Original Article
Withdrawal of Digoxin from Patients with Chronic Heart Failure Treated with Angiotensin-Converting-Enzyme Inhibitors
N Engl J Med 1993; 329:1-7July 1, 1993
- Abstract
Background
Although digoxin is effective in the treatment of patients with chronic heart failure who are receiving diuretic agents, it is not clear whether the drug has a role when patients are receiving angiotensin-converting-enzyme inhibitors, as is often the case in current practice.
Methods
We studied 178 patients with New York Heart Association class II or III heart failure and left ventricular ejection fractions of 35 percent or less in normal sinus rhythm who were clinically stable while receiving digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor (captopril or enalapril). The patients were randomly assigned in a double-blind fashion either to continue receiving digoxin (85 patients) or to be switched to placebo (93 patients) for 12 weeks. Otherwise, their medical therapy for heart failure was not changed.
Results
Worsening heart failure necessitating withdrawal from the study developed in 23 patients switched to placebo, but in only 4 patients who continued to receive digoxin (P<0.001). The relative risk of worsening heart failure in the placebo group as compared with the digoxin group was 5.9 (95 percent confidence interval, 2.1 to 17.2). All measures of functional capacity deteriorated in the patients receiving placebo as compared with those continuing to receive digoxin (P = 0.033 for maximal exercise tolerance, P = 0.01 for submaximal exercise endurance, and P = 0.019 for New York Heart Association class). In addition, the patients switched from digoxin to placebo had lower quality-of-life scores (P = 0.04), decreased ejection fractions (P = 0.001), and increases in heart rate (P = 0.001) and body weight (P<0.001).
Conclusions
These findings indicate that the withdrawal of digoxin carries considerable risks for patients with chronic heart failure and impaired systolic function who have remained clinically stable while receiving digoxin and angiotensin-converting-enzyme inhibitors.
Media in This Article
Figure 1
Kaplan-Meier Analysis of the Cumulative Probability of Worsening Heart Failure in the Patients Continuing to Receive Digoxin and Those Switched to Placebo.Figure 2
Median Changes in Maximal Duration of Exercise after 2, 6, and 12 Weeks in the Patients Continuing to Receive Digoxin and Those Switched to Placebo.Article Activity
- Article
Although digitalis has been used for more than 200 years, its role in the treatment of chronic heart failure has been highly controversial. For many years, the debate surrounding digitalis was focused on the question of its usefulness in patients with normal sinus rhythm. Uncontrolled observations that the withdrawal of digoxin from such patients produced no ill effects aroused concern about the efficacy of the drug1,2. Such concern has recently been allayed, however, by several controlled studies showing that digoxin improves the symptoms and exercise tolerance of patients with normal sinus rhythm whose ventricular systolic function is impaired3-6. The lack of efficacy reported earlier may have been related to the fact that digoxin was withdrawn from patients with normal or nearly normal systolic function who could not have been expected to benefit from the drug3.
Despite evidence from controlled trials supporting its value, the use of digitalis remains controversial. The issue is no longer whether digoxin is effective in chronic heart failure but whether the drug has a role in current practice, when many patients are receiving angiotensin-converting-enzyme inhibitors. Such inhibitors exert hemodynamic and clinical benefits similar or superior to those achieved with digoxin6-11. In addition, they reduce the risk of death,12,13 whereas the effect of digitalis on survival is unknown14. These observations have led some investigators to conclude that digitalis adds little to the treatment of patients receiving converting-enzyme inhibitors, prompting some physicians to withdraw the drug from such patients. This practice has been encouraged by reports that the institution of therapy with captopril or enalapril can prevent the deterioration that follows the withdrawal of digoxin6,9,11. Little is known, however, about the consequences of withdrawing digoxin from patients who are clinically stable and already receiving converting-enzyme inhibitors, since such patients have not been evaluated in previous studies.
To assess the role of digoxin in patients receiving converting-enzyme inhibitors, we conducted the RADIANCE (Randomized Assessment of [the effect of] Digoxin on Inhibitors of the Angiotensin-Converting Enzyme) Study. Our primary objective was to evaluate the effect of the withdrawal of digoxin from patients with chronic heart failure who were clinically stable while receiving digoxin, diuretics, and a converting-enzyme inhibitor.
