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CLINICAL STUDIES

Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure

A randomized, double-blind, placebo-controlled clinical trial

Roger M. Mills, MD, FACC^*, Thierry H. LeJemtel, MD, Darlene P. Horton, MD, Chang-seng Liang, MD, PhD, FACC, Roberto Lang, MD, FACC^||, Marc A. Silver, MD, FACC^¶, Charles Lui, MD, FACC^#, Kanu Chatterjee, MD, FACC^** on Behalf of the Natrecor Study Group¹

^* Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida, USA
Division of Cardiology, Albert Einstein College of Medicine, Bronx, New York, USA
Clinical Research Division, Scios Inc., Mountain View, California, USA
Cardiology Unit, University of Rochester Medical Center, Rochester, New York, USA
^|| Section of Cardiology, University of Chicago, Chicago, Illinois, USA
^¶ Division of Cardiology, Loyola University Medical Center, Maywood, Illinois, USA
^# Division of Cardiology, University of Arizona, Tucson, Arizona, USA
^** Division of Cardiology, University of California San Francisco, San Francisco, California, USA

Manuscript received September 30, 1998; revised manuscript received February 24, 1999, accepted March 31, 1999.

Reprint requests and correspondence: Dr. Roger M. Mills, Desk F-15, Department of Cardiology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195

	Abstract

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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 µg/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 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.

Abbreviations and Acronyms   CI = cardiac index   hBNP = human b-type natriuretic peptide   HF = heart failure   IV = intravenous   MRAP = mean right atrial pressure   PCWP = pulmonary capillary wedge pressure   SBP = systemic systolic blood pressure   SVR = systemic vascular resistance

	Methods

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Subjects/randomization.   For this randomized, double-blind, placebo-controlled study, the investigational review committees of all 16 participating study sites approved the study protocol and informed consent document. Subjects with New York Heart Association class II, III or IV HF were admitted to the hospital and a pulmonary artery flotation catheter was placed at least 90 min before baseline central hemodynamic measurements were made and at least 2 h before the start of study drug. Once all eligibility criteria (Table 1) were met, subjects were randomized into one of four treatment groups: group 1, IV placebo bolus followed by a placebo infusion; group 2, nesiritide 0.25-µg/kg IV bolus followed by an infusion of 0.015 µg/kg/min; group 3, nesiritide 0.5-µg/kg IV bolus followed by an infusion of 0.03 µg/kg/min; or group 4, nesiritide 1.0-µg/kg IV bolus followed by an infusion of 0.06 µg/kg/min. Randomization was stratified by study site. The randomization assigned subjects to treatment groups 1, 2, 3 or 4 in a ratio of 1:1:1:1, using an initial block of size 4 and subsequent blocks of size 8. All of the study drug, including placebo, was prepared in identical infusion bags by study site personnel who were not associated with the subject’s clinical management to ensure blinding.

Study protocol.   Before study drug administration, beta-adrenergic blocking agents and calcium channel blocking agents were withheld for 48 h, and vasodilators, hydralazine and angiotensin-converting enzyme inhibitors were withheld for 12 to 24 h. During study drug infusion, angiotensin-converting enzyme inhibitors, vasodilators, beta-blockers and calcium channel blockers were withheld; digoxin, diuretics and antiarrhythmics were administered as per the protocol if clinically indicated. Central hemodynamics (PCWP, MRAP, SVR, CI), systemic blood pressure and heart rate measurements were obtained at baseline, during the study drug infusion at 1, 3, 6, 10 and 24 h, and at 2 and 4 h postinfusion. Additional measurements were taken during any significant event. Cardiac index was derived from body surface area and the mean of three consecutive thermodilution measurements of cardiac output falling within 15% of each other or the mean of three out of five measurements (where the high and low values were discarded). Total fluid intake and urine output were measured for 24 h after the start of study drug. Blood was drawn for serum chemistry and hematology studies at baseline, within 24 h after discontinuation of study drug and between days 20 and 30. Blood for plasma hBNP levels was drawn 15 min preinfusion, 0.25, 0.5, 1, 3, 6 and 24 h after the start of study drug infusion and at 2, 5, 15, 30, 60, 120 and 240 min after discontinuation of the study drug. Blood was drawn for anti-hBNP antibody levels at baseline and between days 20 and 30. Four hours after discontinuation of study drug infusion, the pulmonary wedge catheter was removed if appropriate, and all previously prescribed medications could resume. Subjects were observed and discharged after follow-up examination. A follow-up telephone call was made on day 7 and day 15 for assessment of adverse events and vital status.

