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(Circulation. 1996;94:2800-2806.)
© 1996 American Heart Association, Inc.

Articles

Carvedilol Inhibits Clinical Progression in Patients With Mild Symptoms of Heart Failure

Wilson S. Colucci, MD; Milton Packer, MD; Michael R. Bristow, MD, PhD; E. Michael Gilbert, MD; Jay N. Cohn, MD; Michael B. Fowler, MD; Steven K. Krueger, MD; Ray Hershberger, MD; Barry F. Uretsky, MD; John A. Bowers, MD; Jonathan D. Sackner-Bernstein, MD; Sarah T. Young, PhD; Terry L. Holcslaw, PhD; Mary Ann Lukas, MD;; for the US Carvedilol Heart Failure Study Group*

the Boston University School of Medicine, Boston, Mass (W.S.C.); the College of Physicians and Surgeons, Columbia University, New York, NY (M.P., J.D.S.-B.); University of Colorado Health Sciences Center, Denver (M.R.B.); University of Utah School of Medicine, Salt Lake City (E.M.G.); University of Minnesota Medical School, Minneapolis (J.N.C.); Stanford University School of Medicine, Palo Alto, Calif (M.B.F.); Nebraska Heart Institute, Lincoln (S.K.K.); University of Oregon School of Medicine, Portland (R.H.); Presbyterian University Hospital, Pittsburgh (B.F.U.); Heart Institute of Nevada, Las Vegas (J.A.B.); and SmithKline Beecham Pharmaceuticals, King of Prussia, Pa (S.T.Y., T.L.H., M.A.L.).

	Abstract

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Background We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction.

Methods and Results Patients (n=366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF) 0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n=232) or placebo (n=134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (P=.008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated.

Conclusions Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

Key Words: carvedilol • heart failure • receptors, adrenergic, beta • antioxidants

	Introduction

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Most trials in patients with heart failure have focused on patients with moderate and severe symptoms who demonstrate continued disability and limitations despite the use of optimal medical therapy. In such patients, the relief of symptoms and improvement in the quality of life is an important goal of therapy. However, the majority of patients with heart failure have only mild symptoms and respond well to medical therapy. These patients manifest little disability and few limitations and therefore are generally not considered candidates for additional treatment. Yet, patients with mild symptoms (eg, NYHA functional class II) remain at risk for clinical progression, despite optimal use of available medications.¹

One of the most important mechanisms that may be responsible for progression of heart failure is activation of the sympathetic nervous system.^{2 3 4 5} This neurohormonal system is activated early in the disease and is the principal system activated in patients with mild symptoms.⁶ This observation suggests that drugs that interfere with the actions of the sympathetic nervous system in heart failure (eg, ß-blockers) may reduce the risk of disease progression in patients with only mild symptoms. However, previous studies of ß-blockers in heart failure have focused on patients with established symptoms with the intent of improving symptoms and the quality of life.^{7 8 9 10 11 12} No study has been specifically designed to determine whether ß-blockers can prevent disease progression in patients with mild symptoms who are responding adequately to medical therapy.

Consequently, when the US Carvedilol Heart Failure Program was being developed to evaluate the effects of the ß-blocker carvedilol, one of the four component trials was specifically designed to test the hypothesis that long-term treatment with this drug inhibits clinical progression in patients with mild symptoms of heart failure and minimal functional limitation on standard therapy consisting of an ACE inhibitor, diuretics, and digitalis. The study reported here is thus one of four prospectively designed trials that shared a common screening procedure but otherwise were independent with regard to their study populations and primary end points.

Carvedilol is a nonselective ß-adrenergic receptor antagonist that also blocks ₁-adrenergic receptors and is a potent antioxidant.^{13 14} Previous studies have demonstrated that carvedilol can improve the clinical status of patients with symptoms of heart failure that had not responded adequately to medical therapy,^{15 16 17 18} but these studies did not address the potential utility of the drug in clinically stable, well-compensated patients.

