Boston, MA - An opinion piece by Dr Eric J Topol (Cleveland Clinic Foundation, OH) in the July 14, 2005 issue of the New England Journal of Medicine takes aim at the clinical viability of nesiritide (Natrecor, Scios) and what appear to be limit-stretching strategies for marketing the drug [1].

"In my view, nesiritide has not yet met the minimal criteria for safety and efficacy," Topol writes. "Until a trial definitively proves that this drug reduces the risk of death or repeated hospitalization for heart failure, there will be questions about the appropriateness of the drug's use or even commercial availability." Nesiritide is approved in the US solely for patients hospitalized with acute decompensated HF.

Topol contends there were weaknesses in the studies that supported nesiritide's Food and Drug Administration approval, including a reliance on short-term hemodynamic measurements and subjective symptoms as primary efficacy measures, rather than hard clinical end points. Also, he writes, those trials showed suggestions of increased risk of renal dysfunction and mortality among the patients who received nesiritide.

In cardiovascular medicine, we learned long ago that therapies directed at surrogate end points . . . can be associated with excess death.

The Perspective is the latest of a series of events, covered in depth by heartwire, that have either questioned or supported the continued use of nesiritide. These include two controversial meta-analyses from Sackner-Bernstein et al suggesting that nesiritide may promote renal dysfunction as well as increase 30-day mortality in its target population [2,3]. Subsequently, Scios invited Dr Eugene Braunwald (Harvard Medical School, Boston, MA) to lead a panel that would evaluate the drug's safety. They ultimately judged nesiritide to be currently acceptable for its indicated population but also called for a series of clinical trials to investigate the concerns.

Topol also slams certain practices of Scios as it markets the drug, including what he sees as unusually blatant encouragement of physicians to prescribe nesiritide off label and to use an unconventional coding strategy when applying for Medicare reimbursement.

In the randomized trial underpinning nesiritide's approval, Vasodilatation in the Management of Acute Congestive Heart Failure (VMAC), only the three-hour changes in pulmonary capillary wedge pressure and self-reported dyspnea were used to gauge the drug's efficacy among the 498 acute-HF patients receiving nesiritide, nitroglycerin, or placebo.

"In cardiovascular medicine, we learned long ago that therapies directed at surrogate end points . . . can be associated with excess death," Topol writes, citing the historical examples of certain antiarrhythmic agents to suppress premature ventricular contractions and inotropic agents to improve LV ejection fraction.

"The FDA approval went forward despite an internal reviewer's critical point that VMAC did not rule out a 50% increase in the risk of death [with nesiritide]," he writes. To heartwire, Topol said the FDA's response to VMAC should have been: "We have concern about this drug, the deaths are going in the wrong direction, the kidney function is definitely a problem, and we need more trials."

"Maybe the drug does save lives. Maybe the drug is fine and reduces hospitalizations. But right now the data don't look good," he said, adding that the most appropriate end point would have been 30-day mortality or repeat hospitalization along with tracking of renal function.

I personally would be satisfied with data that demonstrate clinical benefit with the drug, administered for short periods of time, with reasonable assurance that there is not a substantial excess in mortality associated with that use.

The meta-analyses from Sackner-Bernstein et al "raise important concerns that should be heeded by all clinicians," said Dr Marvin Konstam (Tufts-New England Medical Center, Boston, MA) to heartwire. But he echoed other HF specialists, quoted in prior heartwire stories, in noting a different meta-analysis that encompassed more nesiritide data and told a less severe story of potential risk. In it, he observed, "the suggestion of a mortality excess was much less impressive." Because Scios conducted this meta-analysis, "one has to look at it with a grain of salt," Konstam said. But, he noted, although it too showed nesiritide to be associated with an adverse effect on serum creatinine, it was dose-related and small at currently recommended dosage levels.

Although nesiritide for now has justified its place in clinical medicine, according to Konstam, the drug should be used with caution. "Clearly we need more data, and clearly we need more studies. This is an area of medicine where we are very lacking in well-controlled outcomes data to demonstrate benefit." That's in part because mortality trials in acute decompensated HF "are extremely difficult" to conduct, so he wouldn't insist that a drug that is administered over the short term prove itself long term in such a trial. "I personally would be satisfied with data that demonstrate clinical benefit with the drug, administered for short periods of time, with reasonable assurance that there is not a substantial excess in mortality associated with that use."

Topol also challenges certain practices of Scios as it markets nesiritide to physicians. Scios is waging "an aggressive marketing campaign" that is encouraging physicians to set up facilities where outpatients get serial nesiritide infusions over weeks or months, he writes. The Braunwald panel specified that nesiritide should not be used in this way, which is contrary to the drug's labeling.

We practice medicine in an era in which there is one pharmaceutical-company representative for every five physicians and in which the companies will stretch the limits in their marketing of drugs.

"There are no data to secure the place of serial outpatient infusions, and these centers are all over the US," according to Topol. Physicians who run them "are practicing non-evidence-based medicine, and they're making profits doing it." Withdrawing the drug is the only way to stop the practice, he said. "The serial infusion centers are going to be out there as long as the drug is marketed."

"Companies should not be engaging in practices to market or advance the use of drugs in an off-label fashion," Konstam said. "That should be clear to all of us." He observed that the second Follow-up Serial Infusions of Natrecor (FUSION-2) study is currently exploring the strategy of serial outpatient infusions in patients discharged after an episode of acute decompensated HF. The only physicians who should be using the drug in this way, he said, are the ones participating in that trial.

Scios advises physicians through literature and a toll-free "hotline" on how to set up the infusion centers and bill Medicare for the process of administering nesiritide and observing the patient afterward, "as one would for chemotherapy," according to Topol. The company justifies this approach, he writes, by pointing to billing-code descriptions for chemotherapy that encompass "substances such as monoclonal antibody agents and other biological-response modifiers." Nesiritide, a bioengineered version of human brain-type natriuretic peptide, arguably fits that description.

A theme throughout Topol's Perspective is that problems surrounding nesiritide's approval and use are not isolated. He writes, "We practice medicine in an era in which there is one pharmaceutical-company representative for every five physicians and in which the companies will stretch the limits in their marketing of drugs. The boundary lines that previously separated industry from the FDA and academia have unfortunately become blurred."