Nesiritide: Should You or Shouldn't You Prescribe for Acute HF?

Nesiritide: Should You or Shouldn’t You Prescribe for Acute HF?

By Laszlo Dosa

BOCA RATON, Fla—Beginning early next year, approximately 1900 patients who have dyspnea at rest or with minimal activity will participate in what will be the largest study to date to focus exclusively on acutely decompensated heart failure (HF). It will be conducted at approximately 400 sites in Europe and Latin America to test the safety and efficacy of nesiritide (Natrecor), a recombinant form of human B-type natriuretic peptide, in this patient population.

Yet the debate about whether this agent should be withdrawn from the market continues (see commentary on this topic on page 14). Nesiritide is approved for the intravenous treatment of patients with acutely decompensated congestive HF. After its FDA approval, however, concerns were voiced about some of the data, and debates about its safety as well as efficacy ensued. One such debate was recently held at the 9th Annual Scientific Meeting of the Heart Failure Society of America.

Clyde W. Yancy, MD, of the University of Texas Southwestern Medical Center in Dallas, spoke in defense of nesiritide.

“We are utilizing a novel therapy based on reasonable physiological, biological, and clinical data which for the first time demonstrate positive outcomes in a meaningful way for symptomatic acute decompensated heart failure,” Dr Yancy said.

The Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial, he told IMWR, demonstrated a reduction in pulmonary capillary filling pressure and an improvement in the sensation of dyspnea compared with placebo. “The reduction in pulmonary filling pressures was greater for nesiritide-based therapy than it was for nitroglycerin-based therapy. And the improvement for dyspnea was better for nesiritide versus placebo and was not statistically different for nitroglycerin versus placebo.”

Presenting the opposing view, Jonathan Sackner-Bernstein, MD, a cardiologist practicing in New York, described data from peer-reviewed literature and FDA documents that showed 2 important findings. “Information we published in Circulation and JAMA demonstrated that nesiritide appears likely to be associated with increased risk when used by patients with acute heart failure. That increased risk is in the form of worsening kidney function as well as the risk of death,” Dr Sackner-Bernstein said. “When I looked at the data submitted to the FDA, it did not seem that there were any consistent benefits of nesiritide on symptoms, quality of life, or morbidity, even compared with placebo. That’s why we shouldn’t accept any risk associated with the drug.”

Dr Yancy applauded Dr Sackner-Bernstein and his group for raising necessary questions when dealing with new treatment strategies, because “that is how we learn and discover.” However, he added, “one has to be careful when we take clinical trials that were not designed to test for specific issues, like renal function or mortality, and then attempt to ascribe significance to posthoc findings that may have emerged.”

Dr Sackner-Bernstein cited the federal Food, Drug, and Cosmetic Act in support of his argument, which states that if there is new evidence, together with the evidence available when the drug was approved, that a drug has not been shown to be safe, “approval shall be withdrawn.”

“That language is important. It does not say that the information together should say that the drug should be shown to be dangerous. It says that if all the information together, when viewed from trials that relate to the specific indications for the drug, cannot show that the drug is safe, the drug should be withdrawn,” Dr Sackner-Bernstein added.

Dr Yancy replied that it is important to be careful when data are subjected to an exhaustive reanalysis, particularly when the study groups are not balanced and when the numbers become small. “In my judgment, VMAC was a positive trial. The results are supported by a favorable profile of sound biological, physiological, and human pretrial data, all of which suggest a favorable influence on neurohormones [and] remodeling, the potential to retard fibrosis, and data which substantiate the natriuretic property of this compound. Taken together, the aggregate data create sufficient logical and reasonable evidence that the therapy is effective.”

Drs Yancy and Sackner-Bernstein agree that more data are needed, along with patient populations that are properly matched, to understand what the real issues are. Neither physician wants any harm to come to patients.

Dr Yancy said that “we both are desirous of helping patients, and we can help them with the currently available compound, nesiritide, when it is used on label.”

That, however, is where their agreement ends. Dr Sackner-Bernstein repeatedly argued that since the drug has not been shown to be safe, it should be withdrawn. “As a doctor, I should not be satisfied by giving any drug, in this case nesiritide, which does not have much effect on clinical symptoms, just because no study has proven it dangerous. Treatments need to make patients feel better, suffer less, or stay alive longer—none [of these] have been proven for nesiritide.”

Dr Yancy said “given that we have only one compound that by appropriately designed trials shows a benefit on any meaningful clinical end points in acute decompensated heart failure, I feel comfortable continuing to use that compound as is stated in the label and as further revised by the Nesiritide Review Committee. And I am anxious to see what the future datasets reveal—datasets that will come from larger populations of patients with acute decompensated disease. The way to resolve our questions is with more data. There is no way that a drug withdrawn from the market would ever be studied again in a meaningful way, and there are too many data points of benefit to retreat from the natriuretic paradigm.”

But Dr Sackner-Bernstein insisted that “the data are disturbing. Hemodynamics doesn’t matter if a person does not feel better or live longer. There are no meaningful clinical end points that nesiritide consistently improves in randomized, double-blind trials, and it’s probably dangerous. So why are we using it?”