Braunwald panel recommends limited use of HF drug

Expert panel urges company to begin proactive educational program for physicians.

A panel of cardiologists chaired by Eugene Braunwald, MD, has recommended nesiritide use be strictly limited to patients who present to the hospital with acutely decompensated congestive heart failure who have dyspnea at rest.

The panel met on June 8 and further recommended that nesiritide (Natrecor, Scios Inc.) should not be used for intermittent outpatient infusion, for scheduled repetitive use, to improve renal function, to enhance diuresis or to replace diuretics.

Scios Inc., a unit of Johnson & Johnson, convened the panel after two publications raised questions about the drug’s safety related to renal function and mortality. A recent meta-analysis looked at three randomized trials where nesiritide was administered as a single-blind infusion and inotropes were not mandated as control. Jonathan D. Sackner-Bernstein, MD, and colleagues reported that the 30-day mortality rate was higher for patients treated with the drug than for patients treated with control therapy.

Nesiritide was approved in 2001 for treatment of congestive heart failure.

In a press release, the company noted that the panel has recommended a use for the drug that is slightly narrower than what is outlined in the approved label. Scios said it would be contacting regulatory agencies to discuss how to deal with the recommendation.

Braunwald and other panel members said in their report that the company should immediately begin a proactive educational program for physicians, outlining for them the conditions and circumstances in which the drug should and should not be used.

The panel said company-supported communication with doctors should include review articles of the drug and should include the panel’s recommendations. Any marketing of the drug — both current and future — should be consistent with that educational program, the panel said.

Darlene Horton, MD, senior vice-president at Scios, said the company “appreciates the robust scientific discussion and the thoughtful guidance provided by the panel” and that it is “committed to the continued study of these patients to improve their health and well being.”

For its discussion, the panel reviewed a substantial body of material provided by the company, including the meta-analysis and other published material, heard presentations of additional analyses of data, reviewed plans for future trials and held extensive discussions with the company’s scientific staff. The panel also met in closed-door sessions that were independent of the sponsor, and it prepared the recommendations in those closed-door meetings.

Renal dysfunction

In its consideration of renal function, the panel noted that the drug’s use is associated with a dose-dependent increase in serum creatinine indicating renal dysfunction at doses described in the package insert, including the dose recommended for initiation of treatment.

The panel’s report states that the mechanism for these creatinine changes, “their duration, implications for survival, longer term renal function and other clinical consequences is not clear,” and added that there is no evidence that the drug results in improved renal function.

Braunwald and colleagues recommended studies be done to “clarify the mechanism and reversibility of the observed changes in creatinine.”

Mortality

Nesiritide’s effect on survival is unclear, the panel said. Completed trials show a trend toward increased mortality rate at 30 days, but the confidence intervals around the hazard ratio of approximately 1.3 are “wide,” the panel said.

Also, the number of deaths in a pooled analysis of the six controlled clinical trials was “insufficient to identify or exclude, with confidence, a moderate excess of risk to survival,” the panel wrote.

Additional studies should be conducted, the panel said, due to the small numbers of events in the current database and the “inconclusive nature of these findings.”

Continued study

The panel strongly recommended that enrollment in ongoing trials and planned trials of the drug continue. It endorsed the company’s plan to conduct a trial with several thousand patients that will further assess the benefits and risks of the drug compared to standard therapy.

Included in several recommendations about the trial, the panel said the trial should be initiated without delay and that it be adequately powered to detect an approximately 15% reduction in the combined risk of mortality and cardiorenal morbidities at an early time point (30 to 90 days) and mortality at 180 days.

Other mechanistic studies should be considered, the panel said, including examination of the effect of doses lower than those approved, as well as further study of data from completed trials to look at the drug’s effect in subgroups of patients.

The panel included Braunwald; John C. Burnett Jr., MD; Wilson S. Colucci, MD; Barry M. Massie, MD; John J.V. McMurray, MD; Christopher M. O’Connor, MD; Milton Packer, MD; Ileana Pina, MD; Bertram Pitt, MD; and James Young, MD.