The Renal Subanalysis of ASCEND-HF: The End of Nesiritide as a Cardio-Renal Therapeutic?
Over the last three decades there has been a remarkable explosion in our understanding of the natriuretic peptide system. Prior to 1980, only 1 entry can be found in Medline under the search term "natriuretic peptide" while currently there are >22,500. Through this impressive literature, the concept of the natriuretic peptide as an ideal cardio-renal therapeutics emerged with reports of improvement in renal function, neurohormonal activation, fibrosis, and natriuresis amongst other benefits with these agents.1 As a result, the development of recombinant b-type natriuretic peptide (nesiritide) brought tremendous optimism regarding its potential role in acute decompensated heart failure (ADHF). The drug was approved in 2001 based on a 489 patient trial that did not actually evaluate its cardio-renal effects, but rather demonstrated efficacy via its actions as a vasodilator.2 This took the form of a 2 mmHg greater reduction in pulmonary capillary wedge pressure with no additional relief of dyspnea compared to nitroglycerin, but significant superiority over placebo. However, presumably due to the great enthusiasm for the mechanism of the drug, sales soared to $390 million by 2004 despite the absence of any large studies showing positive clinical outcomes and even some human data indicating an absence of positive cardio-renal effects.3, 4 The widespread enthusiasm for nesiritide ended rather abruptly in 2005 after publication of two meta-analyses by Sackner-Bernstein et al demonstrating a 52% increased risk for worsening renal function (WRF, defined as a >0.5 mg/dl increase in creatinine) and an 80% increased risk for death with nesiritide.5, 6
- Received July 23, 2014.
- Accepted July 28, 2014.