CDU Associate

Data from two significant heart failure trials COMPANION and DEFINITE was published in the May 20 issue of the New England Journal of Medicine (NEJM), and both trials also were the subject of presentations at the Heart Rhythm Society's (formerly the North American Society for Pacing and Electrophysiology; Natick, Massachusetts) annual scientific sessions, in San Francisco, California.

The results of the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial achieved the primary endpoint of a risk reduction for events consisting of either time to death or first hospitalization, for any cause, following implant of cardiac resynchronization therapy (CRT) pacemakers or defibrillators.

The study also showed that treatment with resynchronization therapy defibrillators demonstrated a significant reduction in all-cause mortality.

The COMPANION trial, sponsored solely by Guidant (Indianapolis, Indiana), was a prospective, multi-center, randomized study of patients with advanced heart failure. The patients studied in this trial had diminished function of the left ventricle (an ejection fraction at or below 35%), a wide QRS complex (greater than or equal to 120 milliseconds) and advanced heart failure. The trial included 1,520 patients at 128 centers in the U.S.

The trial used Guidant's Contak TR cardiac resynchronization therapy pacemaker in one patient group and the Contak CD cardiac resynchronization therapy defibrillator in another patient group. The third patient group received optimal drug therapy only. Both CRT pacemakers and CRT defibrillators improve the heart's pumping ability by delivering small electrical impulses that help synchronize contractions of the left ventricle. The left ventricle is the heart's main pumping chamber, and its ability to pump blood is enhanced when the muscular walls contract synchronously. In addition, CRT defibrillators monitor the heart for potentially fatal rhythms. If such a rhythm is detected, a lifesaving shock is delivered, restoring normal heart rhythm and preventing sudden cardiac death.

Preliminary results from the landmark trial, presented at last year's American College of Cardiology (Bethesda, Maryland) scientific sessions, showed that patients were 19% less likely to be hospitalized or die if they received both drugs and CRT. The data also showed a 43% decline in deaths among those patients who received drugs and a CRT-D device to slow down a rapid heartbeat. Researchers enrolled the first chronic heart failure patient for the study in January 2000. By November 2002, the study was halted because of overwhelming data in support of the devices.

"The COMPANION trial proved for the first time that cardiac resynchronization therapy yields significantly improved clinical outcomes over and above optimal drug therapy in patients with advanced heart failure," said Michael Bristow, MD, PhD, of the University of Colorado Health Sciences Center (Denver, Colorado) and COMPANION study co-chairman, in a conference call on the results. Bristow said that while previous clinical trials have demonstrated that CRT devices improve exercise performance and quality of life, "the COMPANION trial went way beyond that, demonstrating that CRT devices improve heart failure natural history, that is, morbidity and mortality."

Guidant noted that while previous clinical studies demonstrated CRT devices improve exercise performance and quality of life only, the COMPANION trial yielded the following results, each as compared to optimal drug therapy alone:

A 19% risk reduction in combined all-cause mortality or first all-cause hospitalization for heart failure patients assigned to receive Guidant's cardiac resynchronization therapy pacemakers

A 20% risk reduction in combined all-cause mortality or first all-cause hospitalization for heart failure patients assigned to receive Guidant's cardiac resynchronization therapy defibrillators

A 36% risk reduction in all-cause mortality for heart failure patients assigned to receive Guidant's CRT defibrillators

Both CRT and CRT with defibrillation reduced symptoms and improved quality of life

The company noted that the results of the study have been submitted to the FDA for review to potentially expand indications and user labeling for Guidant CRT devices.

"In April, Guidant submitted to the [FDA] to potentially expand indications in use and labeling for our cardiac resynchronization therapy devices based on the science of COMPANION," said Fred McCoy, president of the company's Cardiac Rhythm Management business during the call. "We continue to work directly with the Centers for Medicare & Medicaid Services [Baltimore, Maryland] toward the full coverage of not only COMPANION one day, but more urgently . . . SCD-HefT [Sudden Cardiac Death in Heart Failure Trial] based on the science in these large trials. Over the next year a [coverage] decision or decisions are going to be focused on new primary risk factors for sudden cardiac death for the treatment of heart failure stemming out of these two landmark trials."

McCoy noted that the company is gearing up to expand its patient pool further for CRT devices with the MADIT-CRT trial, which is designed to test whether CRT-D devices will slow the progression of heart failure in patients with impaired heart function and little or no symptoms. The trial will determine if earlier intervention with cardiac resynchronization therapy defibrillators can slow a patient's progression from early stage heart failure to late stage heart failure.

According to new data from the DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) trial, patients with heart failure not due to coronary artery disease (non-ischemic) who received an implantable cardioverter defibrillator (ICD) had a statistically significant reduction in their rate of sudden cardiac death compared to patients treated with standard drug therapy.

The DEFINITE trial, whose results were first published at the American Heart Association (AHA; Dallas, Texas) scientific sessions last November in Orlando, Florida, focused on patients with heart failure but excluded those showing symptoms of coronary artery disease. All patients were assigned to receive standard medication for heart failure, including ACE inhibitors, beta-blockers, digoxin and diuretics. The participants in the trial received single-chamber St. Jude Medical (St. Paul, Minnesota) ICDs, including Atlas and Photon Micro VR devices.

In the study, participants were randomized into two groups one receiving standard heart failure drug therapy (control group) and the other receiving drug therapy and a St. Jude ICD. The study's primary endpoint was death from any cause, while sudden arrhythmic death was a secondary endpoint.

The DEFINITE results showed that ICD recipients had a statistically significant reduced risk of sudden cardiac death and a strong although not statistically significant trend toward reduction of overall mortality rates. In addition, the patients with the worst heart failure symptoms showed a statistically significant reduction in overall mortality. DEFINITE is the first large-scale study to focus on potential mortality benefits of ICDs in "non-ischemic" heart failure patients those whose weakened heart muscle is caused by factors unrelated to coronary artery disease.

The DEFINITE study, which began in May 1998, followed 458 participants at 48 medical centers in the U.S. and Israel. Of the 68 deaths in the study, 40 came from the standard-therapy group, while 28 came from the ICD group, a result that approached but did not achieve statistical significance. Overall mortality rates at two years were 14.1% in the control group and 7.9% in the ICD group. Of the total deaths, 17 resulted from sudden cardiac arrhythmias: three in the ICD group, compared to 14 in the standard therapy group.

Although the overall mortality results did not reach the level of statistical significance as defined in the study protocol, the subset of participants in the NYHA (New York Heart Association) Class III heart failure group who received an ICD showed a statistically significant reduction in risk of death from all causes. The NYHA rankings are a measure of patients' assessments of symptoms, ranging from Class I to Class IV (most severe).

"The DEFINITE study demonstrated that ICDs are highly effective in preventing sudden death from cardiac causes in non-ischemic heart failure patients," said lan Kadish, MD, professor of medicine at Northwestern University (Evanston, Illinois), who participated in the trial. "The data also showed a 35% decrease in the relative risk of death from any cause among participants who received ICDs, similar to the MADIT II [Multicenter Automatic Defibrillator Implantation Trial II] trial findings that reported a 31% decrease."

Participants in the trial ranged in age from 21 to 80 years and had a history of symptomatic heart failure, spontaneous ventricular arrhythmias, and a low left-ventricular ejection fraction.