deaths except those due to HF were considered. Data analysis was performed using the Review Manager 4.2.

	Results

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Search results
A total of 6893 references from all databases were found. A total of 1757 reports were identified as potentially relevant, of which 1719 were excluded based on titles and abstracts. Full-text versions of the remaining 38 reports were retrieved for detailed evaluation. Of these, eight reports^{10–14,23–25} of five randomized studies were included for this analysis (Figure 1).

View larger version (11K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Reports evaluated for inclusion in the meta-analysis.

 
Qualitative findings
Five studies met the criteria for inclusion, the Multisite Stimulation in Cardiomyopathies Study (MUSTIC),¹² the Multicenter InSync Randomized Clinical Evaluation (MIRACLE),¹⁰ the MUSTIC AF,¹⁴ the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION)¹¹ (CRT alone and control arms only) and the Cardiac Resynchronization–Heart Failure (CARE-HF)¹³ trials. Although the results of the extension phase of this last trial were recently presented,²⁶ data from the original study will be considered for this analysis. However, in order to also evaluate the effects of CRT considering the data of the extension phase of this last trial, a sensitivity analysis was performed.

Baseline patient characteristics and design of all trials are summarized in Tables 1 and 2. The mean age of the populations ranged between 64 and 68 years. The majority of patients in each trial were male and presented symptoms of advanced HF (NYHA functional class III and IV). In two studies, ischaemic cardiomyopathy was the main aetiologic diagnosis.^10,11,23,24 Although most trials excluded patients with atrial fibrillation, one trial specifically evaluated the effects of CRT in this population.¹⁴ The only trial in which mechanical ventricular dyssynchrony was considered an inclusion criterion was the CARE-HF.¹³ In order to be included, patients in whom the QRS duration ranged between 120 and 150 ms were required to present echocardiographic documentation of ventricular dyssynchrony. MUSTIC AF¹⁴ was the only study to include patients with a pacemaker indication. The rest of the studies excluded patients with sinus node dysfunction, AV block, or other indications for permanent pacemaker implantation.

View this table: [in this window] [in a new window]   Table 1 Baseline clinical characteristics of patients included in the analysed trials

 

View this table: [in this window] [in a new window]   Table 2 Description of the analysed trials

 
In no trial was overall mortality the primary endpoint. In COMPANION^11,24 and CARE-HF¹³ all-cause mortality was part of a combined primary endpoint. In all the studies analyzed, mortality was one of the secondary endpoints (Table 2).

All patients underwent implantation of a pacemaker with CRT capabilities through a trans-venous left ventricular lead implantation. In the COMPANION trial,^11,24 one arm of the study evaluated the effects of CRT-D. In order to establish the effects of CRT alone, this last arm of the study was not included in this analysis. In three trials, all patients received CRT devices and were randomized in a parallel way^10,23 or crossover design^12,14 to CRT on or off. In the two largest trials,^11,13,24 patients were randomized to receive, or not to, a CRT device.

In the COMPANION study,^11,24 13% of the patients in the control group received commercially available implants before reaching the primary endpoint; 2% of the patients in the CRT alone group withdrew from the study. In CARE-HF,¹³ only 5% of the patients assigned to receive optimal medical therapy were actively paced with CRT before reaching the primary endpoint. In the MIRACLE study,^10,23 10 patients in the control group had their CRT device activated. Only one patient in the MUSTIC¹² and one in the MUSTIC AF¹⁴ were switched to active biventricular pacing during the first crossover phase. All results were reported on an intention-to-treat basis.

Weighted mean follow-up was 18.4 months. It ranged from 3 months to 29.4 months depending on the trial. In the COMPANION trial,^11,24 the median duration of follow-up for mortality was 14.8 months in the control group and 16.5 months in the CRT group. In CARE-HF,¹³ mean follow-up for all patients enrolled was 29.4 months.

