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Cuffe MS, Califf RM, Adams, Jr KF, et al. Short-term Intravenous Milrinone for Acute Exacerbation of Chronic
Heart Failure: A Randomized Controlled Trial. JAMA. 2002;287(12):1541–1547. doi:10.1001/jama.287.12.1541
Context Little randomized evidence is available to guide the in-hospital management
of patients with an acute exacerbation of chronic heart failure. Although
intravenous inotropic therapy usually produces beneficial hemodynamic effects
and is labeled for use in the care of such patients, the effect of such therapy
on intermediate-term clinical outcomes is uncertain.
Objective To prospectively test whether a strategy that includes short-term use
of milrinone in addition to standard therapy can improve clinical outcomes
of patients hospitalized with an exacerbation of chronic heart failure.
Design Prospective, randomized, double-blind, placebo-controlled trial conducted
from July 1997 through November 1999.
Setting Seventy-eight community and tertiary care hospitals in the United States.
Participants A total of 951 patients admitted with an exacerbation of systolic heart
failure not requiring intravenous inotropic support (mean age, 65 years; 92%
with baseline New York Heart Association class III or IV; mean left ventricular
ejection fraction, 23%).
Intervention Patients were randomly assigned to receive a 48-hour infusion of either
milrinone, 0.5 µg/kg per minute initially (n = 477), or saline placebo
(n = 472).
Main Outcome Measure Cumulative days of hospitalization for cardiovascular cause within 60
days following randomization.
Results The median number of days hospitalized for cardiovascular causes within
60 days after randomization did not differ significantly between patients
given milrinone (6 days) compared with placebo (7 days; P = .71). Sustained hypotension requiring intervention (10.7% vs 3.2%; P<.001) and new atrial arrhythmias (4.6% vs 1.5%; P = .004) occurred more frequently in patients who received
milrinone. The milrinone and placebo groups did not differ significantly in
in-hospital mortality (3.8% vs 2.3%; P = .19), 60-day
mortality (10.3% vs 8.9%; P = .41), or the composite
incidence of death or readmission (35.0% vs 35.3%; P
CONCLUSION These results do not support the routine use of intravenous milrinone
as an adjunct to standard therapy in the treatment of patients hospitalized
for an exacerbation of chronic heart failure.
Chronic heart failure is one of the most common and life-threatening
cardiovascular conditions, affecting nearly 5 million people in the United
States.1 It causes more than 200 000 deaths
each year2-4 and
is the leading discharge diagnosis among the Medicare population.5,6 Treatment costs for chronic heart failure,
most of which are incurred by inpatients, are more than $30 billion yearly.7 Almost half of the patients with advanced disease
will die within 1 year.8 Hospitalization is
common in these patients and is associated with a poor prognosis.9 From 3 to 6 months after discharge, readmission rates
for chronic heart failure range from 30% to 50%.10-12
Hospitalization for chronic heart failure is often associated with worsening
hemodynamic function,13 which may be partly
responsible for the volume retention that is usually the precipitating factor.
Inotropic agents produce beneficial hemodynamic effects in heart failure patients
and may facilitate earlier achievement of hemodynamic improvement and titration
of standard oral therapy, particularly when used with hemodynamic monitoring
by right-sided heart catheterization.14,15
Milrinone, a commonly used inotropic agent that is labeled for use in
the short-term intravenous treatment of acute exacerbation of chronic heart
failure, has several characteristics that make it physiologically attractive.
It has both inotropic and vasodilator properties, which increase cardiac output
and reduce systemic vascular resistance and pulmonary capillary wedge pressures.16 The drug exerts its hemodynamic effects without excessive
changes in heart rate or increases in myocardial oxygen consumption,16 important because coronary artery disease and chronic
heart failure often coexist.17 Although intravenous
agents (eg, milrinone and dobutamine) are often used as adjuncts to standard
therapy and, with or without hemodynamic guidance, represent a rational approach
to treatment of patients with an acute exacerbation of chronic heart failure,
no placebo-controlled clinical trials have evaluated their proper role.
The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations
of Chronic Heart Failure (OPTIME-CHF) study sought to further evaluate a strategy
that includes the short-term use of milrinone in addition to standard therapy.
Although use of milrinone is indicated for and often used in treatment of
patients with heart failure, the study population of OPTIME-CHF was not in
such a severe state (eg, manifesting cardiogenic shock with end-organ or tissue
hypoperfusion) that, in the opinion of the treating physician, inotropic or
vasopressor agents were absolutely required. The primary hypothesis of this
study was that in this population, short-term treatment with milrinone compared
with placebo would result in fewer days of hospitalization for cardiovascular
events within the 60 days following randomization by either reducing the initial
length of stay or preventing readmission.