Data analysis.   Data were double-key entered into the Sponsor’s clinical database and validated with computerized edit checks. All plasma hBNP and serum anti-hBNP antibody determinations were performed by a single core laboratory at Scios Inc. to ensure consistency. The analyses of hemodynamic responses were performed on the "intent to treat" population. All randomized subjects were included in this population, and subjects are summarized according to the treatment group to which they were randomly assigned. The effect of treatment group was analyzed within the framework of one-way analysis of variance. An overall comparison of the four treatment groups was made with the omnibus F test. Each nesiritide treatment group was compared with the placebo group using a pairwise contrast. Dose–response effect was examined by means of a linear contrast on treatment group using equally spaced scores. When an end point was represented as the change or percent change from baseline, a one-sample t test was run within each treatment group to test for a nonzero mean change from baseline. This test used the within-group estimate of variance, not the pooled estimate from the analysis of variance model. All reported p values are two sided. For this report, p < 0.05 is considered statistically significant. All analysis results were obtained using SAS software (Cary, North Carolina), version 6.12, running on a Digital Equipment Corporation Alphaserver 4100 5/300.

	Results

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Subject enrollment and baseline features.   From 16 study sites, 103 subjects were enrolled. Figure 1 is a flow diagram which accounts for subjects from randomization through the treatment period. No subjects were lost to follow-up. As shown in Table 2, there were no significant differences in demographic or baseline characteristics between treatment groups.

View larger version (24K): [in this window] [in a new window]   Figure 1 Flow diagram of subjects from randomization through the treatment period. 1Did not meet entry hemodynamic criteria. 2Subjects whose infusion terminated before 22 h. BP = blood pressure; CHF = worsening heart failure; CI = cardiac index; NA = not applicable; PCWP = pulmonary capillary wedge pressure. Downward arrows: excessively decreased.

View larger version (29K): [in this window] [in a new window]   Figure 2 Mean observed hemodynamic values: results from baseline (BL) through 24 h of infusion (inf) and 4 h postinfusion. (A) Pulmonary capillary wedge pressure units are mm Hg. (B) Cardiac index units are liters/min/m2. (C) Systemic systolic blood pressure units are mm Hg. (D) Systemic vascular resistance units are dyn/s/cm–5. Open squares: placebo; closed circles: 0.015 µg/kg/min; closed triangles: 0.03 µg/kg/min; open circles: 0.06 µg/kg/min.

Study drug compliance.   Excessive decreases in PCWP during drug infusion requiring a protocol-specified dose reduction occurred in 0 (0%), 4 (18%), 7 (27%) and 9 (35%) subjects in the placebo and three ascending dose nesiritide groups, respectively (p = 0.002 [trend test]). Hypotension led to dose reduction in an additional 1 (3%), 1 (5%), 1 (4%) and 3 (12%) subjects in the placebo and three ascending nesiritide groups, respectively. Five placebo subjects and one subject in the 0.03-µg/kg/min nesiritide dose group terminated study drug infusion prematurely due to worsening congestive HF and were therefore categorized as treatment failures (p = 0.014 [trend test]). Premature termination of study drug infusion because of hypotension or excessive decreases in PCWP was dose related, reported in 0, 0, 2, and 6 subjects in the placebo and 0.015-, 0.03- and 0.06-µg/kg/min nesiritide dose groups, respectively.

