Eric J. Topol, chair of the Department of Cardiovascular Medicine at the Cleveland Clinic, asks, How can a drug that is associated with higher rates of both renal dysfunction and death than placebo — and that costs 50 times as much as standard therapies and for which there are no meaningful data on relevant clinical end points — be given to more than 600,000 patients and be promoted throughout the United States for serial outpatient use, an indication not listed on the label ?

“ In my view, Nesiritide has not yet met the minimal criteria for safety and efficacy,” writes Topol in The New England Journal of Medicine. “ 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. We need a tune-up of our procedures to eliminate indiscriminate use of drugs, such as Nesiritide, when there is not proper evidence of their safety. “

Nesiritide ( Natrecor ) is a recombinant form of human BNP ( B-type natriuretic peptide ), a naturally occurring hormone secreted by the ventricles when a person is in heart failure.
When Natrecor was approved by the FDA in 2001, it was designated for the treatment of acute, decompensated congestive heart failure ( CHF ) in patients with dyspnea at rest or with minimal activity.
Natrecor should be used only in a hospital setting.

In his article Topol points out that a large trial, Vasodilatation in the Management of Acute Congestive Heart Failure ( VMAC ) did not demonstrate any benefit of Nesiritide over Nitroglycerin in terms of death or the need for repeated hospitalization within 30 days.
Despite negative results, in May 2001, the majority of the FDA Advisory Panel recommended granting approval for Nesiritide, and in August 2001, the FDA formally approved the drug.

VMAC was conducted in 498 hospitalized patients who had dyspnea at rest.
Nesiritide was compared with intravenous Nitroglycerin or placebo.
Since there were statistically significant improvements in both the reduction of pulmonary-capillary wedge pressure ( a difference of 4 mmHg ) and the self-reported dyspnea rating with Nesiritide as compared with placebo, Nesiritide was considered to have met the efficacy criteria.

According to Topol, VMAC trial raised a number of concerns about Nesiritide. Only 30 percent of the patients received Furosemide or intravenous diuretics before enrollment, although use of these agents is a standard approach to acute decompensated heart failure.
The dose of Nitroglycerin was not titrated aggressively, and because of the monitoring of the pulmonary-capillary wedge pressure, the "double-blind" assessment was compromised.
The length of stay in the hospital was greater among patients who received Nesiritide than among those given Nitroglycerin (10.0 vs. 8.1 days, P=0.008 ).
An elevation of more than 0.5 mg per deciliter ( 44.2 µmol per liter ) in the serum creatinine level occurred in 27 percent of the patients in the Nesiritide group, as compared with 21 percent of the controls ( P=0.11 ).
There was no increase in urine output with Nesiritide, and subsequent studies have shown that this drug does not have a natriuretic or diuretic effect in patients with decompensated heart failure.
Furthermore, the rate of death at 30 days was 8.6 percent in the Nesiritide group, as compared with 5.5 percent among the controls ( relative risk, 1.56; P=0.20 ).

Recently a meta-analysis, published in JAMA, has assessed the effects of Nesiritide treatment on mortality.
Sackner-Bernstein et al. pooled data from the three trials involving patients whose baseline treatment regimen was not required to include inotropes and for which 30-day mortality data were available.
According to this analysis, there was an 81 percent increase in the death rate with Nesiritide as compared with placebo.

Source: The New England Journal of Medicine, 2005


XagenaMedicine2005