Meta-analysis of Cardiac Resynchronization Therapy Finds Mortality Benefit

March 21, 2003

March 21, 2003 — Multiple randomized trials have consistently shown that cardiac resynchronization therapy (CRT) improves exercise capacity, NYHA class, and quality of life; however, each of these individual studies has yet to establish a clear mortality benefit associated with the therapy. To seek a more exacting relationship between mortality and CRT, researchers from Johns Hopkins (Baltimore, Maryland) conducted a meta-analysis of 11 reports on 4 major CRT trials. Reported in the January 12, 2003 issue of JAMA, the meta-analysis revealed that the therapy did indeed confer a mortality benefit, reducing the rate of death from progressive heart failure (HF) by 51%.[1]

The key to CRT is the restoration of synchronous ventricular contractions.

There are 5 million patients with congestive heart failure (CHF) in the United States, and the incidences of death and hospitalization have climbed to an average of 1.3 million per year, with associated annual costs related to HF treatments nearing $40 billion. The most common cause of CHF is ischemic heart disease, and 30% to 50% of these patients have excessive prolongation of electrical activation of the left ventricle (left bundle branch block). This results in dyssynchrony in left ventricular activation, reduced stroke volume, and cardiac output in hearts that are only marginally compensated. It is known that patients with such conduction abnormalities have a significantly higher risk for mortality compared with other CHF patients.

In recent years, CRT, which involves standard right ventricular septal pacing and additional placement of a pacing electrode through the coronary sinus and into a left lateral coronary vein for permanent epicardial left ventricular pacing, has been shown to be effective in treating this condition by restoring synchronous contractions of the interventricular septum and posterolateral left ventricular wall.

Meta-analysis is based on 4 major CRT trials involving patients without pacemaker indications.

Data for the meta-analysis were based on 11 reports from 4 randomized CRT trials: CONTAK CD,[2,3] InSync ICD,[4,5,6] Multicenter InSync Randomized Clinical Evaluation (MIRACLE),[7,8,9,10,11] and Multisite Stimulation in Cardiomyopathies (MUSTIC).[12] All studies included patients with CHF and ventricular dyssynchrony who presented without conventional pacemaker indications. The CONTAK CD and InSync ICD trials that assessed CRT in conjunction with an implantable converter defibrillator (ICD) also included patients who presented with conventional ICD indications. Baseline clinical characteristics were similar in each of the 4 trials, including age and left ventricular ejection fractions (LVEF) (Table).

Table. Baseline Clinical Characteristics of 4 Randomized CRT (± ICD) Trials
Characteristic CONTAK CD InSync ICD MIRACLE MUSTIC
No of pts (n) 490 554 532 58
Age, mean (yrs) 66 66 64 63
Men (%) 421 (84) 448 (81) 370 (70) 50 (75)
LVEF (%) 21 21 22 23
NYHA Class II-IV II-IV III-IV III
QRS duration (msec) 158 165 166 176
LBBB (%) 271 (54) 382 (69) 426 (80) 58 (87)
Beta-blocker use (%) 236 (47) 335 (60) 296 (56) 19 (28)
LBBB = left bundle branch block; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association
CRT reduced all-cause mortality, HF mortality, and rate of HF hospitalizations.

Researchers found that when data were pooled from 4 trials involving a total of 1634 patients, CRT was associated with a 51% reduction in death from progressive CHF relative to controls. There was a trend toward improvement in all-cause mortality (23% improvement), which did not reach statistical significance because of the short follow-up and small sample size, according to the authors. Also, CRT reduced hospitalization for CHF by 29% (n = 1497). Researchers noted there was no significant reduction in episodes of ventricular tachycardia or ventricular fibrillation compared with control (17.2% vs 18.4% during 3-6 months follow-up) among patients treated with combination ICD/CRT devices.

On the basis of their findings from the meta-analysis, investigators concluded that CRT reduces mortality from progressive HF and HF-related hospitalizations in patients with symptomatic left ventricular dysfunction and ventricular dyssynchrony and also shows a trend toward reducing all-cause mortality.

