The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure
Milton Packer, M.D., Michael R. Bristow, M.D., Ph.D., Jay N. Cohn, M.D., Wilson S. Colucci, M.D., Michael B. Fowler, M.B., B.S., Edward M. Gilbert, M.D., Neil H. Shusterman, M.D., for The U.S. Carvedilol Heart Failure Study Group
Background Controlled clinical trials have shown that beta-blockerscan produce hemodynamic and symptomatic improvement in chronicheart failure, but the effect of these drugs on survival hasnot been determined.
Methods We enrolled 1094 patients with chronic heart failurein a double-blind, placebo-controlled, stratified program, inwhich patients were assigned to one of four treatment protocolson the basis of their exercise capacity. Within each of thefour protocols patients with mild, moderate, or severe heartfailure with left ventricular ejection fractions 0.35 were randomlyassigned to receive either placebo (n = 398) or the beta-blockercarvedilol (n = 696); background therapy with digoxin, diuretics,and an angiotensin-converting–enzyme inhibitor remainedconstant. Patients were observed for the occurrence of deathor hospitalization for cardiovascular reasons during the following6 months (12 months for the group with mild heart failure).
Results The overall mortality rate was 7.8 percent in the placebogroup and 3.2 percent in the carvedilol group; the reductionin risk attributable to carvedilol was 65 percent (95 percentconfidence interval, 39 to 80 percent; P<0.001). This findingled the Data and Safety Monitoring Board to recommend terminationof the study before its scheduled completion. In addition, ascompared with placebo, carvedilol therapy was accompanied bya 27 percent reduction in the risk of hospitalization for cardiovascularcauses (19.6 percent vs. 14.1 percent, P = 0.036), as well asa 38 percent reduction in the combined risk of hospitalizationor death (24.6 percent vs. 15.8 percent, P<0.001). Worseningheart failure as an adverse reaction during treatment was lessfrequent in the carvedilol group than in the placebo group.
Conclusions Carvedilol reduces the risk of death as well asthe risk of hospitalization for cardiovascular causes in patientswith heart failure who are receiving treatment with digoxin,diuretics, and an angiotensin-converting–enzyme inhibitor.
Activation of the sympathetic nervous system is one of the cardinalpathophysiologic abnormalities in patients with chronic heartfailure. Levels of circulating catecholamines increase in patientswith heart failure in proportion to the severity of disease,1and those with the highest plasma levels of norepinephrine havethe most unfavorable prognosis.2 These observations have ledto the hypothesis that sympathetic activation plays an importantpart in the progression of heart failure.3,4 Norepinephrinecan exert adverse effects on the circulation, both directlyand indirectly,5,6 and interference with its actions can retardthe progression of heart failure in animal models of the disease.7,8
These findings have led investigators to propose that sympatheticantagonists (e.g., beta-blockers) might be useful in the managementof heart failure. Such drugs were previously considered to becontraindicated in this disorder because of their short-termadverse effects,9 but studies in Sweden in the 1970s raisedthe possibility that long-term therapy with these drugs mightproduce hemodynamic and clinical benefits.10,11 Controlled trialsof several different beta-blockers have shown that these drugscan reduce symptoms, improve left ventricular function, andincrease functional capacity,12,13,14,15,16,17,18 but recentlarge-scale studies19,20 have not clarified the effects of beta-blockerson morbidity and mortality in patients with heart failure.
Hence, when a large clinical trial program with carvedilol inheart failure was being designed in 1992, we prospectively definedan overall objective of the program to be an evaluation of theeffect of the drug on survival. Our principal goal was to assessthe safety of carvedilol while recognizing its potential toprolong life, demonstrated by the results of experimental studies.7,8,21Carvedilol is a nonselective -receptor antagonist that alsoblocks 1-receptors and, unlike other beta-blockers, exerts antioxidanteffects, which may contribute to its actions in heart failure.22,23,24This report summarizes the effects of carvedilol on survivaland on hospitalization for cardiovascular causes.
