Effect of oral milrinone on mortality in severe chronic heart failure

Milton Packer, Joseph R. Carver, Richard J. Rodeheffer, Russell J. Ivanhoe, Robert DiBianco, Steven M. Zeldis, Grady H. Hendrix, William J. Bommer, Uri Elkayam, Marrick L. Kukin, George I. Mallis, Josephine A. Sollano, James Shannon, P. K. Tandon, David L. DeMets

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Abstract

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 1088 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 Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P =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.

Original languageEnglish (US)
Pages (from-to)1468-1475
Number of pages8
JournalNew England Journal of Medicine
Volume325
Issue number21
StatePublished - Nov 21 1991

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Milrinone
Heart Failure
Mortality
Placebos
Confidence Intervals
Therapeutics
Phosphodiesterase Inhibitors
Survival
Digoxin
Syncope
Left Ventricular Dysfunction
Enzyme Inhibitors
Diuretics
Cyclic AMP
Hypotension
Hospitalization
Hemodynamics
Morbidity

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Packer, M., Carver, J. R., Rodeheffer, R. J., Ivanhoe, R. J., DiBianco, R., Zeldis, S. M., ... DeMets, D. L. (1991). Effect of oral milrinone on mortality in severe chronic heart failure. New England Journal of Medicine, 325(21), 1468-1475.

Effect of oral milrinone on mortality in severe chronic heart failure. / Packer, Milton; Carver, Joseph R.; Rodeheffer, Richard J.; Ivanhoe, Russell J.; DiBianco, Robert; Zeldis, Steven M.; Hendrix, Grady H.; Bommer, William J.; Elkayam, Uri; Kukin, Marrick L.; Mallis, George I.; Sollano, Josephine A.; Shannon, James; Tandon, P. K.; DeMets, David L.

In: New England Journal of Medicine, Vol. 325, No. 21, 21.11.1991, p. 1468-1475.

Research output: Contribution to journalArticle

Packer, M, Carver, JR, Rodeheffer, RJ, Ivanhoe, RJ, DiBianco, R, Zeldis, SM, Hendrix, GH, Bommer, WJ, Elkayam, U, Kukin, ML, Mallis, GI, Sollano, JA, Shannon, J, Tandon, PK & DeMets, DL 1991, 'Effect of oral milrinone on mortality in severe chronic heart failure', New England Journal of Medicine, vol. 325, no. 21, pp. 1468-1475.
Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM et al. Effect of oral milrinone on mortality in severe chronic heart failure. New England Journal of Medicine. 1991 Nov 21;325(21):1468-1475.
Packer, Milton ; Carver, Joseph R. ; Rodeheffer, Richard J. ; Ivanhoe, Russell J. ; DiBianco, Robert ; Zeldis, Steven M. ; Hendrix, Grady H. ; Bommer, William J. ; Elkayam, Uri ; Kukin, Marrick L. ; Mallis, George I. ; Sollano, Josephine A. ; Shannon, James ; Tandon, P. K. ; DeMets, David L. / Effect of oral milrinone on mortality in severe chronic heart failure. In: New England Journal of Medicine. 1991 ; Vol. 325, No. 21. pp. 1468-1475.
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abstract = "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 1088 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.",
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T1 - Effect of oral milrinone on mortality in severe chronic heart failure

AU - Packer, Milton

AU - Carver, Joseph R.

AU - Rodeheffer, Richard J.

AU - Ivanhoe, Russell J.

AU - DiBianco, Robert

AU - Zeldis, Steven M.

AU - Hendrix, Grady H.

AU - Bommer, William J.

AU - Elkayam, Uri

AU - Kukin, Marrick L.

AU - Mallis, George I.

AU - Sollano, Josephine A.

AU - Shannon, James

AU - Tandon, P. K.

AU - DeMets, David L.

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N2 - 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 1088 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.

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