COMPANION trial will reveal more...has implications for future management.

The full results of the Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial, to be presented at the upcoming 2003 American College of Cardiology Scientific Session held in Chicago, Illinois, will help to confirm that CRT with and without ICD capabilities reduces a combined endpoint of death and hospitalization compared with optimal medical management alone. Participants in this study did not have indications for pacing or for an ICD. Candidates for treatment in COMPANION were NYHA class III or IV CHF and had LVEF < 30% and QRS duration of >/= 130 msec. Patients were assigned to conventional medical therapy (20%), conventional medical therapy with CRT pacing (40%), or conventional medical therapy with CRT/ICD (40%). This trial made headlines when it was halted prematurely in November 2001 due to a significant reduction in combined all-cause mortality and all-cause hospitalizations. Although CRT with biventrciular pacing reduced CHF mortality, the greatest mortality reduction occurred in the biventricular pacer/ICD group.

Guidant Corporation (Santa Clara, California), the sponsor of the COMPANION study, had originally received US Food and Drug Administration (FDA) approval for its first-generation CONTAK CD CRT-D (dual CRT/ICD) device in May 2002, and the company announced the FDA approval of its next generation system, CONTAK RENEWAL CRT-D, in January 2003.

The COMPANION study has great clinical and economic implications for the future of HF management. The devices have been criticized for their expensive price (in the range of $20,000 to $25,000), and some clinicians have been reluctant to embrace the technology. These pending results, coupled with those from the second Multicenter Automatic Defibrillator Implantation Trial (MADIT II),[13] which found that patients with an ejection fraction </= 30% were at an increased risk of sudden cardiac death and significantly benefited from ICD therapy, may begin to turn the tide in the medical community in favor of the expanded indications for ICD implantation.

References
  1. Bradley DJ, Bradley EA, Baughman KL, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA. 2003;289:730-740.

  2. Summary of Safety and Effectiveness: Guidant CONTAK CD CRT-D System [report]. US Food and Drug Administration Web site. Available at: http://www.fda.gov/cdrh/pdf/P010012.html.

  3. Guidant Corp P010012. CONTAK CD and Easy Trak Lead System [transcript]. US Food and Drug Administration Center for Devices and Radiological Health Circulatory System Devices Advisory panel meeting; July 10, 2001; Gaithersburg, Md: 11-234.

  4. Abraham WT, Young JB, Leon AR. Medtronic InSync ICD Cardiac Resynchronization System [draft sponsor presentation]. US Food and Drug Administration Center for Devices and Radiological Health Circulatory System Devices Advisory Panel meeting. March 5, 2002; Gaithersburg, Md.

  5. Barold HS, Gray G. Clinical and statistical summary: Medtronic InSync ICD Cardiac Resynchronization System [FDA presentation]. US Food and Drug Administration Center for Devices and Radiological Health Circulatory System Devices Advisory Panel meeting. March 5, 2002; Gaithersburg, Md.

  6. Summary of Safety and Effectiveness: Medtronic InSync ICD Model 7272 [report]. Updated December 2001.

  7. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346:1845-1853.

  8. Abraham WT. Rationale and design of a randomized clinical trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with advanced heart failure: the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). J Card Fail. 2000;6:369-380.

  9. US Food and Drug Administration. Summary of Safety and Effectiveness: Medtronic InSync Biventricular Pacing System [report]. Available at: http://www.fda.gov/cdrh/pdf/p010015.html.

  10. Barold HS. Preliminary Clinical Review of Medtronic's InSync MIRACLE PMA [report]. May 29, 2001.

  11. Medtronic Corporation P010015. Medtronic InSync Atrial Synchronous Biventricular Pacing Device and Attain Lead System [transcript]. US Food and Drug Administration Center for Devices and Radiological Health Circulatory System Devices Advisory Panel meeting; July 10, 2001; Gaithersburg, Md: 236-398.

  12. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344:873-880.

  13. Moss AJ, Zareba W, Hall WJ, et al, for the Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation on a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-883.

By Medscape CRM, Staff Writer

Reviewed by Albert A. Del Negro, MD

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