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Journal Scan: Riding the Nesiritide Wave

Lovato, Luis M. MD

doi: 10.1097/01.EEM.0000405494.46911.37
Journal Scan


When the Food & Drug Administration approved nesiritide in 2001, it was a promising new agent for managing acute heart failure syndrome. At the time, no new intravenous agent had been approved in the United States for acute CHF management in more than a decade. (JAMA 2002;287[12]:1531.) Nesiritide is a recombinant peptide similar to the endogenous B-type natriuretic peptide (BNP) released by the ventricle in response to ventricular stretch and volume overload. Nesiritide has venous and arterial dilation properties, which can theoretically improve hemodynamics in patients with acute heart failure syndrome.

Soon after it was approved, the Vasodilation in the Management of Acute CHF (VMAC) investigators published a randomized controlled trial comparing nesiritide with nitroglycerin and placebo for treating decompensated congestive heart failure. (JAMA 2002;287[12]:1531.) Among other things, this trial showed that after three hours of therapy, nesiritide resulted in a statistically significant decrease in pulmonary capillary wedge pressure (-5.8 mm Hg) when compared with either nitroglycerin (-3.8 mm Hg; p=.03) or placebo (-2.0 mm Hg; p<.001). It also showed a three-hour self-reported improvement in dyspnea over placebo.

Unfortunately, the VMAC study had several flaws. It was hindered by a complicated study design and a relatively small number of patients (n=489) who were distributed across multiple study arms and pathways. Overall, nitroglycerin was underdosed, and dosing varied among the study groups. Additionally, one of the main endpoints, pulmonary artery catheter wedge pressure, was only measured in patients who received a pulmonary artery catheter placed at the discretion of the investigator. Notably, four percent of patients who received nesiritide had hypotension, and these episodes lasted significantly longer than those caused by nitroglycerin.

Nevertheless, the nesiritide tsunami had come ashore, and everyone was eager to catch the wave. At extraordinary expense, its usage skyrocketed for approved and off-label indications to the point where some institutions implemented policies restricting its use (J Clin Pharm Ther 2005;30[5]:447.) Even the American Board of Emergency Medicine contributed to the nesiritide flash flood by making the VMAC study required reading for every board certified emergency physician in the United States as part of the Lifelong Learning and Self-Assessment (LLSA) program. ( Like the Blondie song from the ‘80s, the (nesiri)tide was high.

But even Biblical floods are destined to recede. In March 2005, a meta-analysis of five randomized controlled trials (n=1269) concluded nesiritide administered to patients with acute decompensated heart failure significantly increased the risk of worsening renal function when compared with inotrope-based and non-inotrope-based control therapies. (Circulation 2005;111[12]:1487.) The following month, an even more concerning conclusion from a meta-analysis of three trials suggested nesiritide might be associated with an increased risk of short-term death. (JAMA 2005;293[15]:1900.) Death within 30 days occurred more often among patients randomized to nesiritide (7.2%) vs. control (4.0%); RR 1.74 (0.97-3.12). Technically, the 95% confidence interval for the risk ratio crossed 1.0, meaning risk of death in the nesiritide group actually might have been lower than the control group, but based on the conclusions of both meta-analyses, schools of physicians began swimming against nesiritide, and use of the agent dropped precipitously. (JAMA 2006;296[15]:1877.)

Despite the overwhelming influence each of these articles had on nesiritide usage over the years, the scientific evidence behind the dramatic upsurge and the subsequent fallback was not very compelling in either case.

Finally, 10 years after the decade-long deluge, as the nesiritide waters recede, we have a well-designed, adequately powered, randomized, double-blinded, placebo-controlled trial comparing nesiritide with standard therapy and, for the first time, formidable evidence about the true effect this agent has on acute CHF.

Effect of Nesiritide in Patients with Acute Decompensated Heart Failure

O'Connor CM, Starling RC, et al N Engl J Med


This study compared nesiritide with placebo in patients with acute decompensated heart failure. Both groups also received standard-of-care therapy as determined by the investigator. Key exclusions included hypotension, contraindications to vasodilators, treatment with dobutamine, end-stage renal disease, and severe pulmonary disease. Primary endpoints were self-reported dyspnea at six and 24 hours, 30-day re-hospitalization, and death. Over three years, more than 7,000 patients were enrolled at almost 400 sites on four different continents.

The trial concluded that nesiritide did not result in any clinically significant difference in dyspnea over placebo at six hours (44.5% vs. 42.1%) or at 24 hours (68.2% vs. 66.1%) nor did it result in any difference in re-hospitalization or death at 30 days (9.4% vs. 10.1%; p=0.31). Additionally, nesiritide was not associated with worsening renal function, but like the VMAC study, it was associated with an increased incidence of hypotension (26.6% vs. 15.3%; p<.001).

Ultimately, the trial concluded that nesiritide could “not be recommended for routine use in the broad population of patients with acute heart failure.”

Now down to a trickle, the nesiritide stream is close to running dry. So what are the take-home points? First, it appears that at best, nesiritide is a very expensive agent that overall probably has no effect beyond standard therapy for treating acute CHF, and it carries with it the possible risk of increased hypotension.

But there is a second take-home point that is much more profound. An editorial, “The Lost Decade of Nesiritide” suggests we lost a lot of time and money on this agent and places much of the blame on the FDA and the drug's manufacturer. (N Engl J Med 2011;365[1]:81.) But as physicians, we must also examine our role in this washout. There will never be a drought of mediocre articles with poorly substantiated conclusions. The question is, will we critically analyze or blindly follow? Nesiritide won't be the last tsunami to strike the medical community. The next flood can come at any moment. Nesiritide may go down in medical history as a high-priced, decade-long experiment with no impact on the acute management of CHF. But with hopeful fingers crossed, nesiritide's greatest legacy will be on the lessons learned from riding its wave.

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Dr. Lovato is an associate professor at the David Geffen School of Medicine at UCLA, the director of critical care in emergency medicine at Olive View-UCLA Medical Center, the co-chair for the Emergency Medicine Best Practices Committee for the Los Angeles County Department of Health Services, and an instructor for the National Mega LLSA Review Course (

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