Darlene P. Horton

Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure : A randomized, double-blind, placebo-controlled clinical trial

OBJECTIVES The goal of this study was to further define the role of nesiritide (human b-type natriuretic peptide) in the therapy of decompensated heart failure (HF) by assessing the hemodynamic effects of three doses (0.015, 0.03 and 0.06 microg/kg/min) administered by continuous intravenous (IV) infusion over 24 h as compared with placebo. BACKGROUND Previous studies have shown beneficial hemodynamic, neurohormonal and renal effects of bolus dose and 6-h infusion administration of nesiritide in HF patients. Longer term safety and efficacy have not been studied. METHODS This randomized, double-blind, placebo-controlled multicenter trial enrolled subjects with symptomatic HF and systolic dysfunction (left ventricular ejection fraction < or =35%). Central hemodynamics were assessed at baseline, during a 24-h IV infusion and for 4 h postinfusion. RESULTS One hundred three subjects with New York Heart Association class II (6%), III (61%) or IV (33%) HF were enrolled. Nesiritide produced significant reductions in pulmonary wedge pressure (27% to 39% decrease by 6 h), mean right atrial pressure and systemic vascular resistance, along with significant increases in cardiac index and stroke volume index, with no significant effect on heart rate. Beneficial effects were evident at 1 h and were sustained throughout the 24-h infusion. CONCLUSIONS The rapid and sustained beneficial hemodynamic effects of nesiritide observed in this study support its use as a first-line IV therapy for patients with symptomatic decompensated HF.

Effect of nesiritide versus dobutamine on short-term outcomes in the treatment of patients with acutely decompensated heart failure.

OBJECTIVES This study was designed to determine whether nesiritide, administered for acute decompensated congestive heart failure (CHF), affects healthcare costs by hospital length of stay (LOS), readmissions and short-term mortality, compared to dobutamine. BACKGROUND Dobutamine is a commonly used inotropic treatment for CHF. Although dobutamine may have favorable hemodynamic and symptomatic effects, its use may be associated with side effects such as tachycardia, cardiac arrhythmias and myocardial ischemia. Nesiritide (B-type natriuretic peptide) is a new intravenous (IV) drug that produces hemodynamic and symptomatic improvement through balanced vasodilatory effects, neurohormonal suppression and enhanced natriuresis and diuresis. METHODS From an open-label randomized study of nesiritide versus standard care (SC) in patients with CHF requiring hospitalization, we compared short-term outcome data from patients given nesiritide (0.015 or 0.03 microg/kg per min) with a subgroup of SC patients given dobutamine. A total of 261 patients are included in this analysis. RESULTS Compared to dobutamine, both nesiritide doses were administered for a shorter total duration (p < 0.001), and the total duration of all IV vasoactive therapy (including study drug) was also shorter (p less-than-or-equal 0.012). Although there was no difference in LOS, there was a trend toward decreased readmissions in the two nesiritide groups (8% and 11%, respectively, vs. 20% in the dobutamine group). Six-month mortality was lower in the nesiritide groups. CONCLUSIONS Treatment of decompensated CHF with nesiritide may lead to lower healthcare costs and reduced mortality compared to treatment with dobutamine.

Comparison of the effects of dobutamine and nesiritide (B-type natriuretic peptide) on ventricular ectopy in acutely decompensated ischemic versus nonischemic cardiomyopathy.

