 |
|
Intravenous Nesiritide vs Nitroglycerin for Treatment of Decompensated Congestive Heart Failure
A Randomized Controlled Trial
Publication Committee for the VMAC Investigators
JAMA. 2002;287:1531-1540.
ABSTRACT
| |
Context Decompensated congestive heart failure (CHF) is the leading hospital discharge diagnosis in patients older than 65 years.
Objective To compare the efficacy and safety of intravenous nesiritide, intravenous nitroglycerin, and placebo.
Design, Setting, and Patients Randomized, double-blind trial of 489 inpatients with dyspnea at rest from decompensated CHF, including 246 who received pulmonary artery catheterization, that was conducted at 55 community and academic hospitals between October 1999 and July 2000.
Interventions Intravenous nesiritide (n = 204), intravenous nitroglycerin (n = 143), or placebo (n = 142) added to standard medications for 3 hours, followed by nesiritide (n = 278) or nitroglycerin (n = 216) added to standard medication for 24 hours.
Main Outcome Measures Change in pulmonary capillary wedge pressure (PCWP) among catheterized patients and patient self-evaluation of dyspnea at 3 hours after initiation of study drug among all patients. Secondary outcomes included comparisons of hemodynamic and clinical effects between nesiritide and nitroglycerin at 24 hours.
Results At 3 hours, the mean (SD) decrease in PCWP from baseline was –5.8 (6.5) mm Hg for nesiritide (vs placebo, P<.001; vs nitroglycerin, P = .03), –3.8 (5.3) mm Hg for nitroglycerin (vs placebo, P = .09), and –2 (4.2) mm Hg for placebo. At 3 hours, nesiritide resulted in improvement in dyspnea compared with placebo (P = .03), but there was no significant difference in dyspnea or global clinical status with nesiritide compared with nitroglycerin. At 24 hours, the reduction in PCWP was greater in the nesiritide group (-8.2 mm Hg) than the nitroglycerin group (-6.3 mm Hg), but patients reported no significant differences in dyspnea and only modest improvement in global clinical status.
Conclusion When added to standard care in patients hospitalized with acutely decompensated CHF, nesiritide improves hemodynamic function and some self-reported symptoms more effectively than intravenous nitroglycerin or placebo.
INTRODUCTION
Heart failure occurs in 4.7 million persons living in the United States,1 and is the discharge diagnosis in approximately 3.5 million hospitalizations annually.2 Hospitalizations account for 60% of health care expenditures for heart failure.1-5 Despite its enormous human and economic burden, no new intravenous agents for acutely decompensated congestive heart failure (CHF) have been approved for use in the United States in more than a decade. Furthermore, the rapid relief of symptoms without significant complications or adverse effects of drug therapy have not been addressed previously in patients hospitalized with heart failure.
There is increasing recognition that agents with positive inotropic activity can increase mortality despite acute hemodynamic improvement.6-14 Current guidelines from the American College of Cardiology and the American Heart Association for management of acutely decompensated CHF and decompensation of chronic CHF without cardiogenic shock advocate use of inotropic agents (dobutamine and dopamine) only if administration of morphine, loop diuretics, sublingual and intravenous nitroglycerin, and nitroprusside provide insufficient improvement.1 Yet, intravenous inotropic agents continue to be used commonly for this syndrome.
Nesiritide is a recombinant human brain, or B-type, natriuretic peptide that is identical to the endogenous hormone produced by the ventricle in response to increased wall stress, hypertrophy, and volume overload. Nesiritide has venous, arterial, and coronary vasodilatory properties that reduce preload and afterload, increase cardiac output without direct inotropic effects, improve echocardiographic indices of diastolic function,15-17 and improve symptoms in patients with acutely decompensated CHF,18 without increasing heart rate or proarrhythmia.18-19 In addition, nesiritide has been observed to increase glomerular filtration rate and filtration fraction, suppress the renin-angiotensin-aldosterone axis, and cause natriuresis in patients with decompensated CHF.20-21
The Vasodilation in the Management of Acute CHF (VMAC) study is, to our knowledge, the first large multicenter, randomized, double-blind trial to evaluate the hemodynamic and clinical effects of a natriuretic peptide added to standard care, compared with an intravenous vasodilating agent added to standard care, for management of decompensated CHF in hospitalized patients with dyspnea at rest.
METHODS
Study Organization and Design
The VMAC trial was a prospective, multicenter trial in which the randomization was stratified based on the investigator's clinical decision, prior to randomization, to use a right heart catheter to manage decompensated CHF ("catheterized" or "noncatheterized"). Randomization occurred after patients were confirmed to meet all inclusion and exclusion criteria and informed consent was obtained. Randomization was performed using random permuted blocks within strata (catheterized or noncatheterized), with a block size of 8 for the catheterized strata and of 6 for the noncatheterized strata. Noncatheterized patients were randomly assigned to receive either placebo, nitroglycerin that could be titrated, or fixed-dose nesiritide for the first 3 hours. Catheterized patients were randomly assigned to these same 3 treatment groups or to the adjustable-dose nesiritide group. For placebo patients in both strata, the randomization included a crossover to double-blind treatment with either titratable-dose nitroglycerin or to fixed-dose nesiritide at 3 hours after the primary end points were obtained (Figure 1). Total duration of the treatment was determined by the investigator, but the minimum duration of dosing was specified as 24 hours.
|
|
|
|
Figure 1. Patient Follow-up Throughout the Vasodilation in Management of Acute CHF Trial
CHF indicates congestive heart failure.
|
|
|
The study used a double-blind, double-dummy study drug administration design in which each patient received simultaneous infusions of nitroglycerin/placebo and nesiritide/placebo. Study drug concentrations were adjusted so that the total fluid volume administered would be appropriately low for a patient with decompensated CHF, but so that the treatment groups would receive similar fluid volumes. Nesiritide (Natrecor, Scios Inc, Sunnyvale, Calif) was prepared at a concentration of 10 µg/mL and administered as a 2-µg/kg bolus followed by a fixed-dose infusion of 0.01 µg/kg per minute for 3 hours. Following the first 3 hours, the dose remained the same in the fixed-dose nesiritide group, while for the group assigned to the adjustable-dose nesiritide, investigators could incrementally increase the dose every 3 hours to a maximum of 0.03 µg/kg per minute if the pulmonary capillary wedge pressure (PCWP) was 20 mm Hg or higher and systolic blood pressure was 100 mm Hg or higher (using a 1-µg/kg bolus followed by an increase of 0.005 µg/kg per minute over the previous infusion rate). Downtitration of the nesiritide/placebo infusion flow rate by 30% was permitted according to the investigators' discretion.
Because there is no standard dose of nitroglycerin for heart failure, nitroglycerin (Tridil, DuPont Pharma, Wilmington, Del) was prepared at a concentration of 400 µg/mL, and administration was determined per investigator discretion. The nitroglycerin/placebo infusion could be uptitrated or downtitrated throughout the study to achieve the desired clinical or hemodynamic effect. If study drug was to be decreased or discontinued for any reason, both infusions were to be decreased or stopped simultaneously. Infusion flow rates of both study drugs could be increased or restarted if the patient had a stable blood pressure. In the fixed-dose nesiritide group, doses with infusions greater than 0.01 µg/kg per minute were not permitted at any time.