	Methods

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Study Population
Patients 18 to 85 years old with chronic symptomatic heart failure, defined as dyspnea or fatigue at rest or on exertion for 3 months, and a left ventricular ejection fraction (LVEF) 0.35 by radionuclide ventriculography were enrolled at 54 centers across the United States. Symptoms had to be present for at least 2 months despite treatment with diuretics and an ACE inhibitor (if tolerated). Treatment with digoxin, hydralazine, and nitrates was allowed but not required. During the 1 month before study enrollment, there could be no change in NYHA class, no change in medications or dosages, and no hospitalization for heart failure.

Patients were excluded if any of the following were present: uncorrected primary valvular disease or nondilated or hypertrophic cardiomyopathy; symptomatic or sustained ventricular tachycardia not controlled by antiarrhythmic agents or an implantable defibrillator within the previous 3 months; a myocardial infarction, unstable angina, or coronary artery bypass graft surgery within the previous 3 months; the likelihood of percutaneous transluminal angioplasty, coronary artery bypass graft surgery, or heart transplantation within 12 months; sick sinus syndrome or second- or third-degree heart block unless treated with a non–fixed-rate pacemaker; any condition other than symptomatic heart failure that could limit exercise, such as peripheral vascular disease, pulmonary disease, angina, cor pulmonale, or arthritic, orthopedic, or neurological conditions; a sitting systolic blood pressure <85 mm Hg or uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg); clinically significant hepatic or renal disease; or any illness or disorder that could preclude participation or limit survival. Women with heart failure in the 12 months after childbirth were excluded. Patients treated with any of the following drugs within the 2 weeks before screening were excluded: disopyramide, flecainide, encainide, moricizine, propafenone, sotalol, calcium channel blockers, -adrenergic blockers, ß-adrenergic blockers, labetalol, flosequinan, and monoamine oxidase inhibitors. Patients treated with amiodarone within 3 months before screening were excluded. The study was approved by the institutional review board of each investigative site, and all the patients provided written informed consent.

Study Procedures
Eligibility was determined during a 3-week screening phase during which inclusion and exclusion criteria were determined, and enrollment was stratified by use of a 6-minute corridor walk test.¹⁹ Initially, patients who walked between 425 and 550 m were entered into the trial, and patients who walked <425 m were entered into other protocols.^{20 21 22} Early in the trial (after 9% of patients were entered), the lower cutoff point for walk distance was increased to 450 m. During the screening period, the LVEF was measured by radionuclide ventriculography, the NYHA functional classification was determined, quality of life was assessed by the Minnesota Living With Heart Failure Questionnaire,²³ and the distance walked in 9 minutes on a self-powered treadmill²⁴ was measured. Heart failure symptoms were quantified by use of a symptom score that was determined by patients' answers to seven questions that ranked the severity of their heart failure symptoms and level of well-being on a scale of 0 to 3.¹⁶

Screening was followed by a 2-week challenge phase during which patients received open-label carvedilol (6.25 mg BID). The challenge dosage could be reduced to 3.125 mg BID if the 6.25-mg dosage was not tolerated. Patients who tolerated a carvedilol dosage of 6.25 mg BID during the challenge phase were randomized in a 2:1 ratio of carvedilol to placebo and underwent a 2- to 6-week double-blind up-titration phase, beginning at 12.5 mg BID and proceeding in weekly steps to either the maximum tolerated dosage or the maximum dosage allowed by the protocol (25 mg BID for patients weighing <85 kg; 50 mg BID for heavier patients). Patients then entered a maintenance phase and continued on the established dosage for an additional 12 months. Patients were seen monthly for the first 4 months and then at 6, 9, and 12 months. During the maintenance phase, background therapy of heart failure medications was held constant whenever possible. However, if adverse events occurred, concomitant drug dosages could be adjusted. At each visit, body weight and NYHA classification were ascertained, and the heart failure symptom self-assessment and global patient and physician assessments were performed. At 6 and 12 months, LVEF, quality of life, and 9-minute self-powered treadmill assessments were completed.

