Background Although beta-adrenergic–receptor antagonistsreduce morbidity and mortality in patients with mild-to-moderatechronic heart failure, their effect on survival in patientswith more advanced heart failure is unknown.
Methods A total of 2708 patients with heart failure designatedas New York Heart Association (NYHA) functional class III (in92 percent of the patients) or IV (in 8 percent) and a leftventricular ejection fraction of 35 percent or lower were randomlyassigned to double-blind treatment with either bucindolol (1354patients) or placebo (1354 patients) and followed for the primaryend point of death from any cause.
Results The data and safety monitoring board recommended stoppingthe trial after the seventh interim analysis. At that time,there was no significant difference in mortality between thetwo groups (unadjusted P=0.16). The results presented here arebased on complete follow-up at the time of study termination(average, 2.0 years). There were a total of 449 deaths in theplacebo group (33 percent) and 411 deaths in the bucindololgroup (30 percent, adjusted P=0.13). The risk of the secondaryend point of death from cardiovascular causes was lower in thebucindolol group (hazard ratio, 0.86; 95 percent confidenceinterval, 0.74 to 0.99), as was the risk of heart transplantationor death. In a subgroup analysis, there was a survival benefitin nonblack patients.
Conclusions In a demographically diverse group of patients withNYHA class III and IV heart failure, bucindolol resulted inno significant overall survival benefit.
Beta-blockers have emerged as an important treatment for chronicheart failure. Two recently completed trials, the MetoprololCR/XL Randomized Intervention Trial in Congestive Heart Failure1and the Cardiac Insufficiency Bisoprolol Study II,2 demonstratedstatistically significant and clinically relevant decreasesin the rates of hospitalization and death with beta-adrenergic–receptorantagonists in patients with New York Heart Association (NYHA)class II, III, or IV heart failure. However, mortality in theplacebo group in these trials was only 11 to 13 percent annually,suggesting that the proportion of high-risk, severely ill patientswas low. Furthermore, both studies were performed in largelywhite European populations.
In heart failure, cardiac adrenergic drive and systemic adrenergicdrive are activated in proportion to the severity of symptomsand are strongly prognostic for outcome.3,4,5,6 Since beta-adrenergic–blockingagents initially depress myocardial function7 and may worsensymptoms with initial dosing and upward titration,8 it is notknown whether these agents would be tolerated or whether theywould improve survival among patients with advanced heart failurewho are more dependent on beta-adrenergic support. In addition,it is important to explore the effect of beta-blockade in racialand other demographic groups that have not been studied extensivelyin previous trials.1,2 Blacks represent a substantial proportionof the patients with heart failure in the United States andhave a higher rate of death from heart failure than nonblacks.9,10The Beta-Blocker Evaluation of Survival Trial (BEST) was designedto determine whether bucindolol hydrochloride (Bextra, IncaraPharmaceuticals, Research Triangle Park, N.C.), a nonselectivebeta-adrenergic blocker and mild vasodilator, would reduce therate of death from any cause among patients with advanced heartfailure and to assess its effect in various subgroups definedby ethnic background and demographic criteria — specificallywomen and members of minority groups.
Methods
Study Subjects
The design of the trial has been described previously.11 Allpatients had NYHA class III or IV heart failure that was dueto primary or secondary dilated cardiomyopathy, as well as aleft ventricular ejection fraction of 35 percent or lower. Allpatients were required to have received optimal medical therapy,including the use of angiotensin-converting–enzyme inhibitors(if tolerated), for at least one month. Before the publicationof the results of the Digitalis Investigation Group trial,12digoxin therapy was required, but thereafter its use becamediscretionary. The racial and ethnic classification of the patientswas self-reported. All patients were 18 years old or older andgave written informed consent. The protocol was approved bythe institutional review board of each participating site.
Patients were excluded if they had a reversible cause of heartfailure, uncorrected primary valvular disease, untreated thyroiddisease, obstructive or hypertrophic cardiomyopathy, pericardialdisease, amyloidosis, active myocarditis, a malfunctioning artificialheart valve, or a history of myocardial infarction within theprevious six months. Patients were also excluded if they werecandidates for heart transplantation; if they had undergonea revascularization procedure (a percutaneous transluminal interventionor a coronary-artery bypass procedure) within the previous 60days; if they had unstable angina (requiring treatment withmore than six nitroglycerin tablets per week); if they had aheart rate slower than 50 beats per minute; if they were undergoingtreatment with other investigational agents; if they had a lifeexpectancy of less than 3 years; if they had active liver disease(indicated by a total serum bilirubin concentration of 3.0 mgper deciliter [51 µmol per liter] or higher); if theyhad renal disease (indicated by a serum creatinine level of3.0 mg per deciliter [265 µmol per liter] or higher);or if they had hematologic, gastrointestinal, immunologic, endocrine,metabolic, or central nervous system disease that could adverselyaffect the safety or the efficacy of the study drug. Patientswith decompensated heart failure (i.e., those with evidenceof hypoperfusion, acute pulmonary edema, or hypotension witha systolic blood pressure of less than 80 mm Hg) were excluded,as were active abusers of alcohol (ingesting more than 100 gof ethanol per day) or illicit drugs. Patients were also excludedif they had taken any of the following: calcium-channel–blockingagents (including amlodipine), theophylline, tricyclic antidepressants,monoamine oxidase inhibitors, or beta-agonists within 1 weekbefore the base-line evaluation; beta-adrenergic–blockingagents within 30 days before the base-line evaluation; flecainide,encainide, propafenone, or disopyramide within 2 weeks beforerandomization; or amiodarone within 8 weeks before the base-lineevaluation.
Within 60 days before randomization, patients underwent a gatedradionuclide ventriculographic assessment of the left ventricularejection fraction; within 14 days before randomization, theyunderwent electrocardiography, chest radiography for the measurementof the cardiothoracic ratio, and laboratory blood tests includingmeasurement of plasma norepinephrine in a blood sample obtainedwhen the patient was resting in a supine position. Patientswere included only if their symptoms were considered to be NYHAclass III or IV on the day of randomization after at least sevendays of stability.
Randomization
Patients were randomly assigned by a central coordinating centerto bucindolol or a matched placebo. Randomization was stratifiedat each clinical site according to the underlying cause of heartfailure (the presence or absence of coronary artery disease),the left ventricular ejection fraction (greater than 20 percentvs. 20 percent or lower), sex, and race (black vs. nonblack)and was balanced for each of these factors by means of an adaptiveallocation scheme with a biased coin design.13
Treatment and Follow-up
On the day of randomization, patients were given an initialoral dose of 3 mg of the study medication (bucindolol or placebo),which was repeated twice daily for one week. Subsequently, doseswere increased (as tolerated) on a weekly basis to 6.25 mg,12.5 mg, 25 mg, 50 mg, and (for patients who weighed 75 kg ormore) 100 mg orally twice daily. These increases were slowedor stopped and the doses of diuretics and concomitant medicationsadjusted at the discretion of the investigator on the basisof the patient's response. Patients had follow-up visits at3, 6, and 12 months after randomization, with regular follow-upvisits every 6 months thereafter, for a planned average follow-upof 3 years. Gated radionuclide ventriculographic assessmentof the left ventricular ejection fraction, measurement of theplasma norepinephrine concentration, laboratory blood tests,chest radiography, and electrocardiography were repeated 3 and12 months after randomization.
End Points
The primary end point of the study was death from any cause.Secondary end points included death from cardiovascular causes(defined as death due to pump failure or an ischemic event orsudden death); hospitalization for any reason; hospitalizationbecause of heart failure; a composite of death or heart transplantation;the left ventricular ejection fraction at 3 and 12 months; myocardialinfarction; quality of life; and any change in the need forconcomitant therapy. The cause of death was adjudicated by acentral end-points committee whose members were blinded to thetreatment-group assignments. The results with respect to qualityof life, myocardial infarction, and changes in the need forconcomitant therapy are not reported here.
Statistical Analysis
We estimated that a sample of 2800 patients would be requiredfor the study to detect a 25 percent reduction in annual mortality(from an estimated 15 percent) with bucindolol therapy witha statistical power of 85 percent with use of the log-rank testand a significance level of 5 percent.14,15 The design of thetrial called for an enrollment period of 3 years, a minimumfollow-up of 18 months, and a maximum follow-up of 4.5 years.The trial was monitored by an independent data and safety monitoringboard. The group sequential method of Lan and DeMets,16,17,18with a linear alpha spending function,16 was used for monitoringthe interim data analyses. After the fifth interim analysis,the data and safety monitoring board changed the stopping ruleto a nominal 0.05 level, and this rule was used during the sixthand seventh interim analyses.
