- Email: [email protected]
Design of the Beta-Blocker Evaluation Survival Trial (BEST)
Design
of the Beta-Blocker Evaluation Survival fiial (BEST) The BEST Steering Committee
Central to our current understandin of heart failure is the conce t that compensatory met f anisms that maintain blw s pressure and perfusion ultimately contribute to worsening of ventricular function. Studies of the effect of an iotensin-converting enzyme inhibitors in patients with i! eart failure are consistent with this paradigm.
This manuscript describes a 2,800~patient randomized trial that will definitively determine whettrer sympathetic nervous s stem antagonism with a p blocker prolongs the life o r patients with moderate to severe heart failure. (Am J Cardiol 1995;75: 1220-l 223)
tudies, both controlled and uncontrolled, suggestthat p blockade improves ventricular function in conS gestive heart failure (CHF).l-lo Severaltrials suggestthat
ing patient eligibility. Informed consent will then be obtained for eligible patients. A radionuclide ventriculogram must be performed at a BEST site within 60 days of the proposed randomization. History, physical examination, clinical laboratory studies, chest x-ray, electrocardiogram, and plasma norepinephrine levels will be obtained within 14 days of randomization. The baseline visit will occur 27 days after the initial screening visit to assure clinical stability. Patients must be taking digitalis and an angiotensin-converting enzyme inhibitor unless contraindicated. If CHF is compensated and the patient satisfies inclusion criteria and does not have a reason for exclusion, he/she will be eligible for randomization. Patients will be stratified by hospital, CHF etiology (presence or absenceof coronary artery disease),ejection fraction (< or >0.20), and gender, and will be assigned to a treatment group by an adaptive balancing scheme(“biased coin” randomization). Patients will be randomized to either placebo plus standard CHF treatment or bucindolol plus standardCHF treatment.Patients will be startedon bucindolol3 mg or placebo, titrated as tolerated over a period of 26 weeks to a final doseof 200 or 100 mg/day for patients weighing 275 or ~75 kg, respectively. Titration will be stoppedor slowed if the patient’s heart failure symptomsworsen significantly. After titration, patients will be followed for 218 months (Figures 1 and 2). Study medication dosagemay be reduced or discontinuedin the eventof intolerably worseningCHE Rationale for selection of a p blocker: In controlled trials in which p-1 selective agents were used to treat patients with cardiomyopathy,sudden’cardiacdeathwas not reduced.13*1d Also, secondaryprevention trials that studied p-1 selective agents in patients who had myocardial infarction have failed to show a reduction in suddencardiac death.“18 However, sudden cardiac death was reduced in post-myocardialinfarction patients treatedwith propranolol or timolol, both nonselectivep blockers.“~‘9~20 These data suggestthat nonselective p blqckade may be more effective in reducing mortality than p-1 selective therapy.This is consistent with the fact that 35% to 40% of the p receptors in the failing human ventricular myocardium are of the p-2 type.” It was therefore decided that a nonselective 6 blocker would be most appropriate. In addition, a p blocker wasdesiredthat causesno vasodilation, or as little as possible, to avoid difficulty in determining whether p blockade or vasodilation was responsible for any treatment effect.