Methods
Study Patients
All patients in the study had had symptoms of heart failurefor at least three months and had ejection fractions 0.35, despiteat least two months of treatment with diuretics and an angiotensin-converting–enzymeinhibitor (if tolerated); treatment with digoxin, hydralazine,or nitrates was permitted but not required. Patients were excludedfrom the trial if they had had a major cardiovascular eventor had undergone a major surgical procedure within three monthsof entry into the study, or if they had uncorrected, primaryvalvular disease; active myocarditis; sustained ventriculartachycardia or advanced heart block not controlled by antiarrhythmicintervention or a pacemaker; systolic blood pressure of morethan 160 or less than 85 mm Hg or diastolic blood pressure ofmore than 100 mm Hg; a heart rate of less than 68 beats perminute; clinically important hepatic or renal disease; or anycondition other than heart failure that could limit exerciseor survival. Patients receiving calcium-channel blockers, -or -adrenergic agonists or antagonists, or class IC or III antiarrhythmicagents were also not enrolled. The protocol was approved bythe institutional review boards of all 65 participating institutions;written informed consent was obtained from all patients.
Study Procedures
The patients' eligibility was assessed during a three-week screeningperiod, during which exercise capacity was measured by a six-minutecorridor-walk test. Enrollment was stratified into one of fourtreatment protocols on the basis of the patients' performanceon the exercise test. According to the original design, patientsable to walk between 426 and 550 m when tested were assignedto the mild-heart-failure protocol; those able to walk between150 and 425 m were assigned either to the moderate-heart-failureprotocol or to a dose-ranging protocol, depending on the locationof the study center; and those able to walk only less than 150m were assigned to the severe-heart-failure protocol.
After a base-line evaluation, all patients received 6.25 mgof carvedilol twice daily for two weeks (the open-label portionof the study); if this dose was not tolerated, it could be temporarilyreduced to 3.125 mg twice daily and then later increased. Patientswho could tolerate 6.25 mg twice daily were randomly assignedto receive carvedilol or placebo on a double-blind basis, inaddition to their usual medication. The allocation ratio (ofpatients given carvedilol to patients given placebo) was one-to-onein the moderate-heart-failure protocol and two-to-one in themild- and severe-heart-failure protocols; for these patients,the dose of medication was initially 12.5 mg twice daily andwas increased, if tolerated, to 25 to 50 mg twice daily. Patientsassigned to the dose-ranging protocol were randomly assignedto one of four parallel treatment groups (placebo or 6.25 mg,12.5 mg, or 25 mg of carvedilol, twice daily). For all fourprotocols, the dose was gradually adjusted upward to the targetlevel over a period of 2 to 10 weeks, after which double-blindtherapy was maintained for an additional 6 months (except inthe mild-heart-failure protocol, in which patients were treatedfor an additional 12 months). During this time, the patients'other drug therapies for heart failure were kept constant, unlessside effects occurred that were thought to be related eitherto these other medications or to the study drug itself.
Study Objectives and Monitoring
Because of concern that new drugs for heart failure might increasethe risk of death, the sponsors of the program agreed with theFood and Drug Administration in July 1992 to enroll a sufficientnumber of patients in placebo-controlled trials of carvedilolto rule out (with 95 percent confidence) the risk of a 33 percentincrease in mortality with active therapy, assuming an annualmortality rate of 12 percent in the placebo group. As a resultof these discussions, an evaluation of mortality was prospectivelydefined for the present stratified trial program, primarilyfor reasons of safety, with the intent to enroll 1101 patients.However, since it was anticipated (on the basis of earlier studies)that carvedilol could reduce mortality, all statistical analyseswere two-sided. All deaths were classified by investigatorswho had no knowledge of the patients' treatment assignments.In addition, a major secondary objective of each of the componentprotocols was to evaluate the effect of carvedilol on cardiovascularmorbidity, defined as hospitalization for heart failure or othercardiovascular causes.
A data and safety monitoring board was constituted before recruitmentbegan, met periodically to review the unblinded results, andwas empowered to recommend early termination of the programif its members observed a clinically important treatment effect.No formal rules for stopping the trial were adopted before theinitiation of enrollment.
