(NEJM Part 3)
Discussion
We found that treatment with spironolactone reduced the risk of death from all causes, death from cardiac causes, hospitalization for cardiac causes, and the combined end point of death from cardiac causes or hospitalization for cardiac causes among patients who had severe heart failure as a result of left ventricular systolic dysfunction and who were receiving standard therapy including an ACE inhibitor. Spironolactone also improved the symptoms of heart failure, as measured by changes in the NYHA functional class. The reductions in
the risk of death and hospitalization were observed after 2 to 3 months of treatment and persisted throughout the study (mean follow-up, 24 months). The results were consistent among subgroups. Serious hyperkalemia requiring the discontinuation of treatment was uncommon, occurring in one patient in the placebo group and three in the spironolactone group.
The patients in our study were at higher risk than those in studies of the effects of bisoprolol, (26) digoxin, (27) amlodipine, (28) or carvedilol (29) on heart failure resulting from systolic left ventricular dysfunction and treated with standard therapy, including an ACE inhibitor, but they were at lower risk than patients in a study of the effects of enalapril. (25) The reduction in the risk of death with spironolactone treatment was due to significant decreases in the risk of both death from progressive heart failure and sudden death from cardiac causes. These results are consistent with the current understanding of the effect of aldosterone in patients with heart failure. (30,31,32)
Aldosterone was originally thought to be important in the pathophysiology of heart failure only because of its ability to increase sodium retention and potassium loss. However, in the past several years, research has shown that aldosterone also causes myocardial and vascular fibrosis, (33,34) direct vascular damage, (8) and baroreceptor dysfunction (4) and prevents the uptake of norepinephrine by myocardium. (4,32) The reduction in the risk of death in our study does not appear to be due entirely to an effect of spironolactone on sodium retention or potassium loss; instead, it is likely that spironolactone is also cardioprotective. In our previous dose-finding study, (17) a dose of 25 mg of spironolactone daily had no apparent diuretic effect -- that is, there was no change in total body weight, the sodium-retention score, or urinary sodium excretion. In the present study, spironolactone (mean dose, 26 mg daily) did not have a clinically significant hemodynamic effect. Although we cannot rule out the possibility that spironolactone had some effect on sodium retention in the present study, this effect would most likely be minor, as compared with the effect of the high doses of loop diuretics used. Also, although there was a significant increase from base line in serum potassium concentrations in the patients in the spironolactone group, this change was not clinically important.
The 35 percent reduction in the risk of hospitalization for worsening heart failure may be attributable to the ability of spironolactone to reduce myocardial and vascular fibrosis. Although the exact cause of the reduction in the risk of death in our study remains speculative, we postulate that an aldosterone-receptor blocker can prevent progressive heart failure by averting sodium retention and myocardial fibrosis and prevent sudden death from cardiac causes by averting potassium loss and by increasing the myocardial uptake of norepinephrine. Spironolactone may avert myocardial fibrosis by blocking the effects of aldosterone on the formation of collagen, (5,35,36) which in turn could play a part in reducing the risk of sudden death from cardiac causes, since myocardial fibrosis could predispose patients to variations in ventricular-conduction times and, hence, to reentry ventricular arrhythmias. (32,35,36,37)
Few patients (11 percent) in the spironolactone group were receiving a beta-blocker at base line, and the reduction in the risk of death did not differ significantly between those who were treated with a beta-blocker and those who were not. Since our patients were at higher risk than patients who were evaluated in recent studies of beta-blockers in heart failure, (26,29) studies are needed to examine both the tolerability and the effectiveness of beta-blockers in such a high-risk population as well as the effects of the concomitant use of an aldosterone-receptor blocker and a beta-blocker.
Our finding that an aldosterone-receptor blocker reduced the risk of both morbidity and death among patients who were receiving an ACE inhibitor emphasizes the point that standard doses of an ACE inhibitor do not effectively suppress the production of aldosterone. (7,14) Although higher doses of ACE inhibitors may be more effective than lower doses in reducing the risk of morbidity and death among patients with heart failure, (38) there is no evidence that higher doses suppress aldosterone production more effectively in the long term. ACE inhibitors cannot totally suppress the production of aldosterone, because other factors in addition to angiotensin II (e.g., serum potassium) are important in the production of aldosterone and may override the effects of angiotensin II. (39,40,41) Since aldosterone remains in the circulation, only the presence of an aldosterone-receptor blocker will completely suppress the effects of this hormone.
