Notice: Because of the potential clinical implications, this article and an accompanying editorial
are being released before the publication date, in accordance with the Journal's policy (Angell M
and Kassirer JP. The Ingelfinger Rule revisited. N Engl J Med 1991;325:1371-2). The report and
the editorial will be published in the September 2 issue. (Notice posted July 19, 1999.)
The Effect of Spironolactone on Morbidity and Mortality in
Patients with Severe Heart Failure
Bertram Pitt, Faiez Zannad, Willem J. Remme, Robert Cody, Alain Castaigne, Alfonso Perez, Jolie Palensky,
Janet Wittes, for the Randomized Aldactone Evaluation Study Investigators
Background and Methods. Aldosterone is important in the pathophysiology of heart failure. In a double-blind
study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more
than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and
in some cases digoxin. A total of 822 patients were assigned to receive 25 mg of spironolactone daily, and 841
to receive placebo. The primary end point was death from all causes.
Results. The trial was discontinued early, after a mean follow-up period of 24 months, because an interim
analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46
percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence
interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the
spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death
from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the
spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence
interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement
in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class
(P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with
spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious
hyperkalemia was minimal in both groups of patients.
Conclusions. Blockade of aldosterone receptors by spironolactone, in addition to standard therapy,
substantially reduces the risk of both morbidity and death among patients with severe heart failure.
Aldosterone has an important role in the pathophysiology of heart failure. (1,2,3,4) Aldosterone promotes the
retention of sodium, the loss of magnesium and potassium, sympathetic activation, parasympathetic inhibition,
myocardial and vascular fibrosis, baroreceptor dysfunction, and vascular damage and impairs arterial compliance.
(4,5,6,7,8) Many physicians have assumed that inhibition of the renin-angiotensin-aldosterone system by an
angiotensin-converting-enzyme (ACE) inhibitor will suppress the formation of aldosterone. In addition, treatment
with an aldosterone-receptor blocker in conjunction with an ACE inhibitor has been considered relatively
contraindicated because of the potential for serious hyperkalemia. (9,10)
Consequently, aldosterone-receptor blockers are used infrequently in patients with heart failure. (11,12) There is
increasing evidence to suggest, however, that ACE inhibitors only transiently suppress the production of
aldosterone. (7,13,14,15,16) Furthermore, treatment with the aldosterone-receptor blocker spironolactone at a
daily dose of 12.5 to 25 mg in conjunction with standard doses of an ACE inhibitor, a loop diurectic, and in some
cases digoxin is pharmacologically effective and well tolerated, decreases atrial natriuretic peptide concentrations,
and does not lead to serious hyperkalemia (defined as a serum potassium concentration of at least 6.0 mmol per
liter). (17) On the basis of this information, we designed the Randomized Aldactone Evaluation Study (RALES)
to test the hypothesis that daily treatment with 25 mg of spironolactone would significantly reduce the risk of
death from all causes among patients who had severe heart failure as a result of systolic left ventricular
dysfunction and who were receiving standard therapy, including an ACE inhibitor, if tolerated.
Patients were eligible for enrollment if they had had New York Heart Association (NYHA) class IV heart failure
within the six months before enrollment and were in NYHA class III or IV at the time of enrollment, had been
given a diagnosis of heart failure at least six weeks before enrollment, were being treated with an ACE inhibitor (if
tolerated) and a loop diuretic, and had a left ventricular ejection fraction of no more than 35 percent within the six
months before enrollment (with no clinically significant intercurrent event). Treatment with digitalis and
vasodilators was allowed, but potassium-sparing diuretics were not permitted. Oral potassium supplements were
not recommended unless hypokalemia (defined as a serum potassium concentration of less than 3.5 mmol per
Patients were excluded from the study if they had primary operable valvular heart disease (other than mitral or
tricuspid regurgitation with clinical symptoms due to left ventricular systolic heart failure), congenital heart disease,
unstable angina, primary hepatic failure, active cancer, or any life-threatening disease (other than heart failure).
Patients who had undergone heart transplantation or were awaiting the procedure were also ineligible. Other
criteria for exclusion were a serum creatinine concentration of more than 2.5 mg per deciliter (221 µmol per liter)
and a serum potassium concentration of more than 5.0 mmol per liter. The institutional review boards or ethics
committees of all participating institutions approved the protocol, and all patients gave written informed consent.