Statistical Analysis
The base-line characteristics of the two treatment groups werecompared with use of the t-test and the chi-square statistic.Cumulative survival curves were constructed as time-to-first-eventplots by Kaplan–Meier survivorship methods,25 and differencesbetween the curves were tested for significance by the log-rankstatistic with use of a Cox proportional-hazards regressionmodel (which included the protocol as a covariate).26 The analysesincluded all randomized patients, and all events were assignedto the patients' original treatment group (on the intention-to-treatprinciple). In the analysis of mortality, data on patients werecensored at the time of cardiac transplantation. Differencesbetween treatment groups in post-randomization measures or eventswere evaluated by analysis of variance and with the chi-squarestatistic. All data are reported as means ±SD.
Results
Randomization began on April 29, 1993, and the study was stoppedearly on the recommendation of the Data and Safety MonitoringBoard on February 3, 1995. This decision was based on the findingof a significant effect of carvedilol on survival — aneffect that exceeded all conventional boundaries used to stopclinical trials.27,28
At the time of the study's early termination, 1197 patientshad entered the open-label, run-in period. Of these, 5.6 percentfailed to complete this period because of adverse events (e.g.,worsening heart failure in 1.4 percent and death in 0.6 percent);another 3.0 percent failed to do so because of violations ofthe protocol or for other administrative reasons. Accordingly,1094 patients were randomly assigned to double-blind treatment:398 with placebo and 696 with carvedilol.
The placebo and carvedilol groups were similar in all pretreatmentcharacteristics (Table 1). After randomization and the adjustmentof dosage, patients received a mean total daily dose of 45±27mg of carvedilol or 60±24 mg of placebo; these doseswere maintained at similar levels throughout the study period.Eighty percent of the patients received target doses of thestudy drugs. The duration of therapy ranged from 1 day to 15.1months (median, 6.5 months). No patient was lost to follow-upwith respect to mortality.
Table 1. Pretreatment Characteristics of Patients in the Study.
Effect of Carvedilol on Survival
In the intention-to-treat analysis, there were 31 deaths (7.8percent) in the placebo group and 22 deaths (3.2 percent) inthe carvedilol group; this difference represents a 65 percentdecrease in the risk of death (95 percent confidence interval,39 to 80 percent; P<0.001) in patients assigned to carvedilol(Figure 1). Treatment with the drug was associated with a largedecrease in the risk of dying of progressive heart failure andin the risk of sudden death (Table 2). The reduction in mortalitydue to carvedilol was similar regardless of age, sex, the causeof heart failure, ejection fraction, exercise tolerance, systolicblood pressure, heart rate, or protocol assignment (Table 3).
Figure 1. Kaplan–Meier Analysis of Survival among Patients with Chronic Heart Failure in the Placebo and Carvedilol Groups.Patients in the carvedilol group had a 65 percent lower risk of death than patients in the placebo group (P<0.001).
Table 3. Effect of Placebo and Carvedilol Treatment on Mortality in Patient Subgroups.
Effect of Carvedilol on Cardiovascular Morbidity
During double-blind therapy, 98 patients (14.1 percent) in thecarvedilol group and 78 patients (19.6 percent) in the placebogroup had at least one hospitalization for cardiovascular causes;this difference represents a 27 percent reduction in the riskof hospitalization (95 percent confidence interval, 3 to 45percent; P = 0.036). To avoid the analytic problem of competingrisks (since patients who have died cannot be hospitalized),the effect of carvedilol on the combined risk of death or hospitalizationfor cardiovascular causes was evaluated with the use of a time-to-first-eventanalysis. As tested for significance with use of the log-ranktest, the combined risk of either dying or being hospitalizedfor cardiovascular reasons was reduced from 24.6 percent inthe placebo group to 15.8 percent in the carvedilol group, a38 percent reduction (95 percent confidence interval, 18 to53 percent; P<0.001) (Figure 2).
Figure 2. Kaplan–Meier Analysis of Survival without Hospitalization for Cardiovascular Reasons (Event-free Survival) in the Placebo and Carvedilol Groups.Patients in the carvedilol group had a 38 percent lower risk of death or hospitalization for cardiovascular disease than patients in the placebo group (P<0.001).