The design of the study has been described.18
The OPTIME-CHF was a multicenter, randomized, double-blind, placebo-controlled
trial. Patients who had known systolic chronic heart failure and had been
hospitalized for exacerbation of chronic heart failure no more than 48 hours
earlier were eligible. After approval of each site's institutional review
board and written informed consent was obtained, patients were randomly assigned
to receive an intravenous infusion of either milrinone or saline placebo.
To avoid hypotension, the study drug was administered without a loading dose
at an initial infusion of 0.5 µg/kg per minute, and investigators were
encouraged to continue this rate for 48 hours. The rate could be adjusted
downward to 0.375 µg/kg per minute if hypotension or significant improvement
occurred and upward to 0.75 µg/kg per minute if neither occurred. Treatment
was to continue for at least 48 hours and could be continued for up to 72
hours at the discretion of investigators.
Patients were otherwise treated at the discretion of their physicians,
although recommended guidelines were provided. Guidelines represented steering-committee
consensus of the best conventional therapy during hospitalization for exacerbation
of chronic heart failure, according to the limited published evidence and
outpatient-treatment guidelines.18 These guidelines
were not a formal part of the protocol but rather recommendations to be followed
with study drug infusion. Critical components of these guidelines included
the initiation and upward titration of angiotensin-converting enzyme (ACE)
inhibitors, adequate diuresis, expeditious conversion to oral therapy, and
comprehensive discharge planning. The target dose of ACE inhibitor was defined
as that shown in randomized trials to reduce mortality, or dose-equivalent
for ACE inhibitors for which mortality data were unavailable. Follow-up occurred
at 30 and 60 days after randomization, in person or by telephone.
Eligible patients were at least 18 years of age and had demonstrated
left ventricular ejection fraction below 40% within the past year. Patients
were ineligible if the treating physician judged that intravenous inotropic
therapy was essential (eg, for shock, metabolic acidosis, or severe hypotension).
Patients also were excluded if they had active myocardial ischemia within
the past 3 months, atrial fibrillation with poor ventricular rate control
(>110/min), or sustained ventricular tachycardia or ventricular fibrillation.
Because milrinone is a vasodilator and excreted renally,16
patients with a baseline systolic blood pressure of less than 80 mm Hg or
serum creatinine level higher than 3.0 mg/dL (265 µmol/L) were excluded.
Patients were recruited at 78 US centers from July 1997 through November
1999. Institutional review boards at the hospitals approved the protocol and
consent documents. Data management procedures included source data verification
of 20% of all case-report forms, biannual site-monitoring visits, and standard
double data entry. The primary end point of cardiovascular hospitalization
was monitored against source documents for all patients. A steering committee
provided oversight for the scientific conduct of the study. An independent
safety committee reviewed the safety data after 250, 500, and 750 patients
had completed the in-hospital phase of the protocol to ensure the safety of
the active drug and placebo infusion.
The primary efficacy end point was the total number of days hospitalized
for cardiovascular causes (or days deceased) within the 60 days after randomization,
a period that represents the highest risk for heart failure rehospitalization.19 This composite end point reflects the need to define
therapies that safely decrease the length of index heart failure hospitalization
and reduce rehospitalization, which is common. Acute intravenous hemodynamic
therapy was not expected to affect outcome beyond 60 days. Multisystem disease
and social-support problems frequently coexist with heart failure, and the
primary efficacy of this investigational hemodynamic strategy was evaluated
on cardiovascular hospitalization. Hospital days were defined as inpatient
days and emergency department visit days. Days lost to follow-up and days
deceased were prospectively included in the primary end point to avoid bias
toward a therapy with increased mortality. Site investigators determined whether
individual hospital days were related to cardiovascular causes.
The main secondary outcome included the proportion of cases failing
therapy because of adverse events or worsening heart failure 48 hours after
initiation of therapy. Adverse events included sustained hypotension, defined
as a systolic blood pressure below 80 mm Hg for more than 30 minutes, requiring
intervention; development of myocardial ischemia; significant atrial arrhythmias;
and sustained ventricular arrhythmias (>30 seconds). Investigators determined
worsening heart failure or inadequate improvement on the basis of persistent
pulmonary congestion, inadequate diuresis, or hypotension with organ hypoperfusion.
Other secondary outcomes included the proportion of patients achieving target
doses of ACE-inhibitor therapy and time to achieve target dose, symptoms,
improvement in heart failure score (Table
1),20 length of initial hospitalization,
days of hospitalization for cardiovascular events from initial hospital discharge
to 60 days, days of hospitalization for cardiovascular events within 30 days
after randomization, all-cause hospitalization, and mortality.