Methods
Patient Eligibility
Patients with chronic heart failure were enrolled at 43 centers in the United States and Canada. Heart failure was defined by the presence of dyspnea and fatigue on exertion in association with a left ventricular ejection fraction of 35 percent or less (as assessed by radionuclide ventriculography) and a left ventricular end-diastolic dimension of 60 mm (or 34 mm per square meter of body-surface area) or more (as assessed by two-dimensional echocardiography). All the patients had subjective and objective evidence of reduced exercise capacity, as demonstrated by exertional symptoms (New York Heart Association functional class II or III) and an exercise duration (as assessed by a modified Naughton protocol15) of 2 to 14 minutes, despite treatment for at least three months with digoxin, diuretics, and a converting-enzyme inhibitor. All the patients had normal sinus rhythm; those with a history of supraventricular arrhythmias or sustained ventricular arrhythmias were excluded from the study. Patients could not participate in the study if they had uncorrected primary valvular disease, active myocarditis, or an obstructive, hypertrophic, or restrictive cardiomyopathy. Patients were also excluded if they were less than 18 years old or if they had any of the following conditions: systolic blood pressure ≥ 160 mm Hg or <90 mm Hg or diastolic blood pressure >95 mm Hg; exercise limited by angina, lung disease, or claudication; angina requiring continuous treatment; myocardial infarction within the past 3 months or stroke within the past 12 months; or severe primary pulmonary, renal, or hepatic disease. The protocol was approved by the institutional review boards of all the participating institutions, and informed consent was obtained from all the study patients.
Study Protocol
The patients who fulfilled the criteria for enrollment entered an eight-week, single-blind run-in period during which the doses of background therapy for heart failure were adjusted to achieve optimal clinical benefits and concomitant therapy with direct-acting vasodilators or antiarrhythmic drugs with known cardiovascular effects was withdrawn. The investigators were asked to adjust the dose of digoxin to achieve a serum digoxin concentration of 0.9 to 2.0 ng per milliliter, to modify the dose of diuretic to achieve optimal fluid balance, and to increase the dose of the converting-enzyme inhibitor so that a daily dose of at least 25 mg of captopril or 5 mg of enalapril was achieved. During this run-in period, each patient's clinical status was assessed by a review of symptoms and by determination of the New York Heart Association functional class; quality of life was evaluated by the Minnesota Living with Heart Failure questionnaire16; vital signs were measured, cardiac size and function were determined (by chest radiography, two-dimensional echocardiography, and radionuclide ventriculography); and blood was collected for the evaluation of serum electrolytes and renal function. In addition, the patients underwent at least four maximal treadmill exercise tests (using a modified Naughton protocol15) until the durations of the last two tests were within 60 seconds of each other, and the patients underwent at least three 6-minute walk tests to assess submaximal exercise endurance17. Before randomization, background therapy with diuretics and the converting-enzyme inhibitor was kept constant for at least four weeks, and therapy with digoxin was kept constant for at least two weeks.
After the initial assessments, the patients were randomly assigned in a double-blind fashion either to continue receiving digoxin (the digoxin group) or to receive placebo instead of digoxin (the placebo group) for three months, while the background therapy with diuretics and the converting-enzyme inhibitor remained constant. Randomization was accomplished with a single randomization code (without the use of a central randomization office) and was stratified according to center with a block size of 4. After randomization, symptoms and functional status were examined every 2 weeks; treadmill exercise capacity was measured after 2, 6, and 12 weeks; exercise endurance (six-minute walk) was assessed after 4, 8, and 10 weeks; and quality of life and cardiac function and dimensions were evaluated after 12 weeks. The patients were not permitted to receive open-label digoxin during the study.
Patients were withdrawn from the study if there was both subjective and objective evidence of worsening heart failure severe enough to require a therapeutic intervention (i.e., a change in the background therapy, a visit to the emergency department, or hospitalization). Patients also discontinued their participation because of intolerable adverse reactions. To eliminate any bias in distinguishing between these two possibilities, a committee of investigators uninvolved in the patients' care and unaware of the treatment assignments classified the causes of withdrawal from the study (i.e., worsening heart failure, adverse reaction, or another reason) for all the patients who were withdrawn.
