COMPANION and DEFINITE published: CRT, ICD for HF on threshold of new era

May 19, 2004

Boston, MA - The evidence basis for use of implantable-cardioverter-defibrillator (ICD) and cardiac-resynchronization therapy (CRT) in a broad population of patients with HF has firmed considerably with the publication of two major, randomized, controlled trials[1,2]. The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial and Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE), published in the May 20, 2004 issue of the New England Journal of Medicine, had both started to shape clinical opinion when they were first reported at meetings last year.

 
The release of these new data will increase the pressure on large payers . . . to expand coverage for these devices.
 

The two trials join a cadre of others that have been published or presented at meetings that consistently show significant reduced mortality and hospitalization from CRT-device implantation, in some cases with an ICD, in patients with LV dysfunction and HF. Now in print, with both clinicians and third-party payers watching, COMPANION and DEFINITE could be turning points in the acceptance of electrical-device therapy for patients with cardiomyopathy and HF.

"The release of these new data will increase the pressure on large payers (especially Medicare) to expand coverage for these devices, and it is very likely that the rate of implantation will increase dramatically," writes Dr Mark A Hlatky (Stanford University, CA) in a Perspective in the same issue of the journal[3].

In COMPANION, CRT pacing with or without ICD capability was associated with a significant one-year relative-risk reduction of about 20% for all-cause death or hospitalization when added to optimal medical therapy in patients with ischemic or nonischemic NYHA class 3-4 HF, an LVEF <35%, and a QRS interval of >120 ms. The benefit emerged for both CRT and CRT/ICD therapy. All-cause mortality by itself was significantly reduced by combined CRT/ICD therapy, but there was only a trend for a reduction from CRT on its own. Similar early findings had been presented at the March 2003 American College of Cardiology Scientific Sessions and reported by heartwire .

COMPANION: 12-month outcomes, final results

End point Optimal medical therapy, n=308 (%) Plus CRT, n=617 (%) HR (95% CI) p* Plus CRT/ICD, n=595 (%) RR (95% CI) p*
Primary: all-cause death/hospitalization 68 56 0.81 (0.69-0.96) 0.015 56 0.80 (0.68-0.95) 0.011
Secondary: all-cause death 19 15 0.76 (0.58-1.01) 0.06 12 0.64 (0.48-0.86) 0.004
*p vs optimal medical therapy without device therapy
HR=hazard ratio
CI=confidence intervals
 
We can now conclude that CRT not only makes our heart-failure patients feel better, it helps our patients live longer.
 

"With COMPANION, we can now conclude that CRT not only makes our heart-failure patients feel better, it helps our patients live longer, particularly when combined with a defibrillator," Dr William T Abraham (Ohio State University, Columbus) said to heartwire .

In DEFINITE, medically managed HF patients with nonischemic cardiomyopathy and an LVEF <36% who were implanted with ICDs showed a significant 80% relative reduction in risk of arrhythmic death, a secondary end point, over a mean of 29 months. The primary end point of all-cause mortality only trended toward a reduction with device therapy. The published findings resembled the two-year outcomes reported by heartwire from trial's presentation at the November 2003 American Heart Association Scientific Sessions.

DEFINITE: Outcomes at a mean of 29 months, final results

End point Medical therapy, n=229 (%) Plus ICD therapy, n=229 (%) HR (95% CI) p*
Primary: all-cause death 17.5 12.2 0.65 (0.40-1.06) 0.08
Secondary: arrhythmic sudden death 6.1 1.3 0.20 (0.06-0.71) 0.006
*p vs optimal medical therapy without device therapy
HR=hazard ratio
CI=confidence intervals

Although the primary end-point result didn't reach significance, possibly due to insufficient sample size, DEFINITE complements SCD-HeFT, COMPANION, and other trials that show a pronounced ICD survival benefit in nonischemic cardiomyopathy, Dr Arthur J Moss (University of Rochester, NY) told heartwire. "You're never going to have two trials showing exactly the same thing, but the pattern is overwhelmingly consistent." DEFINITE, he said, "is a good study, and it adds to the expanding literature."

 
You're never going to have two trials showing exactly the same thing, but the pattern is overwhelmingly consistent.
 

Much remains to be learned about how best to use these device therapies, including more effective and stringent risk-stratification criteria to guide patient selection, write Drs Joseph G Rogers and Michael E Cain (Washington University, St Louis, MO) in an accompanying editorial[4]. Still, they add, "we believe the totality of the data supports the value of ICD therapy in patients with NYHA class 2 or 3 heart failure of any cause who have moderate to severe left ventricular systolic dysfunction. Such patients with left bundle-branch block are also candidates for cardiac resynchronization therapy."

COMPANION insights

"The COMPANION study is a critical addition to the data supporting the value of cardiac-resynchronization therapy," write Rogers and Cain in their editorial. Previous trials evaluating CRT in similar populations, they note, have been small and used indirect end points such as exercise performance, remodeling, and quality of life. "The new data on morbidity and mortality are needed confidence builders as we begin to apply these relatively expensive therapies to larger populations."

 
The new data on morbidity and mortality are needed confidence builders.
 

Dr Bruce Wilkoff (Cleveland Clinic Foundation, OH) finds it interesting that, according to the final COMPANION data, "the patients who tended not to benefit were those who did not have their blood pressure well controlled, suggesting that it's pretty important they also be on drugs." The trial, he said, suggests that device therapy isn't an alternative to optimal medical therapy that includes ACE inhibitors and beta blockers. "This is a strong endorsement of aggressive medical and device care for these patients."

According to Dr Marvin A Konstam (New England Medical Center, Boston, MA), both trials underscore the need to give medical therapy a chance before considering device therapy. Many patients with newly diagnosed HF, especially those with nonischemic cardiomyopathy, respond very well to drugs. "We see some patients whose ejection fractions go from 20% to 50% with aggressive medical therapy," Konstam told heartwire .

 
We see some patients whose ejection fractions go from 20% to 50% with aggressive medical therapy.
 

"Patients in these studies . . . tend to be on established, state-of-the-art medical regimens at the time," Konstam said. "So I think it's extremely important to make sure patients are aggressively medically managed and, in the case of new-onset heart failure, that sufficient time is given for medical therapy to take effect. Then explore the patients to see whether device therapy is additionally indicated."

Some DEFINITE views

According to Abraham, "DEFINITE completes the trifecta of MADIT-2, SCD-HeFT, and DEFINITE. Looking at DEFINITE in the context of these other two trials, we really have an overwhelming amount of evidence that supports the fairly routine use of defibrillators as primary prevention for sudden cardiac death." There is, he said, "a very concordant database in both ischemic and nonischemic heart-failure patients."

Wilkoff noted that currently there are no reimbursable ICD indications for patients like the DEFINITE population. The trial, he said, "is a very important step toward covering patients with nonischemic cardiomyopathy."

 
The DEFINITE study is not the definitive word on this topic.
 

But editorialists Rogers and Cain observe that none of the prospective evaluations of prophylactic ICD therapy in high-risk patients with nonischemic cardiomyopathy, of which there are now at least three, have shown a reduction in all-cause mortality. DEFINITE didn't show an overall survival benefit, they propose, because the control group received aggressive, finely tuned medical therapy. In the ICD group, "the trend toward further reduction in mortality is particularly impressive, given the lower-than-expected annual mortality rate in the medical-therapy group." The preliminary results of the much-larger SCD-HeFT trial, which encompassed both cardiomyopathy etiologies, also suggest a mortality benefit in nonischemic patients. Thus, they write, "The DEFINITE study is not the definitive word on this topic."

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