November 30th, 2010
ASCENDing Into the Depths of the Nesiritide Controversy: Questions for Eugene Braunwald
Results of ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial), presented as a late-breaking clinical trial at the AHA meeting, showed that there were no significant differences in the pre-specified endpoint of dyspnea among some 7,000 patients with acute, decompensated HF randomized to receive standard therapy and either continuous intravenous nesiritide or placebo.
This trial was started in response to considerable controversy sparked by two meta-analyses (one in Circulation and the other published in JAMA) over the safety and efficacy of nesiritide, which was being used in growing numbers of heart failure patients. Click here for our news summary and here for the late breaker presentation.
Dr. Eugene Braunwald answers our questions about this trial, this drug, and this controversy. What are your questions or conclusions?
CardioExchange: Despite the subgroup analysis of patients with GFR <60 versus >60, the majority of ASCEND-HF patients appeared to have normal or near-normal creatinines at baseline. Given all the studies to date on nesiritide and renal outcomes, do you think that the use of nesiritide in even mild renal dysfunction should be further investigated or simply avoided altogether?
Braunwald: There is no contraindication to the administration of nesiritide to patients with mild renal dysfunction.
CardioExchange: In light of this trial’s results, are there specific situations where you would recommend that nesiritide be used in addition to standard care at this point in time?
Braunwald: Yes, but only in a limited number of patients. Those with extreme dyspnea who have not responded to intravenous loop diuretics and generic vasodilators (sublingual or IV nitroglycerine or IV Na nitroprusside) but who are not hypotensive.
CardioExchange: What would you consider to be the most important next step that investigators should take in order better define the most appropriate role of nesiritide in clinical practice? And, with what (if any) caveats?
Braunwald: I might consider a trial of low dose nesiritide (0.005 ug/kg/min) in acute pulmonary edema.
CardioExchange: Do you think a controversy like the nesiritide one could happen again? If so, what needs to be done to prevent such an occurrence?
Braunwald: I don’t think that the scenario with nesiritide and the ASCEND-HF trial could have been avoided. The drug was approved for the relief of dyspnea in acute heart failure, and not for reduction of mortality and/or rehospitalization for heart failure. Two meta-analyses of small trials suggested that nesiritide increased mortality and caused worsening of renal function. Once these meta-analyses were published the company that produced nesiritide (Scios) had to choose between taking the drug off the market or sponsoring a huge, expensive clinical outcome trial. They selected the latter course and showed that the results of the meta-analyses were misleading. Other than hypotension, the drug was well tolerated, and did not increase mortality or renal dysfunction. It did reduce dyspnea but not sufficiently to reach the high statistical levels that were pre-specified.
I don’t see much of a future for nesiritide.