The study was terminated early by the Executive Committee on the recommendation of the Data Safety Monitoring Board on the basis of the finding that in the overall trial program, a survival advantage was demonstrated by the patients receiving carvedilol.

Statistical Analysis
The primary end point, progression of heart failure, was defined as (1) death due to heart failure, (2) hospitalization for heart failure (as indicated by investigators on the case report forms), or (3) the need for a sustained increase in heart failure medications. An increase in heart failure medications was defined as a 50% increase in the dosage of diuretic, ACE inhibitor, or vasodilator or the addition of a new class of heart failure medications that was sustained for at least 30 days. The components of the primary end point were scored in a hierarchical order (death took precedence over hospitalization, hospitalization took precedence over an increase in medications) so that patients with more than one of the end points were counted only once. The secondary end points, as specified in the original protocol, were LVEF, NYHA functional class, heart failure score, physician and patient global assessments, quality-of-life assessment, distance walked in the 9-minute self-powered treadmill test, and heart size on chest radiograph. The power calculation for the study was based on the assumption that 25% of the patients in the placebo group would meet the criteria for worsening heart failure and that carvedilol would reduce this risk by 50%.

The analysis of the primary end point was performed on an intention-to-treat basis. The proportion of patients with worsening heart failure was analyzed by the Cochran-Mantel-Haenszel procedure²⁵ stratified by center. All-cause mortality was summarized by treatment group on an intention-to-treat basis by construction of Kaplan-Meier curves for each group and comparison of the distribution of the groups by a log-rank test. The progression of heart failure was also summarized by Kaplan-Meier curves. The analyses of the secondary end points were performed on a per-protocol basis with the last observation carried forward. When the protocol was terminated, the 12-month evaluation was performed whenever possible on patients who had not completed the trial. The change from baseline for all continuous variables was analyzed by an ANOVA that included the effects of study center, treatment group, and their interaction.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
Patient Characteristics
At the time of study termination, 389 patients had received at least one challenge dose of carvedilol. Of these, 366 patients completed the challenge phase and were randomized to placebo (n=134) or carvedilol (n=232). The two groups were balanced with regard to age, sex, race, cause of heart failure, duration of heart failure, NYHA functional class, and LVEF (Table 1). The large majority of patients (84%, placebo; 86%, carvedilol) were in NYHA functional class II, reflecting the entry requirement that they be able to walk 450 to 550 m in a 6-minute walk test. The 6-minute walk distance was similar in the two groups. Essentially all patients in both groups were receiving an ACE inhibitor (98% overall), and the large majority were receiving digitalis (89% overall) and a loop-active diuretic (92% overall).

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Randomized Patients

Patient Disposition
Of the 389 patients who entered the open-blind challenge phase, 23 (5.9%) did not complete this phase. One patient died of worsening heart failure, 2 other patients had worsening of heart failure, and 13 had an adverse experience other than worsening heart failure, most often dizziness or hypotension. The other reasons for not completing the challenge phase were protocol deviation (2 patients), being lost to follow-up (2 patients), and early termination of the study (3 patients).

Of the 366 patients who entered the double-blind phase, 89.6% of placebo and 92.7% of carvedilol patients were still receiving double-blind medication at the time the study was terminated. The mean and median follow-up periods were 213 and 209 days, respectively. Of the 189 carvedilol patients who completed the up-titration phase, 85% achieved their target dosage of 25 mg BID (or 50 mg BID for patients weighing 85 kg). During the double-blind up-titration period, 19.6% of placebo patients and 17.4% of carvedilol patients required an increase in dosage or the addition of a heart failure medication.