Safety
At the end of double-blind therapy, the mean heart rate decreasedsignificantly more in the carvedilol group than in the placebogroup (by 12.6±12.8 beats per minute vs. 1.4±12.2,P<0.001), although neither group had significant changesin systolic or diastolic blood pressure. Frequently reportedadverse reactions are listed in Table 4; those necessitatingdiscontinuation of the study drug are shown in Table 5. Themost common side effect of carvedilol was dizziness, which occurredduring the initiation of therapy or during the dose-adjustmentperiod but which subsided either spontaneously or after theadjustment of concomitant medications; it did not generallylead to the withdrawal of treatment with the study drug. Themost common reason for the discontinuation of double-blind treatmentwas worsening heart failure, which occurred more frequentlyin the placebo group. Overall, 7.8 percent of the placebo groupand 5.7 percent of the carvedilol group discontinued the studymedication because of adverse reactions; 1.5 percent and 1.1percent, respectively, were withdrawn from the study medicationafter cardiac transplantation. When the program was terminated,more patients were receiving or had completed double-blind treatmentin the carvedilol group than in the placebo group (89 percentvs. 83 percent, P = 0.002).
Table 5. Most Frequent Adverse Reactions Leading to Discontinuation of Double-Blind Treatment.
Discussion
The present report indicates that the addition of carvedilolto conventional therapy is associated with a decrease in mortalityamong patients with chronic heart failure. Patients treatedwith carvedilol had a 65 percent lower risk of death than thosegiven placebo during follow-up that averaged 6.5 months andextended to 15 months. The beneficial effect of carvedilol onsurvival was consistent in all evaluated subgroups and was reflectedin a decrease in the risk of death from progressive heart failureas well as in the risk of sudden death. In addition, carvediloltherapy was associated with a 26 percent reduction in hospitalizationfor cardiovascular causes, a 38 percent decrease in the riskof death or hospitalization, and a lower rate of withdrawalfrom the trial due to worsening heart failure.
Previous controlled studies have shown that beta- blockade canimprove cardiac function, reduce the symptoms of heart failure,improve functional capacity, and enhance exercise tolerance.12,13,14,15,16,17,18,19,20Most of these trials were too small to evaluate the effectsof beta-blockers on morbidity or mortality, but one single-centerstudy with carvedilol18 and two multicenter studies with the1-selective agents metoprolol and bisoprolol19,20 suggestedthat long-term beta-blockade may have favorable effects on thecourse of heart failure. In the single-center study,18 treatmentwith carvedilol for four months reduced the risk of cardiovascularevents. In the two multicenter studies,19,20 treatment withmetoprolol for 12 to 18 months or with bisoprolol for 4 to 44months was associated with fewer hospitalizations for worseningheart failure and a reduced risk of clinical deterioration requiringcardiac transplantation. The decrease in hospitalizations forcardiovascular causes seen with carvedilol in our study reaffirmsthese earlier observations.