p blockers may also reduce mortality.“-l4 In the BetaBlocker Heart Attack Trial, patients with a history of heart failure had less cardiac and sudden-deathmortality than those who did noLU Patients with a low ejection fraction in the Cardiac Arrhythmia SuppressionTrial who were treated with p blockade also had a reduction in mortality. I2 The Metoprolol in Dilated Cardiomyopathy trial randomized patients with dilated cardiomyopathy to treatment with metoprolol or placebo.13There was a trend toward reduction in a morbidity and mortality end point in patients treatedwith metoprolol (p = 0.058), but this was due entirely to a reduction in the need for cardiac transplantation. Thus, despite a reasonable theoretical b&is15J6and suggestive clinical studies,‘-lh the concept that p blockers reduce mortality in CHF patients remains unproved. The hypothesis of the Beta-Blocker Evaluation Survival Trial (BEST) is that the addition of p blockade to standard CHF therapy will reduce mortality in patients with moderate to severe ClXF (New York Heart Association functional class III or IV). METHODS Endpoints: The primary end point is total mortality. Secondary end points are total cardiovascular mortality, mortality due to worsening heart failure, sudden death, quality of life, hospitalization and cost, left ventricular ejection fraction after 3 and 12 months of therapy,myocardial infarction, and the effect of CHF etiology and gender on outcome. Study population: Study subjects will be men and women who, at randomization, have compensatedCHF due to idiopathic dilated cardiomyopathyor coronary diseasewith ejection fraction 10.35, are in New York Heart Association functional class III or IV, and are taking an angiotensin-converting enzyme inhibitor, digitalis, and if needed,a diuretic. Patients with a specific indication for, or contraindication to, p blockade will be excluded. Randomization and treatment protocol: A study protocol flow chart is presentedin Figure 1. During an initial screening visit, a determination will be maderegardFrom the National Heart, Lung, and Blood Institute, Bethesda, Mary land. Manuscript received December 9, 1994; revised manuscript received and accepted March 27, 1995. Address for reprints: Michael J. Domanski, MD, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892.
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A decision was made to limit the choice of B block- detect annual mortality reduction of 25%, from 15% to er to one that had demonstrated safety in patients with 11.25%,before adjusting for losses,noncompliance, and moderate to severeheart failure. Only metoprolol, biso- so forth. A 25% reduction was believed by the steering prolol, carvedilol, and bucindolol have been shown to committee to be the smallest effect size of clinical interbe safe,and only bucindolol had dose-rangingdata avail- est. Adjusted (becauseof assumptionsabout lag, loss to able at the time of drug selection. The safety of propra- follow-up, noncompliance, drop-in rate, and heart transnolo1 has not been demonstrated in patients with the plantation rate) cumulative 4.5-year mortality rate estiseverity of heart failure present in BEST patients. Fur- mates of 35% and 30% in the placebo and B-blocker thermore, the limited data available suggest that pro- groups, respectively, resulted in an adjusted 4.5-year mortality reduction of 15%. (6) A 3-month treatment pranolol is poorly tolerated during titration.22.‘3 In light of these data, metoprolol and bisoprolol were benefit lag. Death rates in the 2 groups were assumedto eliminated due to their B-1 selectivity. Carvedilol is well be equal during the initial 3 months of patient followtolerated and produces more B-2 antagonism than meto- up because6 to 9 weeks are neededto titrate bucindolol prolol, but less than bucindolol.2” Furthermore, carve- dose. (7) Loss to follow-up: annual rate 1% (cumulative dilol is a moderately potent vasodilator that could con- rate 5%) for each treatment group. A loss is defined as found evaluation of treatment effect. Bucindolol is a a patient who can no longer be observed for occurrence nonselective B blocker,25,z6is well tolerated in moder- of death. (8) Annual noncompliance rate (permanentdisate to severe heart