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Frequently Asked Questions

Is it recommended to use nesiritide in the outpatient setting?

Background
In 2001, the Food and Drug Administration (FDA) approved nesiritide (Natrecor) for the treatment of acute decompensated congestive heart failure with dyspnea at rest or with minimal activity based on the results of clinical trials in hospitalized patients.1 Nesiritide has been making headline news since its approval. There have been concerns regarding its use such as increases in renal dysfunction and mortality.2 The most recent headline news is the lawsuit filed by the United States, in conjunction with civil lawsuits filed by 2 former employees, against Scios, Inc. and Johnson & Johnson for marketing nesiritide for off-label use in outpatients with less severe heart failure.3 Federal investigators believe this marketing campaign was initiated almost immediately after the approval of nesiritide.

There are 3 main pieces of evidence that refute the use of nesiritide in outpatients with heart failure. In 2005, an expert panel of cardiologists recommended against the use of nesiritide for intermittent outpatient infusions.2 The authors of the Second Follow-Up Serial Infusions of Nesiritide (FUSION II) trial found no reason to use outpatient nesiritide infusions for patients with advanced heart failure (see summary below).4 Lastly, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for management of chronic heart failure do not recommend intermittent or continuous outpatient infusion of nesiritide.5

FUSION II trial
In a prospective, randomized, double-blind, multicenter trial, investigators evaluated the safety and efficacy of intermittent nesiritide infusions in the outpatient setting.4 A total of 920 patients with advanced heart failure classified by ACC/AHA as stage C or D were randomized 2:1 as follows: nesiritide (n=307) or placebo (n=153) infused once weekly and nesiritide (n=306) or placebo (n=154) infused twice weekly. A bolus dose (2 mcg/kg) of nesiritide or placebo was administered followed by an infusion of 0.01 mcg/kg per minute for 4 to 6 hours. The primary endpoint was time to all-cause death or the first hospitalization for cardiovascular or renal causes. The number of cardiovascular and renal hospitalizations, days alive and out of the hospital, and time to cardiovascular death were the secondary endpoints. Both primary and secondary endpoints were evaluated through week 12. Safety endpoints included the evaluation of adverse events, serious adverse events, change in serum creatinine, and change in estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease (MDRD) equation. The serum creatinine was measured at each outpatient visit and assessed based on 3 categories: serum creatinine increase >0.5 mg/dL, serum creatinine increase >100%, and serum creatinine increase ≥50% to ≥2 mg/dL.

At the end of week 12, there was no significant difference between nesiritide combined treatment groups and the combined placebo groups for the primary endpoint, all-cause mortality or cardiovascular and renal hospitalizations (hazard ratio [HR] 1.03; 95% confidence interval [CI] 0.64 to 1.58; p=0.98 and HR 0.99; 95% CI 0.78 to 1.26, respectively for each primary endpoint).4 In addition, no significant difference was found between the combined treatment groups for any of the secondary endpoints at the end of week 12. There was no difference between nesiritide and placebo in percentage of patients experiencing any adverse event (86.9% placebo vs. 88.4% nesiritide, p=0.52), serious adverse events (56.5% placebo vs. 60.2% nesiritide, p=0.32), or adverse events requiring permanent study drug discontinuation (25.5% placebo vs. 26.9% nesiritide, p=0.69). However, 295 (32.4%) patients in the combined nesiritide group experienced hypotension compared to 55 (18%) patients in the combined placebo group (p=0.001). As for renal toxicity, 292 (32.1%) patients in the combined nesiritide group experienced serum creatinine increases >0.5 mg/dL compared to 119 (38.8%) placebo recipients (p=0.046). The increase in eGFR at 12 weeks in patients randomized to nesiritide was not statistically significantly different (p=0.082) compared to placebo.

The authors concluded that intermittent outpatient nesiritide infusions offered no clinical benefit in patients with stage C/D heart failure. Overall, there was no worsening of renal function with nesiritide in the outpatient setting; however, more research is needed in hospitalized patients with acute decompensated heart failure to resolve this safety concern.

Conclusion
The safety and efficacy of nesiritide has been established for the management of acute decompensated heart failure; a use approved by the FDA. However, nesiritide has been surrounded by controversy. Currently, the manufacturers are facing legal issues for allegedly promoting off-label use of nesiritide in outpatient settings. Based on the findings of the FUSION II trial, current practice guidelines, and the statement by the panel of cardiologists, patients with advanced heart failure should not be treated with serial nesiritide infusions in an outpatient setting. Patients with advanced heart failure should be treated with optimal therapy that will control symptoms, reduce hospitalizations, and improve quality of life.

References

  1. Natrecor [package insert]. Mountain View, CA: Scios Inc.; 2007.
  2. US Food and Drug Administration MedWatch. 2005 Safety alert: Natrecor (nesiritide). http://www.fda.gov/medwatch/SAFETY/2005/natrecor2_DHCP.htm. Accessed February 24, 2009.
  3. US Department of Justice. United States join suits against Scios and Johnson & Johnson. http://www.usdoj.gov/opa/pr/2009/February/09-civ-138.html. Accessed February 24, 2009.
  4. Yancy CW, Krum H, Massie BM, et al. Safety and efficacy of outpatient nesiritide in patients with advanced heart failure: results of the second follow-up serial infusions nesiritide (FUSION II) trial. Cir Heart Fail. 2008;1(1):9-16.
  5. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to update the 2001 guidelines for the evaluation and management of heart failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12)e152-e235.