Effects of CRT alone on overall mortality
When pooling data from all five studies together (2371 patients) using a fixed-effect model, CRT alone significantly showed to reduce all-cause mortality by 29% (OR, 0.71; 95% CI, 0.57–0.88) with respect to controls (Figure 2). Among the CRT-treated group, 227 patients died (16.9 %) compared with 213 controls (20.7%). This represents an absolute reduction of 3.8%; 26 patients need to be treated with CRT in order to save one life during the corresponding follow-up. No evidence of statistical heterogeneity was observed between trials regarding this effect (P=0.54). When performing a sensitivity analysis considering the extension phase of the CARE-HF study, the overall mortality reduction afforded by CRT was 34% (OR, 0.66; 95% CI, 0.54–0.82).

View larger version (11K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 2 Effect of CRT alone vs. control on overall mortality.

 
Mode of death
Data on the mode of death (all-cause mortality, mortality due to worsening HF SCD) was reported in all trials.^{10–14,23–25} When considering mortality due to progressive HF, most studies showed a tendency towards a reduction in this mode of death in patients treated with CRT (Figure 3). The only trial to show a significant 45% reduction in mortality due to worsening HF was the CARE-HF trial.¹³ When pooling the data of all trials, a significant 38% relative reduction in this endpoint was observed among patients treated with CRT alone (OR, 0.62; 95% CI, 0.45–0.84). It was observed that 90 patients (6.7%) died due to pump failure in the CRT group as compared with 100 patients (9.7%) randomized to optimal pharmacological therapy. Thirty-three patients need to be treated in order to avoid one death due to worsening HF. No evidence of statistical heterogeneity was observed regarding this effect (P=0.45).

View larger version (10K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 3 Effect of CRT alone vs. control on heart failure mortality.

 
A neutral effect of CRT on SCD was observed (CRT group 6.4% vs. controls 5.9%; OR, 1.04; 95% CI, 0.73–1.46) (Figure 4). There was also no statistical evidence of heterogeneity between trials regarding this effect (P=0.45). However, in CARE-HF,¹³ more SCDs occurred in the control group, whereas in other studies more patients suffering this mode of death were observed among the CRT-treated patients. After the extended phase of the CARE-HF study, a significant reduction in SCD was observed in patients treated with CRT.²⁶ However, even after performing a sensitivity analysis including these results, no effect of CRT on SCD was observed (OR, 0.86; 95% CI, 0.63–1.19).

View larger version (11K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 4 Effect of CRT alone vs. control on sudden cardiac death.

 
Of the total amount of deaths in the control group (213 deaths), 47% were due to progressive HF and 28% were considered to be sudden, whereas in the CRT-treated patients (227 deaths), these represented 39% and 38%, respectively.

	Discussion

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Our analysis demonstrates that CRT alone reduces all-cause mortality in patients with advanced symptoms of HF refractory to standard pharmacological therapy. It does so predominantly by reducing mortality due to progressive HF not affecting SCD.

CRT has recently emerged as an effective treatment for patients with HF. It improves symptoms, QOL, and exercise tolerance in a selected group of patients with systolic HF who present, as a surrogate sign of ventricular dyssynchrony, with a broad QRS complex on the ECG.^10–19,25 Improvement in more objective endpoints like a positive ventricular remodelling effect^{13,16,25,27–29} and admissions due to HF, have also been demonstrated.^{10,12,13,17,23} For patients who suffer from chronic diseases, improvement in QOL is an important treatment goal. When this is cost-effective and achieved without significant side effects, acceptance among the medical community is likely. So far, this has been the case for CRT. The implantation rate of CRT devices has importantly expanded in recent years before conclusive evidence of a survival benefit was demonstrated.

It is only recently that the CARE-HF trial,¹³ demonstrated a significant reduction in overall mortality with CRT alone. Other trials^30,31 and meta-analyses^17–19 confounded the benefits that CRT alone might have on this last endpoint by including in their analysis the effects of CRT-D devices. It is mandatory then to definitively establish to what extent, and in which way CRT alone affects survival. By pooling data from randomized trials that evaluated the effects of CRT alone as compared with optimal pharmacological therapy, this analysis shows that biventricular pacing confers a significant overall survival benefit of 29%. This 3.8% absolute reduction in overall mortality after CRT is similar to the absolute mortality reduction observed with ACE-inhibitors or beta-blockers,^32,33 and was observed on top of the beneficial effects afforded by these life-saving therapies.