Statistical Analysis
The primary objectives of the study, as specified in the original protocol, were to compare the two study groups with respect to (1) rates of withdrawal from the study due to worsening heart failure, (2) time to withdrawal, and (3) changes in exercise tolerance (as assessed by both time and distance). The secondary objectives were to evaluate the effects of discontinuing digoxin therapy on symptoms, quality of life, functional class (as assessed by the investigator), overall progress during the study (as assessed by the patient), and cardiac dimensions and function.
All the analyses were carried out with methods specified before the treatment assignments were revealed. The base-line characteristics of the study groups were compared by an analysis of variance for continuous variables and by the Cochran-Mantel-Haenszel statistic for categorical variables18. Treatment effects were assessed by comparisons between groups, and analyses of all available data were carried out according to the patients' randomized assignments (by the intention-to-treat principle). The frequency of withdrawal from the study due to worsening heart failure and the time to withdrawal were compared between groups by the Pearson chi-square statistic and the log-rank test,19 respectively. The duration of exercise and the distances covered were compared by a nonparametric analysis of covariance (the Cochran-Mantel-Haenszel test), with adjustment for base-line exercise performance, base-line ejection fraction, and study center. The same procedure was used to evaluate functional class and overall progress, except that the P value was adjusted only for the study center. As specified in advance, the patients who were withdrawn from the study because of worsening heart failure were assigned the lowest rank in these analyses, whereas the patients who were withdrawn for other reasons had the last double-blind measurement carried forward to subsequent time points. Changes in symptoms, quality of life, and cardiac dimensions and function were compared by analysis of covariance after adjustment for center, and no rank was assigned to the patients withdrawn from the study. All the analyses were two-sided, and differences with a P value less than 0.05 were considered statistically significant.
Results
Two hundred sixteen patients were evaluated for entry into the study, 38 of whom were not randomized because they did not meet the criteria for eligibility. The remaining 178 patients (136 men and 42 women) entered the double-blind phase of the trial. The cause of heart failure was coronary artery disease in 107 patients, idiopathic cardiomyopathy in 67, and surgically corrected valvular disease in 4; 130 patients had class II symptoms, and 48 patients had class III symptoms. The mean left ventricular ejection fraction was 27 percent. The mean daily dose of digoxin was 0.38 mg (range, 0.125 to 0.50), which produced a mean serum digoxin concentration of 1.2 ng per milliliter (range, 0.5 to 2.2); the mean daily doses of captopril and enalapril were 74 mg and 15 mg, respectively.
Of the 178 patients, 85 were randomly assigned to continue receiving digoxin (the digoxin group), and 93 were assigned to receive placebo instead of digoxin (the placebo group). The two groups were similar with respect to all pretreatment characteristics, including age, sex, cause and severity of heart failure, exercise tolerance, cardiac function and dimensions, vital signs, and the use of digoxin, diuretics, and converting-enzyme inhibitors (Table 1Table 1
Pretreatment Characteristics of the Study Patients.).Effect on Primary End Points
During the 12-week double-blind study period, the clinical severity of heart failure worsened enough to require therapeutic intervention in 23 patients who received placebo but in only 4 patients who continued to receive digoxin (P<0.001). The relative risk of worsening heart failure in the placebo group as compared with the digoxin group was 5.9 (95 percent confidence interval, 2.1 to 17.2). Of the 27 patients with worsening heart failure, 14 required care in the emergency department or hospitalization (12 in the placebo group as compared with 2 in the digoxin group; P = 0.02). Figure 1Figure 1
Kaplan-Meier Analysis of the Cumulative Probability of Worsening Heart Failure in the Patients Continuing to Receive Digoxin and Those Switched to Placebo. shows the probability of clinical deterioration, plotted as a function of time. In general, the patients continuing to receive digoxin remained stable during the study period, whereas there was a high risk of worsening heart failure in the patients receiving placebo (P<0.001). The difference in risk between the two groups increased progressively over time.Maximal treadmill exercise tolerance remained stable in the patients continuing to receive digoxin, but exercise tolerance deteriorated in those switched to placebo. When the patients withdrawn because of worsening heart failure were assigned the lowest rank (as was specified before the study began), the difference in exercise duration between the two study groups after 12 weeks was 43 seconds (P = 0.033) (Figure 2Figure 2
