Nesiritide

In plain language

Nesiritide is a discontinued heart-failure drug, sold as Natrecor, that tells the story of how a promising peptide can fail on the scale of a 7,000-patient trial. It is a copy of BNP, a hormone the heart releases when it is stretched.

Approved in 2001 for the breathlessness of acute heart failure, it dilates blood vessels and helps the kidneys shed salt and water. But safety questions arose, and a 2011 trial of 7,141 patients found no clinical benefit. Use collapsed and the product was discontinued, though the FDA record notes it was not withdrawn for safety or effectiveness reasons.

For students

Nesiritide is recombinant human B-type natriuretic peptide, the 32-residue hormone (about 3,464 Da) released by ventricular myocytes in response to wall stress. It activates guanylate cyclase-coupled natriuretic peptide receptor A, increasing cGMP, producing vasodilation, natriuresis, and suppression of renin-angiotensin-aldosterone signaling.

The natrecor saga is the teaching case: approval on the basis of hemodynamic and symptom endpoints (VMAC trial, 2000), then 2005 meta-analyses suggesting excess kidney injury and mortality, a label change and restricted use, and finally ASCEND-HF (2011, 7,141 patients) showing no difference in dyspnea relief, rehospitalization or death versus placebo. Sales fell from about 300 million dollars to under 100 million within a year of the trial, and the product was later discontinued; the FDA's Drugs@FDA record documents that it was not withdrawn for reasons of safety or effectiveness.

For researchers and instructors

Biochemistry. The BNP molecule itself is pharmacologically sound (Vasopeptidase inhibitors of the same pathway, and newer oral soluble guanylate cyclase stimulators, are active drugs); the failure was clinical-epidemiological, not mechanistic.

Pharmacology. Infusion dosing (2 mcg/kg bolus then 0.01 mcg/kg/min); principal adverse effect is dose-related hypotension, which correlates with its lack of net benefit in outcome trials.

Human evidence. VMAC for approval; ASCEND-HF (n=7,141, NEJM 2011) neutral on all primary and secondary endpoints; meta-analyses (Sackner-Bernstein 2005) triggered the safety reevaluation.

Teaching point. The definitive case study in surrogate versus clinical endpoints in peptide drug development, and the central role of large mortality trials in cardiology.