The predominant modes of death in patients with HF are SCD and death attributed to progression of the disease.^5,34–36 Patients who are mildly symptomatic will more likely die suddenly, whereas those with advanced symptoms are more likely to die due to pump failure.^5,34,36 All patients included in the analysed studies were in advanced stages of HF. As CRT alone directly affects myocardial function and HF profile, it is not surprising that the survival benefit can almost exclusively be attributed to the significant 38% reduction in HF mortality (Figure 5).

View larger version (15K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 5 Relative contribution of each mode of death to overall mortality in patients treated with of CRT alone vs. control.

 
A previous meta-analysis¹⁸ showed a non-significant increase in SCD among patients treated with CRT. In the COMPANION trial,^11,24 a modest increase in this mode of death was observed among patients who underwent CRT compared with control patients. Median time to SCD was shorter in the CRT arm (186 days) than in CRT-D (341 days) and control patients (253 days).²⁴ In those studies with shorter follow-up like MUSTIC¹² and MUSTIC AF,¹⁴ most deaths occurred suddenly during active biventricular pacing. CARE-HF reported a non-significant reduction in SCD in patients undergoing CRT compared with controls (9.4 vs. 7.0%; P=0.25) during follow-up.¹³ When pooling data of all studies together, no effect of CRT on the occurrence of SCD was observed (even after considering the data of the extension phase of CARE-HF).²⁶ Patients whose profile improves after being treated with CRT are less likely of dying due to worsening HF; in this way the relative contribution of SCD to overall mortality increases (Figure 5). This raises the question of what the role of ICD will be in these patients. In the COMPANION study,^11,24 CRT-D significantly increased survival compared with controls and showed a trend towards a beneficial effect when compared with CRT alone. However, not all patients profited from the addition of an ICD. The patients who derived more benefit were those with somewhat better preserved EF, and who had a better symptom profile.³⁷ Furthermore, in the SCD-Heft trial, patients in NYHA functional class III did not benefit from the ICD, as did patients with a lower functional class.³⁸ Having shown an important mortality reduction with CRT alone, and considering that the benefits of adding a defibrillator to the CRT device have not yet been proven,¹⁸ the question whether which CRT candidates should receive additional defibrillator function gains relevance and remains unanswered. Nonetheless, probability of survival, quality of the life prolonged, and mode of death are important aspects that patients and physicians should consider when discussing treatment options and deciding whether to implant, and which device to select.

Our analysis has some potential limitations that should be addressed. Although overall mortality is a reliable endpoint, determination of the mechanism leading to death is sometimes very difficult and not accurate.³⁹ Misclassification of deaths due to pump failure is less likely to occur because symptoms of progressive HF are easily recognized and many patients are admitted during the final stages of their disease. In contrast, it is more likely to misclassify deaths when they occur suddenly because they are frequently thought to be arrhythmic in origin even though other cardiovascular causes could be responsible.

Duration of follow-up varied between the analyzed studies. However, most of the patients were followed for at least 1 year (73%) and the mean weighted follow-up was 18.4 months. It is important to highlight that the observed effects of CRT only apply to the limited follow-up period covered by this meta-analysis.

Another potential limitation of this study is the influence of publication bias. This type of bias can never be completely avoided, although performing an extensive search may minimize it. Though funnel plots were performed, the small number of trials included in our analysis reduces its usefulness.

Some of the data used for this analysis was extracted from public domain reports that did not undergo conventional peer review,^23,24 however, the thorough scrutiny to which these reports were submitted by the US Food and Drug Administration is in favour of their reliability.