Analyses were performed with SAS version 6.12 (SAS Institute Inc, Cary,
NC) and S-Plus version 3.4 (Insightful Corp, Seattle, Wash). They included
all data from all but 2 patients randomized (both had withdrawn consent and
had been randomized to the milrinone treatment group) and were performed on
an intent-to-treat basis including all other patients as randomized. Analyses
were conducted at α = .05 unless otherwise indicated. For the primary
analysis, days with uncertain status because of lack of follow-up were prospectively
and conservatively included as hospitalized in the primary end point; this
principle did not change the outcome results.
Categorical variables were compared between the treatment groups with
the likelihood ratio χ2 statistic, unless event rates warranted
use of the Fisher exact test. The log-rank test was used to compare survival
to 60 days between the treatment groups. Continuous variables were compared
with the Wilcoxon rank sum test. Treatment groups were compared with a Cox
proportional hazards model for the primary outcome. For patients whose clinical
course was not followed to 60 days, the number of days hospitalized for cardiovascular
causes was augmented by the number of days between the date of death or last
contact and day 60. Cox proportional hazards modeling also was used to compare
the length of initial hospitalization, the number of days patients were hospitalized
for cardiovascular causes between discharge and 60 days, and the number of
days patients were hospitalized (all-cause) within 60 days.
The study was designed with an estimated sample size of 500 patients
per treatment group, based on an 80% power to observe a clinically meaningful
difference of 1 hospital day by using a 2-sided test with α = .05 for
comparison. If the primary end point was normally distributed and given an
anticipated SD of 5 days, at least 392 patients per group would be required
if a 2-sample t test was used.
Safety was determined by blinded monitoring of treatment failures and
serious adverse events. Because both treatment groups represented accepted
care, review of the primary end point occurred only at trial completion. The
proportion of patients with treatment failure or at least 1 serious adverse
event between treatment groups was compared by using a Bayesian approach assuming
a noninformative prior.21 The safety committee
was to recommend early termination of the trial to the steering committee
if the Bayesian analyses indicated that P>.95 that
the odds ratio of treatment effect for treatment failure or for the rate of
serious adverse events differed from 1.0. Similarly, P>.90
that the odds ratio of treatment effect differed from 1.0 for mortality was
recommended as a guideline for the safety committee to consider recommending
early termination of the trial.
The trial was terminated because of slow enrollment after 951 patients
had been randomized, with the steering committee and sponsor's agreement after
review of the primary end point in placebo-treated patients. The variance
of the distribution of the primary end point in this group indicated that
the study would retain a power of 77% (compared with 79.5% at 1000 patients)
if terminated at the 940 patients already enrolled in the trial at the time
In all, 951 patients were randomized, of whom 2 withdrew consent before
treatment, leaving 949 patients available for analysis (Figure 1). The 2 groups were well balanced with respect to all but
2 baseline characteristics (Table 2):
there were a mean 2.1 hospitalizations in the prior year for patients randomized
to milrinone vs 1.9 hospitalizations for patients randomized to placebo (P = .04), and milrinone-treated patients were more likely
to have been treated with a calcium channel blocker (15.9% [milrinone] vs
11.2% [placebo]; P = .03). Similarly, apart from
the use of intravenous diuretics at 48 hours (76.9% [milrinone] vs 82.2% [placebo]; P = .02), the care of the 2 treatment groups did not differ
significantly at discharge or in regard to the use of medications at 48 hours
after randomization or of major procedures, including right-sided heart catheterization
Primary efficacy results are shown in Table 4. Treatment with milrinone did not reduce the primary end
point of days hospitalized for cardiovascular causes within 60 days compared
with placebo. The groups did not differ in the length of the initial hospitalization
or number of days of readmission. The milrinone and placebo groups did not
differ significantly in in-hospital mortality or 60-day mortality. The composite
rate of death or readmission within 60 days was similar in the 2 groups (Table 3).
Clinical status was measured by a composite heart failure score, a subjective
questionnaire on health status (not previously validated), and a visual analog
scale.22 Both groups had a significant and
equivalent reduction in heart failure score from baseline at day 3 and even
more so at discharge. Milrinone-treated patients reported that they felt better
than placebo-treated patients, as measured by the visual analog scale at one
point, 30 days (67 vs 63; P = .02); no overall significant
differences or trends were identified for other points. There were no differences
in procedures between the groups: 5.9% of patients had invasive hemodynamic
monitoring by right-sided heart catheterization, 2.5% had mechanical ventilation,
and 7.0% had left-sided heart catheterization during the initial hospitalization.
There was also no significant difference between the groups' reaching the
target dose of ACE inhibitor at 48 hours (40.5% milrinone vs 35.8% placebo; P = .14) and at discharge from initial hospitalization
(43.8% milrinone vs 40.9% placebo; P = .36).
