Guidant cardiac resynchronization therapy defibrillators reduce heart failure mortality and symptoms for both ischemic and non-ischemic patients but may not prevent hospitalizations, according to FDA's Circulatory System Devices Panel.

At a meeting in Gaithersburg, Md. July 28, the panel voted 8-0 to recommend approval of expanded Guidant CRT-D labeling to claim that the devices reduce all-cause mortality risk and heart failure symptoms in the patient population studied in Guidant's 1,520-patient, 12-month COMPANION trial.

The mortality data represent "a very clear statement" of CRT-D benefit, panel consultant John Somberg, MD, American Institute of Therapeutics, Lake Forest, Ill., maintained.

Proposed in an April PMA supplement, the labeling change would affect Guidant's Contak CD , Contak CD 2 , Renewal and Renewal 3 CRT-D devices, which currently are indicated for ischemic heart failure patients considered at high-risk for sudden cardiac death following a myocardial infarction.

Both Guidant's CRT-Ds and CRT-Ps (resynchronization without a defibrillator) are intended to provide ventricular antitachycardia pacing for NYHA Class III and IV heart failure patients who remain symptomatic despite optimal drug therapy, and have a left-ventricular ejection fraction of less than or equal to 35% and a QRS duration of greater than or equal to 120 milliseconds.

The proposed CRT-D labeling change would expand device eligibility to the entire COMPANION population, adding non-ischemic heart failure patients - about 35,000 more patients annually, according to Guidant (¹ Also see "CMS Welcomes SCD-HeFT Data, Awaits COMPANION Study For ICD Review" - Medtech Insight, 15 March, 2004., p. 3).

In COMPANION, mortality reduction with CRT-D was roughly 50% for both non-ischemic and ischemic patients -about 44% and 56% of the study population, respectively - compared with drugs alone.

However, the committee voted 6-2 against recommending approval of Guidant's proposed claim that CRT-Ds reduce the risk of a first all-cause hospitalization.

Guidant requested the hospitalization claim because, in COMPANION, CRT-Ds were associated with a reduction in the composite primary endpoint of all-cause mortality or first all-cause hospitalization. The researchers defined hospitalization as administration of intravenous inotropes or vasoactive drugs for at least four hours and/or a hospital stay extending beyond a calendar date change.

CRT-D patients in COMPANION were less likely than patients treated with optimal medical therapy to require hospitalization during the first year of therapy. However, if hospitalization for the CRT-D implant procedure is included in the comparison, the total number of hospitalizations is about the same for both therapies.

"There was never any question about the mortality data, [but the primary endpoint] is driven by the hospitalization, so the definition of hospitalization is very important and unfortunately it was not handled very well, in my judgment," opined panel consultant Albert Waldo, MD, University Hospitals of Cleveland.

Several panelists argued that the hospitalization data were difficult to interpret since the investigators changed the definition of hospitalization mid-course.

The investigators originally had defined hospitalization as any stay of at least 24 hours and/or four hours of IV-drug treatment. The definition was altered to mean a change in calendar date after researchers discovered that many of the patient report forms did not include exact times of admission and discharge. All hospitalizations in the trial were measured with the calendar-change definition to not bias results, investigators note.

Several panelists also were concerned that patient withdrawals during the trial's 12-month follow-up period were disproportionately higher in the control arm than the CRT-D arm - 21% versus 4%, respectively.

While not endorsing the hospitalization reduction claim, the panel voted unanimously that labeling should include detailed information on the COMPANION hospitalization data.

"I think that if there's even a signal that hospitalization is impacted, as a practitioner who takes care of desperately ill patients with this condition, I think that signal needs to be respected," concluded panel consultant Clyde Yancy, MD, University of Texas, Dallas.

Guidant CRT-D Non-Ischemic Label Expansion Endorsed By FDA Panel

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