	Conclusion

Top Abstract Introduction Methods Results Discussion Conclusion References

 
This meta-analysis demonstrates that CRT alone reduces all-cause mortality in a selected group of patients with advanced symptoms of HF. It predominantly reduces mortality due to worsening HF and does not affect SCD. This observation raises the need of establishing to what extent and which patients will benefit from combining an additional defibrillator function.

Conflict of interest: none declared.

	References

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1. Ho KK, Pinsky JL, Kannel WB, Levy D. (1993) The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol. 22:6A–13A.[Medline]
2. The CONSENSUS Trial Study Group. (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316:1429–1435.[Abstract]
3. The SOLVD Investigators. (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325:293–302.[Abstract]
4. CIBIS-II Investigators and Committees. (1999) The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 353:9–13.[CrossRef][Web of Science][Medline]
5. MERIT-HF Study group. (1999) Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353:2001–2007.[CrossRef][Web of Science][Medline]
6. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341:709–717.[Abstract/Free Full Text]
7. Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, Tavazzi L, Smiseth OA, Gavazzi A, Haverich A, Hoes A, Jaarsma T, Korewicki J, Levy S, Linde C, Lopez-Sendon JL, Nieminen MS, Pierard L, Remme WJ. (2005) Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 26:1115–1140.[Free Full Text]
8. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. (2005) ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 112:e154–e235.[Free Full Text]
9. Roger VL, Weston SA, Redfield MM, Hellermann-Homan JP, Killian J, Yawn BP, Jacobsen SJ. (2004) Trends in heart failure incidence and survival in a community-based population. JAMA 292:344–350.[Abstract/Free Full Text]
10. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. (2002) Cardiac resynchronization in chronic heart failure. N Engl J Med 346:1845–1853.[Abstract/Free Full Text]
11. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM. (2004) Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 350:2140–2150.[Abstract/Free Full Text]
12. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC. (2001) Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 344:873–880.[Abstract/Free Full Text]
13. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. (2005) The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 352:1539–1549.[Abstract/Free Full Text]
14. Leclercq C, Walker S, Linde C, Clementy J, Marshall AJ, Ritter P, Djiane P, Mabo P, Levy T, Gadler F, Bailleul C, Daubert JC. (2002) Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J 23:1780–1787.[Abstract/Free Full Text]
15. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Huth C, Schondube F, Wolfhard U, Bocker D, Krahnefeld O, Kirkels H. (2002) Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol 39:2026–2033.[Abstract/Free Full Text]
16. Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, McKenna W, Fitzgerald M, Deharo JC, Alonso C, Walker S, Braunschweig F, Bailleul C, Daubert JC. (2002) Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 40:111–118.[Abstract/Free Full Text]
17. Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H, Goodman SN, Kass DA, Powe NR. (2003) Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA 289:730–740.[Abstract/Free Full Text]
18. McAlister FA, Ezekowitz JA, Wiebe N, Rowe B, Spooner C, Crumley E, Harling L, Klassen T, Abraham W. (2004) Systematic review: cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med 141:381–390.[Abstract/Free Full Text]
19. Freemantle N, Tharmanathan P, Calvert MJ, Abraham WT, Ghosh J, Cleland JGF. (2006) Cardiac resynchronisation for patients with heart failure due to left ventricular systolic dysfunction—a systematic review and meta-analysis. Eur J Heart Fail 8:433–440.[CrossRef][Web of Science][Medline]
20. Koretz RL. (2002) Methods of meta-analysis: an analysis. Curr Opin Clin Nutr Metab Care 5:467–474.[CrossRef][Web of Science][Medline]