Continuous variables are reported as means ±SD, and reportedP values are for comparisons between treatment groups by thet-test or the Wilcoxon rank-sum test, unless otherwise noted.Categorical variables are reported as proportions, and the reportedP values are for comparisons between the treatment groups bythe chi-square or Fisher's exact test. Cumulative survival curveswere constructed by means of Kaplan–Meier methods,19,20and differences between the treatment groups were evaluatedwith the use of the log-rank test. The Cox proportional-hazardsregression model was used to examine the effect of treatmentin the presence of prespecified covariates.21,22,23,24 All analyseswere conducted in accordance with the intention-to-treat principle.
Because of the change in monitoring boundaries during the trial,it is difficult to calculate an adjusted P value to reflectthe eight analyses of the study results. However, to attemptto adjust for the multiple examinations of the data, we usedas an adjusted P value the null probability of exceeding oneof the seven interim stopping boundaries or, if no interim boundarieswere exceeded, of obtaining a final result at least as extremeas the observed result. We report unadjusted estimates and confidenceintervals for the primary end point, but we report both theunadjusted and adjusted P values. The reported P values forthe secondary study end points have not been formally adjustedfor the number of multiple secondary end points, but they havebeen interpreted in view of the multiple tests conducted. Allreported P values are two-sided.
Results
Characteristics of the Patients
Between May 31, 1995, and December 31, 1998, a total of 2708patients underwent randomization at 90 clinical sites in theUnited States and Canada. The base-line characteristics of thepatients are given in Table 1. No significant differences betweengroups were observed except for slightly higher rates in thebucindolol group of current smoking and of the use of antiarrhythmicdrugs other than amiodarone.
Table 1. Base-Line Clinical Characteristics of the Patients According to Treatment Group.
Follow-up
We report data collected through July 26, 1999. On that day,the data and safety monitoring board recommended the early terminationof the trial after the seventh interim analysis, citing the"totality of evidence regarding the usefulness of -blocker treatmentderived from BEST and other studies." The board's recommendationwas influenced by information that had been accruing from otherstudies of beta-blockers in chronic heart failure and by a concernabout the equipoise of the trial. At the time of this recommendation,there was no significant difference in mortality between thetwo treatment groups (unadjusted P=0.16). On July 29, 1999,the trial was terminated by the study's sponsors (the NationalHeart, Lung, and Blood Institute and the Department of VeteransAffairs). The mean duration of follow-up reported to the timethe study was terminated was 2.0 years.
A total of eight patients (less than 1 percent) — threein the placebo group and five in the bucindolol group —either withdrew consent or were lost to follow-up. The averagedegree of compliance with treatment during the trial, as assessedby pill counts, was 81 percent in both groups. For patientswho were receiving treatment at the time the study was terminated,the mean dose was 76 mg twice daily for the patients in thebucindolol group and 79 mg twice daily for the patients in theplacebo group. During the trial, 25 percent of the patientsin the placebo group and 23 percent of those in the bucindololgroup permanently discontinued the study medication (P=0.16);the rate of use of open-label beta-blockers differed betweenthe groups (10 percent in the placebo group, as compared with6 percent in the bucindolol group; P<0.001) and was higherthan had been anticipated.
Survival
A total of 449 patients in the placebo group (33 percent) died,as did 411 in the bucindolol group (30 percent; hazard ratio,0.90; 95 percent confidence interval, 0.78 to 1.02; unadjustedP=0.10; adjusted P=0.13) (Table 2 and Figure 1) — a nonsignificanttrend. This resulted in annual mortality of 17 percent in theplacebo group as compared with 15 percent in the bucindololgroup.
There were a total of 860 deaths, 449 in the placebo group and 411 in the bucindolol group (log-rank statistic=1.63; unadjusted P=0.10).
Secondary End Points
The rate of death from cardiovascular causes was significantlylower with bucindolol (P=0.04), and the rates of death due topump failure and sudden death were somewhat lower; these resultsare consistent with the overall effect on death from cardiovascularcauses (Table 2). Bucindolol significantly reduced the proportionof patients who had to be hospitalized for illnesses relatedto heart failure, as determined by each local investigator (hazardratio, 0.78; 95 percent confidence interval, 0.69 to 0.88; P<0.001),and there was a nonsignificant difference in favor of bucindololin the proportion of patients who were hospitalized for anyreason (hazard ratio, 0.92; 95 percent confidence interval,0.84 to 1.01; P=0.08). Bucindolol reduced the average numberof hospitalizations and the average number of inpatient daysper patient. The combined end point of death or heart transplantationduring the trial occurred in 32 percent of the patients in thebucindolol group and 35 percent of those in the placebo group(hazard ratio, 0.87; 95 percent confidence interval, 0.77 to0.99; P=0.04). The left ventricular ejection fraction showedgreater improvement with bucindolol therapy than with placeboat 3 months (5.5±7.8 ejection-fraction units, vs. 2.1±6.9in the placebo group; P<0.001) and at 12 months (7.3±10.0ejection-fraction units, vs. 3.3±8.7 in the placebo group;P<0.001).
Other Analyses
With bucindolol therapy, the heart rate was lowered significantlyat 3 months (decrease from base line, 9.4±13.0 beatsper minute, vs. a decrease of 1.3±12.9 in the placebogroup; P<0.001) and at 12 months (a decrease of 8.6±13.9beats per minute, vs. a decrease of 2.1±13.4 in the placebogroup; P<0.001), and the plasma norepinephrine levels werereduced at 3 months (decrease from base line, 72±345pg per milliliter, vs. an increase of 27±300 in the placebogroup; P<0.001) and at 12 months (a decrease of 22±300pg per milliliter, as compared with an increase of 45±309in the placebo group; P<0.001).
Subgroup Analysis
The hazard ratios and 95 percent confidence intervals for themain effects, as estimated with the Cox proportional-hazardsmodel, are presented in Figure 2 for the subgroups that wereprespecified in the protocol. A nominally significant interactioneffect was found only for race (black vs. nonblack) and treatment(2=5.06, P=0.02). With any reasonable adjustment for multiplecomparisons, this finding could be explained as due to chance.The apparent interaction effect for race and treatment reflectsthe lack of benefit observed in blacks (hazard ratio for deathwith bucindolol vs. placebo, 1.17; 95 percent confidence interval,0.89 to 1.53; P=0.27), but there was a significant survivalbenefit in nonblack patients (hazard ratio, 0.82; 95 percentconfidence interval, 0.70 to 0.96; P=0.01).
Figure 2. Hazard Ratios for Death in Prespecified Subgroups of Patients.
Hazard ratios are shown with 95 percent confidence intervals. Hazard ratios with upper confidence limits that are less than 1 represent a survival benefit with bucindolol. Confidence intervals have not been corrected for multiple comparisons. CAD denotes coronary artery disease, LVEF left ventricular ejection fraction, and NYHA New York Heart Association.
We also found a trend toward improved survival with bucindololamong patients with less advanced heart failure: for patientswith NYHA class III heart failure, the hazard ratio for deathwas 0.87 (95 percent confidence interval, 0.75 to 1.01; P=0.06);for those with a left ventricular ejection fraction greaterthan 20 percent, the hazard ratio was 0.83 (95 percent confidenceinterval, 0.69 to 1.00; P=0.05). Similar trends were seen inpatients with and without coronary artery disease. Given thesmall number of patients in our study with NYHA class IV heartfailure, firm conclusions cannot be reached about the effectof bucindolol on mortality in this subgroup.
Adverse Events
The incidence of selected adverse events is presented in Table 3.As expected, the incidence of angina, tachycardia, and palpitationswas significantly reduced with bucindolol therapy. The incidenceof bradycardia, intermittent claudication, diarrhea, dizziness,and hyperglycemia was increased with bucindolol therapy. Theincidence of insomnia and depression was reduced with beta-blockade,and reports of impotence were no more frequent than in the placebogroup.
Table 3. Incidence of Selected Adverse Events According to Treatment Group.
Discussion
We found no significant improvement in overall survival in patientsassigned to receive the beta-blocker bucindolol. The rates ofthe secondary end points of death from cardiovascular causesand hospitalization because of heart failure were significantlyreduced by treatment with bucindolol. The reason for the differencebetween the reduction in mortality in our study and those foundin other recently reported trials of beta-blockers1,2 is notclear. One possibility is that the patient populations studiedwere different. This hypothesis is supported by the observationthat bucindolol had a beneficial effect on the rate of deathin nonblack patients and a nonsignificant benefit in patientswith NYHA class III heart failure that was not dissimilar fromthe effects found in previous trials of beta-blockers conductedin similar patient populations, primarily in Europe.1,2 Alternatively,different pharmacologic properties of the various beta-blockingagents used in the studies could explain the smaller effectin our study. The absence of an early separation between thesurvival curves for the two groups is probably related to thesame factors that caused the study results to be neutral.