Study Population
Patients were included if they had dyspnea at rest due to decompensated CHF that was severe enough to require hospitalization and intravenous therapy. A cardiac etiology for dyspnea was established by estimated or measured elevation of cardiac filling pressures (PCWP  20 mm Hg in catheterized patients) and at least 2 of the following: (1) jugular venous distention, (2) paroxysmal nocturnal dyspnea or 2-pillow orthopnea within 72 hours before study entry, (3) abdominal discomfort due to mesenteric congestion, or (4) a chest x-ray film consistent with decompensated CHF. Patients may have had acute decompensation of chronic heart failure, gradual worsening of chronic heart failure, or new onset of acutely decompensated CHF. Patients who were receiving dobutamine or dopamine but who otherwise met entry criteria were also permitted into the study. Exclusion criteria were: systolic blood pressure lower than 90 mm Hg, cardiogenic shock or volume depletion, any condition that would contraindicate an intravenous vasodilator, acutely unstable clinical status that would not permit a 3-hour placebo period, use of intravenous nitroglycerin that could not be withheld, mechanical ventilation, and anticipated survival of less than 30 to 35 days. Patients with decompensated CHF in the setting of acute coronary syndromes, preserved systolic function, renal failure, or atrial or ventricular arrhythmias were not excluded based on these conditions alone. The use of intravenous vasodilators or inodilators with study drug was not permitted. The study was approved by all participating centers' institutional review boards for clinical investigation, and written informed consent was obtained from each study participant prior to study entry and randomization.
End Points and Measurements
The protocol-specified primary analysis was a comparison of the hemodynamic and clinical effects of nesiritide vs placebo when both were added to standard care. The primary end points were the absolute changes in PCWP (catheterized patients only) and the patient's self-evaluation of dyspnea (all patients) from baseline to 3 hours after the start of study drug. Secondary end points included comparisons between nesiritide and nitroglycerin of the following hemodynamic and clinical effects: onset of effect on PCWP, the effect on PCWP 24 hours after the start of study drug, self-assessed dyspnea and global clinical status, and the overall safety profile. Additional outcomes included comparison of the use of other intravenous vasoactive agents or diuretics, and the effects on other hemodynamic variables. Dyspnea and global clinical status were assessed using a nonvalidated symptom scale that is similar to the symptom scale used in a prior nesiritide trial.17
To avoid potential bias, neither the study staff nor the health care team was allowed to discuss or assist the patient in completing the symptom evaluation form (dyspnea and global clinical status). In the catheterized stratum, symptom evaluation forms were completed before hemodynamic measurements had been obtained at the same time points, and hemodynamic results were not discussed within hearing range of the patient.
During the 3-hour placebo-controlled period, PCWP and pulmonary artery pressures were measured at 15 and 30 minutes, and at 1, 2, and 3 hours in catheterized patients only. In these patients, cardiac output and mean right atrial pressure were measured at 1 and 3 hours. In all patients, vital signs and symptoms (dyspnea and global clinical evaluations) were assessed at 15 and 30 minutes, and at 1, 2, and 3 hours after the start of study drug. After 3 hours, PCWP and pulmonary artery pressure were obtained in catheterized patients at 6, 9, 12, 24, 36, and 48 hours, and when study drug was discontinued (if <48 hours). In all patients, vital signs were assessed every 3 hours for the duration of study drug infusion and at 15-minute intervals for the first hour and 30-minute intervals for the second hour after any dose change, discontinuation, or restarting of the infusion. Dyspnea and global clinical evaluations were repeated at 6 and 24 hours. Serum creatinine level was obtained at baseline, daily through 2 days after discontinuation of study drug, and at study days 14 and 30. General adverse events were assessed through study day 14. Serious adverse events other than death (hospital admissions and nonfatal, life-threatening events) were monitored through study day 30. Mortality was assessed through 6 months.
All patients who received study drug were included in the safety analysis. Symptomatic hypotension was defined prospectively as a significant decrease in blood pressure (in excess of what would be intended with an intravenous vasodilator) and was associated with 1 or more of the following symptoms: lightheadedness, dizziness, feeling faint, or having blurred vision.
Statistical Analyses
Efficacy was analyzed in all treated patients, as randomized, except for 9 patients who were randomized but not treated. These patients were excluded from the analysis because hemodynamic and symptom assessments were not performed. As no dose increases of nesiritide were permitted before 3 hours, the prespecified primary analysis evaluated during the placebo-controlled period was a comparison of the pooled nesiritide dose groups (fixed and adjustable dose) with the placebo group when added to standard care. After 3 hours, placebo patients (who crossover to double-blind, active treatment) were included in the subsequent active treatment comparisons.
For the dyspnea and global clinical status evaluations, 2 groups (nesiritide and nitroglycerin) were compared using a stratified 2-sample Wilcoxon procedure (Van Elteren test) for right heart catheter use to evaluate the following 7-point categorical responses of the patient: markedly, moderately, or minimally improved; no change; or minimally, moderately, or markedly worsened. This nonparametric analysis was prespecified as a supplemental analysis to test the robustness of the primary parametric analysis. However, because the protocol allowed for the use of standard care agents before use of the study drug and during the first 3 hours, a heightened placebo effect and a skewed distribution toward more subjects being improved was anticipated. Furthermore, post-hoc testing showing the lack of normality of the dyspnea data justifies the use of the Van Elteran test for this analysis. A parametric analysis using a 2-way analysis of variance (treatment and right heart catheter use) was also used.
A 1-way analysis of variance model was used for the analysis of mean change from baseline for PCWP and other hemodynamic measurements for catheterized patients. Means are presented with SDs, and medians are provided with interquartile ranges for hemodynamic data, unless otherwise noted.
This study was powered to demonstrate significant differences between nesiritide and placebo for PCWP evaluation among all catheterized patients and for dyspnea evaluation among all patients. Based on a 2-sample Wilcoxon procedure, a sample size of 140 in the placebo and 200 in the nesiritide treatment group had approximately 86% power to detect a treatment difference if the proportion of patients' symptoms were markedly (0% vs 5%), moderately (15% vs 20%), or minimally improved (20% vs 25%); no change (50% vs 40%); or minimally (both 5%), moderately (both 5%) or markedly worsened (5% vs 0%). The assumption of this proportion of responses reflects the anticipation that regardless of therapy, most patients' dyspnea will be improved or unchanged at 3 hours, rather than worsened; and active therapy (plus standard care) will be more effective than placebo (plus standard care). Based on the large-sample z statistic, with the assumption of a population mean (SD) decrease in PCWP of 2 (6) mm Hg in the placebo group and 5 (6) mm Hg in the nesiritide group, a pairwise contrast had 88% power with sample sizes of 60 in the placebo group and 120 in the nesiritide treatment group.
RESULTS
Patient Enrollment
Between October 1999 and July 2000, 498 patients were randomized, of which 489 were treated with study drug (143 nitroglycerin, 204 nesiritide, and 142 placebo) at 55 US study centers. Of the total 489 randomized and treated patients, 246 were in the catheterized stratum and 243 were in the noncatheterized stratum. Approximately 240 patients in each of the catheterized and noncatheterized strata were specified prior to the study (Figure 1).
