Use of Nesiritide to Treat Acute Decompensated Heart Failure

Natriuretic peptides and their actions of natriuresis, diuresis, and vasodilation have been described in the scientific literature for more than 20 years.1,2 Only recently though, a more complete understanding of the actions of natriuretic peptides, their receptors, and their applications has been achieved. With this understanding, new classes of medications have been developed that can target different pathophysiological events in heart failure and offer further treatment options. In this article, we introduce a new drug, human B-type natriuretic peptide (Natrecor or nesiritide), indicated for intravenous treatment of patients with acutely decompensated heart failure who have dyspnea at rest or with minimal activity.3Currently, 3 natriuretic peptides have been identified. Atrial natriuretic peptide (ANP) is produced and released by the atria in response to stretching of the myocardium due to increased intravascular volume. B-type natriuretic peptide (BNP), formerly referred to as brain type, is produced and released by the ventricles in response to pressure overload. ANP and BNP have similar physiological properties, including promoting natriuresis and diuresis, inhibiting the renin-angiotensin-aldosterone system, and possessing vasodilating properties. C-type natriuretic peptide, which is found in the lung, kidney, heart, and vascular endothelium, is a potent vasodilator and inhibitor of vascular cell growth but has minimal diuretic and natriuretic effects.4The roles of these natriuretic peptides are best explained by examining their cardiac and renal effects in patients with congestive heart failure. Cardiac hypertrophy that accompanies myocardial failure leads to an increase in production of ANP and BNP. Release of ANP and BNP into plasma is further stimulated by the stretching of failing atrial and ventricular myocardium.5 The volume-contracting and vasodilating properties of ANP and BNP reduce systemic vascular resistance, decrease intracardiac filling pressure, and improve myocardial performance.5 Natriuretic peptides mediate natriuresis and diuresis through increased renal blood flow, inhibition of the renin-angiotensin-aldosterone system, and direct tubular action. Glomerular filtration rate is increased by dilatation of afferent arterioles and constriction of efferent arterioles. Natriuretic peptides also inhibit angiotensin II–mediated reabsorption of sodium and water in the proximal convoluted tubules.4As the functions and roles of natriuretic peptides continue to unfold, one development that has emerged is the use of measurements of serum concentrations of natriuretic peptides (specifically, rapid tests of BNP levels) to aid in the diagnosis of congestive heart failure. BNP levels are reliable predictors of whether left ventricular dysfunction will be seen on echocardiograms. For some patients, a normal BNP level may eliminate the need for echocardiography.6 When used in conjunction with clinical information, rapid measurement of BNP is useful in establishing or excluding the diagnosis of congestive heart failure in patients with acute dyspnea.7Much of this research into isolating the natriuretic peptides and their receptors has led to the development of new classes of medications that have innovative and unique mechanisms of action. One such medication that is now available commercially is nesiritide (Natrecor), human BNP.Nesiritide has actions similar to those of ANP and BNP just described. In clinical trials, nesiritide produced dose-dependent reductions in pulmonary capillary wedge pressure and systemic arterial pressure in patients with heart failure. Kinetically, the drug has a terminal half-life of 18 minutes; thus after an infusion is stopped, effects would be expected to be seen for up to 1 hour. However, pharmacodynamic evidence suggests that the effects may last longer than 60 minutes. Even though nesiritide is eliminated in part through renal clearance (in addition to proteolysis by endopeptidases), clinical data suggest that dosage adjustment is not necessary in patients with renal insufficiency.3At the recommended dose of 2 μg/kg intravenous bolus administered over 60 seconds followed by a continuous infusion of 0.01 μg/kg per minute, patients report a decrease in dyspnea within 3 hours. Hemodynamic effects are seen almost immediately (within 15 minutes) after beginning the infusion of the drug. These effects include reductions in pulmonary capillary wedge pressure, systolic blood pressure, and mean pulmonary artery pressure. Drug effects on urine output from clinical trials are consistent with the actions of BNP on the