Median Changes in Maximal Duration of Exercise after 2, 6, and 12 Weeks in the Patients Continuing to Receive Digoxin and Those Switched to Placebo.). When the prespecified correction was not carried out (in which case the analysis was biased against digoxin), the difference in exercise duration between the two groups was 42 seconds (P = 0.006). Similarly, exercise endurance (defined as the distance walked in six minutes) remained constant in the patients continuing to receive digoxin but decreased in those receiving placebo. When the patients withdrawn from the study because of worsening heart failure were assigned the lowest rank (as specified in advance), the difference in distance traversed between the groups after 10 weeks was 41 m (P = 0.01) (Figure 3Figure 3
Median Changes in Submaximal Exercise Endurance after 4, 8, and 10 Weeks in the Patients Continuing to Receive Digoxin and Those Switched to Placebo.). When the prespecified correction was not carried out (biasing the analysis against digoxin), the difference between groups was 23 m (P = 0.01).In the patients receiving placebo, the deterioration in clinical status and exercise capacity was associated with a decrease in the serum digoxin concentration from 1.1 ±0.03 ng per milliliter at the time of randomization to negligible levels after 12 weeks. The mean serum digoxin concentration did not change in the patients who continued to receive digoxin.
Effect on Secondary End Points
During the study, both the physicians and the patients were asked about any changes in the patients' overall condition. When the patients' clinical course was assessed by investigators, deterioration in New York Heart Association functional class was reported in 27 percent of those receiving placebo but only 10 percent of those continuing to take digoxin (P = 0.019 when the patients withdrawn from the study were assigned to the lowest rank and P = 0.038 in the absence of such assignment). When the patients assessed their own overall progress, 31 percent of those receiving placebo reported that they felt moderately worse or much worse, as compared with 9 percent of those continuing to receive digoxin (P = 0.007) (Table 2Table 2
Patients' Assessments of Their Overall Progress during the Study.).Even patients who remained in the study (and were not withdrawn because of worsening heart failure) had worsening symptoms when digoxin was discontinued. Among these patients, dyspnea and fatigue each became worse in 38 percent of the patients in the placebo group, but they worsened in 16 and 18 percent, respectively, of the patients in the digoxin group (P = 0.14 and P = 0.04, respectively). After 12 weeks, quality of life (as assessed by the Minnesota Living with Heart Failure questionnaire) improved less frequently and deteriorated more frequently in the patients receiving placebo (33 percent and 48 percent, respectively) than in those continuing to receive digoxin (47 percent and 41 percent, P = 0.04).
Cardiac function and dimensions worsened moderately but significantly in the patients receiving placebo (Table 3Table 3
Comparison of Cardiac Dimensions, Cardiac Function, and Vital Signs before Randomization and after the 12-Week Study Period.). Among the patients who did not drop out of the study, the left ventricular end-systolic and end-diastolic dimensions increased and the left ventricular ejection fraction decreased in the patients receiving placebo as compared with those continuing to receive digoxin. The patients receiving placebo also had decreases in systolic blood pressure and increases in diastolic blood pressure, heart rate, and body weight (Table 3).Adverse Reactions
The overall frequency of side effects was similar in the two treatment groups (56 percent in the placebo group and 49 percent in the digoxin group), but adverse reactions serious enough to require the discontinuation of therapy were significantly more frequent in the patients receiving placebo than in those continuing to receive digoxin (37 percent vs. 14 percent, respectively; P<0.001) (Table 4Table 4
Reasons for Withdrawal from the Study during the Study Period.). This difference was related to the higher incidence of worsening heart failure in the patients receiving placebo. According to the intention-to-treat analysis, three patients in the digoxin group and one patient in the placebo group died during the 12-week study period.Discussion
Our findings indicate that the discontinuation of digoxin therapy in patients with chronic heart failure in normal sinus rhythm who were receiving diuretic agents and a converting-enzyme inhibitor often resulted in clinical deterioration. The withdrawal of digoxin was accompanied by a progressive decline in clinical status (as reflected by a worsening of functional class and exercise tolerance), whereas patients who continued to receive the drug remained stable. The worsening of heart failure was severe enough to require additional treatment in 25 percent of the patients who discontinued digoxin but in only 5 percent of those who continued to receive the drug; in half these patients, emergency care or hospitalization was required. Even in the patients who were able to complete the study, the withdrawal of digoxin therapy was accompanied by a worsening of symptoms, exercise tolerance, and quality of life. These observations indicate that the discontinuation of digoxin carries considerable hazards for patients with heart failure, even those who have mild symptoms, are clinically stable, and are receiving optimal medical therapy.