Baseline Characteristics
Baseline clinical characteristics were similar among patients in the study groups (Table 1) except that more patients in the nesiritide group were men. All patients had dyspnea at rest (or New York Heart Association class IV symptoms) at study entry, 84% had chronic decompensated CHF that was classified as class III or class IV prior to decompensation, and most had clinical evidence of fluid overload (jugular venous distention in 89%, rales in 73%, and pedal edema in 73%). Other important baseline clinical findings included an acute coronary syndrome in 12%, preserved systolic function (ejection fraction >40%) in 15%, renal insufficiency (serum creatinine 2.0 mg/dL [176.8 µmol/L]) in 21%, and diabetes in 47%. Many patients had a history of significant arrhythmias including atrial fibrillation or fib/flutter (35%), nonsustained ventricular tachycardia (22%), sudden death (8%), ventricular fibrillation (6%), and sustained ventricular tachycardia (13%). The mean (SD) left ventricular ejection fraction was 27% (14%). Mean (SD) systolic blood pressure at trial entry was 121 (22) mm Hg. Ninety patients (18%) had a baseline systolic blood pressure of 100 mm Hg or lower and 107 patients (22%) had a baseline systolic blood pressure of 140 mm Hg or higher. In catheterized patients, mean PCWP was 27.8 (6.3) mm Hg and mean (SD) cardiac index was 2.2 (0.73) L/min per m2.
|
|
|
|
Table 1. Baseline Characteristics
|
|
|
The long-term use of cardiac medications also was well balanced between the nesiritide and nitroglycerin groups, with the exception that more nesiritide patients were receiving a class III antiarrhythmic at baseline (P = .02; Table 2), were given an intravenous vasoactive medication within 24 hours before study drug, and had study drug added to ongoing therapy with dobutamine or dopamine (Table 1 and Table 2).
|
|
|
|
Table 2. Baseline and Concomitant Cardiac Medication Use*
|
|
|
Dosing and Administration
The median time of study drug exposure was the same in both the nesiritide and nitroglycerin groups (24-25 hours). The percentage of nesiritide and nitroglycerin patients who received study drug for 24 to 72 hours (69% vs 71%, respectively) and more than 72 hours (6% and 5%, respectively) was also similar. During both the placebo-controlled and active-controlled periods, the nitroglycerin infusion was titrated to higher doses in catheterized patients than in noncatheterized patients. At the 3-hour time point, when the primary end points were measured, a mean (SD [median {25th, 75th percentile}]) dose of 42 (61 [13 {10, 40}]) µg/min of nitroglycerin was administered to catheterized patients, whereas a dose of 29 (38 [13 {10, 20}]) µg/min of nitroglycerin was administered to noncatheterized patients. Additional nitroglycerin uptitration from 3 to 24 hours occurred in catheterized patients (to a mean [SD {median; 25th, 75th percentile}] dose of 56 [64 {20; 13, 80}] µg/min) but not in noncatheterized patients (dose of 27 [31 {13; 7, 27}] µg/min). The titrated doses of nitroglycerin lowered blood pressure to a comparable or greater degree than nesiritide (Table 3). Nesiritide was administered as a fixed dose in most patients. Of the 62 patients randomized to the adjustable-dose group, only 23 patients had an increase in the nesiritide dose; some dose adjustments (10/23) were up to a maximum of 0.015 µg/kg per minute.
|
|
|
|
Table 3. Hemodynamic Variables: Baseline Value and Change With Treatment*
|
|
|
Efficacy
The reduction in PCWP was significantly greater in the nesiritide group than in the nitroglycerin or placebo group, starting with the first measurement at 15 minutes (Figure 2A and Table 3). Mean changes in PCWP from baseline at 3 hours were -5.8 (6.5) mm Hg for nesiritide (vs placebo, P<.001; vs nitroglycerin, P = .03), –3.8 (5.3) mm Hg for nitroglycerin (vs placebo, P = .09), and –2 (4.2) mm Hg for placebo. Nesiritide and nitroglycerin were also associated with significantly greater mean reductions in pulmonary vascular resistance than placebo at 1 hour. Nesiritide significantly reduced pulmonary vascular resistance at 3 hours (Table 3). Nesiritide was associated with greater mean reductions in mean right atrial pressure compared with placebo at 1 and 3 hours. Nitroglycerin significantly lowered mean right atrial pressure compared with placebo at 3 hours, but not at the earlier time points (Table 3). Nesiritide, but not nitroglycerin, significantly increased cardiac index and lowered systemic vascular resistance at 1 hour compared with placebo. There were no differences in change in cardiac index among nesiritide, nitroglycerin, or placebo groups at 3 hours (Table 3). Effects on systolic blood pressure through 3 hours were similar with nesiritide and nitroglycerin (Table 3). Nesiritide also was associated with greater mean reductions in systolic and mean pulmonary artery pressure than both nitroglycerin and placebo at every time point through 3 hours (data not shown). There were no significant differences between nitroglycerin and placebo in reductions in systolic or mean pulmonary artery pressure at any time point through 3 hours.
|
|
|
|
Figure 2. Changes From Baseline in Pulmonary Capillary Wedge Pressure
Asterisk indicates P<.05 for nesiritide or nitroglycerin compared with placebo; dagger, P<.05 for nesiritide compared with nitroglycerin.
|
|
|
At 24 hours, the mean (SD) reduction in PCWP was significantly greater with nesiritide (-8.2 mm Hg) than nitroglycerin (-6.3 mm Hg) (P = .04), with no evidence of attenuation of effect (Figure 2B). At 36 and 48 hours, there were no significant differences in PCWP reduction in the nesiritide and nitroglycerin groups, but PCWP was obtained in only about 50% of catheterized patients at 36 hours and in only a third of patients at 48 hours. At 24 hours, the mean decreases in systolic blood pressure were not significantly different in the nesiritide and nitroglycerin groups (–8.7 and –8.1 mm Hg, respectively, P = .54).
The differences between nesiritide and placebo or nitroglycerin in the effect on PCWP are not explained by the higher percentage of nesiritide patients who had study drug added to ongoing therapy with dobutamine or dopamine. Among patients who were not receiving ongoing dobutamine or dopamine therapy, the 3-hour mean (SD) change in PCWP was -3.4 (5.4) mm Hg for nitroglycerin (n = 51; nitroglycerin vs placebo, P = .15); -6.5 (6.8) mm Hg for nesiritide (n = 99; nesiritide vs nitroglycerin, P = .004); and -1.7 (4.4) mm Hg for placebo (n = 48; nesiritide vs placebo, P<.001).
The second primary end point (Figure 3A), the patient's self-assessment of dyspnea at 3 hours, was significantly improved in the nesiritide group compared with the placebo group (P = .03), although improvement in dyspnea scores in the nesiritide and nitroglycerin groups were not significantly different (P = .56). At 3 hours (Figure 3B), there were no significant differences in improvement in global clinical status in the nesiritide group compared with the nitroglycerin group (P = .55) or the placebo group (P = .07).
|
|
|
|
Figure 3. Outcomes at 3 and 24 Hours for All Treated Patients by Randomization Group
|
|
|
During the first 24 hours of treatment, there was evidence of progressive improvement in dyspnea and global clinical status over time with both active infusions. No significant differences were found between the nesiritide and nitroglycerin group for dyspnea at 24 hours (P = .13; Figure 3C). For the global clinical status in all patients, using a parametric analysis, nesiritide, when compared with nitroglycerin, was associated with significant improvement at 24 hours (2-way analysis of variance, P = .04), but showed a nonsignificant trend toward improvement when nonparametric analysis was used (Van-Elteren test, P = .08; Figure 3D).