Among the patients in our study with NYHA functional class IIIheart failure, the annual mortality rate was 16 percent in theplacebo group, as compared with 12 percent in the Cardiac InsufficiencyBisoprolol Study II and 13 percent in the Metoprolol CR/XL RandomizedIntervention Trial in Congestive Heart Failure. For patientswith NYHA class IV heart failure, the annual mortality ratein the placebo group was 28 percent, as compared with 20 percentin the Cardiac Insufficiency Bisoprolol Study II. These datasuggest that within each NYHA class, we enrolled more patientswith advanced heart failure or coexisting conditions than didthe other two trials. If the severity of the heart failure modulatesthe effect of treatment with beta-blocking agents, the lossof adrenergic support that results from the initiation of beta-blockertherapy may not be as well tolerated in patients with more advanceddisease. Also, the myocardium may have less capacity to respondto treatment, perhaps because there is less viable myocardium.
We enrolled a substantial number of women, and the results didnot demonstrate a sex-related effect of bucindolol. However,the data did suggest the possibility that bucindolol may bebeneficial in nonblack but not in black patients. Although theseresults may represent a chance finding, the observed interactionraises the possibility of differences between racial groupsin the response to beta-blockers in patients with chronic heartfailure. Other studies of hypertensive patients25,26 and patientswith heart failure10,27,28 have also suggested the possibilityof a difference between racial groups in the response to treatmentwith angiotensin-converting–enzyme inhibitors and beta-blockers.Two studies of beta-blocking agents in patients with heart failurehave reported similar results in blacks and in nonblacks; oneof these studies, however, was conducted in a population withmild-to-moderate heart failure and reported a total of only14 deaths in black patients treated with placebo or carvedilol,29and the other study was extremely small, with a cohort of only54 patients.30
Although it is likely that the differences in the observed effecton mortality in black and nonblack populations have many determinants(including, as described above, the possibility that the differenceis a chance finding), blacks may have race-specific responsesto pharmacologic therapy for cardiovascular disease. The geneticor other reasons for heterogeneous responses to such therapyin different racial groups are currently unknown but may includedifferences in the renin–angiotensin system31,32 or thebeta-adrenergic pathway.33 Chance and more advanced ventriculardysfunction cannot be excluded as possible reasons for the differentialeffect.
Another possible explanation for the apparent difference betweenthe results of our study and those of other studies of beta-blockersand mortality may derive from the unique pharmacologic propertiesof bucindolol. Bucindolol is a nonselective beta-blocking agent34without intrinsic sympathomimetic activity in the human heart34,35,36,37;because of its mild vasodilator effect36 and low inverse agonistproperties (the ability of an antagonist to inactivate active-statereceptors),38 bucindolol is well tolerated in patients withadvanced heart failure. Strong 2-adrenergic blockade and onlyweak 1-blocking properties39 make bucindolol uniquely sympatholyticamong beta-blocking agents that have been evaluated in trialsin patients with heart failure.40,41 In fact, in our study,the 19 percent reduction in systemic norepinephrine levels (ascompared with the change in placebo group) at three months wassimilar to the 23 percent reduction that was associated withtreatment with the centrally acting sympatholytic agent moxonidinein the Effect of Sustained-Release Moxonidine on Mortality andMorbidity in Patients with Congestive Heart Failure trial (unpublisheddata). In that study, moxonidine increased mortality by morethan 50 percent, which led to the premature termination of thetrial.42 Unlike receptor blockade, sympatholysis produces anirreversible loss of adrenergic support to the failing heart,which may be deleterious early in the course of therapy in patientswith advanced heart failure. This property could also have hada mitigating effect on the mortality-lowering aspects of beta-receptorblockade in our study.
There is no longer any doubt that beta-blockers have a rolein the treatment of mild-to-moderate (NYHA class II to III)chronic heart failure. Our findings raise questions about theefficacy of these agents in blacks and in patients with moreadvanced heart failure, as well as about the equivalency ofbeta-blockers. In doing so, it makes clear the need for studiesthat examine the mechanism of the heterogeneity of responseto beta-blockers and for clinical trials that directly evaluatebeta-blockers in blacks and in patients with NYHA class IV heartfailure.
Supported by the Division of Epidemiology and Clinical Applicationsof the National Heart, Lung, and Blood Institute and the Departmentof Veterans Affairs Cooperative Studies Program, through aninteragency agreement. Additional support was provided by IncaraPharmaceuticals, which supplied bucindolol and placebo.
* The study investigators are listed in the Appendix.
Source Information
The BEST Manuscript Writing Committee (Eric J. Eichhorn, M.D., Michael J. Domanski, M.D., Heidi Krause-Steinrauf, M.S., Michael R. Bristow, M.D., Ph.D., and Philip W. Lavori, Ph.D.) takes responsibility for the content of this article.
Address reprint requests to Dr. Eichhorn at the Cardiac Catheterization Laboratory (IIIA2), University of Texas Southwestern and Dallas Veterans Affairs Medical Center, 4500 S. Lancaster, Dallas, TX 75216, or at eric.eichhorn{at}utsouthwestern.edu.
References
MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-2007. [CrossRef][Web of Science][Medline]
CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13. [CrossRef][Web of Science][Medline]
Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819-823. [Abstract]
Kay DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 1995;26:1257-1263. [Abstract]
Francis GS, Cohn JN, Johnson G, Rector TS, Goldman S, Simon A. Plasma norepinephrine, plasma renin activity, and congestive heart failure: relations to survival and the effects of therapy in V-HeFT II. Circulation 1993;87:Suppl V:V-140.
Packer M, Lee WH, Kessler PD, Gottlieb SS, Bernstein JL, Kukin ML. Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure. Circulation 1987;75:Suppl IV:IV-80.
Hall SA, Cigarroa CG, Marcoux L, Risser RC, Grayburn PA, Eichhorn EJ. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with -adrenergic blockade. J Am Coll Cardiol 1995;25:1154-1161. [Abstract]
Eichhorn EJ, Bristow MR. Practical guidelines for initiation of -adrenergic blockade in patients with chronic heart failure. Am J Cardiol 1997;79:794-798. [CrossRef][Web of Science][Medline]
Dries DL, Exner DV, Gersh BJ, Cooper HA, Carson PE, Domanski MJ. Racial differences in the outcome of left ventricular dysfunction. N Engl J Med 1999;340:609-616. [Erratum, N Engl J Med 1999;341:298.] [Free Full Text]
The BEST Steering Committee. Design of the Beta-Blocker Evaluation of Survival Trial (BEST). Am J Cardiol 1995;75:1220-1223. [CrossRef][Web of Science][Medline]
The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-533. [Free Full Text]
Efron B. Forcing a sequential experiment to be balanced. Biometrika 1971;58:403-417. [Free Full Text]
Lakatos E. Sample size determination in clinical trials with time-dependent rates of losses and noncompliance. Control Clin Trials 1986;7:189-199. [CrossRef][Web of Science][Medline]
Lakatos E. Sample size based on the log-rank statistic in complex clinical trials. Biometrics 1988;44:229-241. [Erratum, Biometrics 1988;44:923.] [CrossRef][Web of Science][Medline]
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659-663. [Free Full Text]
Lan KKG, Rosenberger WF, Lachin JM. Use of spending functions for occasional or continuous monitoring of data in clinical trials. Stat Med 1993;12:2219-2231. [Web of Science][Medline]
Lan KKG, Lachin JM. Implementation of group sequential logrank tests in a maximum duration trial. Biometrics 1990;46:759-770. [CrossRef][Web of Science][Medline]
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.
SAS (r) proprietary software, release 6.12. Cary, N.C.: SAS Institute, 1996.
Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34:187-202.
S-PLUS: version 3.4. Seattle: Insightful, 1998 (software).
Harrell FE. Predicting outcomes: applied survival analysis and logistic regression. Charlottesville: School of Medicine, University of Virginia, 1996.
Harrell FE. Design and Hmisc S-PLUS function libraries: S-PLUS 2000. Seattle: Insightful, June 1999 (software).
Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. N Engl J Med 1993;328:914-921. [Erratum, N Engl J Med 1994;330:1689.] [Free Full Text]
Johnson JA, Burlew BS, Stiles RN. Racial differences in beta-adrenoceptor-mediated responsiveness. J Cardiovasc Pharmacol 1995;25:90-96. [Medline]
Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the Vasodilator-Heart Failure trials. J Card Fail 1999;5:178-187. [CrossRef][Medline]
Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med 2001;344:1351-1357. [Free Full Text]
Yancy C, Fowler MB, Colucci WS, Gilbert EM, Lukas MA, Young ST. Response of black heart failure patients to carvedilol. J Am Coll Cardiol 1997;29:Suppl A:284A-284A.abstract
Freudenberger R, Kalman J, Mannino M, Buchholz-Varley C, Ocampo O, Kukin M. Effect of race in the response to metoprolol in patients with congestive heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. J Am Coll Cardiol 1997;80:1372-1374.