Our findings do not support the hypothesis that the use of converting-enzyme inhibitors obviates the need for digoxin in patients with chronic heart failure. In several earlier studies, the deterioration seen in patients after the discontinuation of digoxin did not occur when converting-enzyme inhibitors were substituted for digoxin6,9,11. This observation suggested that such inhibitors might interfere with a mechanism that is activated after the withdrawal of digoxin and that is important in the pathogenesis of worsening heart failure. Since digoxin suppresses the release of renin by virtue of its inhibitory action on renal tubular Na+/K+-ATPase,20-22 its withdrawal may be expected to increase the activity of the renin-angiotensin system, which could lead to clinical deterioration; this effect would be blocked by a converting-enzyme inhibitor. However, the findings of the present study in patients receiving converting-enzyme inhibitors are similar to those of previous studies carried out in patients who were not receiving converting-enzyme inhibitors3-6. As in the present study, the discontinuation of digoxin in these earlier reports was associated with a deterioration of symptoms,3-6 maximal exercise capacity,5 and submaximal exercise endurance4; the patients switched from digoxin to placebo also had an increased need for therapeutic interventions (including higher doses of diuretics and more frequent visits to the emergency department and hospitalizations)4-6. The similarity between our findings and those of earlier studies suggests that converting-enzyme inhibitors do not diminish the efficacy of digoxin in patients with heart failure in normal sinus rhythm.
An interesting finding in the present study is that the clinical deterioration observed after the withdrawal of digoxin in many patients was delayed, frequently occurring weeks after the drug was presumably cleared from the circulation. During the second half of the study (6 to 12 weeks after randomization), clinical deterioration was seen in 10 patients who were withdrawn from digoxin but in none who continued to receive the drug, and it is possible that the Kaplan-Meier plots showing the probability of worsening heart failure in the two treatment groups would have continued to diverge if the study had continued beyond 12 weeks. Although this pattern of response may be related to the persistence of digoxin in body stores or at active sites, the delayed deterioration seen in this study after the withdrawal of active therapy is similar to (although in the opposite direction from) the delayed improvement seen when effective drugs are introduced into the medical therapy of patients with chronic heart failure23-25. The physiologic explanation for the occurrence of such delayed effects is unknown, but their existence suggests that the usefulness of digoxin in an individual patient with heart failure may require months to assess adequately. Consequently, previous studies in which brief periods of withdrawal from a drug were used may have underestimated the efficacy of the drug3,4,6,8,10,26-28.
Our study does not permit elucidation of the mechanism by which digoxin produces clinical benefits in patients with chronic heart failure. The drug increases the contractility of the failing heart, and the loss of the positive inotropic effect may explain why cardiac performance deteriorated after the withdrawal of the drug, as reflected by a decrease in the left ventricular ejection fraction and pulse pressure and an increase in cardiac dimensions. In fact, it is likely that we underestimated the magnitude of these hemodynamic efects, since cardiac performance was not reevaluated in the patients who were withdrawn from the study because of clinical deterioration. However, since there may be little relation between these hemodynamic actions and the clinical response to digoxin,29,30 other mechanisms may have a role in mediating the effects of the drug. Short- and long-term therapy with digoxin reduces the activation of the sympathetic nervous system in patients with chronic heart failure,8,21,31 possibly by sensitizing cardiac and aortic baroreceptors, thereby reducing the outflow of sympathetic impulses from the central nervous system31. This neurohormonal effect of digoxin can be demonstrated even in patients who are receiving a converting-enzyme inhibitor7. Unfortunately, neurohormonal variables were not measured in the present study, but our finding that heart rate and body weight increased after the substitution of placebo for digoxin suggests that the withdrawal of digoxin was associated with the activation of neurohormonal systems. Although the importance of this neurohormonal action remains unknown, the inhibitory actions of digoxin on the sympathetic nervous system can be expected to complement the inhibitory action of converting-enzyme inhibitors on the renin-angiotensin system.