Safety
During the placebo-controlled period, any adverse event occurred in 39 (27%) nitroglycerin, 36 (18%) nesiritide, and 20 (14%) placebo patients (Fisher exact test, P = .02); headache in 17 (12%) nitroglycerin, 11 (5%) nesiritide, and 3 (2%) placebo patients (P = .003); and abdominal pain in 4 (3%) nitroglycerin patients only (P = .01) (Table 4). There were significantly fewer adverse events in nesiritide patients than nitroglycerin patients during the placebo-controlled period (Fisher exact test; P = .04).
|
|
|
|
Table 4. Adverse Events During First 24 Hours After Start of Study Drug
|
|
|
During the first 24 hours after the start of nitroglycerin, headache (20%) was the most common adverse event reported. During the first 24 hours of treatment with nesiritide, headache (8%) occurred significantly less frequently than with nitroglycerin (Fisher exact test, P<.001; Table 4). There were no significant differences in the frequency or severity of ischemic events, asymptomatic or symptomatic hypotension or arrhythmias between nitroglycerin and nesiritide groups in the first 24 hours. Symptomatic hypotension occurred in 5% of nitroglycerin patients and in 4% of nesiritide patients. Angina occurred in 2% of patients in each of the nitroglycerin and nesiritide groups. Most hypotension events were mild or moderate; 1 patient in each treatment group experienced an event that was classified as severe. Most events resolved either spontaneously or with an intravenous volume challenge of 250 mL (or less). Duration of hypotension events was significantly longer with nesiritide, as expected due to its longer half-life than that of nitroglycerin (18-minute half-life for nesiritide22 and 2.5-minute half-life for nitroglycerin23). The mean duration of symptomatic hypotension was 2.2 hours for nesiritide and 0.7 hours for nitroglycerin (2-sample Wilcoxon test; P = .002). No event of symptomatic hypotension led to adverse sequelae in either treatment group.
Through 30 days, there were 3 myocardial infarctions reported in nitroglycerin patients and 2 in nesiritide patients. Through 30 days, there were no significant differences in the frequency of serious adverse events or pattern of changes in serum creatinine that occurred in nitroglycerin or nesiritide patients. Through 30 days, 48 (23%) nitroglycerin and 50 (20%) nesiritide patients were readmitted to the hospital for any cause (Fisher exact test, P = .36). Readmission for acutely decompensated CHF occurred in 27 (13%) nitroglycerin and 20 (7%) nesiritide patients. Through 7 days, deaths occurred in 1 (0.5%) nitroglycerin and 4 (1.5%) nesiritide patients. None of these deaths was believed to be due to either study drug. There was no significant difference in 6-month mortality for nitroglycerin 20.8% (95% confidence interval, 15.5%-26.5%) vs nesiritide patients 25.1% (95% confidence interval, 20.0%-30.5%; P = .32).
COMMENT
The VMAC trial is, to our knowledge, the first trial in patients with acutely decompensated CHF to demonstrate efficacy of a new drug class (nesiritide, B-type natriuretic peptide) when added to standard care in comparison with both placebo and nitroglycerin. This randomized, double-blind trial enrolled severely ill patients with acutely decompensated CHF and dyspnea at rest and many clinically important comorbidities including acute coronary syndromes, atrial and ventricular arrhythmias, preserved systolic function, and renal insufficiency.
The VMAC trial design reflects the balance between the need to obtain efficacy data pertaining to both hemodynamic and clinical benefit and to do so in a heterogeneous, critically ill patient population that is already receiving standard care medications. Three hours was chosen as the primary end point to allow enough time for an additive symptom effect to occur between an active agent (plus standard care) and the anticipated high rate of early symptom improvement in patients who received placebo (plus standard care). Due to the severity of illness in the intended patient population, it was deemed unethical by the investigator to treat patients with placebo for more than 3 hours or to insist on discontinuation of baseline standard therapies, including intravenous diuretics and inotropic agents. To compare a fixed-dose regimen of nesiritide with a standard dosing regimen of nitroglycerin (ie, titrated regimen) in a double-blinded fashion, a double-dummy study drug administration design was used. Because there is no standard dose or dosing range for nitroglycerin for decompensated heart failure, all dosing of nitroglycerin was left to the investigators' discretion. As the first large decompensated CHF study in which clinical symptoms (rather than hemodynamics alone) were a primary end point, we created a customized categorical dyspnea scale in which patients were required to have dyspnea at rest at baseline.
This trial demonstrated that nesiritide significantly reduced PCWP more than standard care plus nitroglycerin or placebo, and these effects were sustained for at least 24 hours. At 3 hours, nesiritide (when added to standard care) also led to a significant improvement in dyspnea compared with placebo (a prespecified primary end point), but not a significant improvement compared with nitroglycerin. Because patients were concomitantly receiving other drugs (such as intravenous diuretics) to ameliorate their symptoms, improvement was generally expected in all treatment groups. The adverse effect profile of nesiritide was similar to that of nitroglycerin, except for headache and abdominal pain, which occurred more commonly with nitroglycerin.
In comparison with prior trials of nesiritide in decompensated CHF, the dose of nesiritide used in VMAC (2-µg/kg bolus followed by a 0.01-µg/kg per minute infusion) used a larger bolus dose and a lower infusion dose than previously studied doses. The dosing regimen of nesiritide in VMAC was selected from other candidate dosing regimens using a pharmacokinetic/pharmacodynamic model that predicted the following effects compared with a previously studied dosing regimen: a more rapid onset of effect on PCWP and systolic blood pressure, a sustained effect on PCWP over at least 24 hours, and less effect on systolic blood pressure than higher infusion doses.24 In this study, this dose was effective at improving hemodynamics and symptoms and was associated with less hypotension than has been observed at higher doses.18 When investigators had the opportunity to increase the nesiritide dose, only 23 of 62 adjustable-dose nesiritide patients underwent an increase in the dose, suggesting that the initial dosing regimen was effective in most patients.
The VMAC trial is the largest and most comprehensive evaluation of intravenous nitroglycerin in decompensated CHF. Nitroglycerin is a commonly used intravenous agent for decompensated CHF because it leads to beneficial hemodynamic actions, is well tolerated without proarrhythmic effects, and prevents worsening of ischemic events. In VMAC, the hemodynamic effects of intravenous nitroglycerin were significantly less, and symptomatic effects were similar, but less pronounced, than those observed with nesiritide during the first 24 hours. It is possible that better and more rapid amelioration of hemodynamic abnormalities could have occurred if higher doses of intravenous nitroglycerin were used. However, the investigator-chosen doses used in this trial were within the dose ranges described in other clinical heart failure studies,25-30 recommended by the current American College of Cardiology/American Heart Association guidelines for management of acutely decompensated CHF.1 Nitroglycerin was pharmacologically active at the doses studied in VMAC as evidenced by the rate of headache (20%) and the effect of nitroglycerin on blood pressure.
Results of the VMAC trial also are useful in distinguishing the role of natriuretic peptides, vasodilators, and inotropes as therapy for acutely decompensated CHF. As VMAC characterized the relative efficacy and safety profiles of nitroglycerin and nesiritide, both of which have vasodilating properties, VMAC also confirmed that these agents do not lead to life-threatening arrhythmias or ischemic events. The hemodynamic and symptom improvement with nesiritide, coupled with a safety profile similar to that of nitroglycerin, suggests that the use of nesiritide may decrease the role of inotropes in the treatment for acutely decompensated CHF.
In this study of patients with acutely decompensated CHF, nesiritide resulted in improvement in hemodynamics and some self-reported symptoms more effectively and with fewer adverse effects than intravenous nitroglycerin. This trial suggests that nesiritide, in addition to diuretics (intravenous and/or oral), is a useful addition to initial therapy of patients hospitalized with acutely decompensated CHF.