Bloem LJ, Manatunga AK, Pratt JH. Racial difference in the relationship of an angiotensin I-converting enzyme gene polymorphism to serum angiotensin I-converting enzyme activity. Hypertension 1996;27:62-66. [Free Full Text]
Rotimi C, Puras A, Cooper R. Polymorphisms of renin-angiotensin genes among Nigerians, Jamaicans, and African Americans. Hypertension 1996;27:558-563. [Free Full Text]
Moore JD, Mason DA, Green SA, Hsu J, Liggett SB. Racial differences in the frequencies of cardiac beta(1)-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C. Hum Mutat 1999;14:271-271. [Medline]
Hershberger RE, Wynn JR, Sundberg L, Bristow MR. Mechanism of action of bucindolol in human ventricular myocardium. J Cardiovasc Pharmacol 1990;15:959-967. [Web of Science][Medline]
Sederberg J, Wichman SE, Lindenfeld J, et al. Bucindolol has no intrinsic sympathomimetic activity (ISA) in nonfailing human ventricular preparations. J Am Coll Cardiol 2000;35:Suppl A:207A-207A.abstract
Gilbert EM, Anderson JL, Deitchman D, et al. Long-term -blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med 1990;88:223-229. [CrossRef][Web of Science][Medline]
Bristow MR, Roden RL, Lowes BD, Gilbert EM, Eichhorn EJ. The role of third generation -blocking agents in chronic heart failure. Clin Cardiol 1998;21:Suppl 1:I-3. [Erratum, Clin Cardiol 1999;22:ia.]
Yoshikawa T, Port JD, Asano K, et al. Cardiac adrenergic receptor effects of carvedilol. Eur Heart J 1996;17:Suppl B:8-16.
Uchida W, Kimura T, Satoh S. Presence of presynaptic inhibitory 1-adrenoceptors in the cardiac sympathetic nerves of the dog: effects of prazosin and yohimbine on sympathetic neurotransmission to the heart. Eur J Pharmacol 1984;103:51-56. [Medline]
Lowes BD, Lindenfeld JA, Gilbert EM, et al. Differential effects of-blocking agents on adrenergic activity. Circulation 2000;102:Suppl II:II-628.abstract
Gilbert EM, Abraham WT, Olsen S, et al. Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 1996;94:2817-2825. [Free Full Text]
The following people contributed to the Beta-Blocker Evaluationof Survival Trial (BEST): Steering Committee: E. Eichhorn (studycochairman), M. Domanski (study cochairman), H. Krause-Steinrauf(study biostatistician), J. Anderson, K. Boardman, M. Bristow,P. Carson, C. Colling, B. Greenberg, P. Lavori, J. Lindenfeld,D. Ward (Incara Pharmaceuticals), R. Zelis. Data and SafetyMonitoring Board: E. Braunwald (chairman), R. Cody, G. Francis,K. Davis, M. Ezekowitz, G. Knatterud. End Point Committee: P.Carson (cochairman), S. Gottlieb (cochairman), I. Anand, H.Krause-Steinrauf, C. O'Connor, J. Plehn, M. Silver, M. White.Recruitment Committee: P. Carson, C. Colling, M. Domanski, E.Eichhorn, N. Friedberger, B. Greenberg, H. Krause-Steinrauf,J. Lindenfeld, J. Salerno, J. Wood. Monitoring Committee: M.Bristow, B. Greenberg, H. Krause-Steinrauf, P. Lavori, M. Schleman(Astra-Merck), D. Ward (Incara Pharmaceuticals), R. Zelis. SubstudiesCommittee: M. Bristow, W. Colucci, M. Domanski, E. Eichhorn,S. Gottlieb, H. Krause-Steinrauf, S. Kubo, P. Lavori, T. LeJemtel, D. Mann, R. Zelis, M. Zile. Closeout Committee: K. Boardman,C. Colling, E. Eichhorn, H. Krause-Steinrauf, J. Lindenfeld,L. Marcoux, Y. Rosenberg, K. Urbanek, D. Ward (Incara Pharmaceuticals),J. Wood. National Research Study Coordinator: L. Marcoux. BESTInvestigational Group: Albany Medical Center — R. Capone,K. Edmunds; Albert Einstein College of Medicine — T. LeJemtel,M. Jones, J. Varela; Baptist Memorial Hospital — F. McGrewIII, S. Duffy; Baylor College of Medicine — G. Torre-Amione,J. Farmer, C. Foreman, J. Vinluan; Cardiology of Tulsa —D. Ensley, M. Dixon; Cedars–Sinai Medical Center —S. Khan, R. Verne, L. Defensor; Cleveland Clinic Foundation— J. Young, J. Del Valle; Cook County Hospital —J. Matthew, R. Rajanahally, P. Chong; Dartmouth Hitchcock MedicalCenter — J. Plehn, R. Palac, C. Carlson; Duke UniversityMedical Center — C. O'Connor, R. Larsen, A. Sykes; ElmhurstHospital Center — J. De Leon, M. Fussner; George WashingtonUniversity — R. Katz, A. Cangialosi; Georgetown UniversityHospital — D. Pearle, A. Baughn, S. Kelly; Grady MemorialHospital — R. Schlant, V. Jeffries; Heart Care Midwest— B. Clemson, M. Pierson, D. Best; Hospital of the Universityof Pennsylvania — E. Loh, M. St. John Sutton, F. Pickering;Johns Hopkins Hospital — P. Kessler, J. Hare, G. Edness;LDS Hospital — J. Anderson, D. Renlund, C. Maycock, K.Walker; Louisiana State University — J. Ghali, B. Cowan;Loyola University Medical Center — M. Silver, B. Pisani,M. Morrow, D. Jednachowski; Maricopa Medical Research Foundation— R. Patel, M. Dachman, C. Foley; Mayo Clinic, Rochester— L. Olson, R. Frantz, S. Eifert-Rain; Mayo Clinic, Scottsdale— R. Lee, G. LeBrun; MCP Hahnemann University —S. Brozena, J. Treacy, C. Del Bello; Medical College of Virginia— M. Peberdy, M. Flattery; Medical College of Wisconsin— J. Hosenpud, S. Mauermann, J. Gosset; Medical Universityof South Carolina — A. Van Bakel, G. Hendrix, M. Schulz,J. Evans; Minneapolis Heart Institute — W. Pedersen, L.Corriveau; Montreal Heart Institute — M. White, D. Leclerc,L. Whitton, J. Rjouleau; Morristown Memorial Hospital —J. Banas, Jr., J. Heric; National Naval Medical Center —D. Ferguson, J. Hardin, J. Bryant; Nebraska Heart Institute— S. Krueger, V. Norton, P. Vermas, S. Harre; New EnglandMedical Center — J. Udelson, P. Wedge; Oklahoma Foundationfor Cardiology Research — R. Kipperman, Y. Zhang; OregonHealth Sciences University — R. Hershberger, M. Guillotte,D. Burgess; New Mexico Heart Institute — K. Heilman III;Pennsylvania State University Hospital — J. Boehmer, R.Lenker-Battista; Robert Wood Johnson Medical School —J. Kostis, D. Hoagland; Shands Hospital, University of Florida— C. Pepine, J. Aranda, P. Morgan, D. Leach; St. John'sMercy Medical Center — H. Kennedy, P. Abele, L. Mezei,B. Von Ritter; University of Texas Southwestern — C. Yancy,C. Debes; Washington University School of Medicine — E.Geltman, K. Carbone, C. Hinden; University of Alabama MedicalCenter — W. Rogers, V. Bittner, G. Blackburn; Universityof California, San Diego, Medical Center — B. Greenberg,A. Contasti, D. Hermann; University of Cincinnati — W.Abraham, G. Bhat, S. MacDonald, R. Trupp; University of ColoradoHealth Science Center — M. Bristow, B. Lowes, J. Lindenfeld,D. Ferguson; University of Connecticut Health Center —W. Hager, M. Barry, L. Kearney; University of Florida HealthScience Center — A. Miller, G. Tripp; University of IowaHospital — R. Oren, C. Pies, M. Duncan; University ofMaryland — M. Fisher, M. Cines, J. Marshall; UniversityMedical Center, University of Arizona — P. Fenster, T.Struiksma; University of Minnesota Hospital — S. Kubo,A. Bank, L. Witte; University of Mississippi Medical Center— C. Moore, T. Guy, T. Thomas; University of Montreal— F. Sestier, L. Day, D. Sauard; University of North