failure,6,7~9*10~25,27 is only a weak continuation of study medication) in the bucindolol vasodilator,z5 and lowers plasma norepinephrine lev- group, 10%in the first year and 2%/year for the next 3.5 els.6.27For these reasons.bucindolol was chosen as the years. Outcomes of noncompliant patients are counted B-blocking agent for BEST Sample size: Sample size will be evaluated by the method of Lakatos28,29 becausethis method Flow chart of Study provides sample size estimates History, exam, New York Heart Association for tests based on the log rank functional class, quality of life, current statistic after adjusting for commedications, clinical laboratory, consent, radionuclide ventriculogram, electrocardiogram, plex trial characteristic.s,such as chest x-ray (see text for time-frame with staggered accrual, time-varying respect to randomization) hazardratios, treatmenteffectlag, Entrance EF SO.35 losses to follow-up, noncomplicriteria NYHA Class III-IV ance, and heart transplantation. The adjustmentwasaccomplished History, exam, New York Heart Association by assuminga placebo deathrate functional class quality of life, norepinephrine, cU=ent medicine m and percent mortality reduction with treatment in a “perfect” trial and then adjusting the rates Randomization stratified by hospital basedon a scheduleover time of ~~~~~~ +/- coronary artery disease patient withdrawals, noncompliance, and so forth. The observed mortality reduction after this adjustment will be lower than before adjustment.Stratificationwill not be incorporated into the samHistory, exam, radionuclide ventriculogram, clinical laboratory, chest x-ray, electrocardiogram. ple size calculations. Instead, avnorepinephrine, New York Heart Association erage rates across strata will be functional class, quality of life assumed. A samplesize of 2,800 ( 1,400 History. exam, New York Heart Association functional class, quality of life per group) will be calculated based on the following assumpHistory, exam. radionuclide ventriculogram, tions (annual rates refer to years clinical laboratory, chest x-ray, electrocardiogram, on the study, not calendar time): norepinephrine, New York Heart Association (1) Significance level (type I functional class, quality of life error): 2-sided significance test History, exam, New York Heart Association at the p = 0.05 level. (2) Power: functional class, quality of life 85%. (3) Uniform patient accrual over 3 years, H-month minimal follow-up, 3-year averagefollow18 mo. to 4.5 yrs follow-up up, 4.5-year total study duration. (4) Annual placebo group mortality rate of 15% (conservative FIGURE 1. Flow chart of study. EF = ejection fraction; NYHA = New York Heart Associaestimate4~5*10~2g). (5) Study target: tion functional class. CORONARY ARTERY DISEASE/DESIGN
OF THE BEST STUDY
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in the group to which they are randomized. (9) Drop-in rate (patients assignedto placebo given bucindolol): 0%. (10) Heart transplantation: 1.85%/year for the placebo group and 0.37% for the bucindolol group. Assumptions are that all sites recruit equal numbers of patients-40% women, with a 1% transplant rate in women, transplant rate for the Department of Veterans Affairs (VA) men of lS%/year, 3%lyear transplant rate for non-VA men. The different transplantation rates reflect the rates found in the Metoprolol in Dilated Cardiomyopathy trial13 and the fact that lower transplant rates are expectedto occur in VA-recruited patients. Transplants are assumedto occur after 1 year becausepatients on the transplant list, or those likely to be on the list within the first 6 months after randomization, are excluded. Becausetransplantation may not be random, censoring patients at the time of transplantation could introduce bias. Hence, posttransplant patient outcomesaccrue to the group to which they were randomized. Mortality rates in the sample size calculations will be adjusted by assuming that 80% of patients receiving transplants would have died within 1 year without a transplant. This will lower the expected mortality rate preferentially in the placebo group and will have the net effect of diminishing the observed mortal-
