© 2002 European Society of Cardiology
OPTIME in CHF trial: rethinking the use of inotropes in the management of worsening chronic heart failure resulting in hospitalization
a Division of Cardiology, Northwestern University Medical School 201 E. Huron Street, Galter 10-240, Chicago, IL 60611, USA
b Duke University Medical Center Durham, NC, USA
c Advocate Illinois Masonic Medical Center Chicago, IL, USA
* Corresponding author. Tel.: +1-312-695-0051; fax: +1-312-695-1434 E-mail address: m-gheorghiade{at}northwestern.edu
Key Words: Chronic heart failure • Milrinone • Hospitalization • OPTIME
Received June 11, 2002; Revised August 9, 2002; Accepted September 17, 2002
Chronic heart failure (CHF) affects nearly 5 million individuals and causes more than 200 000 deaths each year in the US alone [1]. Worsening CHF is a rapidly growing clinical problem resulting in almost 1 million admissions yearly in the US and it is a marker of poor prognosis [2]. The readmission rates within 6 months after discharge range from 30 to 50% [3].
The hospitalized patients with worsening CHF present with dyspnea and systemic and/or pulmonary congestion as a result of high left ventricular filling pressures due to volume overload. In these patients, the immediate goals are to achieve hemodynamic improvement without causing myocardial injury and to implement life saving therapies that include angiotensin converting enzyme (ACE) inhibitors and beta-blockers.
Randomized evidence for the treatment of worsening CHF resulting in hospitalization was, until very recently, not available. Milrinone, an inotropic agent with vasodilator properties, has been approved for several years by the US Food and Drug Administration (FDA) for short-term intravenous use in patients with decompensated CHF. It is frequently prescribed in addition to standard therapy in this setting. Its proper role, however, had not previously been well defined in randomized placebo-controlled trials.
The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME–CHF) study, recently published in Ref. [4], was the first carefully designed randomized placebo-controlled trial to assess the utility and safety of short-term intravenous milrinone in patients admitted with worsening CHF. The trial randomized 951 patients to a 48–72 h infusion of intravenous milrinone or placebo in addition to standard therapy that included diuretics, ACE inhibitors, digoxin and beta-blockers. All patients had an indication for milrinone, but they did not absolutely require inotropic support for low cardiac output (hypotension and/or end-organ hypoperfusion). The study excluded patients with hypotension, defined as systolic blood pressure <80 mmHg, patients with atrial fibrillation with a ventricular rate >110 beats/min and those with severe renal impairment. To avoid hypotension, the study drug was administered without a loading dose at an initial infusion of 0.50 µg/kg min. The rate could be adjusted downward to 0.375 µg/kg min if hypotension or significant improvement occurred.
The primary objective of the study was to determine if short-term use of intravenous milrinone would translate to fewer hospitalized days for cardiovascular events within 60 days following randomization, a period that represents the highest risk for CHF rehospitalizations [5]. One of the secondary objectives was to assess if milrinone reduced treatment failures within 48 h following randomization, defined as: (1) adverse events attributable to study infusion (hypotension, myocardial ischemia, atrial or ventricular arrhythmias), (2) continued worsening of CHF and (3) failure to achieve adequate clinical improvement at completion of 48 h of study infusion (continued pulmonary congestion, inadequate diuresis or continued dyspnea). Other secondary end points were the ability of the study drug to improve clinical outcome (as measured by visual analog scale, heart failure score and subjective questionnaire) [6,7], to increase the proportion of patients able to achieve target dose of ACE inhibitors and to assess its effect on mortality.
The patients enrolled in this study had left ventricular systolic dysfunction. Patients were also persistently symptomatic with pulmonary rales, jugular venous distension or a third heart sound despite receiving standard therapy for approximately 15 h, the average time between admission and randomization. A significant proportion had coronary artery disease (51%), coronary revascularization (42%), diabetes (44%) and atrial fibrillation (34%). Medical therapy was similar in both groups with the majority of patients receiving diuretics (90%), ACE inhibitors or angiotensin receptor blockers (82%), digoxin (70%) and beta-blockers (22%).
The median number of days hospitalized for cardiovascular causes was 6 in the milrinone group and 7 in the placebo group, a difference that was not statistically significant.