AUTHOR INFORMATION
Author Contributions: Dr Young, as principal investigator, had full access to all of the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Young, Abraham, Warner Stevenson, Horton, Elkayam, Bourge.
Acquisition of data: Young, Abraham, Warner Stevenson, Horton, Elkayam, Bourge.
Analysis and interpretation of data: Young, Abraham, Warner Stevenson, Horton, Elkayam.
Drafting of the manuscript: Young, Abraham, Horton.
Critical revision of the manuscript for important intellectual content: Young, Abraham, Warner Stevenson, Horton, Elkayam, Bourge.
Statistical expertise: Horton.
Obtained funding: Horton.
Administrative, technical, or material support: Young, Horton.
Study supervision: Young, Abraham, Warner Stevenson, Horton, Elkayam, Bourge.
Funding/Support: This trial was funded by a grant from Scios Inc, Sunnyvale, Calif.
Role of the Sponsor: The study sponsor used a steering committee of academic advisors, with Dr Young as chairman of the committee, who were intimately involved in the preparation and design of the trial. The sponsor was involved in monitoring the study in accordance with federal regulations and good clinical research practices. The sponsor analyzed the database with input from the steering committee. Dr Young was involved in all aspects of the analysis and interpretation of data as well as preparation, review, and approval of the manuscript. Dr Young had complete control of the contents of the manuscript.
Financial Disclosures: Drs Warner Stevenson, Elkayam, and Young are consultants for Scios Inc.
Corresponding Author and Reprints: James B. Young, MD, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave/F25, Cleveland, OH 44195 (e-mail: youngj{at}ccf.org).
VMAC Committees, Investigators, and Centers: Publication Committee: James B. Young, Cleveland Clinic Foundation; William T. Abraham, University of Kentucky, Lexington; Lynne Warner Stevenson, Brigham and Women's Hospital; Darlene P. Horton, Scios Inc; Uri Elkayam, Los Angeles County-USC Medical Center; Robert C. Bourge, University of Alabama, Birmingham. Steering Committee: James B. Young (chairperson), Cleveland Clinic Foundation; William T. Abraham, University of Kentucky, Lexington; Lynne Warner Stevenson, Brigham and Women's Hospital; Charles L. Emerman, MetroHealth Medical Center; Darlene P. Horton (sponsor representative). Statistical Analysis: Mei L. Cheng, Scios Inc. Nesiritide Pharmacokinetic/Pharmacodynamic Modeling: Nancy Sambol, University of California, San Francisco. Investigators and Centers (in alphabetical order by center): Albert Einstein Hospital (Thierry LeJemtel); Baylor College of Medicine (Guillermo Torre); Beth Israel Deaconess Medical Center (Andrew Burger); Buxmont Cardiology Associates, Lifemark Medical Center (Mitchell Greenspan); Cardiac Centers of LA at Willis Knighton Heart Institute (Jalal Ghali); Cardiology Associates of Gainesville (Steven F. Roark); Cardiovascular Medicine of Virginia at Pratt Medical Center Ltd (Robert Vranian); Cardiovascular Research Institute of Dallas (Martin Berk); Cardiovascular Research Institute of Southern California (Ronald Karlsberg); Care Group (Mary N. Walsh); Christ Hospital and Medical Center (Marc A. Silver); Community Hospital East (Edward Harlamert); Dartmouth Hitchcock Medical Center (Bruce D. Hettleman); Dorn Research Institute (Constantine Hassapoyannes); Durham VA Medical Center (Frederick R. Cobb); George Washington University Medical Center (Jacob Varghese); HeartCare Midwest (Alan Chu); Heart Center, Huntsville Hospital (W. Herbert Haught); Heart Institute of St Petersburg (Michael E. McIvor, Gregg Schuyler); Hennepin County Medical Center (Steven R. Goldsmith); Hillsboro Cardiology (Steven Promisloff); Jacksonville Center for Clinical Research (Michael Koren); Jacksonville Heart Center (Jay Dinerman); Johns Hopkins Hospital (Joshua Hare); Los Angeles County-USC Medical Center (Uri Elkayam); Med-Tech Research Inc (Salah El Hafi); Medical Research Consortium at Winona Memorial Hospital (Jack Hall); MediQuest Research Group Inc (Robert Feldman); Montefiore Medical Center (Robert Moskowitz); Mount Sinai Medical Center (Marrick Kukin, Gervasio Lamas); Northwestern Memorial Hospital (William Cotts); Oregon Health Sciences University (Ray Hershberger); Roudebush VA Medical Center (Lincoln E. Ford); Rush-Presbyterian-St Luke's Medical Center (Walter Kao); St Paul Heart Clinic (Alan J. Bank); San Diego Cardiac Center (Peter M. Hoagland); San Diego Cardiovascular Research Associates (George Dennish); Scripps Clinic, Heart, Lung, Vascular Center (Allen D. Johnson); Stern Cardiovascular Center (Frank A. McGrew); University of Alabama at Birmingham (Mark F. Aaron, Robert C. Bourge); University of Arizona Health Sciences Center (Charles Y. Lui); University of California, San Francisco Medical Center (Teresa DeMarco); James A. Haley Veterans Hospital, Tampa, Fla (Doug Schocken); University of Cincinnati Medical Center (Lynne Wagoner); University of Florida Medical Center, Jacksonville (Alan B. Miller); University of Florida Health Sciences Center, Gainesville (James A. Hill); University of Iowa Hospitals and Clinics (Ron M. Oren); University of Kansas Medical Center (David Wilson); University of Louisville Research Foundation (Geetha Bhat); University of Maryland Medical System (Stephen S. Gottlieb); University of Miami/Jackson Memorial Medical Center (Stephen M. Mallon); University of Missouri Health Sciences Center (Hanumanth Reddy); University of Rochester Medical Center (Chang-seng Liang); University of South Dakota School of Medicine (Kevin Vaska); University of Washington Medical Center (Daniel Fishbein); Vanderbilt University Medical Center (John R. Wilson); VA Medical Center IIIB (A. Maziar Zafari); Watson Clinic (Kevin Browne).
REFERENCES
| |
1. Williams J, Bristow M, Fowler M, et al. Guidelines for the evaluation and management of heart failure. J Am Coll Cardiol. 1995;26:1376-1398.
ISI
| PUBMED
2. Graves E, Gillum B. 1994 Summary: National Hospital Discharge Survey: Advance Data. Atlanta, Ga: National Center for Health Statistics; 1996:17.
3. Brophy JM, Deslauriers G, Boucher B, Rouleau JL. The hospital course and short-term prognosis of patients presenting to the emergency room with decompensated congestive heart failure. Can J Cardiol. 1993;9:219-224.
ISI
| PUBMED
4. Rame JE, Sheffield MA, Dries DL, et al. Outcomes Following Discharge From an Urban County Hospital Emergency Room With a Primary Diagnosis of Heart Failure. Orlando, Fla: American College of Cardiology; 2001. Presentation 3.
5. Konstam M, Dracup K, Baker D. Heart Failure: Evaluation and Care of Patients With Left Ventricular Systolic Dysfunction. Rockville, Md: Agency for Health Care Policy and Research; 1994.
6. Dies F, Krell M, Whitlow P. Intermittent, ambulatory dobutamine infusion in severe chronic cardiac failure. Br J Clin Pract. 1986;40:37-39.
7. Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet. 1990;336:1-6.
FULL TEXT
|
ISI
| PUBMED
8. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med. 1991;325:1468-1475.
ABSTRACT
9. Packer M, Medina N, Yushak M. Failure of low doses of amrinone to produce sustained hemodynamic improvement in patients with severe chronic congestive heart failure. Am J Cardiol. 1984;54:1025-1029.
FULL TEXT
|
ISI
| PUBMED
10. Feldman AM, Bristow MR, Parmley WW, et al. Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med. 1993;329:149-155.
FREE FULL TEXT
11. Califf R, Adams K, McKenna W, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure. Am Heart J. 1997;134:44-54.
FULL TEXT
|
ISI
| PUBMED
12. Packer M. Sudden unexpected death in patients with congestive heart failure: a second frontier. Circulation. 1985;72:681-685.
FREE FULL TEXT
13. Massie BM, Berk MR, Brozena SC, et al. Can further benefit be achieved by adding flosequinan to patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an angiotensin converting enzyme inhibitor? Circulation. 1993;88:492-501.
FREE FULL TEXT
14. Clarkson PB, Wheeldon NM, MacFadyen RJ, et al. Effects of brain natriuretic peptide on exercise hemodynamics and neurohormones in isolated diastolic heart failure. Circulation. 1996;93:2037-2042.
FREE FULL TEXT
15. Clarkson PB, Wheeldon NM, Macleod C, Coutie W, MacDonald TM. Brain natriuretic peptide. Clin Sci (Colch). 1995;88:159-164.
PUBMED
16. Zellner C, Protter A, Ko E, et al. Coronary vasodilator effects of BNP. Am J Physiol. 1999;276:H1049-H1057.
17. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med. 2000;343:246-253.
FREE FULL TEXT
18. Burger A, Dennish G, Horton D, Koren M, Torre G. Nesiritide therapy for decompensated CHF is not proarrhythmic. J Am Coll Cardiol. 2000;35:172.
19. Jensen KT, Eiskjaer H, Carstens J, Pedersen EB. Renal effects of brain natriuretic peptide in patients with congestive heart failure. Clin Sci (Colch). 1999;96:5-15.
PUBMED
20. Chen HH, Grantham JA, Schirger JA, Jougasaki M, Redfield MM, Burnett JC Jr. Subcutaneous administration of brain natriuretic peptide in experimental heart failure. J Am Coll Cardiol. 2000;36:1706-1712.
FREE FULL TEXT
21. Hobbs RE, Mills RM. Therapeutic potential of nesiritide (recombinant b-type natriuretic peptide) in the treatment of heart failure. Exp Opinion Invest Drugs. 1999;8:1063-1072.
22. Kirsten R, Nelson K, Kirsten D, Heintz B. Clinical pharmacokinetics of vasodilators, part II. Clin Pharmacokinet. 1998;35:9-36.
FULL TEXT
|
ISI
| PUBMED
23. Sambol NC, Liu CY, Horton DP. Simulations of Pulmonary Capillary Wedge Pressure (PCWP) and Systolic Blood Pressure (SBP) with various regimens of nesiritide. Clin Pharmacol Ther. 2001;69:90.
24. Dupuis J, Lalonde G, Lebeau R, Bichet D, Rouleau JL. Sustained beneficial effect of a seventy-two hour IV infusion of nitroglycerin in patients with severe chronic congestive heart failure. Am Heart J. 1990;120:625-637.
FULL TEXT
|
ISI
| PUBMED
25. Larsen AI, Goransson L, Aarsland T, Tamby JF, Dickstein K. Comparison of the degree of hemodynamic tolerance during IV infusion of nitroglycerin versus nicorandil in patients with congestive heart failure. Am Heart J. 1997;134:435-441.
FULL TEXT
|
ISI
| PUBMED
26. Earl GL, Stanek EJ, Spinler SA. IV nitroglycerin tolerance in patients with ischemic cardiomyopathy and congestive heart failure. Pharmacotherapy. 1998;18:203-209.
ISI
| PUBMED
27. Natarajan D, Khurana TR, Karhade V, Nigam PD. Sustained hemodynamic effects with therapeutic doses of IV nitroglycerin in congestive heart failure. Am J Cardiol. 1988;62:319-321.
FULL TEXT
|
ISI
| PUBMED
28. Young JB, Pratt CM, Farmer JA, et al. Specialized delivery systems for intravenous nitroglycerin: are they necessary? Am J Med. 1984;76:27-37.
FULL TEXT
|
ISI
| PUBMED
29. Bayley S, Valentine H, Bennett ED. The haemodynamic responses to incremental doses of intravenous nitroglycerin in left ventricular failure. Intensive Care Med. 1984;10:139-145.
FULL TEXT
|
ISI
| PUBMED
30. Armstrong PW, Watts DG, Moffat JA. Steady-state pharmacokinetic haemodynamic studies of intravenous nitroglycerin in congestive cardiac failure. Br J Clin Pharmacol. 1983;16:385-390.
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED LETTER
Nesiritide vs Nitroglycerin for Decompensated Congestive Heart Failure
Scott Dunavant, William Rifkin, and James B. Young
JAMA. 2002;288(5):571-573.
EXTRACT
| FULL TEXT
RELATED ARTICLES
Short-term Intravenous Milrinone for Acute Exacerbation of Chronic Heart Failure: A Randomized Controlled Trial
Michael S. Cuffe, Robert M. Califf, Kirkwood F. Adams, Jr, Raymond Benza, Robert Bourge, Wilson S. Colucci, Barry M. Massie, Christopher M. O'Connor, Ileana Pina, Rebecca Quigg, Marc A. Silver, Mihai Gheorghiade, and for the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure Investigators
JAMA. 2002;287(12):1541-1547.
ABSTRACT
| FULL TEXT
Treatment of Acute Heart Failure: Out With the Old, In With the New
Philip A. Poole-Wilson
JAMA. 2002;287(12):1578-1580.
EXTRACT
| FULL TEXT
March 27, 2002
JAMA. 2002;287(12):1587-1588.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
The impact of early standard therapy on dyspnoea in patients with acute heart failure: the URGENT-dyspnoea study
Mebazaa et al.
Eur Heart J 2009;0:ehp458v1-ehp458.
ABSTRACT
| FULL TEXT
Pharmacists' role in facilitating evidence-based prescribing for unlabeled use of medications
Macaulay et al.
Am J Health Syst Pharm 2009;66:1735-1739.
FULL TEXT
Effects of tolvaptan on dyspnoea relief from the EVEREST trials
Pang et al.
Eur Heart J 2009;30:2233-2240.
ABSTRACT
| FULL TEXT
Therapeutic potential of infused cardiac natriuretic peptides in myocardial infarction
Richards
Heart 2009;95:1299-1300.
FULL TEXT
Intravenous therapy for hypertensive emergencies, part 1
Rhoney and Peacock
Am J Health Syst Pharm 2009;66:1343-1352.
ABSTRACT
| FULL TEXT
Prolonged effects of B-type natriuretic peptide infusion on cardiac remodeling after sustained myocardial injury
George et al.
Am. J. Physiol. Heart Circ. Physiol. 2009;297:H708-H717.
ABSTRACT
| FULL TEXT
Palliative care in congestive heart failure.
Goodlin
J Am Coll Cardiol 2009;54:386-396.
ABSTRACT
| FULL TEXT
Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide
Pan et al.