After the initial evaluation, patients were randomly assigned in a double-blind fashion to receive either 25 mg of
spironolactone (Aldactone, Searle, Skokie, Ill.) once daily or a matching placebo. After eight weeks of treatment,
the dose could be increased to 50 mg once daily if the patient showed signs or symptoms of progression of heart
failure without evidence of hyperkalemia. If hyperkalemia developed at any time, the dose could be decreased to
25 mg every other day; however, the investigator was encouraged first to adjust the doses of concomitant
medications. Follow-up evaluations and laboratory measurements, including measurements of serum potassium,
were conducted every 4 weeks for the first 12 weeks, then every 3 months for up to 1 year and every 6 months
thereafter until the end of the study. Additional clinical laboratory tests were also performed at weeks 1 and 5.
Serum potassium was also measured at week 9 in patients for whom the dose was increased to 50 mg. Study
medication could be withheld in the event of serious hyperkalemia, a serum creatinine concentration of more than
4.0 mg per deciliter (354 µmol per liter), intercurrent illness, or any condition in which such a course was deemed
medically necessary to protect the patient's best interests. However, all patients remained in the study so that we
could track hospitalizations and deaths.
An independent data and safety monitoring board periodically reviewed the results in a blinded fashion. Event
committees whose members were unaware of the patients' treatment assignments assessed the causes of death
and reasons for hospitalization.
The primary end point of the study was death from any cause. Secondary end points included death from cardiac
causes, hospitalization for cardiac causes, the combined incidence of death from cardiac causes or hospitalization
for cardiac causes, and a change in the NYHA class. The effect of spironolactone was also assessed with the use
of six prerandomization variables: left ventricular ejection fraction, the cause of heart failure, the serum creatinine
concentration, age, the use of ACE inhibitors, and the use of digitalis.
The analysis of death from all causes (the primary end point) included all patients, according to the
intention-to-treat principle. Kaplan-Meier (18) methods were used to construct cumulative survival curves for the
two groups. The primary comparison between the two groups was based on a log-rank test. (19) Cox
proportional-hazards regression models (20) were developed to explore the effects of base-line variables on the
estimated effect of spironolactone. Formal assessment of efficacy used a group sequential monitoring plan with a
Lan-DeMets (21) stopping boundary and an O'Brien-Fleming (22) spending function.
The sample size was calculated on the basis of the following assumptions: the mortality rate in the placebo group
would be 38 percent, the risk of death would be 17 percent lower in the spironolactone group than in the
placebo group, and approximately 5 percent of the patients in the spironolactone group would discontinue
treatment during each year of the study. (23) The power of the study to detect a difference between treatment
groups was set at 90 percent (with a two-tailed (alpha) level of 0.05).
At each of its meetings, the data and safety monitoring board evaluated the available data for evidence of efficacy
and safety and calculated the cumulative type I error with respect to efficacy. In two large studies of patients with
heart failure, (24,25) the distributions of the time to death were nonexponential; therefore, the computations for
group sequential monitoring of mortality from all causes were based on life-table calculations of event rates. The
critical z value required to establish that treatment with spironolactone was efficacious was 2.02, corresponding
to a P value of 0.043.
Randomization was begun on March 24, 1995; recruitment was completed on December 31, 1996, with
follow-up scheduled to continue through December 31, 1999. However, at the fifth planned interim analysis, the
observed effect of spironolactone on the risk of death from all causes exceeded the prespecified critical z value.
Hence, the trial was stopped on August 24, 1998, after a mean follow-up of 24 months, on the recommendation
of the data and safety monitoring board. The analysis includes all events through midnight on August 24, 1998.
A total of 1663 patients from 195 centers in 15 countries underwent randomization: 841 were assigned to receive
placebo and 822 were assigned to receive spironolactone. As shown in Table 1, the two groups had similar
characteristics at base line. Seven patients (three in the placebo group and four in the spironolactone group) who
had a history of NYHA class IV heart failure were in NYHA class II at the time of randomization. During the
study, 414 patients (200 in the placebo group and 214 in the spironolactone group) discontinued treatment
because of a lack of response, because of adverse events, or for administrative reasons. Treatment was stopped
in an additional 19 patients (11 in the placebo group and 8 in the spironolactone group) because of the need for
heart transplantation; 2 patients, both of whom were in the placebo group, died after heart transplantation.
