Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.
BACKGROUND
Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined.


METHODS
We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months).


RESULTS
As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo.


CONCLUSIONS
Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.
Packer
M
M
Division of Cardiology, Mount Sinai School of Medicine, New York, NY.
Carver
J R
JR
Rodeheffer
R J
RJ
Ivanhoe
R J
RJ
DiBianco
R
R
Zeldis
S M
SM
Hendrix
G H
GH
Bommer
W J
WJ
Elkayam
U
U
Kukin
M L
ML
D000368:Aged; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D004311:Double-Blind Method; D004341:Drug Evaluation; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000188:drug therapy / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020105:Milrinone; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D015996:Survival Rate
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D020105:Milrinone