Yet previous trials in heart failure have not demonstrated areduction in mortality during beta-blockade. In the two multicenterstudies,19,20 treatment with metoprolol or bisoprolol did notsignificantly decrease the risk of death. One of the trialsretrospectively noted a reduction in mortality only among patientswith nonischemic dilated cardiomyopathy.20 In contrast, in ourstudy, carvedilol therapy was associated with a decrease inmortality, and the benefits of the drug were apparent in allthe subgroups we examined, including patients with underlyingischemic heart disease. The fact that two earlier multicenterstudies did not find an effect on survival may have been relatedto the sample sizes, to the study designs, or to chance. Alternatively,the effects of carvedilol on survival may differ from thoseof other beta-blockers. Unlike metoprolol and bisoprolol, carvedilolblocks both 1- and 2-adrenergic receptors, reduces cardiac norepinephrinelevels, and does not elicit up-regulation of cardiac -receptors.29,30,31Furthermore, unlike other beta-blockers, carvedilol has potentantioxidant effects,24 which may protect against the continuingloss of cardiac myocytes that characterizes the progressionof heart failure.21,32
The initiation of therapy with carvedilol in our study producedside effects consistent with its antiadrenergic actions, butmost of these reactions disappeared — either spontaneouslyor after the adjustment of concomitant medications — anddid not require the discontinuation of double-blind treatment.Thus, most patients were able to tolerate target doses of carvedilol.The most feared side effect of beta-blockade — worseningheart failure during the initiation of therapy — was notan important limitation of treatment; 5.9 percent of the patientshad this side effect during the open-label period, and an additional5.1 percent in the carvedilol group and 4.1 percent in the placebogroup had this reaction after increases in dose during the earlyphases of double-blind therapy. It must be emphasized, however,that carvedilol therapy was initiated in the study with extremecare by physicians experienced in the management of heart failure,who followed specific guidelines that encouraged changes inconcomitant medications to ensure the safety of the patient.Furthermore, our program recruited few patients with New YorkHeart Association class IV heart failure,33 and patients whorequired hospitalization for intravenous drug support were notenrolled. Hence, our study does not allow any conclusions tobe drawn about the safety of carvedilol when it is administeredwithout rigorous supervision or in bedridden patients with advancedheart failure.
To enhance the safety of patients, therapy with carvedilol wasinitiated in small doses that were gradually increased overa period of several weeks. This cautious approach has been followedin studies of other beta-blockers12,13,14,15,16,17,18,19,20,34and is designed to minimize the adverse effects that may occurafter the abrupt withdrawal of the homeostatic support providedby the sympathetic nervous system. Despite such care, however,the frequency of early side effects was expected to be highenough potentially to unblind both the patient and the investigatoras to the treatment-group assignment. To avoid this difficulty,we required patients to complete a two-week, open-label periodbefore randomly assigning them to double-blind therapy; thisdesign feature has been part of many trials studying survivalin heart failure19,35,36 and of all previous controlled trialswith carvedilol. The use of an open-label period not only allowsdrug-related side effects to subside before randomization (thusmaintaining the blindedness of the study) but also enhancesthe study's power, since a trial is less likely to detect atrue effect on survival if patients are randomly assigned totreatment that cannot be maintained for the planned length ofthe study. Although deaths may occur during the open-label period,they cannot be validly assigned to either the treatment or theplacebo group, since they may be related either to the naturalhistory of heart failure or to carvedilol. Fortunately, themortality rate during the two-week, open-label period was low(0.6 percent) and was similar to — if not less than —the rate in the preceding three weeks (1.7 percent), duringwhich patients were being screened for the program but werereceiving only their usual medications for heart failure.
Our findings should be interpreted with the knowledge that thetrial program had several unusual characteristics for a studyof the effect of a drug on survival. Most such trials are designedas long-term studies in which nonfatal events are consideredto be secondary end points. In our program, however, the individualprotocols were designed first to evaluate nonfatal end pointsas components of a single stratified trial program, and thenmortality was specified a priori to assess safety and potentialbenefit. As a result, the duration of follow-up was short andfixed. Although several trials examining mortality in heartfailure have also used a fixed follow-up period,19,37 such adesign necessarily reduces the number of events that can beobserved. This explains why, although the annual mortality inour placebo group (14 to 15 percent) was similar to that inmany studies,35,38 we recorded only 53 deaths (since the averagefollow-up was only 6.5 months). This limited experience restrictsour ability to reach conclusions about the true magnitude orpersistence of any effect on survival. Yet it should be notedthat the number of events during follow-up in our trial wasnot small if morbidity and mortality are combined; 25 percentof the placebo group died or were hospitalized for cardiovascularreasons, and this combined rate was substantially lower in thecarvedilol group. Furthermore, a long follow-up period may notbe possible if the finding of a large treatment effect leadsthe Data and Safety Monitoring Board to recommend early terminationof a study, as occurred in this case; the mean duration of follow-upin the present program was similar to that in other trials thathave been terminated early.36,39,40 Fortunately, long-term dataon carvedilol have recently become available from a trial of415 patients with mild-to-moderate heart failure due to ischemicheart disease who were treated for 18 to 24 months. In thatstudy, carvedilol reduced the combined risk of death or hospitalizationby 26 percent (Sharpe N: personal communication) — a findingsimilar to the 38 percent reduction in mortality and hospitalizationwe observed.