The results of the present study raise but fail to resolve two important issues with regard to the role of digoxin in chronic heart failure. First, as in previous controlled studies with digoxin,3,4,27-30 we evaluated the efficacy of the drug by using doses selected so that they would achieve a serum digoxin concentration between 0.9 and 2.0 ng per milliliter. This strategy resulted in the administration of doses of digoxin higher than those commonly used in clinical practice. Whereas physicians commonly prescribe digoxin in daily doses of 0.125 to 0.25 mg, the average daily dose of digoxin in our study was 0.38 mg, and 60 to 70 percent of our patients received daily doses greater than 0.25 mg. It is not clear, however, that such doses are required to produce clinical benefits in patients with chronic heart failure, since digoxin was effective in a large study in which lower doses were prescribed5. Further studies are needed to elucidate the dose-response relations of digoxin in patients with heart failure and to determine whether these relations are altered in the presence of a converting-enzyme inhibitor. Until such data are available, it is likely that physicians will continue to prescribe doses of digoxin lower than those shown to be effective in controlled trials; a similar pattern characterizes the use of converting-enzyme inhibitors in heart failure.
Second, although we observed serious adverse reactions less frequently in the digoxin group than in the placebo group, the present study cannot adequately evaluate the safety of digoxin in patients with chronic heart failure treated with converting-enzyme inhibitors. Since the trial was designed to involve the withdrawal of active therapy, all the patients had tolerated digoxin well for long periods before entering the trial. Patients who could not tolerate digoxin therapy were not enrolled, and thus it is not surprising that no adverse reactions attributable to the drug were seen. A similar pattern of safety might not have been observed if we had enrolled patients who had never received digoxin and had added the drug (or placebo) to background therapy. Furthermore, since the present study was designed to evaluate the effect of digoxin on functional capacity, we did not observe a sufficient number of deaths to permit any insight into the effect of digoxin on survival. This issue is being evaluated in an ongoing study of 8000 patients with heart failure treated with converting-enzyme inhibitors32.
In conclusion, the present study demonstrates that the withdrawal of digoxin carries considerable risks for patients with chronic heart failure and impaired systolic function in normal sinus rhythm who are receiving diuretic agents and converting-enzyme inhibitors. These findings support a continuing role for the drug in clinical practice.
Supported by a grant from Burroughs Wellcome Co. The study was coordinated by G.H. Besselaar Associates.
Source Information
From the Mount Sinai School of Medicine, New York (M.P.); Henry Ford Hospital, Detroit (M.G.); Baylor College of Medicine, Houston (J.B.Y.); the University of Medicine and Dentistry of New Jersey, Camden (P.J.C.); the University of North Carolina, Chapel Hill (K.F.A.); Ohio State University School of Medicine, Columbus (R.J.C.); the Arizona Heart Institute, Tucson (L.K.S.); the Washington Hospital Center, Washington, D.β(L.V.V.); G.H. Besselaar Associates, Princeton, N.J. (L.A.G.); and Burroughs Wellcome Co., Research Triangle Park, N.β(M.K.J.).
Address reprint requests to Dr. Packer at the Division of Circulatory Physiology and Center for Heart Failure Research, Columbia University, College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032.