Carolina— K. Adams, V. Johnson, S. Clarke; University of PittsburghMedical Center — D. McNamara, M. Losego, Y. Cannon; Universityof Rochester Medical Center — C. Seng-Liang, E. Perkins,D. Petrie, J. Armstrong; University of Utah Health Science Center— E. Gilbert, K. Volkman, J. Housley; University of WisconsinHospital and Clinics — P. Rahko, P. Wiederholt, C. VanderArk;Watson Clinic — K. Browne, S. Collins; Yale–NewHaven Hospital — T. Ramahi, K. Rohlfs; Veterans AffairsMedical Center (VAMC) Baltimore — S. Gottlieb, N. Greenberg;VAMC Boston — M. Slawsky, L. Keane; VAMC Bronx —L. Baruch, P. Patacsil, T. Jamil; VAMC Charleston — M.Zile, M. Knotts, L. Harrell; VAMC Dallas — P. Grayburn,L. Marcoux; VAMC Denver — R. Bies, B. Hattler, K. Thompson,B. Watson; VAMC Durham — F. Cobb, G. Dodson, T. Thomas;VAMC Fresno — P. Deedwania, E. Carbajal, R. Kanefield;VAMC Hines — H. Loeb, A. Henrick; VAMC Houston —D. Mann, S. Eiswirth, B. Bozkurt, A. Desmai; VAMC Jackson —T. Srivastava, J. Voelkel; VAMC Lexington — A. Cross,D. Booth, L. Shockey; VAMC Little Rock — H. Dinh, E. Smith,B. Cotter; VAMC Long Beach — H. Olson, S. Saniga-Parker;VAMC Madison — P. Kosolcharoen, L. Williams; VAMC Memphis— K. Ramanathan, L. Johnson; VAMC Minneapolis —I. Anand, S. Ziesche, A. Holmstrom, S. Berg; VAMC Newington— R. Suri, J. Folger; VAMC Portland — E. Murphy,K. Martin, N. Valone; VAMC Richmond — P. Mohanty, E. Gavis;VAMC St. Louis — W. Martin, C. Inman, S. Witry; VAMC Salem— N. Jarmukli, D. Atkins, T. Gibson; VAMC San Francisco— B. Massie, S. Ammon, D. Bello, E. Der; VAMC San Diego— R. Shabetai, R. Cremo; VAMC Sepulveda — M. Heng,C. Lyu, S. Heng; VAMC San Antonio — D. Murray, J. Anderson,J. Dugan; VAMC Tampa — G. Cintron, J. Parks III; VAMCTucson — S. Goldman, D. Carroll, J. Ohm; VAMC Washington,D.C. — P. Carson, D. Lee. VA Palo Alto Cooperative StudiesProgram Coordinating Center: P. Lavori, H. Krause-Steinrauf,S. Thaneemit-Chen, V. Krishnan, K. Urbanek, J. Wood, N. Friedberger,J. Cockroft, C. Kerner, M. Penick, K. Green, S. King, Z. Zhang,K. Mahadocon, C. Franciscus, A. Kim, W. Chen, L. Nielsen, L.Rupper, D. Romero, C. Welte. National Heart, Lung, and BloodInstitute Study Operations: M. Domanski, Y. Rosenberg, D. Follmann.VA Cooperative Studies Program Clinical Research Pharmacy CoordinatingCenter: C. Colling, K. Boardman, J. Peterson. Clinical ResearchAssociates: L. Blanski, J. Hartman, A. Herring, C. Orcutt, K.Sheridan, J. Brehm, S. Lichtenberger, J. Bruce, A. Turpin, M.Norris.
Triposkiadis, F., Karayannis, G., Giamouzis, G., Skoularigis, J., Louridas, G., Butler, J.
(2009). The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.. J Am Coll Cardiol
54: 1747-1762
[Abstract][Full Text]
Foley, P. W.X., Leyva, F., Frenneaux, M. P.
(2009). What is treatment success in cardiac resynchronization therapy?. Europace
11: v58-v65
[Abstract][Full Text]
Dorn, G. W. II, Liggett, S. B.
(2009). Mechanisms of Pharmacogenomic Effects of Genetic Variation within the Cardiac Adrenergic Network in Heart Failure. Mol. Pharmacol.
76: 466-480
[Abstract][Full Text]
Ahmed, M. I., White, M., Ekundayo, O. J., Love, T. E., Aban, I., Liu, B., Aronow, W. S., Ahmed, A.
(2009). A history of atrial fibrillation and outcomes in chronic advanced systolic heart failure: a propensity-matched study. Eur Heart J
30: 2029-2037
[Abstract][Full Text]
Klapholz, M.
(2009). {beta}-Blocker Use for the Stages of Heart Failure. Mayo Clin Proc.
84: 718-729
[Abstract][Full Text]
Cresci, S., Kelly, R. J., Cappola, T. P., Diwan, A., Dries, D., Kardia, S. L.R., Dorn, G. W. II
(2009). Clinical and genetic modifiers of long-term survival in heart failure.. J Am Coll Cardiol
54: 432-444
[Abstract][Full Text]
McAlister, F. A., Wiebe, N., Ezekowitz, J. A., Leung, A. A., Armstrong, P. W.
(2009). Meta-analysis: {beta}-Blocker Dose, Heart Rate Reduction, and Death in Patients With Heart Failure. ANN INTERN MED
150: 784-794
[Abstract][Full Text]
Vilardaga, J.-P., Bunemann, M., Feinstein, T. N., Lambert, N., Nikolaev, V. O., Engelhardt, S., Lohse, M. J., Hoffmann, C.
(2009). Minireview: GPCR and G Proteins: Drug Efficacy and Activation in Live Cells. Mol. Endocrinol.
23: 590-599
[Abstract][Full Text]
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.
(2009). 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol
53: e1-e90
[Full Text]
Jessup, M., Abraham, W. T., Casey, D. E., Feldman, A. M., Francis, G. S., Ganiats, T. G., Konstam, M. A., Mancini, D. M., Rahko, P. S., Silver, M. A., Stevenson, L. W., Yancy, C. W.
(2009). 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol
53: 1343-1382
[Full Text]
2009 WRITING GROUP TO REVIEW NEW EVIDENCE AND UPDA, , Jessup, M., Abraham, W. T., Casey, D. E., Feldman, A. M., Francis, G. S., Ganiats, T. G., Konstam, M. A., Mancini, D. M., Rahko, P. S., Silver, M. A., Stevenson, L. W., Yancy, C. W.
(2009). 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in Collaboration With the International Society for Heart and Lung Transplantation. Circulation
119: 1977-2016
[Full Text]
2005 WRITING COMMITTEE MEMBERS, , 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.
(2009). 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in Collaboration With the International Society for Heart and Lung Transplantation. Circulation
119: e391-e479
[Full Text]
Kim, E. S.H., Menon, V.
(2009). Status of Women in Cardiovascular Clinical Trials. Arterioscler. Thromb. Vasc. Bio.
29: 279-283
[Full Text]
Willenheimer, R.
(2009). The current role of beta-blockers in chronic heart failure: with special emphasis on the CIBIS III trial. Eur Heart J Suppl
11: A15-A20
[Abstract][Full Text]
Go, A. S., Yang, J., Gurwitz, J. H., Hsu, J., Lane, K., Platt, R.
(2008). Comparative Effectiveness of Different {beta}-Adrenergic Antagonists on Mortality Among Adults With Heart Failure in Clinical Practice. Arch Intern Med
168: 2415-2421
[Abstract][Full Text]
Rosskopf, D., Michel, M. C.
(2008). Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine. Pharmacol. Rev.
60: 513-535
[Abstract][Full Text]
Authors/Task Force Members, , Dickstein, K., Cohen-Solal, A., Filippatos, G., McMurray, J. J.V., Ponikowski, P., Poole-Wilson, P. A., Stromberg, A., van Veldhuisen, D. J., Atar, D., Hoes, A. W., Keren, A., Mebazaa, A., Nieminen, M., Priori, S. G., Swedberg, K., ESC Committee for Practice Guidelines (CPG), , Vahanian, A., Camm, J., De Caterina, R., Dean, V., Dickstein, K., Filippatos, G., Funck-Brentano, C., Hellemans, I., Kristensen, S. D., McGregor, K., Sechtem, U., Silber, S., Tendera, M., Widimsky, P., Zamorano, J. L., Document Reviewers, , Tendera, M., Auricchio, A., Bax, J., Bohm, M., Corra, U., della Bella, P., Elliott, P. M., Follath, F., Gheorghiade, M., Hasin, Y., Hernborg, A., Jaarsma, T., Komajda, M., Kornowski, R., Piepoli, M., Prendergast, B., Tavazzi, L., Vachiery, J.-L., Verheugt, F. W. A., Zamorano, J. L., Zannad, F.
