Heart drug may increase risk of death

WASHINGTON, April 19 (UPI) -- A team of cardiologists said Tuesday their analysis of data on the medication Natrecor obtained from the manufacturer suggests it could be placing heart-failure patients at an increased risk of death.

Natrecor -- generic name nesiritide -- is manufactured by Scios Inc. of Fremont, Calif., and is used for the treatment of heart-failure patients with shortness of breath. It recently has come under scrutiny because of a report last month in the journal Circulation that suggested it might impair kidney function.

The current study -- based on an analysis of clinical trials conducted by Scios as well as data from the Food and Drug Administration -- found patients treated with Natrecor were 80 percent more likely to die in the month after they received the drug than those who received older and less-expensive drugs, such as nitroglycerin and diuretics.

"Most people would agree this is pretty alarming," said Dr. Jonathan Sackner-Bernstein, director of clinical research at the Heart Failure and Cardiomyopathy Center at North Shore University Hospital in Manhasset, N.Y. He was involved in both studies.

The latest study appears in the April 20 issue of the Journal of the American Medical Association.

Sackner-Bernstein, who also serves as a consultant to the FDA's cardiovascular and renal drugs advisory committee, told United Press International that pooling data together from different studies is not the best way to assess mortality risk, but he added this is the best available evidence and "this is a pretty strong signal" that needs to be investigated.

The FDA and Scios disagreed with the results of the JAMA study, saying all of the data to date on the drug do not indicate an increased risk of death. Scios has conducted at least 13 studies on Natrecor.

"Most of this is not really new information," Dr. Robert Temple, director of FDA's Office of Medical Policy, told UPI. "The results of all but one of the studies are already reflected in (the drug's) labeling and were discussed before the cardiovascular and renal drugs advisory committee" prior to the drug's approval.

Temple said the advisory committee reached the consensus that Natrecor did not pose a threat of increased risk of death and recommended the drug be approved. He said that continues to be the position of the FDA, but the agency will be watching additional studies involving Natrecor that are ongoing and will ask Scios to modify labeling of the drug to include the results of seven studies. The labeling currently contains information from only five or six of the earlier studies, he said.

"Our full data set which includes the three studies looked at in (JAMA study) does not support the finding of these authors (of the JAMA study)," Mark Wolfe, a spokesman for Scios' parent company Johnson and Johnson, told UPI.

Wolfe said the drug is "highly effective" for the treatment of heart failure, but added his company takes "any question about the safety of Natrecor seriously."

For that reason, Scios has asked esteemed cardiologist Dr. Eugene Braunwald, of Harvard Medical School, to head a panel of heart experts who will review the data on the drug -- a move the company announced last week apparently in response to the Circulation article that raised the issue of kidney problems.

Wolfe said the members of the panel will be chosen by Braunwald and will be independent of Scios.

A secretary in Braunwald's office told UPI all calls about Natrecor were being referred to Scios.

Temple said the FDA would consider the conclusions of the Braunwald panel.

In the JAMA study, Sackner-Bernstein and colleagues reviewed three clinical trials conducted by Scios involving 485 patients with heart failure who received Natrecor compared with 377 who did not. Thirty-five patients in the Natrecor group died within 30 days compared to 15 in the group that did not get the drug.

Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, a consumer watchdog in Washington, said the study shows "a very definite problem."

"Although ultimately it would be better to confirm this with a large-scale trial ... for the time being this should be a last resort drug," Wolfe told UPI. "Ultimately, this should translate into a black-box warning on labeling." A black box is the most serious warning used by FDA on the package insert of a drug to alert physicians and consumers to serious side effects.

Dr. Stephen Gottlieb, director of the Cardiac Care Unit at the University of Maryland Medical Center, told UPI he agreed further studies should be conducted to determine not only the safety, but also the benefits of Natrecor.

"The drug probably needs studies to look at real outcomes, whether patients who received the drug compared to placebo do better, have shorter hospitalizations, what happens to their renal function, what happens to their mortality," Gottlieb said.

He added he does not prescribe Natrecor to his patients because the available data has not persuaded him it is more effective than other less-expensive drugs.

Sackner-Bernstein said he expected the findings to change the way physicians use Natrecor in their patients.

"If this paper doesn't change the way people practice, then I'm a little bit scared about the way people apply evidence to medicine," he said.

He added he hopes the findings will spur Scios to conduct a study to determine how great the risk of death is with Natrecor.

"We hope this paper ... will provide them the impetus to take the next step ... and do a trial to define this risk more precisely," he said.

--

Steve Mitchell is UPI's Medical Correspondent. E-mail: sciencemail@upi.com