ity reduction. (11) Sample size will not be adjusted for the use of the implantable cardioverter-defibrillator because only about 1% of patients with heart failure are expectedto receive these devices and becausethere was no evidence for a differential implant rate between the 2 groups. Study organization: The steeringcommittee will oversee all aspectsof the study. An executive committee, a subset of the steering committee, will be composed of the National Heart, Lung, and Blood Institute (NHLBI) and VA co-chairmen. coordinating center principal investigator, and 22 clinical site principal investigators. The executive committee will provide study direction between steering committee meetings. The Data and Safety Monitoring Board will review the protocols of the main study and substudies,monitor study progress,and makerecommendationsto the NHLBI and the VA regarding study conduct. Current statusof the study: Randomization will begin in April 1995. Acknowledgment: The BEST Steering Committee acknowledges the important contribution of the Department of Veterans Affairs planning committee listed
STUDY SCHEDULE Month from Randomization Randomization
FIGURE2. Study schedule. Association
Class
Plasma Norepinephrine
Current Medications
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below and that of the committees that participated in the approval processincluding the Clinical Applications and Prevention Advisory Committee (NHLBI), the National Heart, Lung, and Blood Advisory Committee (NHLBC), and the Cooperative Studies Executive Committee of the Department of VeteransAffairs. Department of Veterans Affairs Planning Committee: Eric J. Eichhom, MD. Michael Bristow, MD, Peter Carson, MD, John O’Connell, MD, Paul Sobotka, MD, Cindy Colling, RPh, MS, Jeffrey Anderson, MD, Kelvin K. Lee, PhD, Henry Loeb, MD, Marika K. Iwane, MPH, PhD, StephenS. Gottlieb, MD, and Philip Lavori, PhD. APPENDIX BEST steering committee: Jeffrey L. Anderson, MD, University of Utah; Barry Greenberg, MD. University of California, San Diego: William Boden, MD, VA Medical Center, Boston: Heidi Krause-Steinrauf, MS (Study Biostatistician), VA Medical Center, Palo Alto; Michael R. Bristow. MD, University of Colorado: Robert Zelis, MD. Penn State University Medical Center; Peter Carson, MD, VA Medical Center, Washington, DC.: Philip W. La&, PhD, VA Medical Center, Palo Alto. (Coordinating Center Principal Investigator); Cindy Coiling, RPh, MS, VA Medical Center. Albuquerque; JoAnn Lindenfeld, MD, University of Colorado: Michael J. Domanski, MD (NHLBI Co-Chairman of BEST), National Heat. Lung. and Blood Institute, Bethesda, Maryland; Daniel Deykin. MD (ex offcioJ, VA Cooperative Studies Program; Eric J. Eicbbom, MD (VA Co-Chairman of BEST), VA Medical Center, Dallas.
and energetics in patients with non-ischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. JAm Co/l Cardiof 1994;24:131~1320. 9. Pollock SG, Roytash J, Loytash C, Craddock G, Smucker ML. Usefulness of bucindolol in congestive heat failure. Am J Cardiol 1990;66:603607. 10. Bristow MR. O’Connell JB, Gilbert EM, French WJ, Letherman G, Kantmwitz NE, Otie J, Smucker J, Smucker ML, Marshall G, Kelly P, Peitchman D, Anderson JL, for the Bucindolol Investigators. Dose-response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Circuhrion 1994;89:1632-1642. 11. Chadda K. Goldstein S, Byington R, Curb J. Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulariorz 1986; 73:503-j 10. 12. Kennedy HL, Barker A, Brooks MM, Bergstrand R, Hutber M, Goldstein S. Beanlands DS, Bigger JT, and the CAST Investigators. Beta-blocker therapy and mortality in the Cardiac Arrhythmia Suppression Trial (CAST) (abstr). Circularion 1992:86(suppl I):I-403. 13. Waagstein F, Bristow MR. Swedbag K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR. Goss FG. Hjalmarson A. for the Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancer 1993;342: 1141-l 146. 14. CIBIS Investizators and Committees. A randomized trial of beta-blockade in heart failure: the-Cardiac Insufficiency Bisoprolol Study (CIBIS). Circuhion 1994:90:1665-l 673. 15. Eichbom EJ. The paradox of P-adrenergic blockade for the management of congestive heat failure. Am J bled 1992;92:527-538. 16. Packer M, Lee WH, Kessler PD. Gottlieb SS, Bernstein JL, Kukin ML. Role of neurohormonal mechanisms in determining survival in patients with severer chronic heart failure. Circulation 1987;75(suppl IV):IV-s&IV-92. 17. Lopressor Intervention Trial Research Group. The Lopressor intervention trial: multicentre study of metoprolol in survivors of acute myocardial infarction. Etrr Heart J 1987;8:105&1064 18. ISIS-1 Collaborative Group. Mechanisms for the early mortality reduction produced bv beta-blockade started earlv in acute mvocardial infarction. Lancer 1988:l: 921-923. 19. Beta