Proc. Natl. Acad. Sci. USA 2009;106:11282-11287.
ABSTRACT
| FULL TEXT
Are BNP Changes During Hospitalization for Heart Failure a Reliable Surrogate for Predicting the Effects of Therapies on Post-Discharge Mortality?
Gheorghiade and Pang
J Am Coll Cardiol 2009;53:2349-2352.
FULL TEXT
End points for clinical trials in acute heart failure syndromes.
Allen et al.
J Am Coll Cardiol 2009;53:2248-2258.
ABSTRACT
| FULL TEXT
Cinaciguat (BAY 58-2667) Improves Cardiopulmonary Hemodynamics in Patients With Acute Decompensated Heart Failure
Lapp et al.
Circulation 2009;119:2781-2788.
ABSTRACT
| FULL TEXT
Soluble Guanylate Cyclase: Not a Dull Enzyme
Boerrigter and Burnett
Circulation 2009;119:2752-2754.
FULL TEXT
Pharmacodynamics of a Novel Designer Natriuretic Peptide, CD-NP, in a First-in-Human Clinical Trial in Healthy Subjects
Lee et al.
J Clin Pharmacol 2009;49:668-673.
ABSTRACT
| FULL TEXT
2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation
Hunt et al.
J Am Coll Cardiol 2009;53:e1-e90.
FULL TEXT
2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation
Jessup et al.
J Am Coll Cardiol 2009;53:1343-1382.
FULL TEXT
2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in Collaboration With the International Society for Heart and Lung Transplantation
2009 WRITING GROUP TO REVIEW NEW EVIDENCE AND UPDA et al.
Circulation 2009;119:1977-2016.
FULL TEXT
2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in Collaboration With the International Society for Heart and Lung Transplantation
2005 WRITING COMMITTEE MEMBERS et al.
Circulation 2009;119:e391-e479.
FULL TEXT
Acute heart failure syndromes.
Gheorghiade and Pang
J Am Coll Cardiol 2009;53:557-573.
ABSTRACT
| FULL TEXT
Acute heart failure syndromes in patients with coronary artery disease early assessment and treatment.
Flaherty et al.
J Am Coll Cardiol 2009;53:254-263.
ABSTRACT
| FULL TEXT
Heart Failure and Cardiac Pulmonary Edema
Hollenberg
ACCP Crit Care Med Brd Rev 2009;20:117-128.
FULL TEXT
Acute Hemodynamic Effects of Tolvaptan, a Vasopressin V2 Receptor Blocker, in Patients With Symptomatic Heart Failure and Systolic Dysfunction: An International, Multicenter, Randomized, Placebo-Controlled Trial
Udelson et al.
J Am Coll Cardiol 2008;52:1540-1545.
ABSTRACT
| FULL TEXT
Assessment of renal hemodynamic effects of nesiritide in patients with heart failure using intravascular Doppler and quantitative angiography.
Elkayam et al.
J Am Coll Cardiol Img 2008;1:765-771.
ABSTRACT
| FULL TEXT
Hemodynamic Effects and Safety of Nesiritide in Neonates with Heart Failure
Simsic et al.
J Intensive Care Med 2008;23:389-395.
ABSTRACT
Effects of Continuous Aortic Flow Augmentation in Patients With Exacerbation of Heart Failure Inadequately Responsive to Medical Therapy: Results of the Multicenter Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy (MOMENTUM)
Greenberg et al.
Circulation 2008;118:1241-1249.
ABSTRACT
| FULL TEXT
Preliminary Experience With Nesiritide in Pediatric Patients Less Than 12 Months of Age
Ryan et al.
J Intensive Care Med 2008;23:321-328.
ABSTRACT
Clinical trials update from Heart Rhythm 2008 and Heart Failure 2008: ATHENA, URGENT, INH study, HEART and CK-1827452
Coletta et al.
Eur J Heart Fail 2008;10:917-920.
ABSTRACT
| FULL TEXT
Arginine Vasopressin Antagonists for the Treatment of Heart Failure and Hyponatremia
Finley et al.
Circulation 2008;118:410-421.
FULL TEXT
Vasodilator therapy for decompensated heart failure.
Yancy
J Am Coll Cardiol 2008;52:208-210.
FULL TEXT
Design, Synthesis, and Actions of a Novel Chimeric Natriuretic Peptide: CD-NP.
Lisy et al.
J Am Coll Cardiol 2008;52:60-68.
ABSTRACT
| FULL TEXT
Effect of atrial natriuretic peptide on left ventricular remodelling in patients with acute myocardial infarction
Kasama et al.
Eur Heart J 2008;29:1485-1494.
ABSTRACT
| FULL TEXT
The Tumultuous Journey of Nesiritide: Past, Present, and Future
Burnett and Korinek
Circ Heart Fail 2008;1:6-8.
FULL TEXT
Safety and Efficacy of Outpatient Nesiritide in Patients With Advanced Heart Failure: Results of the Second Follow-Up Serial Infusions of Nesiritide (FUSION II) Trial
Yancy et al.
Circ Heart Fail 2008;1:9-16.
ABSTRACT
| FULL TEXT
B-type natriuretic peptide infusions in acute myocardial infarction
Hillock et al.
Heart 2008;94:617-622.
ABSTRACT
| FULL TEXT
Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis
Peacock et al.
Emerg. Med. J. 2008;25:205-209.
ABSTRACT
| FULL TEXT
A proposal to standardize dyspnoea measurement in clinical trials of acute heart failure syndromes: the need for a uniform approach
Pang et al.
Eur Heart J 2008;29:816-824.
ABSTRACT
| FULL TEXT
Contemporary Trends in the Pharmacological and Extracorporeal Management of Heart Failure: A Nephrologic Perspective
Kazory and Ross
Circulation 2008;117:975-983.
ABSTRACT
| FULL TEXT
Overview of emerging pharmacologic agents for acute heart failure syndromes
De Luca et al.
Eur J Heart Fail 2008;10:201-213.
ABSTRACT
| FULL TEXT
Effects of Tezosentan on Symptoms and Clinical Outcomes in Patients With Acute Heart Failure: The VERITAS Randomized Controlled Trials
McMurray et al.
JAMA 2007;298:2009-2019.
ABSTRACT
| FULL TEXT
Impact of Nesiritide on Renal Function in Patients With Acute Decompensated Heart Failure and Pre-Existing Renal Dysfunction: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Witteles et al.
J Am Coll Cardiol 2007;50:1835-1840.
ABSTRACT
| FULL TEXT
Effect of nesiritide on renal function in patients admitted for decompensated heart failure
Arora et al.
QJM 2007;100:699-706.
ABSTRACT
| FULL TEXT
Biomarkers in Heart Failure: Does Prognostic Utility Translate to Clinical Futility?
Maisel
J Am Coll Cardiol 2007;50:1061-1063.
FULL TEXT
Intermittent Outpatient Nesiritide Infusion Reduces Hospital Admissions in Patients With Advanced Heart Failure
Schwarz et al.
J CARDIOVASC PHARMACOL THER 2007;12:232-236.
ABSTRACT
Nesiritide and renal function after cardiac surgery
Dunn and Sachak
Am J Health Syst Pharm 2007;64:1582-1584.
FULL TEXT
Levosimendan vs Dobutamine for Patients With Acute Decompensated Heart Failure: The SURVIVE Randomized Trial
Mebazaa et al.
JAMA 2007;297:1883-1891.
