Long-term use of milrinone increased morbidity and mortality in severe congestive heart failure
ACP J Club. 1992 Mar-April;116:46. doi:10.7326/ACPJC-1992-116-2-046
Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med. 1991 Nov 21;325:1468-75.
To determine the effect of milrinone, a positive inotropic agent, on survival of patients with chronic heart failure.
Randomized, double-blind, placebo-controlled trial.
Multicenter trial with 119 centers in the United States and Canada.
Patients were selected with chronic congestive heart failure that remained severe (dyspnea at rest or on exertion with a left ventricular ejection fraction ≤ 0.35) despite conventional therapy (diuretics, digoxin, converting enzyme inhibitor) for at least 4 weeks. Exclusion criteria included obstructive valvular heart disease; active myocarditis; hypertrophic or amyloid cardiomyopathy; uncorrected thyroid disease; malfunctioning artificial heart valve; severe angina pectoris; myocardial infarction within 3 months; systolic blood pressure < 85 mm Hg; serum potassium < 3.5 mmol/L. 1088 patients were enrolled, with 561 assigned to milrinone and 527 to placebo; no patients were lost during the median 6.1-month follow-up.
Milrinone, 10 mg orally 4 times a day, or matching placebo was given in addition to conventional treatment. The milrinone dose could be titrated up or down according to clinical response.
Main outcome measure
Mortality from all causes.
The 2 treatment groups had similar pretreatment characteristics. The trial was stopped 5 months early because of adverse effects of milrinone on survival. There were 168 deaths in the milrinone-treated group (30%) and 127 deaths in the placebo group (24%). By intention-to-treat analysis, milrinone treatment was associated with a 28% relative increase in overall mortality (95% CI 1% to 61%, P = 0.038) and a 34% increase in cardiovascular mortality (CI 6% to 69%, P = 0.016). The effect of milrinone was adverse in all predefined subgroups, including those defined by left ventricular fraction, cause of heart failure, functional class, serum sodium and creatinine levels, age, sex, angina, cardiothoracic ratio, or ventricular tachycardia. Mortality was significantly increased in 3 subgroups: those with New York Heart Association class IV heart failure, low serum sodium level, or markedly increased cardiothoracic ratio. Patients in the milrinone group did not improve in functional capacity, suffered more adverse effects (P = 0.006) and were hospitalized more often (P = 0.04).
Long-term therapy with oral milrinone increased the morbidity and mortality of patients with severe congestive heart failure.
Source of funding: Sterling Research Group.
Address for article reprint: Dr. Milton Packer, Center for Heart Failure Research, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA.
The prognosis for patients with severe heart failure is poor, with up to 50% mortality in the first year. Cardiac transplantation, left ventricular assistance devices, and cardiomyoplasty are all possible interventions, but they are expensive and of limited availability or are of uncertain value. There is still, therefore, a need to find safe and effective drugs that will improve the outcome for the 10% or so of the adult population purported to have significant heart failure each year.
Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve function and survival among patients with severe heart failure (1). There has also been hope that increasing intracellular cyclic adenosine monophosphate (cAMP), by inhibiting its breakdown through phosphodiesterase inhibition, would prove effective. Drugs that increase intracellular cAMP have been shown to have positive hemodynamic effects.
Amrinone, one such phosphodiesterase inhibitor, is no longer available partly because of its adverse effects. The study by Packer and colleagues will probably send milrinone to the same fate. The trial was well devised and clinically based. It kept patients on all other appropriate medications, including ACE inhibitors, and allowed physicians to make appropriate changes to nonstudy drugs as they thought necessary. The main findings of lack of functional improvement, increased hospitalization, and increased mortality in the milrinone group, which resulted in the trial being terminated early, indicate that any benefits seen in animal models with phosphodiesterase inhibition are not translated into patient benefit. The hunt must go on.
A. H. Gershlick, MD
University of LeicesterLeicester, United Kingdom
A. H. Gershlick, MD
University of Leicester
Leicester, United Kingdom