Although there was no significant difference in treatment failures defined
by progression of chronic heart failure, treatment failures caused by adverse
events by 48 hours were more common in milrinone-treated patients
(Table 5 and
Table 6). This treatment failure rate reflects the increased incidence
of sustained hypotension and atrial fibrillation in the milrinone-treated
patients. During index hospitalization, serious sustained hypotension (systolic
blood pressure of ≤80 mm Hg for at least 30 minutes and requiring intervention)
was more common in the milrinone group. Milrinone use was also associated
with new atrial arrhythmias during the index hospitalization and trended toward
an association with more serious ventricular arrhythmias. Multivariable predictors
of any new arrhythmia during the index hospitalization included milrinone
use (P = .001), lack of previous myocardial infarction
(P = .04), use of amiodarone (P = .02), and systolic blood pressure less than 90 mm Hg (P = .047).
In Cox proportional hazards multivariable analysis, independent baseline
predictors of increased days hospitalized included higher serum urea nitrogen
level (P<.001), lower systolic blood pressure
(P<.001), male sex (P
= .008), number of previous hospitalizations (P =
.002), worse New York Heart Association classification (P = .008), and hyponatremia (P = .03).
The OPTIME-CHF study is, to our knowledge, the first large, placebo-controlled
clinical trial designed to clarify the role of milrinone, a commonly used
intravenous inotropic agent approved by the Food and Drug Administration in
treatment of patients hospitalized for an exacerbation of chronic heart failure.
The underlying rationale for the study was that the known hemodynamic improvements
with short-term intravenous milrinone administration would translate into
clinical benefit measured by shorter hospitalizations, improved symptoms,
or improved dosing of standard therapy. In this study, however, the routine
addition of intravenous milrinone, even though labeled for this indication,
did not demonstrate any benefit in the duration of hospitalization, dosing
of ACE inhibitor, or symptoms. The 48-hour infusion of milrinone was associated
with increased early treatment failures, particularly caused by new atrial
arrhythmias and significant hypotension. This excess of adverse events did
not clearly translate into overall significantly longer hospitalizations,
increased readmission, or mortality.
The clinical characteristics of this population were typical of patients
with worsening chronic heart failure.19 They
were generally older, had significant comorbidities, and showed clinical findings
of volume overload. Nearly all had New York Heart Association class III or
IV symptoms at baseline, had been hospitalized the previous year, and were
manifesting significant signs of persistent volume overload an average of
15 hours after admission. Such patients with chronic heart failure who required
admission would be treated with intravenous diuresis and titration of standard
oral therapy and, in many cases, with inotropic agents.
Achieving better hemodynamics earlier in hospitalization might allow
increases in ACE inhibitor dose to more desirable levels before discharge.
Some evidence suggests that the short-term use of milrinone can aid in the
upward titration of ACE inhibitors to doses known to improve outcomes.15,23 If true, long-term benefits could
result. In this trial, however, ACE inhibitor dosing was not significantly
improved with active milrinone treatment.
Regardless of hemodynamic improvement or impact on length of stay, drug
efficacy must be balanced with safety. Survival in chronic heart failure relates
more closely to severity of left ventricular dysfunction, neurohormonal abnormalities,
and the extent and progression of coronary disease than to hemodynamics.17 Hospitalization more closely relates to worsening
of the hemodynamic profile and volume retention, often the result of a high-sodium
diet, hypertension, ischemia, or a combination of these. Particular concern
remains over the risks associated with positive inotropic agents: studies
with drugs of this and similar classes have shown that short-term improvements
in hemodynamics may correlate inversely with mortality.24
Most agents studied have a common mechanism of action that results in elevated
myocardial cyclic adenosine monophosphate through either β-receptor agonism
or phosphodiesterase inhibition. Although these agents are hemodynamically
effective with short-term use, their long-term use, including use of oral
milrinone, particularly in patients with more advanced chronic heart failure,
has been strongly associated with increased mortality or morbidity.25
The OPTIME-CHF study had several limitations. It did not directly address
patients with acutely decompensated chronic heart failure for whom inotropic
therapy was felt to be essential (eg, low cardiac output state with tissue
hypoperfusion), although this is an area in which physicians may disagree.
For all patients, milrinone was used within its labeled indication. This study
was not structured to assess patients for self-limited ventricular tachycardia,
a known adverse effect of milrinone. Although the excess adverse events did
not result in significantly increased mortality, this study was inadequately
powered to evaluate mortality.
The OPTIME-CHF study enrolled a population of patients with severe chronic
heart failure and for whom inotropic therapy was indicated but not, in the
opinion of the investigators, essential. Literature and practice suggest that
the patients enrolled in this study are typical of heart failure patients
admitted to US hospitals. No benefit from milrinone treatment was observed
in hospital days, other measurements of chronic heart failure improvement,
or the ability to institute oral drugs that improve long-term prognosis, although
milrinone caused an increase in early adverse events related to hypotension
and atrial arrhythmias. Our results do not support the routine use of milrinone
in patients hospitalized with an exacerbation of chronic heart failure.
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