Progression of Heart Failure
Clinical progression of heart failure occurred in 20.9% (28/134) of placebo patients and 11% (25/232) of carvedilol patients, reflecting a 48% (P=.008) reduction in the primary end point (Fig 1). The relative risk of heart failure progression was 0.52 (CI, 0.32 to 0.85). The reduction in the overall progression of heart failure end point was paralleled by similar reductions in each of the component end points. No deaths in the carvedilol group were attributed to heart failure, whereas 4 placebo patients (3%) died of heart failure (sudden death, 2; pump failure, 2). Hospitalization for worsening heart failure occurred less often in carvedilol patients (4%, 9/232) than placebo patients (6%, 8/134). Likewise, the need to increase heart failure medications occurred less often in carvedilol patients (6.9%, 16/232) than placebo patients (11.9%, 16/134). The most common increases in heart failure medications were as follows. Diuretics were increased or added in 6% of placebo patients and 5.8% of carvedilol patients; the dosage of ACE inhibitor was increased in 4.5% of placebo patients but no carvedilol patients; other vasodilators were increased or added in 1.5% of placebo patients and 1.3% of carvedilol patients. The beneficial effect of carvedilol continued to be significant even if the increase in heart failure medication component was removed from the analysis (P=.049).

View larger version (25K): [in this window] [in a new window]   Figure 1. Effect of carvedilol on the clinical progression of heart failure (CHF) in 366 patients randomized to carvedilol (n=232) or placebo (n=134). The progression of heart failure was defined as death due to heart failure, hospitalization for heart failure, or the need to increase heart failure medications.

Kaplan-Meier analysis demonstrated that the beneficial effect of carvedilol was evident early in therapy (after 50 days) and increased gradually to the end of the trial (Fig 2). The beneficial effect of carvedilol on the progression of heart failure was not affected by sex, age, race, cause of heart failure, or LVEF (Table 2).

View larger version (15K): [in this window] [in a new window]   Figure 2. Kaplan-Meier plot of the progression of heart failure in patients randomized to carvedilol or placebo, as described in Fig 1. Carvedilol reduced the occurrence of heart failure progression by 48% (P=.007). The relative risk of heart failure was 0.52 (CI, 0.32 to 0.85).

View this table: [in this window] [in a new window]   Table 2. Effect of Carvedilol on the Progression of Heart Failure in Subgroups

All-Cause Mortality
Analyzed on an intention-to-treat basis, 4.0% (5/134) of placebo patients and 0.9% (2/232) of carvedilol patients died during double-blind therapy (risk ratio, 0.231; CI, 0.045 to 1.174; P=.048). Three placebo patients and one carvedilol patient underwent cardiac transplantation and were censored from the data.

Functional Classification
From baseline to the study end point, the NYHA functional class improved in 12% of carvedilol patients versus 9% of placebo patients, whereas it worsened in 4% of carvedilol patients versus 15% of placebo patients (Table 3). The distribution of the changes in NYHA functional classes from baseline to study end point was more favorable in carvedilol than in placebo patients (P=.003).

View this table: [in this window] [in a new window]   Table 3. Effect of Carvedilol on Measures of Clinical Status From Baseline to Study End Point

Heart Failure Symptom Score
Changes in the heart failure symptom score over the course of the trial differed directionally in the treatment groups (Table 3). The symptom score worsened in placebo patients but improved in carvedilol patients (P=.006).

Patient and Physician Global Assessments
Throughout the study, more carvedilol patients than placebo patients rated their heart failure symptoms as improved (Table 3). The difference between carvedilol and placebo was significant at the study end point (P=.013). Likewise, the physician global assessment indicated a greater improvement in carvedilol than placebo patients from baseline to study end point (P<.001). Importantly, for both the patient and physician assessments, the percentage of patients rated as worse was less in the carvedilol group.

Quality of Life
All scores (total, physical, and emotional dimensions) on the Minnesota Living With Heart Failure Questionnaire at study end point improved more in carvedilol than in placebo patients, but none of these differences reached statistical significance (Table 3).

Ejection Fraction
The LVEF was available at 12 months or the time of study termination in 266 patients. At baseline, the mean LVEF was similar in the placebo (0.22) and carvedilol (0.22) patients. The mean change in LVEF was larger in carvedilol (0.10) than in placebo (0.03) patients (P<.001) (Fig 3).