kidney. To measure the effects, in a clinical trial, diuretic therapy was discontinued 4 hours before administration of nesiritide and was not resumed until after urine output had been measured 6 hours after the nesiritide was administered. Urine output increased in a dose-dependent manner with the nesiritide infusion.8Colucci et al8 compared 2 doses of nesiritide (a bolus of 0.3 μg followed by an infusion of 0.015 μg/kg per minute versus a bolus of 0.6 μg followed by an infusion of 0.030 μg/kg per minute) with both placebo and the standard treatment for decompensated heart failure (dobutamine, milrinone, nitroglycerin, or sodium nitroprusside). The 432 patients in that study were recruited from 66 medical centers and randomly assigned to treatment groups. Baseline characteristics were similar in the different arms of the study and also among the treatment groups within the arms. The arm that compared the nesiritide with placebo was double blinded, whereas the arm that compared nesiritide with standard therapy was open label to drug but not dose. To be included in the study, patients had to have symptomatic heart failure that warranted admission to the hospital in the opinion of the attending physician.Global clinical status was assessed by both the patient and the physician at baseline and 6 hours later. In the comparative arm, global clinical status was also assessed 24 hours after baseline and at the end of therapy. A 5-category scale was used (markedly better, better, no change, worse, and markedly worse). Dyspnea and fatigue were also evaluated specifically in the same time frame by using a 3-category scale (improved, no change, or worse).The efficacy arm showed significant improvement in the patients’ evaluation of global clinical status. Sixty percent of patients receiving nesiritide 0.015 μg/kg per minute and 67% of patients receiving nesiritide 0.030 μg/kg per minute gave a rating of better or markedly better than baseline, whereas only 14% of patients receiving placebo gave these ratings (P<.001). Physicians’ assessments also differed significantly between groups, with ratings of better or markedly better in 55% of patients receiving nesiritide 0.015 μg/kg per minute, 77% of patients receiving nesiritide 0.030 μg/kg per minute, and only 5% of patients receiving placebo (P<.001). The improvement in dyspnea and fatigue from baseline was also significant when compared with placebo (P<.001).The comparative arm showed improvement in global clinical status, dyspnea, and fatigue 6 hours and 24 hours after the infusion was started and at the end of therapy for both nesiritide groups and the group receiving standard therapy. However, this difference was not significant. Weight loss was similar among patients in all 3 groups, but patients receiving nesiritide received smaller amounts of diuretics (P<.001).Nesiritide resulted in improved hemodynamic function and rapid and sustained improvements in clinical status. It was as effective as the current standard treatments. These results were seen in patients with decompensated heart failure, whereas most other studies have involved patients with a more stable clinical status. This study also used patient-oriented evidence in addition to hemodynamic outcomes. This difference is important because most studies evaluate only hemodynamic data, which may not always correspond to improved signs and symptoms. Bias may have been introduced in the comparative arm because of the open-label design. However, because the physicians’ evaluations corresponded to the patients’ evaluations, bias is unlikely.Although nesiritide is a new medication, various institutions have developed protocols for its use (written communication, Alison Tran, Harper University Hospital, Detroit Medical Center, Detroit, Mich., August 2002; written communication Kristen H. Schwetschenau, Veteran Affairs Medical Center, Cincinnati, Ohio, August 2002). Several essential components must be included in protocols for nesiritide; examples include indications and restrictions for use as well as guidelines for monitoring hemodynamic parameters before and during infusion. Specific dosing information must also be specified, including bolus dose, infusion, when to adjust the rate, and monitoring of hemodynamic parameters if need be.The discovery of the natriuretic peptides almost 20 years ago has led to many advances, primarily in the diagnosis of heart failure but also in the treatment of patients with acute decompensated heart failure. More clinical experience and postmarketing surveillance is needed to determine exactly how safe and tolerable nesiritide is in the hands of practicing nurses, pharmacists, and physicians.