James A. Shannon

Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure

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 Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P =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

Clinical and prognostic significance of serum magnesium concentration in patients with severe chronic congestive heart failure: The Promise Study

OBJECTIVES The aim of this study was to determine the prognostic significance of alterations in serum magnesium in patients with moderate to severe congestive heart failure. BACKGROUND Reductions in serum magnesium have been postulated to play a role in promoting arrhythmias and to have an adverse impact on survival in congestive heart failure, although support for this postulate is lacking. METHODS Serum magnesium levels were measured in 1,068 patients enrolled in a survival study of class III or IV heart failure at the time of double-blind randomization to milrinone, a phosphodiesterase inhibitor, or placebo. All patients received conventional therapy with digoxin, diuretic drugs and a converting enzyme inhibitor throughout the trial. The median follow-up period was 6.1 months (range 1 day to 20 months). RESULTS Patients with high serum magnesium (defined as > or = 1.9 mEq/liter, n = 242) were less likely to survive than were patients with a normal magnesium level (n = 627) (p < 0.05, risk ratio = 1.41). Patients with a low magnesium level (defined as < or = 1.5 mEq/liter, n = 199) had no difference in survival compared with the group with a normal magnesium level (p = NS, risk ratio = 0.89). At baseline, the patients in the high magnesium group were older and had more severe functional and renal impairment. An analysis after adjustment for these variables demonstrated no difference in survival comparing the low, normal and high magnesium groups. Although the three groups had no difference in frequency of ventricular tachycardia, length of longest run or frequency of ventricular premature beats on baseline Holter monitoring, the group with hypomagnesemia had more frequent ventricular couplets. CONCLUSIONS Serum magnesium does not appear to be an independent risk factor for either sudden death or death due to all causes in patients with moderate to severe heart failure. Hypomagnesemia is associated with an increase in the frequency of certain forms of ventricular ectopic activity, but this is not associated with an increase in clinical events. The higher mortality rate among the patients with hypermagnesemia is attributable to older age, more advanced heart failure and renal insufficiency.

STUDIES ON THE CHEMOTHERAPY OF THE HUMAN MALARIAS. VII. THE ANTIMALARIAL ACTIVITY OF PAMAQUINE

Pamaquine, synthesized in 1926, was introduced in the treatment of malaria as a schizonticide. It was soon found, however, that the great schizonticidal activity which it possessed in cathemerium malaria of canaries did not obtain in the human malarias. It was shown to be relatively ineffective in acute attacks of vivax malaria and to have only minimal activity against the asexual forms of P. falciparum, although it did eradicate the gametocytes in this infection. In addition, the general usefulness of pamaquine was limited by the frequent occurrence of toxic effects with doses in the therapeutic range. Nonetheless, evidence was advanced favoring both a prophylactic (1, 2, 3) and curative action (4) in vivax malaria. The toxicity of the drug and an incomplete understanding of the biology of vivax malaria led the commission on malaria of the Health Organization of the League of Nations (5) to state that its prophylactic action was not practical and to discount the work of Sinton on its curative action (4). The commission recommended that pama-

Science and Social Purpose

Discussions of contem-porary science too often focus on the painful and disruptive effects of a reduction in federal support-an inevitable consequence of general constraints on federal expenditures. They are less than helpful in the broad analysis of the general support system itself. It would be wvell to acknowledge that there are fundamental imperfections in present federal mechanisms for the support of science, and that the ultimate patrons of science, the public, have not been given an understanding of science that can serve as a base for its continued support and evolution. A simple return to larger funding of research would mitigate some of the immediately urgent problems, but this alone would not adequately serve the long-term needs of science. Here I explore the basis for this conviction, as xvell as its implications for evolution of science policy. The urgent tasks that now confront the scientific community. though not simple, are quite clear. 1) The scientific community must adjust itself to less than optimum funding. at least for the present, while retaining the essential strength of the scientific enterprise. 2) It must seek out the imperfections

Medicine, Public Policy and the Private Sector

Abstract The development of a sound public policy for medicine requires awareness not only of the internal needs of the profession, but also of the economic and social pressures in areas of medical research, training and practice. Progress in correcting deficiencies in these areas has been halting and fragmentary; improvements have been urged, but their substantive nature not defined. Private organizations (the AMA, Association of American Medical Colleges, specialty groups) tend to have a limited outlook; whereas the instruments of government are subject to political pressures and the need for compromise. To provide the capability needed to deal with the broad problems of medicine and its interface with society, a new institution, a National Academy of Medicine, should be established. Such an Academy, independent but also associated with the National Academies of Science and Engineering, should serve effectively to guide policy and action in matters involving medical sciences, education and services.

The National Institutes of Health: Programmes and Problems

Mr President, Fellows of the Royal Society and guests, I am deeply conscious of the honour implicit in the invitation to address the members of this distinguished Society. The honour is the greater because you have asked me to make some observations on the role of the National Institutes of Health—the first of which came into existence only three decades ago and which assumed their present form as recently as 1950—before a body which has rendered outstanding service to the progress of science for more than three centuries. Your interest in the work of such an institution reflects, of course, the traditionally cosmopolitan outlook of The Royal Society. I am reminded that the first number of your Philosophical Transactions was concerned, according to its subtitle, with ‘giving some Accompt of the present undertakings, studies and labours of the Ingenious in many considerable parts of the world.’ This, from my point of view, is happily phrased. Those of us who have the task of administering support for medical research, within a broad interpretation, and with a view to ensuring freedom of action to the investigator and of doing so within a governmental frame-work which—at least by British standards—tends towards the formal, and the inflexible, must necessarily be counted among the Ingenious.