21. DerSimonian R and Laird N. (1986) Meta-analysis in clinical trials. Contr Clin Trial 7:177–188.
22. Higgins JP, Thompson SG, Deeks JJ, Altman DG. (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560.[Free Full Text]
23. Barold H. Preliminary clinical review of Medtronic's InSync MIRACLE PMA (Report). http://www.fda.gov/cdrh/pdf/p010015.html.(26 September 2005).
24. Proestel S. Preliminary clinical review of COMPANION PMA (Report). http://www.fda.gov/ohrms/dockets/ac/04/briefing/...(26 September).
25. Duncan A, Wait D, Gibson D, Daubert JC. (2003) Left ventricular remodelling and haemodynamic effects of multisite biventricular pacing in patients with left ventricular systolic dysfunction and activation disturbances in sinus rhythm: sub-study of the MUSTIC (Multisite Stimulationin Cardiomyopathies) trial. Eur Heart J 24:430–441.[Abstract/Free Full Text]
26. Cleland JGF, Tavazzi L, Freemantle N. CARE-HF long-term effects of cardiac resynchronization on mortality in the CARE-HF extension study. Hot Lines and Clinical Trial Updates 2005. ESC Congress 2005SeptemberStockholm.
27. Ghio S, Freemantle N, Clenland JFG, Serio A, Magrini G, Scelsi L, Pasotti M, Stefemann B, Tavazzi L. (2005) Long-term ventricular reverse remodeling with cardiac resynchronization therapy. Results from the CARE-HF trial. Circulation 112:II-672.
28. St John Sutton MG, Plappert T, Abraham WT, Smith AL, DeLurgio DB, Leon AR, Loh E, Kocovic DZ, Fisher WG, Ellestad M, Messenger J, Kruger K, Hilpisch KE, Hill MR. (2003) Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 107:1985–1990.[Abstract/Free Full Text]
29. Stellbrink C, Breithardt OA, Franke A, Sack S, Bakker P, Auricchio A, Pochet T, Salo R, Kramer A, Spinelli J. (2001) Impact of cardiac resynchronization therapy using hemodynamically optimized pacing on left ventricular remodeling in patients with congestive heart failure and ventricular conduction disturbances. J Am Coll Cardiol 38:1957–1965.[Abstract/Free Full Text]
30. Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, Boehmer JP, Higginbotham MB, De Marco T, Foster E, Yong PG. (2003) Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol 42:1454–1459.[Abstract/Free Full Text]
31. Young JB, Abraham WT, Smith AL, Leon AR, Liberman R, Wilkoff B, Canby RC, Schroeder JS, Liem LB, Hall S, Wheelan K. (2003) Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 289:2685–2694.[Abstract/Free Full Text]
32. Garg R and Yusuf S. (1995) Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 273:1450–1456.[Abstract/Free Full Text]
33. Brophy JM, Joseph L, Rouleau JL. (2001) Beta-blockers in congestive heart failure. A Bayesian meta-analysis. Ann Intern Med 134:550–560.[Abstract/Free Full Text]
34. Jong P, Vowinckel E, Liu PP, Gong Y, Tu JV. (2002) Prognosis and determinants of survival in patients newly hospitalized for heart failure: a population-based study. Arch Intern Med 162:1689–1694.[Abstract/Free Full Text]
35. Cleland JG, Erhardt L, Murray G, Hall AS, Ball SG. (1997) Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. A report from the AIRE Study Investigators. Eur Heart J 18:41–51.[Web of Science][Medline]
36. Poole-Wilson PA, Uretsky BF, Thygesen K, Cleland JG, Massie BM, Ryden L. (2003) Mode of death in heart failure: findings from the ATLAS trial. Heart 89:42–48.[Abstract/Free Full Text]
37. Bristow MR, Saxon LA, DeMarco T, Boehmer J, Galle E, Ecklund F, Feldman A. (2005) What does an ICD add to CRT in advanced heart failure patients? An analysis of major clinical endpoints in the CRT vs. CRT-D groups in the COMPANION trial. Circulation 112:II-673.
38. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH. (2005) Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 352:225–237.[Abstract/Free Full Text]
39. Jordaens L. (2000) The classification of sudden death in clinical trials. In Alliot E, Clementy J, Prystowsky EN (Eds.). Fighting Sudden Cardiac Death: A Worldwide Challenge(Futura Pub Co, Armonk) pp. 29–38.

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