C heart failure (CHF) involves many complex autonomic and neurohormonal responses (such as activation of the renin-angiotensin-aldosterone and sympathetic systems) that can exert deleterious effects on the heart, leading to further cardiac decompensation. Inotropic therapy with dobutamine can improve cardiac hemodynamics, but also may cause arrhythmogenesis.1,2 Nesiritide (B-type natriuretic peptide, an endogenous cardiac hormone) is a systemic arterial and venous vasodilator,3–5 and has been shown to significantly reduce symptoms and improve hemodynamics in hospitalized patients with acute decompensated CHF without increasing heart rate. Nesiritide also suppresses norepinephrine, endothelin-1, and the renin-angiotensin-aldosterone system while promoting natriuresis.6–8 In the Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Nesiritide Therapy (PRECEDENT) trial, dobutamine was associated with significant increases in ventricular tachycardia (VT) and heart rate, especially in patients without a history of VT, suggesting that proarrythmic effects may be due to sympathetic activation of a dormant substrate.9 In contrast, nesiritide was associated with an actual reduction in VT without an increase in heart rate. The objective of this study was to determine the differential effects of dobutamine and nesiritide on ventricular arrhythmias and on heart rate in patients with ischemic and nonischemic cardiomyopathy. • • • The PRECEDENT trial was a prospective, randomized, multicenter, open-label, active-control safety study designed to compare the relative safety of dobutamine and 2 fixed doses of nesiritide with respect to their effect on ventricular arrhythmias and heart rate. Eligible patients included subjects who were 18 years of age, had a history of New York Heart Association class III or IV CHF, and were hospitalized for symptomatic, decompensated CHF requiring intravenous vasoactive therapy. Exclusion criteria included myocardial infarction within 48 hours before entry into the study, presence of cardiogenic shock, systolic blood pressure 90 mm Hg, or any condition that contraindicated intravenous vasodilators. Patients were randomized in a 1:1:1 ratio to treatment with 0.015 g/kg/min of nesiritide, 0.03 g/kg/min of nesiritide, or dobutamine 5 g/kg/min. Assignment to nesiritide or dobutamine was open label; assignment to the 2 nesiritide doses was double-blinded. Three-channel, 24-hour ambulatory electrocardiographic recordings were obtained in all patients during the 24 hours immediately before randomization and start of the study drug (baseline tape), and during the first 24 hours of study drug treatment (treatment tape). The primary end points were changes from baseline in (1) mean hourly repetitive beats, which are the total number of beats involved in ventricular couplets or runs of VT, (2) mean hourly ventricular premature complexes (VPCs), and (3) average heart rate. Secondary end points included the frequency of VT, ventricular triplets, and number of couplets/24 hours. Information concerning the etiology of the patient’s cardiomyopathy was systematically obtained as part of the recruitment and follow-up procedure of the PRECEDENT study. Patients were classified as having ischemic cardiomyopathy when left ventricular dysfunction was present in addition to 1 of the following conditions: a definite history of coronary artery disease, myocardial infarction, coronary artery bypass surgery, symptomatic coronary disease with drug treatment, electrocardiogram diagnostic of old myocardial infarction, or cardiac catheterization with 1 vessel with 70% diameter stenosis and/or occlusions. All other patients who did not fulfill these criteria were included in the nonischemic group. Of the 246 patients in the PRECEDENT study, 129 were classified as having an ischemic cardiomyopathy, whereas 117 had nonischemic cardiomyopathy. About half of those with nonischemic cardiomyopathy had an idiopathic etiology (48%), followed by hypertension (23%), valvular disease (9%), and alcoholinduced (3%) or drug-induced (3%) cardiomyopathies. Baseline characteristics were generally similar in the ischemic and nonischemic cardiomyopathy groups and across the dobutamineand nesiritidetreated patients (Table 1). In the ischemic cardiomyopathy group, more patients in the dobutamine-treated group had undergone percutaneous transluminal coronary angioplasty or coronary artery bypass surgery, whereas a history of sudden death or near sudden death occurred more often in patients treated with 0.030 g/kg/min of nesiritide. In the ischemic and nonischemic cardiomyopathy From Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; RAMBAM Medical Center, Haifa, Israel; and Scios Inc., Sunnyvale, California. Dr. Burger’s address is: Beth-Israel Deaconess Medical Center, Non-invasive Cardiology Laboratory, Baker 3, 1 Deaconess Road, Boston, Massachusetts 02215. E-mail: aburger@caregroup.harvard.edu. Manuscript received October 24, 2002; revised manuscript received and accepted February 11, 2003.