The fact that spironolactone significantly reduced the risk of both morbidity and death among the high-risk patients in our study with only a very low incidence of serious hyperkalemia can be attributed to our previous efforts in determining an effective and safe dose of spironolactone when used in conjunction with an ACE inhibitor. (17) We found that spironolactone at a dose of 12.5 to 25 mg daily was pharmacologically effective in blocking the aldosterone receptors and decreasing atrial natriuretic peptide concentrations and that serious hyperkalemia occurred most frequently with daily doses of 50 mg or greater. (17) In the present study, therefore, spironolactone therapy was initiated at a daily dose of 25 mg, and physicians were given the option of reducing the dose to 25 mg every other day if serum potassium concentrations started to rise to a hyperkalemic level or of increasing the dose to 50 mg daily after eight weeks in patients who had symptoms or signs of worsening heart failure but no evidence of hyperkalemia. It should be emphasized, however, that a serum creatinine concentration of more than 2.5 mg per deciliter and a serum potassium concentration of more than 5.0 mmol per liter were exclusion criteria. In addition, the long-term use of agents known to interact with spironolactone, increase the risk of hyperkalemia, or do both was not allowed. Although potassium supplements were used by 29 percent of the patients in the spironolactone group, the benefit of spironolactone in these patients was similar to that in patients who did not use potassium supplements.
Overall, spironolactone therapy was tolerated well: 8 percent of the patients in the spironolactone group discontinued treatment because of adverse events, as compared with 5 percent of the patients in the placebo group. This difference was due in part to a significant incidence of gynecomastia or breast pain among men in the spironolactone group (P<0.001). The rate of discontinuation of treatment because of this event was higher in the spironolactone group than in the placebo group (2 percent vs. 0.2 percent, P=0.006). Gynecomastia has previously been observed in patients who were treated with spironolactone. (42,43) Specifically, gynecomastia has been reported to occur in 6.9 percent of men who received daily doses of spironolactone of 50 mg or less for hypertension. (43) The use of a selective aldosterone-receptor antagonist such as eplerenone, which has a lower affinity for androgen and progesterone receptors than does
spironolactone, (44) may minimize the risk of gynecomastia. The risk of gynecomastia should not, however, be an argument against the use of spironolactone in men with severe heart failure, since spironolactone reduces the risk of both morbidity and death. The effectiveness and risks of treatment with spironolactone in patients at lower risk than those in our study, such as those with less severe heart failure, will require further prospective study.
Our finding that an aldosterone-receptor antagonist, when used in conjunction with an ACE inhibitor, reduces the risk of both death from progressive heart failure and sudden death from cardiac causes contributes to our understanding of the pathophysiology of heart failure and has implications for the treatment of patients with other conditions in which ACE inhibitors are beneficial, such as patients with hypertension and those who have had a myocardial infarction.
Supported by a grant from Searle, Skokie, Ill.
Preliminary data were presented at the American Heart Association meeting, Dallas, November 8-11, 1998.
Appendix
In addition to the authors, the following persons participated in the study:
Data and Safety Monitoring Board -- D. Julian (chair), J.-P. Boissel, C. Furberg, H. Kulbertus, S. Pocock;