(2008). ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J
29: 2388-2442
[Full Text]
Dickstein, K., Cohen-Solal, A., Filippatos, G., McMurray, J. J.V., Ponikowski, P., Poole-Wilson, P. A., Stromberg, A., van Veldhuisen, D. J., Atar, D., Hoes, A. W., Keren, A., Mebazaa, A., Nieminen, M., Priori, S. G., Swedberg, K.
(2008). ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail
10: 933-989
[Full Text]
Gohler, A., Conrads-Frank, A., Worrell, S. S., Geisler, B. P., Halpern, E. F., Dietz, R., Anker, S. D., Gazelle, G. S., Siebert, U.
(2008). Decision-analytic evaluation of the clinical effectiveness and cost-effectiveness of management programmes in chronic heart failure. Eur J Heart Fail
10: 1026-1032
[Abstract][Full Text]
Johnson, J. A.
(2008). Ethnic Differences in Cardiovascular Drug Response: Potential Contribution of Pharmacogenetics. Circulation
118: 1383-1393
[Full Text]
Conen, D., Torres, J., Ridker, P. M
(2008). Differential Citation Rates of Major Cardiovascular Clinical Trials According to Source of Funding: A Survey From 2000 to 2005. Circulation
118: 1321-1327
[Abstract][Full Text]
Fonarow, G. C., Yancy, C. W., Albert, N. M., Curtis, A. B., Stough, W. G., Gheorghiade, M., Heywood, J. T., McBride, M. L., Mehra, M. R., O'Connor, C. M., Reynolds, D., Walsh, M. N.
(2008). Heart Failure Care in the Outpatient Cardiology Practice Setting: Findings From IMPROVE HF. Circ Heart Fail
1: 98-106
[Abstract][Full Text]
Prisant, L. M., Thomas, K. L., Lewis, E. F., Huang, Z., Francis, G. S., Weaver, W. D., Pfeffer, M. A., McMurray, J. J.V., Califf, R. M., Velazquez, E. J.
(2008). Racial Analysis of Patients With Myocardial Infarction Complicated by Heart Failure and/or Left Ventricular Dysfunction Treated With Valsartan, Captopril, or Both. J Am Coll Cardiol
51: 1865-1871
[Abstract][Full Text]
Vittorio, T. J., Zolty, R., Kasper, M. E., Khandwalla, R. M., Hirsh, D. S., Tseng, C.-H., Jorde, U. P., Ahuja, K.
(2008). Differential Effects of Carvedilol and Metoprolol Succinate on Plasma Norepinephrine Release and Peak Exercise Heart Rate in Subjects With Chronic Heart Failure. J CARDIOVASC PHARMACOL THER
13: 51-57
[Abstract]
Fantoni, C., Regoli, F., Ghanem, A., Raffa, S., Klersy, C., Sorgente, A., Faletra, F., Baravelli, M., Inglese, L., Salerno-Uriarte, J. A., Klein, H. U., Moccetti, T., Auricchio, A.
(2008). Long-term outcome in diabetic heart failure patients treated with cardiac resynchronization therapy. Eur J Heart Fail
10: 298-307
[Abstract][Full Text]
Granger, C. B
(2007). Carvedilol was more effective than metoprolol for preventing cardiovascular events in heart failure. Evid. Based Med.
12: 141-141
[Full Text]
Lunkenheimer, P. P., Redmann, K., Cryer, C. W., Batista, R. V., Stanton, J. J., Niederer, P., Anderson, R. H.
(2007). Beta-blockade at low doses restoring the physiological balance in myocytic antagonism. Eur. J. Cardiothorac. Surg.
32: 225-230
[Abstract][Full Text]
Patel, J., Heywood, J. T.
(2007). Mode of Death in Patients With Systolic Heart Failure. J CARDIOVASC PHARMACOL THER
12: 127-136
[Abstract]
Momary, K. M.
(2007). Cardiovascular Pharmacogenomics. Journal of Pharmacy Practice
20: 265-276
[Abstract]
Ong, H T
(2007). beta blockers in hypertension and cardiovascular disease. BMJ
334: 946-949
[Full Text]
Taylor, M. R.G., Slavov, D., Ku, L., Di Lenarda, A., Sinagra, G., Carniel, E., Haubold, K., Boucek, M. M., Ferguson, D., Graw, S. L., Zhu, X., Cavanaugh, J., Sucharov, C. C., Long, C. S., Bristow, M. R., Lavori, P., Mestroni, L., for the Familial Cardiomyopathy Registry and the B,
(2007). Prevalence of Desmin Mutations in Dilated Cardiomyopathy. Circulation
115: 1244-1251
[Abstract][Full Text]
Nasr, I. A., Bouzamondo, A., Hulot, J.-S., Dubourg, O., Le Heuzey, J.-Y., Lechat, P.
(2007). Prevention of atrial fibrillation onset by beta-blocker treatment in heart failure: a meta-analysis. Eur Heart J
0: ehl484v1-6
[Abstract][Full Text]
Bibbins-Domingo, K., Fernandez, A.
(2007). BiDil for Heart Failure in Black Patients: Implications of the U.S. Food and Drug Administration Approval. ANN INTERN MED
146: 52-56
[Abstract][Full Text]
Dzau, V. J., Antman, E. M., Black, H. R., Hayes, D. L., Manson, J. E., Plutzky, J., Popma, J. J., Stevenson, W.
(2006). The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part II: Clinical Trial Evidence (Acute Coronary Syndromes Through Renal Disease) and Future Directions. Circulation
114: 2871-2891
[Full Text]
Gheorghiade, M., Sopko, G., De Luca, L., Velazquez, E. J., Parker, J. D., Binkley, P. F., Sadowski, Z., Golba, K. S., Prior, D. L., Rouleau, J. L., Bonow, R. O.
(2006). Navigating the Crossroads of Coronary Artery Disease and Heart Failure. Circulation
114: 1202-1213
[Full Text]
Groban, L., Butterworth, J.
(2006). Perioperative management of chronic heart failure.. Anesth. Analg.
103: 557-575
[Abstract][Full Text]
Liggett, S. B., Mialet-Perez, J., Thaneemit-Chen, S., Weber, S. A., Greene, S. M., Hodne, D., Nelson, B., Morrison, J., Domanski, M. J., Wagoner, L. E., Abraham, W. T., Anderson, J. L., Carlquist, J. F., Krause-Steinrauf, H. J., Lazzeroni, L. C., Port, J. D., Lavori, P. W., Bristow, M. R.
(2006). A polymorphism within a conserved beta1-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc. Natl. Acad. Sci. USA
103: 11288-11293
[Abstract][Full Text]
Ahmed, A., Aban, I. B., Weaver, M. T., Aronow, W. S., Fleg, J. L.
(2006). Serum digoxin concentration and outcomes in women with heart failure: A bi-directional effect and a possible effect modification by ejection fraction. Eur J Heart Fail
8: 409-419
[Abstract][Full Text]
Lechat, P.
(2006). The evolution of heart failure management over recent decades: from CONSENSUS to CIBIS. Eur Heart J Suppl
8: C5-C12
[Abstract][Full Text]
Funck-Brentano, C.
(2006). Beta-blockade in CHF: from contraindication to indication. Eur Heart J Suppl
8: C19-C27
[Abstract][Full Text]
Vanoli, E., Adamson, P. B.
(2006). What does the future hold for the management of chronic heart failure?. Eur Heart J Suppl
8: C51-C57
[Abstract][Full Text]
Brady, A J B, Poole-Wilson, P A
(2006). ESC-CHF: guidelines for the aspirational and the practical.. Heart
92: 437-440
[Abstract][Full Text]
Pleger, S. T., Koch, W. J.
(2006). The yin and yang of increased beta-adrenergic signaling: beta1-adrenergic genetic polymorphism and protection against acute myocardial ischemic injury. Am. J. Physiol. Heart Circ. Physiol.
290: H1408-H1409
[Full Text]
Gillespie, N. D
(2006). The diagnosis and management of chronic heart failure in the older patient. Br Med Bull
75-76: 49-62
[Abstract][Full Text]
Taylor, A. L., Wright, J. T. Jr, Cooper, R. S., Psaty, B. M., Taylor, A. L., Wright, J. T. Jr, Cooper, R. S., Psaty, B. M.
(2005). Importance of Race/Ethnicity in Clinical Trials: Lessons From the African-American Heart Failure Trial (A-HeFT), the African-American Study of Kidney Disease and Hypertension (AASK), and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Circulation
112: 3654-3666
[Full Text]
Jost, A., Rauch, B., Hochadel, M., Winkler, R., Schneider, S., Jacobs, M., Kilkowski, C., Kilkowski, A., Lorenz, H., Muth, K., Zugck, C., Remppis, A., Haass, M., Senges, J., for the HELUMA study group,
(2005). Beta-blocker treatment of chronic systolic heart failure improves prognosis even in patients meeting one or more exclusion criteria of the MERIT-HF study. Eur Heart J
26: 2689-2697
[Abstract][Full Text]
Cohen-Solal, A., Rouzet, F., Berdeaux, A., Le Guludec, D., Abergel, E., Syrota, A., Merlet, P.