View larger version (43K): [in this window] [in a new window]   Figure 3. Effect of carvedilol on left ventricular ejection fraction measured at baseline and study end point (P<.001 vs placebo).

Nine-Minute Self-Powered Treadmill
The distances walked in 9 minutes on the self-powered treadmill decreased slightly from baseline to study end point in both placebo and carvedilol patients but did not differ between the treatment groups.

Heart Size
There were no changes in the cardiothoracic index in either group.

Adverse Experiences
The most common adverse experiences during all phases of the trial were dizziness, fatigue, dyspnea, and heart failure. During the open-label challenge phase, dizziness, fatigue, and dyspnea occurred in 15%, 12%, and 12% of patients, respectively. The other most common adverse experiences during the challenge phase were chest pain (7%), diarrhea (5%), headache (5%), hypotension (5%), nausea (5%), cardiac failure (4%), and weight increase (4%).

The most frequent adverse experiences during the double-blind up-titration and maintenance phases are shown in Table 4. Adverse experiences were the reason for withdrawal in similar proportions of placebo (5%) and carvedilol (5%) patients (Table 5). The most frequent adverse experiences leading to withdrawal during the double-blind up-titration and maintenance phases were heart failure and fatigue, both of which were more common in the placebo group.

View this table: [in this window] [in a new window]   Table 4. Adverse Experiences During the Double-Blind Up-Titration and Maintenance Phases*

View this table: [in this window] [in a new window]   Table 5. Most Frequent Adverse Experiences Leading to Withdrawal During the Double-Blind Titration and Maintenance Phases, %

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix References

 
The major new finding of this study is that therapy with carvedilol reduced the clinical progression of heart failure in patients who were only mildly symptomatic. We prospectively defined clinical progression as the occurrence of death due to heart failure, hospitalization for heart failure, or the need for a sustained increase in heart failure medications. Carvedilol treatment reduced the occurrence of clinical progression, so defined, from 21% to 11%, a decrease of 48%. The beneficial effect of carvedilol on clinical progression was independent of patient age, sex, or race, cause of heart failure, and baseline LVEF. In addition, the beneficial effect of carvedilol remained significant even if the medication change component was removed from the analysis.

The individual components of this composite primary end point were assessed in a hierarchical order, so that only the most serious end point was counted for each patient. Thus, the occurrence of death took priority over the need for hospitalization, which in turn took priority over the need to increase heart failure medications on an outpatient basis. Carvedilol caused parallel reductions in all three components of the primary end point: death due to heart failure, hospitalization for heart failure, and the need to increase heart failure medications. Thus, the beneficial effect of carvedilol was due to comparable effects on three measures of clinical disease progression. This congruence of the individual components of the composite end point adds credence to the conclusion that carvedilol exerted an overall beneficial effect on disease progression.

Although the number of patients who died was small and does not allow conclusions about the effect of carvedilol on mortality in this study, the reductions in mortality due to heart failure and all-cause mortality are qualitatively and quantitatively consistent with the effect of carvedilol observed in the 1094 patients enrolled in the overall stratified trial program.^{20 21 22 26} This observation provides evidence that the improvement in the other components of the composite primary end point and secondary end points (eg, LVEF, symptoms) did not occur at the expense of an adverse effect on survival.

Many but not all of the secondary end points were improved by carvedilol treatment. Consistent with observations in several earlier studies,^{15 16 17 18} carvedilol increased the LVEF. The magnitude of this effect, an average increase of 10%, is comparable to that observed with carvedilol and other ß-blockers in more symptomatic populations.^{15 16 17 18 20 21 22} Carvedilol improved several measures of clinical status, including NYHA functional classification, heart failure symptom score, and both patient and physician global assessments. The congruence of these distinct measures of clinical status strongly supports the conclusion that carvedilol exerted a beneficial effect on clinical symptoms. Perhaps most important, for each of these clinical measures, carvedilol reduced the number of patients who were rated as worse over the course of the study. This finding further suggests that carvedilol reduced the progression of clinical heart failure.