Primary End-Point Committee -- J. Blumenfeld, J.A. Ramires; Nonfatal Hospitalization End-Point Committee -- S. Sasayama (chair), C. Brilla, D. Duprez, R. Munoz;
Medical Monitors -- D. Asner, B. Roniker; Investigators: Belgium -- P. Block, G. Boxho, J.-M. Chaudron, V. Conraads, J. Creplet, P. De Salle, F. Deman, D. Duprez, O. Gurnee, G. Heyndrickx, S. Janssens, G. Jouret, C. Mortier, L. Pierard, P. Timmermans, J.L. Vandenbossche, W. Van Mieghem, J. Vanwelden, J. Vincke; Brazil -- F.M. Albanesi Filho, F.A. de Almeida, J.C.A. Ayoub, E.T. Barbosa, M. Batlouni, L.C. Bodanese, R.M. Carrasco, A.C. de C. Carvalho, I. Castro, O.R. Coelho, D. Dauar, C. Drumond Neto, G.S. Feitosa, R.A. Franken, P.C.B.V. Jardim, C. Mady, M.F. de C. Maranhao, J.A. Marin Neto, L.F. de Miranda, J.C. Nicolau, W. Oigman, W.A. de Oliveira Junior, W.C. Pereira Filho, J.A.F. Ramires, J.J.F. Rapozo Filho, S. Rassi, J.M. Ribeiro, J.P. Ribeiro, P.R.F. Rossi, J.F.K. Saraiva, A.S. Sbissa, M.A.D. da Silva, J.E. de Sigueira, J. Souza Filho;
Canada -- I.M. Arnold, D. Beanlands, C. Koilppillai, S. Lepage, A. Morris, M. White; France -- F. Albert, G. Amat, F. Apffel, M.C. Aumont, S. Baleynaud, P. Battistella, J. Beaune, L. Bonnefoy, A. Bonneau, J. Bonnet, M. Bory, J.P. Bousser, J.A. Boutarin, B. Charbonnier, A. Cohen, A. Cohen-Solal, M.T. Courbet-Andrejak, A. Cribier, F. Delahaye, C. D'Ivernois, J.P. Doazan, V. Dormagen, H. Douard, F. Dravet, A. Dutoit, J.M. Fayard, M. Ferriere, C. Fournier, Y. Frances, F. Funck, M. Galinier, L.F. Garnier, P. Gibelin, P. Gosse, B. Grivet, L. Guize, B. d'Hautefeuille, A. Heraudeau, J.F. Huret, L. Janin-Manificat, G. Jarry, Y. Jobic, E. Jullien, J.C. Kahn, K. Khalife, A. Koenig, F. Latour, C. Leclercq, F. Leclercq, L. Ledain, H. Le Marec, S. Levy, J.M. Mallion, P. Maribas, G. Mialet, P.L. Michel, J.P. Millet, B. Moquet, J.P. Normand, T. Olive, P. Poncelet, J. Ponsonnaille, J. Puel, A. Rifai, P. Sans, J.P. Simon, M. Toussaint, A. Verdun, B. Veyre, S. Werquin;
Germany -- C. Brilla, G. Riegger, M. Zehender; Japan -- Y. Aizawa, M. Hori, H. Inoue, H. Kasanuki, A. Kitabatake, M. Matsuzaki, S. Ogawa, M. Omata, S. Sasayama, A. Takeshita, Y. Yazaki, M. Yokoyama; Mexico -- L. Avila, F.J. Guerrero, H. Gutierrez-Leonard, J.L. Leyva-Garza; the Netherlands -- P.J.L.M. Bernink, H. Fintelman, J.A. Kragten, J.B.L. ten Kate, D.J.A. Lok, A.R. Ramdat Misier, G.P. Molhoek, G.M.G. Paulussen, L.H.J. van Kempen, D.J. van Veldhuisen, L.G.P.M. van Zeijl, A.J.A.M. Withagen;
New Zealand -- H. Ikram; South Africa -- J.D. Marx, D.P. Naidoo; Spain -- J.M. Aguirre, S. Alcasena, M. Artaza, J. Azpitarte, J.R. Berrazueta, A. Castro-Beiras, P. Conthe, A. Cortina, J.M. Cruz-Fernandez, J. Farre, I. Ferreira, M. Garcia-Moll, V. Lopez-Garcia-de-Aranda, J.L. Lopez-Sendon, R. Munoz, F. Navarro, J. Palomo, J.M. Ribera-Casado, J.L. Rodriguez-Lambert, J. Soler-Soler, E. de-Teresa, J.A. de-Velasco;
Switzerland -- P. Delafontaine, O.M. Hess, L. Kappenberger, G. Noll, W. Rutishauser, J. Sztajzel; United Kingdom -- A.J.S. Coats, T.S. Callaghan, A.D. Struthers;
United States -- G.W. Dec, P. Deedwania, J. Nicklas, K.T. Weber; Venezuela -- N. Lopez, S. Waich.
Source Information
From the Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor (B.P., R.C.); the Centre d'Investigation, Clinique de Nancy, Nancy, France (F.Z.); STICARES, Cardiovascular Research Foundation, Rotterdam, the Netherlands (W.J.R.); the Service de Cardiologie, Hopital Henri Mondor, Creteil, France (A.C.);
Global Medical Operations, Searle, Skokie, Ill. (A.P.); and the Statistics Collaborative, Washington, D.C. (J.P., J.W.). Address reprint requests to Dr. Pitt at the Division of Cardiology, University of Michigan Medical Center, 3910 Taubman, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0366.
Other investigators are listed in the Appendix.
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