Our finding that carvedilol reduces morbidity and mortalitysupports the hypothesis that a beta-blocker can favorably influencethe course of disease in patients with heart failure. However,because carvedilol exerts pharmacologic effects atypical ofand in addition to its action on adrenergic receptors,22,23,24experience with this drug does not allow us to conclude thatall beta-blockers will favorably alter the natural history ofthis disorder. The question of whether other beta-blockers (suchas metoprolol, bisoprolol, and bucindolol) prolong survivalin heart failure is being addressed in ongoing trials.
Supported by grants from SmithKline Beecham Pharmaceuticalsand Boehringer–Mannheim Therapeutics.
* The U.S. Carvedilol Heart Failure Study Group investigatorsare listed in the Appendix.
Source Information
From the College of Physicians and Surgeons, Columbia University, New York (M.P.); University of Colorado Health Sciences Center, Denver (M.R.B.); University of Minnesota Medical School, Minneapolis (J.N.C.); Boston University School of Medicine, Boston (W.S.C.); Stanford University School of Medicine, Palo Alto, Calif. (M.B.F.); University of Utah School of Medicine, Salt Lake City (E.M.G.); and SmithKline Beecham Pharmaceuticals, King of Prussia, Pa. (N.H.S.).
Address reprint requests to Dr. Packer at the Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032.
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Appendix
The following centers and principal investigators composed theU.S. Carvedilol Heart Failure Study Group: Albuquerque, N.M.— Lovelace Scientific Resources, L. Kuo; Baltimore —Johns Hopkins University Hospital, E. Kasper and A.M. Feldman;Union Memorial Hospital, H. Meilman and D. Goldscher; and Universityof Maryland, S.S. Gottlieb; Beverly Hills, Calif. — CardiovascularResearch Institute of Southern California, R. Karlsburg; Boston— Boston City Hospital, R.H. Falk; Brigham and Women'sHospital, W.S. Colucci and W. Carlson; Massachusetts GeneralHospital, G.W. Dec; and New England Medical Center, J.E. Udelson;Bronx, N.Y. — Albert Einstein College of Medicine, T.H.Le Jemtel; Chapel Hill, N.C. — University of North Carolina,K. Adams; Cleveland— Cleveland Clinic, R. Hobbs; Columbus— Ohio State University Hospital, R.J. Cody; Dallas —University of Texas Southwestern Medical Center, C.W. Yancy;and Veterans Affairs Medical Center (VAMC), E. Eichhorn; Denver— University of Colorado, M.R. Bristow; East Meadow, N.Y.— Nassau County Medical Center, E. Brown and I. Freeman;Elmhurst, N.Y. — Elmhurst Hospital Center, N. Kantrowitz;Falls Church, Va. — INOVA Health System, J. Kiernan, J.O'Brien, and P. Carson; Grosse Pointe, Mich. — Henry FordHealth System and Pierson Clinic, V. Kinhal; Houston —Baylor College of Medicine, J. Young; University of Texas MedicalSchool, G. Schroth and S.E. El Hafi; Jackson — Universityof Mississippi Medical Center, J. O'Connell; Jacksonville —University of Florida, A. Miller; Las Vegas — Heart Instituteof Nevada, J.A. Bowers; Lincoln — Nebraska Heart Institute,S. Krueger; Los Angeles — University of Southern CaliforniaSchool of Medicine, V. DeQuattro; Madison — Universityof Wisconsin School of Medicine, P.S. Rahko; Memphis —University of Tennessee School of Medicine, K.B. Ramanathan;Miami — University of Miami, E. deMarchena; Mineola, N.Y.— Cardiovascular Medical Associates, M. Goodman; and WinthropUniversity Hospital, R. Steingart; Minneapolis — Universityof Minnesota Medical School, S. Kubo and J.N. Cohn; Nashville— Vanderbilt University Medical Center, J.R. Wilson andT.