ABSTRACT
| FULL TEXT
Immunoreactivity and Guanosine 3',5'-Cyclic Monophosphate Activating Actions of Various Molecular Forms of Human B-Type Natriuretic Peptide
Heublein et al.
Hypertension 2007;49:1114-1119.
ABSTRACT
| FULL TEXT
Effect of Nesiritide Infusion Duration on Renal Function in Acutely Decompensated Heart Failure Patients
Chow et al.
The Annals of Pharmacotherapy 2007;41:556-561.
ABSTRACT
| FULL TEXT
Effects of Oral Tolvaptan in Patients Hospitalized for Worsening Heart Failure: The EVEREST Outcome Trial
Konstam et al.
JAMA 2007;297:1319-1331.
ABSTRACT
| FULL TEXT
Short-term Clinical Effects of Tolvaptan, an Oral Vasopressin Antagonist, in Patients Hospitalized for Heart Failure: The EVEREST Clinical Status Trials
Gheorghiade et al.
JAMA 2007;297:1332-1343.
ABSTRACT
| FULL TEXT
Alternate Circulating Pro-B-Type Natriuretic Peptide and B-Type Natriuretic Peptide Forms in the General Population
Lam et al.
J Am Coll Cardiol 2007;49:1193-1202.
ABSTRACT
| FULL TEXT
Management of acute decompensated heart failure
Allen and O'Connor
CMAJ 2007;176:797-805.
ABSTRACT
| FULL TEXT
Acute Phosphodiesterase 5 Inhibition Mimics Hemodynamic Effects of B-Type Natriuretic Peptide and Potentiates B-Type Natriuretic Peptide Effects in Failing But Not Normal Canine Heart
Forfia et al.
J Am Coll Cardiol 2007;49:1079-1088.
ABSTRACT
| FULL TEXT
Nesiritide Administration in Patients With Left Ventricular Dysfunction Undergoing Coronary Artery Bypass Surgery
Belenkie
J Am Coll Cardiol 2007;49:727-728.
FULL TEXT
Effects of Perioperative Nesiritide in Patients With Left Ventricular Dysfunction Undergoing Cardiac Surgery: The NAPA Trial
Mentzer et al.
J Am Coll Cardiol 2007;49:716-726.
ABSTRACT
| FULL TEXT
Emerging Therapies for the Management of Decompensated Heart Failure: From Bench to Bedside
deGoma et al.
J Am Coll Cardiol 2006;48:2397-2409.
ABSTRACT
| FULL TEXT
Risk of worsening renal function with nesiritide following cardiac surgery
Kristeller et al.
Am J Health Syst Pharm 2006;63:2351-2353.
ABSTRACT
| FULL TEXT
Haemodynamic and clinical effects of ularitide in decompensated heart failure
Mitrovic et al.
Eur Heart J 2006;27:2823-2832.
ABSTRACT
| FULL TEXT
Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure.
Gheorghiade et al.
JAMA 2006;296:2217-2226.
ABSTRACT
| FULL TEXT
Intact acute cardiorenal and humoral responsiveness following chronic subcutaneous administration of the cardiac peptide BNP in experimental heart failure
Chen et al.
Eur J Heart Fail 2006;8:681-686.
ABSTRACT
| FULL TEXT
Clinical profile, contemporary management and one-year mortality in patients with severe acute heart failure syndromes: The EFICA study
Zannad et al.
Eur J Heart Fail 2006;8:697-705.
ABSTRACT
| FULL TEXT
Use of nesiritide before and after publications suggesting drug-related risks in patients with acute decompensated heart failure.
Hauptman et al.
JAMA 2006;296:1877-1884.
ABSTRACT
| FULL TEXT
Risk of death associated with nesiritide in patients with acutely decompensated heart failure.
Aaronson and Sackner-Bernstein
JAMA 2006;296:1465-1466.
FULL TEXT
Nesiritide: trials and tribulations.
Arora
J CARDIOVASC PHARMACOL THER 2006;11:165-169.
ABSTRACT
Perioperative management of chronic heart failure.
Groban and Butterworth
Anesth. Analg. 2006;103:557-575.
ABSTRACT
| FULL TEXT
Clinical application of the natriuretic peptides in heart failure
Chen and Burnett
Eur Heart J Suppl 2006;8:E18-E25.
ABSTRACT
| FULL TEXT
Bronchodilator effect of infused B-type natriuretic Peptide in asthma.
Akerman et al.
Chest 2006;130:66-72.
ABSTRACT
| FULL TEXT
The rise and fall of Natrecor for congestive heart failure: implications for drug policy.
Kesselheim et al.
Health Aff (Millwood) 2006;25:1095-1102.
ABSTRACT
| FULL TEXT
Relevance of Brain Natriuretic Peptide in Preload-Dependent Regulation of Cardiac Sarcoplasmic Reticulum Ca2+ ATPase Expression
Kogler et al.
Circulation 2006;113:2724-2732.
ABSTRACT
| FULL TEXT
Nonhypotensive Low-Dose Nesiritide Has Differential Renal Effects Compared With Standard-Dose Nesiritide in Patients With Acute Decompensated Heart Failure and Renal Dysfunction
Riter et al.
J Am Coll Cardiol 2006;47:2334-2335.
FULL TEXT
Nesiritide: The Latest Drug for Treating Heart Failure
Fontana
Crit Care Nurse 2006;26:39-47.
FULL TEXT
The role of natriuretic peptides in cardioprotection
Nishikimi et al.
Cardiovasc Res 2006;69:318-328.
ABSTRACT
| FULL TEXT
Clinical Presentation, Management, and In-Hospital Outcomes of Patients Admitted With Acute Decompensated Heart Failure With Preserved Systolic Function: A Report From the Acute Decompensated Heart Failure National Registry (ADHERE) Database
Yancy et al.
J Am Coll Cardiol 2006;47:76-84.
ABSTRACT
| FULL TEXT
Perioperative Effects and Safety of Nesiritide Following Cardiac Surgery in Children
Simsic et al.
J Intensive Care Med 2006;21:22-26.
ABSTRACT
Acute Heart Failure Syndromes: Current State and Framework for Future Research
Gheorghiade et al.
Circulation 2005;112:3958-3968.
FULL TEXT
Nesiritide for outpatient treatment of heart failure
Bauer and Randazzo
Am J Health Syst Pharm 2005;62:2639-2642.
FULL TEXT
Early Ultrafiltration in Patients With Decompensated Heart Failure and Diuretic Resistance
Costanzo et al.
J Am Coll Cardiol 2005;46:2047-2051.
ABSTRACT
| FULL TEXT
Drug Treatment of Systolic and of Diastolic Heart Failure in Elderly Persons
Aronow
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2005;60:1597-1605.
ABSTRACT
| FULL TEXT
Vasopressin Antagonism in Heart Failure
Goldsmith and Gheorghiade
J Am Coll Cardiol 2005;46:1785-1791.
ABSTRACT
| FULL TEXT
Nesiritide--not verified.
Sackner-Bernstein et al.
NEJM 2005;353:1525-1527.
FULL TEXT
Reliability of Nesiritide Infusion via Non-Primed Tubing and Heparin-Coated Catheters
Onat et al.
The Annals of Pharmacotherapy 2005;39:1617-1619.
ABSTRACT
| FULL TEXT
Effect of cardiopulmonary bypass and surgical intervention on the natriuretic hormone system in children
Costello et al.
J. Thorac. Cardiovasc. Surg. 2005;130:822-829.
ABSTRACT
| FULL TEXT
|
