CHICAGO—Two clinical studies have provided groundbreaking results that should spark changes in the management of acute heart failure resulting in hospitalization. One of the studies unexpectedly found that milrinone, an inotropic agent long used as short-term intravenous (IV) therapy for acute exacerbations of chronic heart failure, has no benefit and may even cause harm.[1]

This was the first randomized placebo-controlled trial of milrinone for acute heart failure, despite the drug’s extensive history of use for that condition, Mihai Gheorghiade, MD, a principal investigator in the trial, told PULMONARY REVIEWS. “Until now, this therapy has been empiric,” added Dr. Gheorghiade, Professor of Medicine at Northwestern University Feinberg Medical School in Chicago.

The other study was unique as well: It was the first large, randomized, controlled trial of nesiritide for decompensated congestive heart failure (CHF). The results showed that nesiritide, a recombinant human brain natriuretic peptide, is at least as effective as nitroglycerin and perhaps somewhat more so.[2] No new IV treatments for acute heart failure have been approved for use in the United States in more than a decade.

MILRINONE VS PLACEBO

The milrinone study included 949 adults who had been hospitalized for exacerbations of chronic heart failure during the prior 48 hours. These patients all had had a left ventricular ejection fraction below 40% within the previous year. They were randomized to receive 48 to 72 hours of either IV milrinone or saline placebo in double-blind fashion.

To prevent hypotension, milrinone was started without a loading dose at 0.5 µg/kg/min. The patients’ physicians were encouraged to maintain that rate for 48 hours. The dosage could be reduced to 0.375 µg/kg/min, however, if hypotension developed or if the patient significantly improved. Other treatments were used at the discretion of the patients’ physicians.

The milrinone and placebo groups were well matched in all but two baseline characteristics: the mean number of hospitalizations in the past year and the likelihood of receiving a calcium-channel blocker. Both were slightly greater in the milrinone group.

There was no statistically significant difference between groups in the main outcome measure—the amount of time spent hospitalized for cardiovascular causes within 60 days of randomization. During that interval, the milrinone and placebo groups spent an average of six and seven days, respectively, in the hospital for such causes.

There were also no significant differences between groups regarding in-hospital mortality (3.8% for milrinone, 2.3% for placebo), 60-day mortality (10.3% vs 8.9%), or the combined incidence of death or readmission (35.0% vs 35.3%). Furthermore, both groups showed similar improvements in heart failure scores on study day 3 and at discharge. Milrinone-treated patients did report feeling substantially better on day 30 than did placebo recipients, however.

Importantly, the rate of treatment failure caused by adverse events was much higher for milrinone than for placebo (12.6% vs 2.1%). This finding reflects a higher incidence of sustained hypotension and of new atrial fibrillation with milrinone, the investigators reported.

They concluded that their results do not support the routine use of milrinone in patients hospitalized with exacerbations of chronic heart failure. “Milrinone should not be first- or even second-line in these patients,” Dr. Gheorghiade asserted. “Only if nothing else works—diuretics, digoxin, angiotensin-converting enzyme inhibitors, etc—should it be considered.”

NESIRITIDE VS NITROGLYCERIN

The nesiritide study subjects were 489 adults with resting dyspnea who required hospitalization and IV therapy for decompensated CHF. Patients were divided into two groups based on the physician’s decision to use a pulmonary arterial catheter. There were 246 patients in the catheterized group and 243 in the non-catheterized group.

In addition to receiving standard care (diuretics, etc), all the patients were randomly assigned in double-blind fashion to nitroglycerin, placebo, or fixed-dose nesiritide; catheterized patients could also be randomized to adjustable-dose nesiritide. For placebo recipients, random group assignments included double-blind crossover to nitroglycerin or fixed-dose nesiritide after three hours.

The active drug therapies were administered in double-dummy fashion (simultaneously with placebo). In all cases, nesiritide was prepared in a concentration of 10 µg/mL and delivered as a bolus of 2 µg/kg followed by an infusion of 0.01 µg/kg/min for three hours.

After that, the dosage remained the same in the fixed-dose group. The adjustable-dose group, however, could receive incremental dosage increases every three hours up to a maximum of 0.03 µg/kg/min, depending on the pulmonary capillary wedge pressure (PCWP) and systolic blood pressure. Nesiritide treatment could also be titrated downward by 30% at the physicians’ discretion.

Because nitroglycerin has no standard dose for heart failure, it was prepared in a concentration of 400 µg/mL and delivered under the investigators’ supervision. It could be titrated upward or downward throughout the study to achieve the desired clinical or hemodynamic effect. The two primary end points of the study were changes in PCWP and patients’ reports of dyspnea after three hours of treatment or placebo.

Other than a higher proportion of men in the nesiritide group, the three treatment cohorts had similar baseline clinical characteristics. The median duration of treatment was about the same for nesiritide and nitroglycerin recipients (24 to 25 hours).

After three hours, a larger PCWP decline was observed in the nesiritide group than in the nitroglycerin and placebo cohorts (-5.8 mm Hg vs -3.8 and -2.0 mm Hg, respectively); a similar difference between nesiritide and nitroglycerin was found after 24 hours.

The authors acknowledged that more of the patients in the nesiritide group had been given dopamine or dobutamine during the study. However, this did not explain the greater improvement in the nesiritide recipients: When all patients given dopamine or dobutamine were removed from the analysis, the decrease in PCWP was still almost twice as great in the nesiritide group as in the nitroprusside cohort (-6.5 mm Hg vs -3.4 mm Hg).

Relative to placebo, nesiritide and nitroglycerin comparably improved systolic blood pressure, pulmonary vascular resistance, systemic vascular resistance, and dyspnea. Nesiritide produced slightly better improvements in right atrial pressure and cardiac index after one hour of treatment, however, and it was associated with somewhat larger drops in systolic and mean pulmonary artery pressure during the first three hours.

The three treatment groups had comparable adverse event rates (nesiritide, 18%; nitroglycerin, 27%; placebo, 14%). Nitroglycerin more often caused headaches and abdominal pain, however.

Nesiritide is a useful adjunct to standard hospital care for decompensated CHF, the investigators concluded.

—Timothy Begany

References
1. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287:1541-1547.
2. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287:1531-1540.

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