-K. Yeoh; New Haven, Conn. — Yale University Schoolof Medicine, F. Lee; New York — Columbia–PresbyterianMedical Center, J. Sackner-Bernstein, G. W. Neuberg, and M.Packer; Mount Sinai Medical Center, M. Kukin; and St. Luke's–RooseveltMedical Center, M. Klapholz; Northport, N.Y. — VAMC, G.Mallis; Oklahoma City — University of Oklahoma and VAMC,U. Thadani; Park Ridge, Ill. — Lutheran General Hospital,R.P. Sorkin; Philadelphia — Temple University Hospital,I. Pina; Phoenix, Ariz. — Carl T. Hayden VAMC, J.V. Felicetta;Pittsburgh — Presbyterian University Hospital, B. Uretskyand S. Murali; and Western Pennsylvania Hospital, A. Gradman;Portland — Oregon Health Sciences Center, R. Hershberger;Richmond — Medical College of Virginia, G.W. Vetrovec;Rochester, Minn. — Mayo Medical School, L.J. Olson; Rochester,N.Y. — University of Rochester Medical Center, C.-S. Liang;Salt Lake City — University of Utah, E.M. Gilbert; SanDiego, Calif. — Cardiology Associates Medical Group ofEast San Diego, L. Yellen; and Sharp Rees–Stealy MedicalCenter, H. Ingersoll; San Francisco — California PacificMedical Center, S. Woodley; and VAMC, B.M. Massie; Sellersville,Pa. — Buxmont Cardiology Associates, M. Greenspan; St.Louis — St. Louis University Medical Center, L.W. Miller,S.H. Jennison, A.J. Lonigro, and H. Stratman; Stanford, Calif.— Stanford University School of Medicine, M.B. Fowler;Summit, N.J. — Overlook Hospital, J.J. Gregory; Torrance,Calif. — Harbor–UCLA Medical Center, K.A. Narahara;Tucson — University of Arizona Medical Center, S. Butman;Washington, D.C. — Georgetown University Hospital, D.Pearle; Winston-Salem, N.C. — Bowman Gray School of Medicine,F. Kahl; and Worcester — University of Massachusetts MedicalCenter, L. Heller.
Committee members were as follows: Executive Committee —M. Packer, M.R. Bristow, J.N. Cohn, W.S. Colucci, M.B. Fowler,and E.M. Gilbert; Data and Safety Monitoring Board — A.M.Katz (chair), T. Bashore, C.E. Davis, and P. Kowey; Biostatistics— J. Hosking and S.T. Young; and Study Operations andMonitoring — N.H. Shusterman, M.A. Lukas, A. Flagg, T.Holcslaw, and L.G. Parchman.
Digoxin in Patients with Heart Failure
Umans V. A., Cornel J. H., Hic C., Soto J., Avendaño C., Vilchez F. G., Böhm M., Zoneraich S., Yusuf S., Gorlin R., Garg R., Packer M.
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337:129-131, Jul 10, 1997.
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Hunt, S. A., Abraham, W. T., Chin, M. H., Feldman, A. M., Francis, G. S., Ganiats, T. G., Jessup, M., Konstam, M. A., Mancini, D. M., Michl, K., Oates, J. A., Rahko, P. S., Silver, M. A., Stevenson, L. W., Yancy, C. W., Antman, E. M., Smith, S. C. Jr, Adams, C. D., Anderson, J. L., Faxon, D. P., Fuster, V., Halperin, J. L., Hiratzka, L. F., Hunt, S. A., Jacobs, A. K., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B.
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0.35 were randomly assigned to receive either placebo (n = 398) or the beta-blocker carvedilol (n = 696); background therapy with digoxin, diuretics, and an angiotensin-converting–enzyme inhibitor remained constant. Patients were observed for the occurrence of death or hospitalization for cardiovascular reasons during the following 6 months (12 months for the group with mild heart failure). 
-receptor antagonist that also blocks 
1-receptors and, unlike other beta-blockers, exerts antioxidant effects, which may contribute to its actions in heart failure.22,23,24 This report summarizes the effects of carvedilol on survival and on hospitalization for cardiovascular causes. 