Safety.   A 24-h continuous IV infusion of nesiritide was generally well tolerated. The most frequently reported adverse events during nesiritide infusion were decreases in blood pressure and excessively decreased PCWP. These events were dose related and are consistent with the pharmacologic action of the drug. Hypotension during study drug infusion was reported in 2 (7%), 1 (5%), 3 (12%) and 7 (27%) of the subjects in the placebo and 0.015-, 0.03- and 0.06-µg/kg/min nesiritide dose groups, respectively (p = 0.027 [trend test]). However, the hypotension was often asymptomatic and usually did not require intervention. Symptomatic hypotension during study drug infusion was reported in only 2 (7%), 1 (5%), 1 (4%) and 4 (15%) of the subjects in the placebo and three ascending dose groups, respectively (p = 0.346 [trend test]). Nausea during study drug infusion was reported in 0 (0%), 2 (9%), 0 (0%) and 4 (15%) of the subjects in the placebo and 0.015-, 0.03- and 0.06-µg/kg/min nesiritide dose groups, respectively (p = 0.068 [trend test]). No other adverse events appeared to be associated with nesiritide administration in a dose-related manner.

Nonsustained ventricular tachycardia was reported during study drug infusion in three subjects, all of whom were in the 0.03-µg/kg/min nesiritide dose group. During the two weeks after study drug administration, nonsustained ventricular tachycardia was reported in two placebo subjects and in three, five and zero subjects in the three ascending dose nesiritide groups, respectively. The lack of a dose-related incidence of nonsustained ventricular tachycardia during and after study drug administration suggests that these events are consistent with the expected prevalence of an underlying substrate for ventricular arrhythmias in this study population. Sustained ventricular tachycardia was not reported in any subject through day 14.

Three deaths occurred during the 15-day study follow-up period, one each in the placebo group, the 0.03-µg/kg/min nesiritide group and the 0.06-µg/kg/min nesiritide group. Two additional deaths were reported after day 15, both in the placebo group. None of these deaths was believed to be study related.

None of the subjects tested (n = 59) developed anti-hBNP antibody in the follow-up period.

Human b-type natriuretic peptide blood levels.   Blood levels of hBNP achieved steady state before 3 h of infusion. Three-hour levels for group 1 (placebo) were 835 ± 989 pg/ml, and for groups, 2, 3 and 4 were 2,985 ± 1,440, 3,711 ± 2,063 and 6,456 ± 4,272 pg/ml, respectively.

	Discussion

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This double-blind, placebo-controlled study of 103 subjects with symptomatic decompensated HF showed that a 24-h continuous IV infusion of nesiritide resulted in rapid and sustained beneficial hemodynamic effects and was well tolerated in this patient population. As early as 1 h after the start of therapy (the first time point measured in this study), as well as after 24 h of infusion, the hemodynamic effects of nesiritide include a marked reduction in preload coupled with a decrease in afterload, facilitating an increase in stroke volume and cardiac output. Hemodynamic parameters promptly returned to baseline after the infusion was discontinued after 24 h without evidence of a rebound effect.

Hemodynamic effects.   The pharmacologic effect of hBNP at the cellular level is mediated by increases in cyclic guanosine monophosphate which lead to relaxation of vascular smooth muscle (12). Hemodynamically, these effects manifest as clinically significant balanced vasodilation, reducing both systemic vascular resistance and central venous pressure with no evidence of tolerance. This balanced vasodilator effect facilitates improved forward cardiac output at reduced filling pressures, almost certainly by redistribution of mitral regurgitant flow, as observed with other vasodilators (13,14). Reduction of systemic venous pressure may also improve left ventricular function in some advanced HF patients through ventricular interdependence (15,16). In addition, reduction in left ventricular filling pressure may improve myocardial perfusion, resulting in improvement in both systolic and diastolic function, particularly in patients with obstructive coronary disease (17).