Subjective health status improved markedly and by a similar degree both in the milrinone and placebo group, with 90% of the patients feeling better at discharge; however, the subjective health status score declined by day 60. The visual analog scale improved at discharge and remained stable at day 60 in both groups. Both groups had a significant and similar reduction in the heart failure score from baseline to day three that declined further by the time of discharge (Fig. 1).
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No significant differences were observed between the two treatment groups in reaching target doses of ACE inhibitors at 48 h or at discharge.
Treatment failures at 48 h were more common in the milrinone group (20.6%) when compared to placebo (9.2%) (Fig. 2). This difference was largely due to the hypotensive episodes, defined as sustained systolic blood pressure <80 mmHg requiring intervention. There were more episodes of new atrial fibrillation in the milrinone group (4.6%) when compared to placebo (1.5%) and a trend toward new complex ventricular arrythmias (milrinone 3.4% vs. placebo 1.5%).
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The in-hospital mortality was 3.8 and 2.3% and the 60 days mortality was 10.3 and 8.9% for the milrinone and the placebo treated patients, respectively (Fig. 3). This study was inadequately powered to evaluate overall mortality. In the Cox proportional hazards multivariate analysis, the following variables were independent predictors of increased mortality: worse NYHA class, higher blood urea nitrogen, hyponatremia, lower systolic blood pressure or age [8]. On a subsequent subgroup analysis, the patients with coronary disease receiving milrinone had a higher mortality and rehospitalization rate at 60 days compared to the placebo group [9].
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The OPTIME–CHF trial is important for several reasons:
(1) It demonstrated that double-blinded, randomized placebo-controlled clinical trials evaluating treatment strategies (in addition to standard therapy) for worsening CHF resulting in hospitalization can and should be performed.
(2) The death plus readmission rate at 60 days was very high (35%) in the overall population, regardless of treatment assignment. The high event rate was present despite the fact that patients with severe CHF were not included in the study, as noted in the accompanying editorial by Poole-Wilson [10]. In addition, the OPTIME–CHF population was managed by cardiologists who had experience in treating heart failure patients and who were provided with guidelines for maximizing standard therapies [7]. This observation demonstrates the urgent need to develop therapies and treatment strategies that effectively reduce the high morbidity and mortality in this population.
(3) The results from the OPTIME–CHF confirm the observations of earlier chronic inotropic trials suggesting that hemodynamic improvement does not consistently translate into clinical benefit. Thus, milrinone should not be routinely used in patients admitted for worsening CHF who are similar to the OPTIME–CHF population.
(4) Milrinone was approved by the FDA for use in patients with worsening CHF based solely on data demonstrating hemodynamic improvement. The results from the OPTIME–CHF trial suggest that future trials should assess not only hemodynamics, but also symptoms and post discharge outcomes. These trials need to be conducted even in the case of ‘established’ therapies.
(5) Recent trials have generated the hypothesis that short-term treatments used in patients admitted with worsening CHF may have long-term effects on morbidity and mortality. The OPTIME–CHF trial showed a tendency toward increased mortality in the milrinone group, both in the inpatient phase and at 60 days, even though the medication was used for only 48–72 h. Similarly, the short-term use of dobutamine in patients admitted for worsening CHF was associated with higher mortality at 6 months when compared to the lowest dose of nesiritide used (PRECEDENT trial [11,12]) or levosimendan (LIDO trial [13]).
(6) Given the high event rate over a short period of time observed in the OPTIME–CHF trial, future trials investigating treatments for patients admitted with worsening CHF can evaluate efficacy end-points in a smaller number of patients than those typically required for outpatient CHF trials.
(7) In the OPTIME–CHF trial [4] patients admitted for worsening CHF had a higher incidence of diabetes and atrial fibrillation as compared to stable CHF patients [1]. These observations are important to consider when developing future treatment strategies and designing clinical trials.
Currently, no published guidelines exist for the management of patients admitted with worsening CHF [1]. Data from recent published trials [4,11–13] suggest that existing therapies may not be as safe and effective as originally hypothesized. An evidence-based approach to the inpatient phase of this disease is critical and more randomized trials are needed to evaluate the old and the new treatment strategies.
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