A Comparison of Oral Milrinone, Digoxin, and Their Combination in the Treatment of Patients with Chronic Heart Failure

We randomly assigned 230 patients in sinus rhythm with moderately severe heart failure to treatment with digoxin, milrinone, both, or placebo. The effects of each were compared during a 12-week, double-blind trial. Treatment with milrinone or digoxin significantly increased treadmill exercise time as compared with placebo (by 82 and 64 seconds respectively; 95 percent confidence limits, 44 and 123, and 30 and 100). Both treatments reduced the frequency of decompensation from heart failure, from 47 percent with placebo to 34 percent with milrinone (P<0.05; 95 percent confidence limits, 22 and 46) and 15 percent with digoxin (P<0.01; 95 percent confidence limits, 7 and 26). However, the clinical condition of 20 percent of the patients taking milrinone deteriorated within two weeks after treatment was begun, as compared with only 3 percent of those taking digoxin (P<0.05). The left ventricular ejection fraction at rest was not significantly changed by milrinone (+0.2 percent; 95 percent confidence limits, -1.5 and 1.9), but it was increased by digoxin (+1.7 percent; P<0.01; 95 percent confidence limits, -0.03 and 3.4) and decreased by placebo (-2.0 percent; 95 percent confidence limits, -3.8 and -0.1). Three-month survival was related inversely to the base-line ejection fraction. Analysis of mortality from all causes according to the intention to treat suggested an adverse effect of milrinone (P = 0.064). After adjustment for an excess of patients with lower ejection fractions randomly assigned to receive milrinone, this trend was not significant (P = 0.26). Increased ventricular arrhythmias occurred more frequently in patients who received milrinone than in those who did not (18 vs. 4 percent; P<0.03). We conclude that milrinone significantly increased exercise tolerance and reduced the frequency of worsened heart failure. However, in the population of patients studied, milrinone or the combination of milrinone and digoxin offered no advantage over digoxin alone. Furthermore, our data suggest that milrinone may aggravate ventricular arrhythmias. (N Engl J Med 1989; 320:677–83.), CHRONIC heart failure is a common, progressively debilitating condition with a poor prognosis.¹ Treatment is aimed at improving the contractile state of the myocardium, reducing ventricular preload and afterload, and counteracting excessive compensatory mechanisms such as fluid retention and increased sympathetic activity.² Cardiac glycosides represent the only available positive inotropic agents for long-term oral treatment, and controversy surrounds the magnitude of benefit derived from their administration, especially in patients in sinus rhythm.^{3 4 5 6} Their clinical use is also troubled by a narrow ratio of therapeutic to toxic dosage^{7 8 9} and unknown effects on disease progression and survival, especially after myocardial infarction.^{9 10 11} Milrinone….