The quality of life, as assessed by the Minnesota Living With Heart Failure Questionnaire, showed small improvements that favored the carvedilol patients, but these did not achieve statistical significance. Given the consistent improvements in several other measures of clinical status, the reason for the failure to detect a treatment effect on quality of life is not clear. It is possible that because of the mild functional limitation of this study population, baseline quality of life was relatively good and therefore difficult to improve. The premature termination of this study may have contributed as well by limiting both the numbers of patients available for analysis and the duration of treatment. When a ß-blocker is used in patients with heart failure, the first several weeks of therapy may be associated with adverse experiences (eg, dizziness) that often subside and do not preclude a good long-term outcome.²⁷ Since the benefits of these agents (eg, increase in LVEF) may require months to become manifest,^{28 29} patients followed for only a few weeks may not have sufficient time to experience an improvement in quality of life.

Two other objective end points, exercise duration on the self-powered treadmill and cardiothoracic index, were not improved. Although the 9-minute self-powered treadmill test was initially viewed as a measure of submaximal exercise capacity, it is now apparent that this test often results in a maximal effort in patients with heart failure.³⁰ It is therefore not surprising that it was unable to detect a treatment effect of carvedilol, since heart rate response to exercise, an important determinant of maximal exercise capacity, is reduced by ß-adrenergic antagonists. The lack of change in the cardiothoracic index suggests that there was not a marked change in heart size.

Carvedilol therapy was well tolerated in this population. Of the patients randomized to carvedilol, the major adverse effects were related to ß-adrenergic blockade and/or -adrenergic blockade and included hypotension, bradycardia, and dizziness. Approximately 4% of patients did not tolerate carvedilol during the open-label challenge phase. Therefore, the results of this study do not reflect patients who were not able to tolerate a low challenge dose of the drug. During the subsequent double-blind up-titration and maintenance phases, these effects were generally mild, were manageable by adjustment of the medical regimen, and did not necessitate withdrawal from the study. Thus, patients who tolerate a challenge dose of carvedilol have a high likelihood of being successfully initiated on the drug. However, it is important to emphasize that in this study, carvedilol was administered under highly controlled conditions by a relatively small number of experienced heart failure investigators. By design, patients were seen frequently during the initiation of therapy, close attention was paid to any deterioration in heart failure signs and symptoms, and appropriate adjustments in the medical regimen were made quickly.

A potential limitation of this study is that events during the open-label challenge period were not included in the primary end-point analysis. During this period, 1 patient died of heart failure and 3 were hospitalized for heart failure. However, even when a worst-case analysis was performed and all events occurring during the run-in period were assigned to carvedilol, treatment with the drug was still associated with a significant reduction in the risk of the primary end point (P=.002).

In summary, this study demonstrates that carvedilol, used in conjunction with digitalis, diuretics, and an ACE inhibitor, reduces the clinical progression of heart failure in patients with mildly symptomatic heart failure. The ability of carvedilol to reduce the progression of clinical heart failure in patients receiving an ACE inhibitor suggests that this drug may play an important part in the therapeutic regimen of patients with mild heart failure.

	Acknowledgments

 
This study was supported by a grant from SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, and Boehringer Mannheim Therapeutics, Mannheim, Germany.

	Footnotes

 
Reprint requests to Dr Wilson S. Colucci, Cardiomyopathy Program, Boston Medical Center, 1 Boston Medical Center Place, Boston, MA 02118.

*The Carvedilol Heart Failure Study Group Investigators are listed in the "Appendix."

	Appendix

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The following investigators and institutions participated in this trial.

