Intravenous Nesiritide vs Nitroglycerin for Treatment of Decompensated
Congestive Heart Failure

A Randomized Controlled Trial

 JAMA. 2002;287:1531-1540

Author Information <http://jama.ama-assn.org/issues/v287n12/rfull/#aainfo>
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
JOC11168
Heart failure occurs in 4.7 million persons living in the United States, 1
<http://jama.ama-assn.org/issues/v287n12/rfull/#r1>  and is the discharge
diagnosis in approximately 3.5 million hospitalizations annually. 2
<http://jama.ama-assn.org/issues/v287n12/rfull/#r2>  Hospitalizations
account for 60% of health care expenditures for heart failure. 1-5
<http://jama.ama-assn.org/issues/v287n12/rfull/#r1>  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
<http://jama.ama-assn.org/issues/v287n12/rfull/#r6>  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 <http://jama.ama-assn.org/issues/v287n12/rfull/#r1>  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
<http://jama.ama-assn.org/issues/v287n12/rfull/#r15>  and improve symptoms
in patients with acutely decompensated CHF, 18
<http://jama.ama-assn.org/issues/v287n12/rfull/#r18>  without increasing
heart rate or proarrhythmia. 18
<http://jama.ama-assn.org/issues/v287n12/rfull/#r18> , 19
<http://jama.ama-assn.org/issues/v287n12/rfull/#r19>  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
<http://jama.ama-assn.org/issues/v287n12/rfull/#r20> , 21
<http://jama.ama-assn.org/issues/v287n12/rfull/#r21>
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
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_f1.html> ). 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
<http://jama.ama-assn.org/issues/v287n12/rfull/#r17>
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
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_f1.html> ).
Baseline Characteristics

Baseline clinical characteristics were similar among patients in the study
groups ( Table 1
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t1.html> ) 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
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t2.html> ), 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
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t1.html>  and
Table 2
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t2.html> ).
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
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t3.html> ).
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 2
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_f2.html> A and
Table 3
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t3.html> ). 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
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t3.html> ).
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
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t3.html> ).
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
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t3.html> ).
Effects on systolic blood pressure through 3 hours were similar with
nesiritide and nitroglycerin ( Table 3
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t3.html> ).
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 2
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_f2.html> B). 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 3
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_f3.html> A), 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 3
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_f3.html> B), 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 3
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_f3.html> C). 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 3
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_f3.html> D).
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
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t4.html> ). 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
<http://jama.ama-assn.org/issues/v287n12/fig_tab/joc11168_t4.html> ). 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 nesiritide 22
<http://jama.ama-assn.org/issues/v287n12/rfull/#r22>  and 2.5-minute
half-life for nitroglycerin 23
<http://jama.ama-assn.org/issues/v287n12/rfull/#r23> ). 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 <http://jama.ama-assn.org/issues/v287n12/rfull/#r24>  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 <http://jama.ama-assn.org/issues/v287n12/rfull/#r18>  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
<http://jama.ama-assn.org/issues/v287n12/rfull/#r25>  recommended by the
current American College of Cardiology/American Heart Association guidelines
for management of acutely decompensated CHF. 1
<http://jama.ama-assn.org/issues/v287n12/rfull/#r1>  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] <mailto:[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.