I. Waagstein F. Hjalmarson A. Vamauskas E, Wallentin I. Effect of chronic betaadrenergic receptor blockade in congestive cardiomyopathy. Br Heart J’ 1975;37: 1022-1036. 2. Swedberg K, Hjalmarson A. Waagstein F, Wallentin I. Adverse effects of betablockade withdrawal in patients with congestive cardiomyopathy. Br HearrJ 1980; 44:131142. 3. Engelmeier RS, O’Connell JB, Walsh R. Rad N, Scanlon PJ. Gunnar RM. Improvement in symptoms and exercise tolerance by metoprolol in patients aith dilated cardiomyopathy: a double-blind. randomized, placebo-controlled trial. Circularion 1985;72:53&546. 4. Heilbnmn S, Shah P, Bristow M, Valentine H, Ginsburg R, Fowler M. Increased P-receptor density and improved response to catecholamine stimulation during long term metoprolol therapy in heart failure from dilated cardiomyopathy. Circhtion 1989;79:483190. 5. Waagstein F, Caidahl K, Wallsntin I, Begh C, Hjalmarson A. Long term pblockade in dilated cardiomyopathy. Circrrlation 1989;80:55 l-563. 6. Gilbert EM, Anderson JL. Deitchman D, Yanowitz FG, O’Connell JB, Renlund DC, Bartholomew M, Me&y PC. Lanabee P, Bristoa MR. Chronic P-blockervasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med 1990;88:223-229. 7. Eichhom EJ, Bedotto JB, Malloy CR, Hatfield BA, Deitchman D, Brown M, Willard IE, Gmybum PA. Effect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure: improvements in hemodynamic, contractile. and diastolic performance with bucindolol. Cirruhtion 1990,82:4731183. 8. Eichbom EJ, Heesch CM. Bamett JH, Alvarez LG. Fass SM, Graybum PA. Hatfield BA, Marcoux LG. Malloy CR. Effect of metoprolol on myocardial function
Blocker Heart Attack Study Group: The Beta-Blocker Heart Attack Trial. JAMA 1981;216:2073-2074. 20. Pedersen TR. Six-year follow-up of the Norwegian Multicenter Study on tim0101after acute myocardial infarction. N Engl J Med 1985;3 13: 1055-1058. 21. Bristow MR, Ginsburg R, Umans V, Foaler 111,Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S, Stinson EB. PI- and P,-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective P,-receptor downregulation in heat failure. Circ Res 1986:59:297-309. 22. Stephen SA. Unwanted effects of propranolol. Am J Cardiol 1966;18:463-$72. 23. Bristow MR. Pathophysiologic and phamtacologic rationales for clinical management of chronic heart failure with beta-blocking agents. Am J Cardiol 1993:71: 12c-22c. 24. Btistow
M, Lasabee P, Minobe W, Roden R, Slarl L, Klein J. Hundwerger D, Port J, Mulbr-Buckman B. Receptor pharmacology of carvedilol in the human heart. J Cardiovmc Pharmncol 1992; 19(suppl 1):568-580. 25. Eichhom E. Effects of hucindolol in heart failure. Am J Cardioll993:71: ICdC. 26. Hershberger R, Wynn J, Sundberg L, Bristow M. Mechanism of action of bucindolol in human centricular myocardium. J Cardiowsc Pfmmacol 1990: 15: 959-967. 27. Woodley
SL. Gilbert EM, Anderson IL. O’Connell JB. Deitchman D, Yanowitz FG, Me&y PC, Volkman K. Renlund DG, Btistow MR. P-blockade with bucindolol in heart failure due to ischemic vs idiopathic dilated cardiomyopathy. Circe[ation 1991;84:242&2441. 28. Lakatos E. Sample sire determination in clinical trials with time-dependent rates of losses and noncompliance. Corrrrolled C/in TriaO 1986;189-199. 29. Lakatos E. Sample size based on the Logrank statistic in complex clinical trials. Biomerrics 1988;44?29-241.
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of the Beta-Blocker Evaluation Survival fiial (BEST) The BEST Steering Committee
Central to our current understandin of heart failure is the conce t that compensatory met f anisms that maintain blw s pressure and perfusion ultimately contribute to worsening of ventricular function. Studies of the effect of an iotensin-converting enzyme inhibitors in patients with i! eart failure are consistent with this paradigm.