Kirkwood A. Adams, Chapel Hill, NC (University of North Carolina); John A. Bowers, Las Vegas, Nev (Heart Institute of Nevada); Michael R. Bristow, Denver, Colo (University of Colorado Health Sciences Center); Edward Brown, Israel Freeman, East Meadow, NY (Nassau County Medical Center); Samuel Butman, Tucson, Ariz (University Medical Center); William Carlson, Boston, Mass (Harvard Community Health Plan); Wilson S. Colucci, Evan Loh, Boston, Mass (Brigham and Women's Hospital); Robert Cody, Columbus, Ohio (Ohio State University Hospital); G. William Dec, Boston, Mass (Massachusetts General Hospital); Eduardo deMarchena, Miami, Fla (University of Miami); Vincent DeQuattro, Los Angeles, Calif (University of Southern California School of Medicine); Eric Eichhorn, Dallas, Tex (Dallas Veterans Administration Medical Center); Salah Eddin El Hafi, Houston, Tex; Rodney Falk, Boston, Mass (Boston City Hospital); Michael B. Fowler, Stanford, Calif (Stanford University Cardiovascular Medicine); E. Michael Gilbert, Salt Lake City, Utah (University of Utah); Alan Gradman, Pittsburgh, Pa (Western Pennsylvania Hospital); John J. Gregory, Summit, NJ (Overlook Hospital); Ray Hershberger, Portland, Ore (Oregon Health Sciences); Robert Hobbs, Cleveland, Ohio (Cleveland Clinic–South); Henry Ingersoll, San Diego, Calif (Sharp Rees-Stealy Medical Group Center); Frederic Kahl, Winston-Salem, NC (Bowman-Gray School of Medicine); Niki Kantrowitz, Elmhurst, NY (Elmhurst Hospital Center); Ronald Karlsberg, Beverly Hills, Calif; Edward Kasper, Arthur M. Feldman, Baltimore, Md (The Johns Hopkins Hospital); Joseph Kiernan, John O'Brien, Peter E. Carson, Falls Church, Va (INOVA Health System Institute of Research and Education); Vithal Kinhal, Gross Point Farm, Mich (Pierson Clinic); Marc Klapholz, New York, NY (St Luke's Hospital); Steven Krueger, Lincoln, Neb (Nebraska Heart Institute); Spencer H. Kubo, Jay N. Cohn, Minneapolis, Minn (University of Minnesota Medical School); Thierry LeJemtel, Bronx, NY (Albert Einstein College of Medicine); Forrester Lee, New Haven, Conn (Yale School of Medicine); Chang-Seng Liang, Rochester, NY (University of Rochester Medical Center); Andrew J. Lonigro, Henry Stratmann, St Louis, Mo (St Louis University Medical Center School of Medicine); George Mallis, Northport, NY (Northport Veterans Administration); Barrie Massie, San Francisco, Calif (Veterans Administration Medical Center); Henry Meilman, David Goldscher, Baltimore, Md (Bay Cardiovascular Associates Union Memorial Hospital); Leslie W. Miller, Stephen H. Jennison, St Louis, Mo (St Louis University); Kenneth A. Narahara, Torrance, Calif (Harbor-UCLA Medical Center); Gerald Neuberg, Milton Packer, New York, NY (Columbia Presbyterian Medical Center); John O'Connell, Jackson, Miss (University of Mississippi Medical); Lyle James Olson, Rochester, Minn (Mayo Medical School); Ilena Pina, Philadelphia, Pa (Temple University); Peter S. Rahko, Madison, Wis (University of Wisconsin); Richard P. Sorkin, Park Ridge, Ill (Lutheran General Hospital); Richard Steingart, Mineola, NY (Winthrop University Hospital); Udho Thadani, Oklahoma City, Okla (University of Oklahoma); James E. Udelson, Boston, Mass (New England Medical Center); Barry Uretsky, Pittsburgh, Pa (Presbyterian University Hospital); George W. Vetrovec, Richmond, Va (Medical College of Virginia); John R. Wilson, Tiong-Keat Yeoh, Nashville, Tenn (Vanderbilt University Medical Center); Clyde W. Yancy, Dallas, Tex (University of Texas Southwestern Medical Center); Laurence Yellen, San Diego, Calif (Cardiology Associates Medical Group of East San Diego, Inc); and James Young, Houston, Tex (Baylor College of Medicine).

Received August 5, 1996; revision received October 7, 1996; accepted October 7, 1996.

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