Intravenous Nesiritide vs Nitroglycerin
for Treatment of Decompensated Congestive Heart Failure
A Randomized Controlled Trial
JAMA. 2002;287:1531-1540
Publication Committee for the VMAC Investigators
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.
JAMA. 2002;287:1531-1540
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.
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.
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).
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.
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.
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).
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).
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/Article Information
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).
Corresponding Author and Reprints:
James B. Young, MD, Department of Cardiovascular Medicine, Cleveland Clinic
Foundation, 9500 Euclid Ave/F25, Cleveland, OH 44195 (e-mail: [log in to unmask]).
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.
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.