(2005). Effects of Carvedilol on Myocardial Sympathetic Innervation in Patients with Chronic Heart Failure. JNM
46: 1796-1803
[Abstract][Full Text]
Krum, H., Haas, S. J., Eichhorn, E., Ghali, J., Gilbert, E., Lechat, P., Packer, M., Roecker, E., Verkenne, P., Wedel, H., Wikstrand, J.
(2005). Prognostic benefit of beta-blockers in patients not receiving ACE-Inhibitors. Eur Heart J
26: 2154-2158
[Abstract][Full Text]
Singh, B. N.
(2005). {beta}-Adrenergic Blockers as Antiarrhythmic and Antifibrillatory Compounds: An Overview. J CARDIOVASC PHARMACOL THER
10: S3-S14
[Abstract]
Reiffel, J. A.
(2005). Drug and Drug-Device Therapy in Heart Failure Patients in the Post-COMET and SCD-HeFT Era. J CARDIOVASC PHARMACOL THER
10: S45-S58
[Abstract]
Developed in Collaboration With the American Colle, , Endorsed by the Heart Rhythm Society, , 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.
(2005). ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult--Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol
46: 1116-1143
[Full Text]
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.
(2005). ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult--Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation
112: 1825-1852
[Full Text]
Paterson, D. J.
(2005). Targeting Arterial Chemoreceptor Over-Activity in Heart Failure With a Gas. Circ. Res.
97: 201-203
[Full Text]
The National Heart, Lung, and Blood Institute Work,
(2005). Major Clinical Trials of Hypertension: What Should Be Done Next?. Hypertension
46: 1-6
[Abstract][Full Text]
Authors/Task Force Members, , Swedberg, K., Writing Committee:, , Cleland, J., Dargie, H., Drexler, H., Follath, F., Komajda, M., Tavazzi, L., Smiseth, O. A., Other Contributors, , Gavazzi, A., Haverich, A., Hoes, A., Jaarsma, T., Korewicki, J., Levy, S., Linde, C., Lopez-Sendon, J.-L., Nieminen, M. S., Pierard, L., Remme, W. J.
(2005). Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J
26: 1115-1140
[Full Text]
Al-Hesayen, A., Azevedo, E. R., Floras, J. S., Hollingshead, S., Lopaschuk, G. D., Parker, J. D.
(2005). Selective versus nonselective {beta}-adrenergic receptor blockade in chronic heart failure: differential effects on myocardial energy substrate utilization. Eur J Heart Fail
7: 618-623
[Abstract][Full Text]
Mann, D. L., Bristow, M. R.
(2005). Mechanisms and Models in Heart Failure: The Biomechanical Model and Beyond. Circulation
111: 2837-2849
[Full Text]
Grayburn, P. A., Appleton, C. P., DeMaria, A. N., Greenberg, B., Lowes, B., Oh, J., Plehn, J. F., Rahko, P., St. John Sutton, M., Eichhorn, E. J., the BEST Trial Echocardiographic Substudy Investig,
(2005). Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure: The Beta-blocker Evaluation of Survival Trial (BEST). J Am Coll Cardiol
45: 1064-1071
[Abstract][Full Text]
Yancy, C. W., Benjamin, E. J., Fabunmi, R. P., Bonow, R. O.
(2005). Discovering the Full Spectrum of Cardiovascular Disease: Minority Health Summit 2003: Executive Summary. Circulation
111: 1339-1349
[Full Text]
Flather, M. D., Shibata, M. C., Coats, A. J.S., Van Veldhuisen, D. J., Parkhomenko, A., Borbola, J., Cohen-Solal, A., Dumitrascu, D., Ferrari, R., Lechat, P., Soler-Soler, J., Tavazzi, L., Spinarova, L., Toman, J., Bohm, M., Anker, S. D., Thompson, S. G., Poole-Wilson, P. A., on behalf of the SENIORS Investigators,
(2005). Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J
26: 215-225
[Abstract][Full Text]
McMurray, J.
(2005). Making sense of SENIORS. Eur Heart J
26: 203-206
[Full Text]
Yan, A. T., Yan, R. T., Liu, P. P.
(2005). Narrative Review: Pharmacotherapy for Chronic Heart Failure: Evidence from Recent Clinical Trials. ANN INTERN MED
142: 132-145
[Abstract][Full Text]
McMurray, J. J.V., Pfeffer, M. A.
(2004). The year in heart failure. J Am Coll Cardiol
44: 2398-2405
[Full Text]
Lalukota, K., Cleland, J. G.F., Ingle, L., Clark, A. L., Coletta, A. P.
(2004). Clinical trials update from the Heart Failure Society of America: EMOTE, HERB-CHF, BEST genetic sub-study and RHYTHM-ICD. Eur J Heart Fail
6: 953-955
[Abstract][Full Text]
Ghali, J. K.
(2004). Cerebroprotection mediated by angiotensin II. J Am Coll Cardiol
44: 2097-2097
[Full Text]
Taylor, A. L., Ziesche, S., Yancy, C., Carson, P., D'Agostino, R. Jr., Ferdinand, K., Taylor, M., Adams, K., Sabolinski, M., Worcel, M., Cohn, J. N., the African-American Heart Failure Trial Investiga,
(2004). Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure. NEJM
351: 2049-2057
[Abstract][Full Text]
Tomaselli, G. F., Zipes, D. P.
(2004). What Causes Sudden Death in Heart Failure?. Circ. Res.
95: 754-763
[Abstract][Full Text]
Satwani, S., Dec, G. W., Narula, J.
(2004). {beta}-Adrenergic Blockers in Heart Failure: Review of Mechanisms of Action and Clinical Outcomes. J CARDIOVASC PHARMACOL THER
9: 243-255
[Abstract]
Cleland, J. G.F., Loh, P. H., Freemantle, N., Clark, A. L., Coletta, A. P.
(2004). Clinical trials update from the European Society of Cardiology: SENIORS, ACES, PROVE-IT, ACTION, and the HF-ACTION trial. Eur J Heart Fail
6: 787-791
[Abstract][Full Text]
Bristow, M.R., Krause-Steinrauf, H., Nuzzo, R., Liang, C.-S., Lindenfeld, J., Lowes, B.D., Hattler, B., Abraham, W.T., Olson, L., Krueger, S., Thaneemit-Chen, S., Hare, J.M., Loeb, H.S., Domanski, M.J., Eichhorn, E.J., Zelis, R., Lavori, P.
(2004). Effect of Baseline or Changes in Adrenergic Activity on Clinical Outcomes in the {beta}-Blocker Evaluation of Survival Trial. Circulation
110: 1437-1442
[Abstract][Full Text]
Nichol, G., Kaul, P., Huszti, E., Bridges, J. F.P.
(2004). Cost-Effectiveness of Cardiac Resynchronization Therapy in Patients with Symptomatic Heart Failure. ANN INTERN MED
141: 343-351
[Abstract][Full Text]
Task Force Members, , Lopez-Sendo, J., Swedberg, K., McMurray, J., Tamargo, J., Maggioni, A. P., Dargie, H., Tendera, M., Waagstein, F., Kjekshus, J., Lechat, P., Pedersen, C. T., ESC Committee for Practice Guidelines, , Priori, S. G., Alonso Garcia, M. A., Blanc, J.-J., Budaj, A., Cowie, M., Dean, V., Deckers, J., Fernandez Burgos, E., Lekakis, J., Lindahl, B., Mazzotta, G., McGregor, K., Morais, J., Oto, A., Smiseth, O. A., Document Reviewers, , Alonso Garcia, M. A., Ardissino, D., Avendano, C., Lundqvist, C. B., ment, D. C., Drexler, H., Ferrari, R., Fox, K. A., Julian, D., Kearney, P., Klein, W., ber, L. K., Mancia, G., Nieminen, M., Ruzyllo, W., Simoons, M., Thygesen, K., Tognoni, G., Tritto, I., Wallentin, L.
(2004). Expert consensus document on {beta}-adrenergic receptor blockers: The Task Force on Beta-Blockers of the European Society of Cardiology. Eur Heart J
25: 1341-1362
[Full Text]
Gluckman, T. J., Baranowski, B., Ashen, M. D., Henrikson, C. A., McAllister, M., Braunstein, J. B., Blumenthal, R. S.