Appendix
In addition to the study authors, the following centers and principal investigators participated in the RADIANCE Study: Cardiology Associates, Allentown, Pa.: J. Sandberg and C. Yurick; Maryland General Hospital, Baltimore: D. Goldscher and S. DePetris; University of Maryland and Veterans Affairs Medical Center, Baltimore: M. Fisher and N. Greenberg; University of Calgary and Foothills Hospital, Calgary, Alta.: D.E. Manyari and L. Shindel; University of North Carolina, Chapel Hill: J.H. Patterson, S. Clarke, and S.V. O'Quinn; Clearlake, Calif.: R. Detje and C. Chisolm; Case Western Reserve University and St. Luke's Hospital, Cleveland: J.I. Krall and M.K. Shelton; University Hospitals of Cleveland, Cleveland: M. Munger and M. Chance; Ohio State University School of Medicine, Columbus: G. Haas and L. Janusch; Metroplex Clinical Research Center, Dallas: S.L. Cohen and S.M. Rush; University of Colorado School of Medicine, Denver: R. Rothbart and G. Bailey; Henry Ford Hospital, Detroit: V. Hall; Palomar Medical Group, Escondido, Calif.: R.M. Stein and R. Siebert; Greenbrae, Calif.: J. Sklar and C. Clay; Mesaba Clinic, Hibbing, Minn.: R.R. Moyer and L.M. Hill; Baylor College of Medicine, Houston: M. Francis; Cardiovascular Consultants of Nevada, Las Vegas: A. Rhodes and R. Vanselow; Jersey Research Foundation, Linwood, N.J.: P.M. Kirschenfeld, B.E. Ojserkis, R. Matheson, and D. Stanley; St. Mary Medical Center, Long Beach, Calif.: S. Tobias and C. Tayek; Los Angeles: H.L. Alpern and M. Takatani; Peabody Medical Group, Memphis, Tenn.: J. Galyean and S.J. Smith; University of Wisconsin and Sinai Samaritan Medical Center, Milwaukee: T. Bajwa and C. Maglio; Louisiana Cardiovascular Research Center, New Orleans: W. Smith and T. Serpas; Columbia University, College of Physicians and Surgeons, New York: J. Coromilas, G. Radasolovich, D. Pinsky, and S. Jozak; Mount Sinai School of Medicine and Bronx Veterans Affairs Hospital, New York: M. Kukin, M. Abittan, Z. Neuwirth, and D. Ahern; Oklahoma Medical Research Foundation, Oklahoma City: C. Corder and G.A. Evans; University of Nebraska Medical Center, Omaha: J.R. Campbell, D.V. O'Dell, and J. Coleman; Cardiology Research Associates, Ormond Beach, Fla.: J.J. Walker and D. Tracey; Burns Medical Center, Petroskey, Mich.: H.T. Colfer, C. Shaw, and K. Graham; University of California, Davis: G. Hilliard and B. Holmes; Minerva Consertal, Sacramento, Calif.: N. Awan and L. Sears; Wilford Hall Medical Center, U.S. Air Force, San Antonio, Tex.: L. Spaccavento and M.J. Burns; Mercy Hospital and Medical Center, San Diego, Calif.: W.A. Pitt and M. Hundley; Sharp Rees-Stealy Medical Group, San Diego, Calif.: H. Ingersoll and M. Jimenez; University of California, San Francisco: K. Chatterjee, C. Klinski, and D. Lau; University of Sherbrooke, Sherbrooke, Que.: J.-L. Rouleau and L. Charbonneau; Veterans Affairs Medical Center, St. Louis: G. Williams and R. Genovely; St. Louis: R.N. Riner and C. Bode; Ventura Heart Institute, Thousand Oaks, Calif.: I. Loh, J. Melvin, and C. Smith; Arizona Heart Institute, Tucson: L. Davis; University of Arizona College of Medicine, Tucson: S. Butman and J. Wild; Washington Hospital Center, Washington, D.C.: R. Powers and A. Silverman; and Colima Internal Medicine Group, Whittier, Calif.: A. Dauer and V. Holt.
Steering Committee: M. Packer (chair), K. Chatterjee, R. Cody, M. Gheorghiade, S. Goldstein, and J. Young. Data and Safety Monitoring Board: R. Gorlin, G.S. Francis, M. Jessup, and J. Wilson.
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