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Nesiritide: Were the signals missed amid the marketing?

Issue: July 2012

ByJohn Noviasky, PharmD, BCPS

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New medications to manage HF are few and far between. So, when nesiritide came along, the HF community was excited. The connection between the initial marketing of nesiritide and utilization patterns are notable. Unfortunately, the continued story tells of a downward spiral in nesiritide use after re-analysis of existing data.

The purpose of this article is to assess the initial release and marketing of nesiritide (Natrecor, Scios) and to determine whether there were clues that may have suggested overzealous marketing statements.

Initial marketing and limitations

The initial marketing of nesiritide included several focuses, which, when reflected upon, may provide insight to the unraveling of nesiritide.

 

John Noviasky

 

Michael Kelberman

First, nesiritide was marketed as “duplicating the endogenous response to HF.” Although it is true that the body matches the endogenous response to HF by releasing a chemical physiologically equivalent to nesiritide when cardiac filling pressures are increased, there is no evidence that this alone improves outcomes. Indeed, another “natural” response to HF is increased angiotensin activity and adverse CV remodeling, neither of which is beneficial in the long term.

Second, “nesiritide may decrease length of stay.” The decreased length of stay argument was based on an approximate 1-day decrease in time of active infusion of nesiritide compared with time of active infusion of dobutamine. The assumption was that the decreased infusion time for nesiritide should translate to decreased hospitalization stay. However, the decreased time on infusion data is from an open-label study that showed no difference in patient length of stay. Additionally, evidence from randomized, masked Vasodilation in the Management of Acute CHF (VMAC) study, published in the Journal of the American Medical Association in 2002, does not support decreased length of hospitalization stay with use of nesiritide.

Third, “treatment with nesiritide is associated with fewer hospital readmissions.” These data were cited as stemming from the VMAC study. Although the VMAC study publication included the expected demographics and multiple analyses of outcomes, it was missing many important analyses that would have been helpful to better understand the data. The publication was lacking information and data from several important areas:

• Thirty-day readmission rate due to acutely decompensated HF was 13% and 7% in the nitroglycerin and nesiritide groups, respectively. However no statistical test was provided to determine level of significance.
• The total amount of diuresis is not mentioned, and an average of 123 mL/hour of fluid removed by nitroglycerin was not different than the 123.7 mL/hour of fluid removed by nesiritide. In addition, there was little/no difference in diuretic use comparing the groups.
• The length of stay was not included in the publication. Data provided to the FDA as part of the new drug application (NDA) indicate the average length of stay for patients on nitroglycerin was 8.1 days vs. 10 days for nesiritide. The percent patients still hospitalized at 30 days was 5% in the nitroglycerin group vs. 7% in the nesiritide group.
• Although mortality at 6 months is included in the publication, mortality at 30 days was not mentioned. This was 5.1% and 8.1% for nitroglycerin and nesiritide, respectively (P=.2).
• The readmission rate after taking into account contribution of length of stay and 30-day mortality on readmissions, bewas 13% and 12.2% for the nitroglycerin and nesiritide groups, respectively.

Had some of the above information been included in the original VMAC publication, a more balanced approach may have been utilized to more appropriately place nesiritide within the spectrum of available pharmacotherapies within the HF armamentarium, rather than the whole arsenal.

Importance of the evidence-based approach

The take-home point of this article is to remember the importance of the evidence-based approach in evaluating new therapies — more so than marketing tactics and review papers.

The principles of evaluating outcomes of importance to the disease state investigated (eg, mortality, length of stay, readmission for the case of HF), rather than focusing on surrogate markers (eg, pulmonary capillary wedge pressure), would have been instrumental in the case of nesiritide.

Another principle of the evidenced-based approach is to prioritize the type of data provided based on the study design used to collect it (for example, a randomized controlled trial is preferable to a case-control observational design).

Although the VMAC trial was a well-designed, randomized, double blind trial — and was the most sophisticated clinical trial of nesiritide at that time — unfortunately, important data generated by that study were omitted from the publication in 2002, preventing a comprehensive understanding of the data.

Other recent data

Since the publication of the VMAC study, other data have been published.

Sackner-Bernstein and colleagues published results of two meta-analyses of nesiritide’s effect on renal function and mortality.

In 2011, O’Connor and investigators published data from the ASCEND-HF study, a company-sponsored, randomized, placebo-controlled trial of more than 7,000 patients, with results indicating no difference in dyspnea or rehospitalization with nesiritide. The conclusion from ASCEND-HF was that nesiritide cannot be recommended for routine use in patients with acute HF. It is possible that this conclusion could have been forecast a decade earlier with a more careful analysis and presentation of all the data available at that time.

John Noviasky, PharmD, BCPS, is clinical pharmacy coordinator at Upstate University Hospital at Community General Hospital, Syracuse, N.Y. Michael Kelberman, MD, FACC, is a cardiologist at Mohawk Valley Heart Institute, Utica, N.Y.

Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor in the department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Editorial Board. For suggestions for future topics for this column, contact her at dehoff@cop.ufl.edu.