(2004). A Practical and Evidence-Based Approach to Cardiovascular Disease Risk Reduction. Arch Intern Med
164: 1490-1500
[Abstract][Full Text]
Ko, D. T., Hebert, P. R., Coffey, C. S., Curtis, J. P., Foody, J. M., Sedrakyan, A., Krumholz, H. M.
(2004). Adverse Effects of {beta}-Blocker Therapy for Patients With Heart Failure: A Quantitative Overview of Randomized Trials. Arch Intern Med
164: 1389-1394
[Abstract][Full Text]
Zaugg, M., Schulz, C., Wacker, J., Schaub, M. C.
(2004). Sympatho-modulatory therapies in perioperative medicine. Br J Anaesth
93: 53-62
[Abstract][Full Text]
Jessup, M., Pina, I. L.
(2004). Is it important to examine gender differences in the epidemiology and outcome of severe heart failure?. J. Thorac. Cardiovasc. Surg.
127: 1247-1252
[Full Text]
Julius, S., Alderman, M. H., Beevers, G., Dahlof, B., Devereux, R. B., Douglas, J. G., Edelman, J. M., Harris, K. E., Kjeldsen, S. E., Nesbitt, S., Randall, O. S., Wright, J. T. Jr
(2004). Cardiovascular risk reduction in hypertensive black patients with left ventricular hypertrophy: The life study. J Am Coll Cardiol
43: 1047-1055
[Abstract][Full Text]
Sackner-Bernstein, J. D., Skopicki, H. A.
(2004). Racing away from bias. J Am Coll Cardiol
43: 785-786
[Full Text]
Metra, M., Nodari, S., Dei Cas, L.
(2004). Current guidelines in the pharmacological management of chronic heart failure. Journal of Renin-Angiotensin-Aldosterone System
5: S11-S16
[Abstract]
Ghali, J. K., Krause-Steinrauf, H. J., Adams, K. F. Jr, Khan, S. S., Rosenberg, Y. D., Yancy, C. W. Jr, Young, J. B., Goldman, S., Peberdy, M. A., Lindenfeld, J.
(2003). Gender differences in advanced heart failure: insights from the BEST study. J Am Coll Cardiol
42: 2128-2134
[Abstract][Full Text]
Baker, J. G., Hall, I. P., Hill, S. J.
(2003). Agonist and Inverse Agonist Actions of {beta}-Blockers at the Human {beta}2-Adrenoceptor Provide Evidence for Agonist-Directed Signaling. Mol. Pharmacol.
64: 1357-1369
[Abstract][Full Text]
Lohse, M. J., Engelhardt, S., Eschenhagen, T.
(2003). What Is the Role of {beta}-Adrenergic Signaling in Heart Failure?. Circ. Res.
93: 896-906
[Abstract][Full Text]
Eichhorn, E. J., Grayburn, P. A., Mayer, S. A., St John Sutton, M., Appleton, C., Plehn, J., Oh, J., Greenberg, B., DeMaria, A., Frantz, R., Krause-Steinrauf, H., for the BEST Investigators,
(2003). Myocardial Contractile Reserve by Dobutamine Stress Echocardiography Predicts Improvement in Ejection Fraction With {beta}-Blockade in Patients With Heart Failure: The {beta}-Blocker Evaluation of Survival Trial (BEST). Circulation
108: 2336-2341
[Abstract][Full Text]
Bello, D., Shah, D. J., Farah, G. M., Di Luzio, S., Parker, M., Johnson, M. R., Cotts, W. G., Klocke, F. J., Bonow, R. O., Judd, R. M., Gheorghiade, M., Kim, R. J.
(2003). Gadolinium Cardiovascular Magnetic Resonance Predicts Reversible Myocardial Dysfunction and Remodeling in Patients With Heart Failure Undergoing {beta}-Blocker Therapy. Circulation
108: 1945-1953
[Abstract][Full Text]
Lindenfeld, J., Ghali, J. K., Krause-Steinrauf, H. J., Khan, S., Adams, K. Jr, Goldman, S., Peberdy, M. A., Yancy, C., Thaneemit-Chen, S., Larsen, R. L., Young, J., Lowes, B., Rosenberg, Y. D., BEST Investigators,
(2003). Hormone replacement therapy is associated with improved survival in women with advanced heart failure. J Am Coll Cardiol
42: 1238-1245
[Abstract][Full Text]
Petitti, D. B.
(2003). New hope for hormone replacement and the heart?. J Am Coll Cardiol
42: 1246-1248
[Full Text]
Toyama, T., Hoshizaki, H., Seki, R., Isobe, N., Adachi, H., Naito, S., Oshima, S., Taniguchi, K.
(2003). Efficacy of Carvedilol Treatment on Cardiac Function and Cardiac Sympathetic Nerve Activity in Patients with Dilated Cardiomyopathy: Comparison with Metoprolol Therapy. JNM
44: 1604-1611
[Abstract][Full Text]
Domanski, M., Krause-Steinrauf, H., Deedwania, P., Follmann, D., Ghali, J. K., Gilbert, E., Haffner, S., Katz, R., Lindenfeld, J., Lowes, B. D., Martin, W., McGrew, F., Bristow, M. R., BEST Investigators,
(2003). The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial. J Am Coll Cardiol
42: 914-922
[Abstract][Full Text]
Liang, C.-s.
(2003). Sympatholysis and cardiac sympathetic nerve function in the treatment of congestive heart failure. J Am Coll Cardiol
42: 549-551
[Full Text]
Maack, C., Bohm, M., Vlaskin, L., Dabew, E., Lorenz, K., Schafers, H.-J., Lohse, M. J., Engelhardt, S.
(2003). Partial Agonist Activity of Bucindolol Is Dependent on the Activation State of the Human {beta}1-Adrenergic Receptor. Circulation
108: 348-353
[Abstract][Full Text]
Bouzamondo, A., Hulot, J.-S., Sanchez, P., Lechat, P.
(2003). Beta-blocker benefit according to severity of heart failure. Eur J Heart Fail
5: 281-289
[Abstract][Full Text]
Baker, J. G., Hall, I. P., Hill, S. J.
(2003). Agonist Actions of "{beta}-Blockers" Provide Evidence for Two Agonist Activation Sites or Conformations of the Human {beta}1-Adrenoceptor. Mol. Pharmacol.
63: 1312-1321
[Abstract][Full Text]
Nohria, A., Tsang, S. W., Fang, J. C., Lewis, E. F., Jarcho, J. A., Mudge, G. H., Stevenson, L. W.
(2003). Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure. J Am Coll Cardiol
41: 1797-1804
[Abstract][Full Text]
Shekelle, P. G., Rich, M. W., Morton, S. C., Atkinson, Col. S. W., Tu, W., Maglione, M., Rhodes, S., Barrett, M., Fonarow, G. C., Greenberg, B., Heidenreich, P. A., Knabel, T., Konstam, M. A., Steimle, A., Warner Stevenson, L.
(2003). Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: A meta-analysis of major clinical trials. J Am Coll Cardiol
41: 1529-1538
[Abstract][Full Text]
-blocker treatment derived from BEST and other studies." The board's recommendation was influenced by information that had been accruing from other studies of beta-blockers in chronic heart failure and by a concern about the equipoise of the trial. At the time of this recommendation, there was no significant difference in mortality between the two treatment groups (unadjusted P=0.16). On July 29, 1999, the trial was terminated by the study's sponsors (the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs). The mean duration of follow-up reported to the time the study was terminated was 2.0 years. 
2=5.06, P=0.02). With any reasonable adjustment for multiple comparisons, this finding could be explained as due to chance. The apparent interaction effect for race and treatment reflects the lack of benefit observed in blacks (hazard ratio for death with bucindolol vs. placebo, 1.17; 95 percent confidence interval, 0.89 to 1.53; P=0.27), but there was a significant survival benefit in nonblack patients (hazard ratio, 0.82; 95 percent confidence interval, 0.70 to 0.96; P=0.01). 
1-blocking properties39 make bucindolol uniquely sympatholytic among beta-blocking agents that have been evaluated in trials in patients with heart failure.40,41 In fact, in our study, the 19 percent reduction in systemic norepinephrine levels (as compared with the change in placebo group) at three months was similar to the 23 percent reduction that was associated with treatment with the centrally acting sympatholytic agent moxonidine in the Effect of Sustained-Release Moxonidine on Mortality and Morbidity in Patients with Congestive Heart Failure trial (unpublished data). In that study, moxonidine increased mortality by more than 50 percent, which led to the premature termination of the trial.42 Unlike receptor blockade, sympatholysis produces an irreversible loss of adrenergic support to the failing heart, which may be deleterious early in the course of therapy in patients with advanced heart failure. This property could also have had a mitigating effect on the mortality-lowering aspects of beta-receptor blockade in our study. 
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