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The safety and efficacy of long-term oral milrinone therapy were evaluated over a 2 1/2 year period in 100 patients who had severe congestive heart failure despite conventional therapy. Long-term oral milrinone therapy (27 +/- 8 mg/day initial dose) was well tolerated; drug-related side effects occurred in only 11% of patients and led to drug withdrawal in only 4% of patients. Of 94 patients evaluated after 1 month of therapy, 51% had improved by at least one New York Heart Association functional class. Despite hemodynamic and clinical improvements, life table analysis showed a 39% mortality rate at 6 months and a 63% mortality rate at 1 year of therapy. Characteristics at study entry that predicted death within 6 months included more advanced functional class, impaired renal function, lower right ventricular ejection fraction, presence of nonsustained ventricular tachycardia on 24 hour ambulatory electrocardiography, more impaired baseline hemodynamic function and absence of clinical improvement after 1 month of milrinone therapy. Multivariate analysis selected lower baseline cardiac index and aortic systolic pressure as the most significant variables in predicting death; patients who died of progressive heart failure had less frequent use of antiarrhythmic drugs and greater increases in furosemide and milrinone doses during long-term follow-up than did those who died suddenly. Thus, although milrinone is well tolerated and produces early symptomatic benefits in approximately half of patients with congestive heart failure refractory to conventional therapy, there is no evidence that it improves the high baseline mortality in this disorder.

Milrinone and dobutamine were compared in 15 patients with New York Heart Association functional class III and IV congestive heart failure. Dobutamine and milrinone were administered intravenously according a graded titration schedule up to maximum doses (14 micrograms/kg/min and 75 micrograms/kg, respectively) or until increased ventricular ectopy or a reduction in left ventricular end-diastolic pressure to 10 mm Hg or less occurred. Although both agents markedly increased cardiac index, milrinone caused a significantly greater reduction in left and right heart filling pressures and mean arterial pressure than did dobutamine, and for any given increase in dP/dt, milrinone caused a greater reduction in systemic vascular resistance than did dobutamine. Thus, the hemodynamic effects of milrinone are best represented by a combination of the actions of dobutamine, a positive inotropic agent, and a vasodilator such as nitroprusside, which causes both arterial and venous dilation. The positive inotropic responses of individual patients to dobutamine (5 micrograms/kg/min) and milrinone (25 micrograms/kg) were compared. The increases in dP/dt with both agents were variable, and correlated poorly (r = .50; p = .059). Patients were divided into two groups: Group I consisted of eight patients in whom the ratio of the increase in dP/dt with dobutamine vs milrinone was greater than 1.0 (good dobutamine responders); group II consisted of seven patients in whom this ratio was less than 1.0 (poor dobutamine responders).(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the relative contributions of milrinone's positive inotropic and vasodilator actions in patients with severe congestive heart failure, the drug was administered by constant infusion directly into the left main coronary artery of 11 patients with New York Heart Association functional class III or IV heart failure. Intracoronary infusion of milrinone at rates up to 50 micrograms/min had no effect on mean arterial pressure or systemic vascular resistance but resulted in dose-related increases in peak positive dP/dt (+21%), stroke volume index (+18%), and stroke work index (+21%) and decreases in heart rate (-3%), mean right atrial pressure (-25%), and left ventricular end-diastolic pressure (-17%). In eight patients, intravenous administration (75 micrograms/kg) after the intracoronary infusion resulted in significant decreases in mean arterial pressure (-14%) and systemic vascular resistance (-40%), further increase in stroke volume index compared with intracoronary administration, and further decreases in mean right atrial and left ventricular end-diastolic pressures compared with intracoronary administration. These data indicate that milrinone exerts both positive inotropic and vasodilator actions that contribute significantly to the drug's overall hemodynamic effect.

Milrinone is a potent positive inotropic and vascular smooth muscle-relaxing agent in vitro, and therefore, it is not known to what extent each of these actions contributes to the drug's hemodynamic effects in patients with heart failure. In 11 patients with New York Heart Association class III or IV congestive heart failure, incremental intravenous doses of milrinone were administered to determine the dose-response relationships for heart rate, systemic vascular resistance, and inotropic state, the latter measured by peak positive left ventricular derivative of pressure with respect to time (dP/dt). To clarify further the role of a positive inotropic action, the relative effects of milrinone and nitroprusside on left ventricular stroke work and dP/dt were compared in each patient at doses matched to cause equivalent reductions in mean arterial pressure or systemic vascular resistance, indices of left ventricular afterload. Milrinone caused heart rate, stroke volume, and dP/dt to increase, and systemic vascular resistance to decrease in a concentration-related manner. At the two lowest milrinone doses resulting in serum concentrations of 63 +/- 4 and 156 +/- 5 ng/ml, respectively, milrinone caused significant increases in stroke volume and dP/dt, but no changes in systemic vascular resistance or heart rate. At the maximum milrinone dose administered (mean serum concentration, 427 +/- 11 ng/ml), heart rate increased from 92 +/- 4 to 99 +/- 4 bpm (P less than 0.01), mean aortic pressure fell from 82 +/- 3 to 71 +/- 3 mmHg (P less than 0.01), right atrial pressure fell from 15 +/- 2 to 7 +/- 1 mmHg (P less than 0.005), left ventricular end-diastolic pressure fell from 26 +/- 3 to 18 +/- 3 (P less than 0.005), stroke volume index increased from 20 +/- 2 to 30 +/- 2 ml/m2 (P less than 0.005), stroke work index increased from 14 +/- 2 to 21 +/- 2 g X m/m2 (P less than 0.01), and dP/dt increased from 858 +/- 54 to 1,130 +/- 108 mmHg/s (P less than 0.005). When compared with nitroprusside for a matched reduction in mean aortic pressure or systemic vascular resistance, milrinone caused a significantly greater increase in stroke work index at the same or lower left ventricular end-diastolic pressure. Milrinone caused a concentration-related increase in dP/dt (32% increase at maximum milrinone dose), whereas nitroprusside had no effect. These data in patients with severe heart failure indicate that in addition to a vasodilating effect, milrinone exerts a concentration-related positive inotropic action that contributes significantly to the drug's overall hemodynamic effects. The positive inotropic action occurs at drug levels that do not exert significant chronotropic or vasodilator effects.