Nesiritide—A New Drug for the Treatment of CHF

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA has approved nesiritide, a new drug for treating inpatients with acutely decompensated congestive heart failure (CHF). Nesiritide represents a new approach to treating CHF. It is a 32 amino acid, recombinant B-type human natriuretic peptide that mimics the action of the endogenous counterpart. Its primary effects are a reduction in pulmonary capillary wedge pressure and systemic arterial pressure in patients with heart failure. Nesiritide is marketed under the trade name Natrecor by Scios Inc. of Sunnyvale, Calif.

Indications

Nesiritide is indicated for the treatment of patients with acutely decompensated CHF who have dyspnea at rest or with minimal activity.1

Dosage

The recommended dose is 2 µg/kg as an intravenous bolus followed by a continuous infusion of 0.01 µg/kg/min. There is limited experience with the use of nesiritide beyond 48 hours.1 Nesiritide is eliminated in a manner proportional to body weight and the product is dosed accordingly. Nesiritide is incompatible with, and should not be coadministered with several other compounds including heparin (including heparin-coated catheters), insulin, ethacrynate sodium, bumetamide, enalaprilat, hydralazine, furosemide, and sodium metabisulfite.1

Nesiritide is available as 1.5 mg vials.

Potential Advantages

Nesiritide has been shown to reduce dyspnea in patients with decompensated CHF compared to placebo.1,2 Improvement in pulmonary capillary wedge pressure, dyspnea, or fatigue was similar to that reported for others drugs such as dobutamine, nitroglycerin, dopamine, or amrinone.2 In a comparative trial with nitroglycerin, the Vasodilation in the Management of Acute CHF (VMAC) trial, nesiritide caused fewer overall side effects.3 Tachycardia or ventricular tachyarrhythmias has not been reported with nesiritide.1 In the Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Nesiritide (PRECEDENT) study, dobutamine was associated with significantly greater incidences of ventricular ectopy and tachycardia.5

Tachyphylaxis has not been reported.1

Potential Disadvantages

Hypotension is the most common dose-related adverse effect. While the incidence of hypotension was similar between nesiritide and nitroglycerin, when it occurred, the intensity and duration of this effect was longer with nesiritide (2.2 hours vs 0.7 hours).1 Blood pressure should be monitored closely during nesiritide administration. The use of other drugs, which may cause hypotension, must be done with caution. In some susceptible patients, those with severe heart failure, nesiritide may cause azotemia. Nesiritide can only be given intravenously and up to 48 hours. Following discontinuation of the drug, the effect (eg, pulmonary capillary wedge pressure) returns to within 10% of baseline within 2 hours.1

Comments

The natriuretic peptide family consist of 3 peptides: atrial natriuretic peptide, brain or B-type natriuretic peptide, and C-type peptide.4 Nesiritide is B-type peptide produced by recombinant DNA technology using the Escherichia coli system and is identical to endogenous B-type peptide. Endogenous B-type peptide is released by the ventricular myocardium in response to such factors as stretching of the wall, volume overload, or pressure overload.5 Levels are increased in patients with CHF and appear to be associated with the progression of clinical symptoms.6,7 B-type natriuretic peptide has been proposed as a screening tool for left ventricular dysfunction.8

In CHF patients, nesiritide has been shown to improve clinical symptoms (eg, dyspnea), reduce pulmonary capillary wedge pressure, and suppression of the reninangiotensin-aldosterone system. Improvement is generally seen within 15 minutes and reaches 95% of the 3-hour effect within 1 hour. In the clinical trials, the primary end points were changes in pulmonary capillary wedge pressure and improvement is dyspnea after 3 hours. The benefit dissipates within 2 hours after discontinuation. At doses higher than the currently recommended dose, 50-56% of patients who received nesiritide were rated as improved compared to 12% given placebo.2 With the currently approved dose, the comparative rates were not reported by the manufacturer other than to indicate that they were statistically significant (P = 0.034; n = 489).1 The FDA originally turned down the drug in April 1999 and a lower dose study was conducted at the FDA’s request. The VMAC trial, which compared nesiritide with IV nitroglycerin or placebo, was designed to address the issues raised by the FDA such as safety and tachyphylaxis.5

No improvement in survival has been seen with nesiritide compared to other drugs such as nitroglycerin, dobut amine, nitroprusside, milrinone, amrinone, or dopamine.1

Nesiritide will cost about $800 (2 vials) for a 48-hour administration.

Clinical Implications

It is estimated that approximately 5 million Americans have heart failure, and decompensation is the most common reason for the hospitalization. The condition is characterized with symptoms of dyspnea and fatigue. Nesiritide has been shown to improve these symptoms rapidly and at least as effectively as currently available drugs with some potential advantages. Scios will develop a CHF patient registry, the Acutely Decompensated Heart Failure Registry (ADHERE) and will launch a physician education program. The latter was at the request of the FDA advisory committee.

References

1. Natrecor Product Information. Scios Inc. August 2001.

2. Colucci WS, et al. N Engl J Med. 2000;343:246-253.

3. Colucci WS. J Cardiac Fail. 2001;7:92-100.

4. Levin ER, et al. N Engl J Med. 1998;339:321-328.

5. Hobbs RE, et al. Exp Opin Invest Drugs. 2001;10(5): 935-942.

6. Clerico A, et al. J Endocrinol Invest. 1998;21:170-179.

7. Friedl W, et al. Clin Chim Acta. 1999;281:121-126.

8. Maisel AS, et al. Am Heart J. 2001;141:367-374.