This manuscript describes a 2,800~patient randomized trial that will definitively determine whettrer sympathetic nervous s stem antagonism with a p blocker prolongs the life o r patients with moderate to severe heart failure. (Am J Cardiol 1995;75: 1220-l 223)
tudies, both controlled and uncontrolled, suggestthat p blockade improves ventricular function in conS gestive heart failure (CHF).l-lo Severaltrials suggestthat
ing patient eligibility. Informed consent will then be obtained for eligible patients. A radionuclide ventriculogram must be performed at a BEST site within 60 days of the proposed randomization. History, physical examination, clinical laboratory studies, chest x-ray, electrocardiogram, and plasma norepinephrine levels will be obtained within 14 days of randomization. The baseline visit will occur 27 days after the initial screening visit to assure clinical stability. Patients must be taking digitalis and an angiotensin-converting enzyme inhibitor unless contraindicated. If CHF is compensated and the patient satisfies inclusion criteria and does not have a reason for exclusion, he/she will be eligible for randomization. Patients will be stratified by hospital, CHF etiology (presence or absenceof coronary artery disease),ejection fraction (< or >0.20), and gender, and will be assigned to a treatment group by an adaptive balancing scheme(“biased coin” randomization). Patients will be randomized to either placebo plus standard CHF treatment or bucindolol plus standardCHF treatment.Patients will be startedon bucindolol3 mg or placebo, titrated as tolerated over a period of 26 weeks to a final doseof 200 or 100 mg/day for patients weighing 275 or ~75 kg, respectively. Titration will be stoppedor slowed if the patient’s heart failure symptomsworsen significantly. After titration, patients will be followed for 218 months (Figures 1 and 2). Study medication dosagemay be reduced or discontinuedin the eventof intolerably worseningCHE Rationale for selection of a p blocker: In controlled trials in which p-1 selective agents were used to treat patients with cardiomyopathy,sudden’cardiacdeathwas not reduced.13*1d Also, secondaryprevention trials that studied p-1 selective agents in patients who had myocardial infarction have failed to show a reduction in suddencardiac death.“18 However, sudden cardiac death was reduced in post-myocardialinfarction patients treatedwith propranolol or timolol, both nonselectivep blockers.“~‘9~20 These data suggestthat nonselective p blqckade may be more effective in reducing mortality than p-1 selective therapy.This is consistent with the fact that 35% to 40% of the p receptors in the failing human ventricular myocardium are of the p-2 type.” It was therefore decided that a nonselective 6 blocker would be most appropriate. In addition, a p blocker wasdesiredthat causesno vasodilation, or as little as possible, to avoid difficulty in determining whether p blockade or vasodilation was responsible for any treatment effect.
p blockers may also reduce mortality.“-l4 In the BetaBlocker Heart Attack Trial, patients with a history of heart failure had less cardiac and sudden-deathmortality than those who did noLU Patients with a low ejection fraction in the Cardiac Arrhythmia SuppressionTrial who were treated with p blockade also had a reduction in mortality. I2 The Metoprolol in Dilated Cardiomyopathy trial randomized patients with dilated cardiomyopathy to treatment with metoprolol or placebo.13There was a trend toward reduction in a morbidity and mortality end point in patients treatedwith metoprolol (p = 0.058), but this was due entirely to a reduction in the need for cardiac transplantation. Thus, despite a reasonable theoretical b&is15J6and suggestive clinical studies,‘-lh the concept that p blockers reduce mortality in CHF patients remains unproved. The hypothesis of the Beta-Blocker Evaluation Survival Trial (BEST) is that the addition of p blockade to standard CHF therapy will reduce mortality in patients with moderate to severe ClXF (New York Heart Association functional class III or IV). METHODS Endpoints: The primary end point is total mortality. Secondary end points are total cardiovascular mortality, mortality due to worsening heart failure, sudden death, quality of life, hospitalization and cost, left ventricular ejection fraction after 3 and 12 months of therapy,myocardial infarction, and the effect of CHF etiology and gender on outcome. Study population: Study subjects will be men and women who, at randomization, have compensatedCHF due to idiopathic dilated cardiomyopathyor coronary diseasewith ejection fraction 10.35, are in New York Heart Association functional class III or IV, and are taking an angiotensin-converting enzyme inhibitor, digitalis, and if needed,a diuretic. Patients with a specific indication for, or contraindication to, p blockade will be excluded. Randomization and treatment protocol: A study protocol flow chart is presentedin Figure 1. During an initial screening visit, a determination will be maderegardFrom the National Heart, Lung, and Blood Institute, Bethesda, Mary land. Manuscript received December 9, 1994; revised manuscript received and accepted March 27, 1995. Address for reprints: Michael J. Domanski, MD, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892.