Patients who discontinued treatment were followed by means of regularly scheduled telephone calls to determine
their vital status. After 24 months of follow-up, the mean daily dose of study medication for the patients who
continued to receive treatment was 31 mg in the placebo group and 26 mg in the spironolactone group.
There were 386 deaths in the placebo group (46 percent) and 284 deaths in the spironolactone group (35
percent), representing a 30 percent reduction in the risk of death (relative risk of death among the patients in the
spironolactone group, 0.70 by a Cox proportional-hazards model; 95 percent confidence interval, 0.60 to 0.82;
P<0.001) (Figure 1 and Table 2). A total of 314 deaths in the placebo group (37 percent) and 226 deaths in the
spironolactone group (27 percent) were attributed to cardiac causes, representing a 31 percent reduction in the
risk of death from cardiac causes (relative risk, 0.69; 95 percent confidence interval, 0.58 to 0.82; P<0.001).
The reduction in the risk of death among the patients in the spironolactone group was attributed to significantly
lower risks of both death from progressive heart failure and sudden death from cardiac causes (Table 2).
The reduction in the risk of death among patients in the spironolactone group was similar in analyses of all six
prespecified subgroups as well as in retrospective analyses performed according to sex, NYHA class, base-line
serum potassium concentration, use of potassium supplements, and use of beta-blockers (Figure 2). The
estimated beneficial effect was similar across geographic regions.
Death from Cardiac Causes and Hospitalization for Cardiac Causes
During the trial, 336 patients in the placebo group and 260 patients in the spironolactone group were hospitalized
at least once for cardiac reasons (Table 2). In total, there were 753 hospitalizations for cardiac causes in the
placebo group and 515 in the spironolactone group, representing a 30 percent reduction in the risk of
hospitalization for cardiac causes among patients in the spironolactone group (relative risk, 0.70; 95 percent
confidence interval, 0.59 to 0.82; P<0.001) (Table 2). Analysis of the combined end point of death from cardiac
causes or hospitalization for cardiac causes revealed a 32 percent reduction in the risk of this end point among
patients in the spironolactone group as compared with those in the placebo group (relative risk, 0.68; 95 percent
confidence interval, 0.59 to 0.78; P<0.001) (Table 3).
Changes in NYHA Class
Three categories were used to assess changes in the symptoms of heart failure: improvement, no change, and
worsening or death. The condition of patients who were in NYHA class III at base line was considered to have
improved if they were in NYHA class I or II at the end of the study and considered to have worsened if they
were in NYHA class IV (or had died). The condition of patients who were in NYHA class IV at base line was
considered to have improved if they were in NYHA class I, II, or III at the end of the study; other patients in
NYHA class IV at base line either had no change at the end of the study or died. In the placebo group, the
condition of 33 percent of the patients improved; it did not change in 18 percent, and it worsened in 48 percent.
In the spironolactone group, the condition of 41 percent of the patients improved; it did not change in 21 percent,
and it worsened in 38 percent. The difference between groups was significant (P<0.001 by the Wilcoxon test).
There were no significant differences between the two groups in serum sodium concentration, blood pressure, or
heart rate during the study. The median creatinine and potassium concentrations did not change in the placebo
group during the first year of follow-up, the period for which the data were most complete. During the same
period, however, the median creatinine concentration in the spironolactone group increased by approximately
0.05 to 0.10 mg per deciliter (4 to 9 µmol per liter) and the median potassium concentration increased by 0.30
mmol per liter. The differences between the two groups were significant (P<0.001) but were not clinically
Table 4 lists the adverse reactions in the two groups. Serious hyperkalemia occurred in 10 patients in the placebo
group (1 percent) and 14 patients in the spironolactone group (2 percent, P=0.42). Gynecomastia or breast pain
was reported by 10 percent of the men in the spironolactone group and 1 percent of the men in the placebo
group (P<0.001), causing more patients in the spironolactone group than in the placebo group to discontinue
treatment (10 vs. 1, P=0.006).
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
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.
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
Supported by a grant from Searle, Skokie, Ill.
Preliminary data were presented at the American Heart Association meeting, Dallas, November 8-11, 1998.
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.
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.
Copyright © 1999 by the Massachusetts Medical Society. All rights reserved.