Nesiritide is not an inotrope and is not dependent on adrenergic receptors or cyclic adenosine monophosphate for pharmacologic efficacy. Our data show no increase in either heart rate or systolic blood pressure during nesiritide infusion, indicating that the beneficial hemodynamic effects produced do not entail an increase in myocardial oxygen consumption.

Effects on diuresis.   We did not observe greater urine output during the nesiritide infusion compared with placebo in this study. This is difficult to interpret given the lack of baseline urine output measurements as well as the discordant use of diuretics between treatment groups during study drug infusion. However, the lack of an increase in urine output during nesiritide infusion does conflict with the independent findings of Marcus et al. (10) and LeJemtel et al. (18, personal communication), whose studies describe a moderate increase in urine output during nesiritide infusion compared with placebo.

Clinical trial design.   The design of this trial required a trade-off between assessment of therapeutic efficacy, which would have allowed more liberal dose titration, and assessment of the hemodynamic changes associated with the specific drug doses. The hemodynamic results observed most likely underestimate the sustained hemodynamic benefits of nesiritide because of dose reductions and subject withdrawals, in essence removing several patients with prompt and beneficial responses to the drug from continued treatment. The lack of a linear dose–response relationship in the observed hemodynamic responses in this intent-to-treat population might represent statistical variation due to small sample size or the effect of down-titration and withdrawal for excessive pharmacologic response. A linear dose response to increasing doses of nesiritide has been documented in other studies (10,18). Nonetheless, all three doses of nesiritide administered in this study resulted in beneficial effects on cardiac hemodynamics, such as decreases in PCWP and increases in CI.

Safety.   Although the highest dose studied here (0.06 µg/kg/min) resulted in the greatest effects on most hemodynamic parameters, it was also associated with a higher incidence of adverse events (such as hypotension and nausea) than the lower two doses, and premature terminations of study drug infusion due to these adverse events were more frequent in this group. Conversely, adverse events in the two lower dose groups were infrequent and generally tolerable. This suggests that doses of nesiritide in the range of 0.015 to 0.03 µg/kg/min provide an optimal safety/efficacy profile for this clinical indication.

Conclusions.   The rapid and sustained beneficial hemodynamic effects observed during nesiritide administration in this study support the use of this agent as a first-line intravenous therapy for patients with symptomatic, decompensated congestive HF.

	Acknowledgments

 
The authors would like to thank the subinvestigators, study coordinators, pharmacists and nurses from the participating study sites for their contribution to the study. Principal Investigators of the Natrecor Study Group are listed alphabetically with their corresponding institution: William Abraham, MD, University of Colorado Health Sciences Center, Denver, Colorado; Kanu Chatterjee, MD, University of California San Francisco, San Francisco, California; Cara East, MD, Baylor University Medical Center; Dallas, Texas; Allen D. Johnson, MD, Scripps Clinic & Research Foundation, La Jolla, California; Walter Kao, MD, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois; Stuart D. Katz, MD, Columbia-Presbyterian Medical Center, New York, New York; Marrick Kukin, MD, Mt. Sinai Medical Center, New York, New York; Roberto Lang, MD, University of Chicago Hospital, Chicago, Illinois; Thierry LeJemtel, MD, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York; Chang-Seng Liang, MD, PhD, FACC, University of Rochester Medical Center, Rochester, New York; Charles Lui, MD, University of Arizona, Tucson, Arizona; Roger Mills, MD, FACC, University of Florida Shands Hospital, Gainesville, Florida; Barry P. Rosenzweig, MD, New York University Medical Center, New York, New York; Marc A. Silver, MD, FACP, FACC, Loyola University Medical Center, Maywood, Illinois; and Vasant N. Udhoji, MD, FACC, West Los Angeles Veterans Administration Medical Center, Los Angeles, California.

	Footnotes

 
This study was supported by a grant from Scios Inc., Mountain View, California.

¹ The investigators of the Natrecor Study Group and their affiliated institutions are listed under Acknowledgments.

	References

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