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A decision was made to limit the choice of B block- detect annual mortality reduction of 25%, from 15% to er to one that had demonstrated safety in patients with 11.25%,before adjusting for losses,noncompliance, and moderate to severeheart failure. Only metoprolol, biso- so forth. A 25% reduction was believed by the steering prolol, carvedilol, and bucindolol have been shown to committee to be the smallest effect size of clinical interbe safe,and only bucindolol had dose-rangingdata avail- est. Adjusted (becauseof assumptionsabout lag, loss to able at the time of drug selection. The safety of propra- follow-up, noncompliance, drop-in rate, and heart transnolo1 has not been demonstrated in patients with the plantation rate) cumulative 4.5-year mortality rate estiseverity of heart failure present in BEST patients. Fur- mates of 35% and 30% in the placebo and B-blocker thermore, the limited data available suggest that pro- groups, respectively, resulted in an adjusted 4.5-year mortality reduction of 15%. (6) A 3-month treatment pranolol is poorly tolerated during titration.22.‘3 In light of these data, metoprolol and bisoprolol were benefit lag. Death rates in the 2 groups were assumedto eliminated due to their B-1 selectivity. Carvedilol is well be equal during the initial 3 months of patient followtolerated and produces more B-2 antagonism than meto- up because6 to 9 weeks are neededto titrate bucindolol prolol, but less than bucindolol.2” Furthermore, carve- dose. (7) Loss to follow-up: annual rate 1% (cumulative dilol is a moderately potent vasodilator that could con- rate 5%) for each treatment group. A loss is defined as found evaluation of treatment effect. Bucindolol is a a patient who can no longer be observed for occurrence nonselective B blocker,25,z6is well tolerated in moder- of death. (8) Annual noncompliance rate (permanentdisate to severe heart failure,6,7~9*10~25,27 is only a weak continuation of study medication) in the bucindolol vasodilator,z5 and lowers plasma norepinephrine lev- group, 10%in the first year and 2%/year for the next 3.5 els.6.27For these reasons.bucindolol was chosen as the years. Outcomes of noncompliant patients are counted B-blocking agent for BEST Sample size: Sample size will be evaluated by the method of Lakatos28,29 becausethis method Flow chart of Study provides sample size estimates History, exam, New York Heart Association for tests based on the log rank functional class, quality of life, current statistic after adjusting for commedications, clinical laboratory, consent, radionuclide ventriculogram, electrocardiogram, plex trial characteristic.s,such as chest x-ray (see text for time-frame with staggered accrual, time-varying respect to randomization) hazardratios, treatmenteffectlag, Entrance EF SO.35 losses to follow-up, noncomplicriteria NYHA Class III-IV ance, and heart transplantation. The adjustmentwasaccomplished History, exam, New York Heart Association by assuminga placebo deathrate functional class quality of life, norepinephrine, cU=ent medicine m and percent mortality reduction with treatment in a “perfect” trial and then adjusting the rates Randomization stratified by hospital basedon a scheduleover time of ~~~~~~ +/- coronary artery disease patient withdrawals, noncompliance, and so forth. The observed mortality reduction after this adjustment will be lower than before adjustment.Stratificationwill not be incorporated into the samHistory, exam, radionuclide ventriculogram, clinical laboratory, chest x-ray, electrocardiogram. ple size calculations. Instead, avnorepinephrine, New York Heart Association erage rates across strata will be functional class, quality of life assumed. A samplesize of 2,800 ( 1,400 History. exam, New York Heart Association functional class, quality of life per group) will be calculated based on the following assumpHistory, exam. radionuclide ventriculogram, tions (annual rates refer to years clinical laboratory, chest x-ray, electrocardiogram, on the study, not calendar time): norepinephrine, New York Heart Association (1) Significance level (type I functional class, quality of life error): 2-sided significance test History, exam, New York Heart Association at the p = 0.05 level. (2) Power: functional class, quality of life 85%. (3) Uniform patient accrual over 3 years, H-month minimal follow-up, 3-year averagefollow18 mo. to 4.5 yrs follow-up up, 4.5-year total study duration. (4) Annual placebo group mortality rate of 15% (conservative FIGURE 1. Flow chart of study. EF = ejection fraction; NYHA = New York Heart Associaestimate4~5*10~2g). (5) Study target: tion functional class. CORONARY ARTERY DISEASE/DESIGN
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in the group to which they are randomized. (9) Drop-in rate (patients assignedto placebo given bucindolol): 0%. (10) Heart transplantation: 1.85%/year for the placebo group and 0.37% for the bucindolol group. Assumptions are that all sites recruit equal numbers of patients-40% women, with a 1% transplant rate in women, transplant rate for the Department of Veterans Affairs (VA) men of lS%/year, 3%lyear transplant rate for non-VA men. The different transplantation rates reflect the rates found in the Metoprolol in Dilated Cardiomyopathy trial13 and the fact that lower transplant rates are expectedto occur in VA-recruited patients. Transplants are assumedto occur after 1 year becausepatients on the transplant list, or those likely to be on the list within the first 6 months after randomization, are excluded. Becausetransplantation may not be random, censoring patients at the time of transplantation could introduce bias. Hence, posttransplant patient outcomesaccrue to the group to which they were randomized. Mortality rates in the sample size calculations will be adjusted by assuming that 80% of patients receiving transplants would have died within 1 year without a transplant. This will lower the expected mortality rate preferentially in the placebo group and will have the net effect of diminishing the observed mortal-
ity reduction. (11) Sample size will not be adjusted for the use of the implantable cardioverter-defibrillator because only about 1% of patients with heart failure are expectedto receive these devices and becausethere was no evidence for a differential implant rate between the 2 groups. Study organization: The steeringcommittee will oversee all aspectsof the study. An executive committee, a subset of the steering committee, will be composed of the National Heart, Lung, and Blood Institute (NHLBI) and VA co-chairmen. coordinating center principal investigator, and 22 clinical site principal investigators. The executive committee will provide study direction between steering committee meetings. The Data and Safety Monitoring Board will review the protocols of the main study and substudies,monitor study progress,and makerecommendationsto the NHLBI and the VA regarding study conduct. Current statusof the study: Randomization will begin in April 1995. Acknowledgment: The BEST Steering Committee acknowledges the important contribution of the Department of Veterans Affairs planning committee listed
STUDY SCHEDULE Month from Randomization Randomization
FIGURE2. Study schedule. Association
Class
Plasma Norepinephrine
Current Medications
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below and that of the committees that participated in the approval processincluding the Clinical Applications and Prevention Advisory Committee (NHLBI), the National Heart, Lung, and Blood Advisory Committee (NHLBC), and the Cooperative Studies Executive Committee of the Department of VeteransAffairs. Department of Veterans Affairs Planning Committee: Eric J. Eichhom, MD. Michael Bristow, MD, Peter Carson, MD, John O’Connell, MD, Paul Sobotka, MD, Cindy Colling, RPh, MS, Jeffrey Anderson, MD, Kelvin K. Lee, PhD, Henry Loeb, MD, Marika K. Iwane, MPH, PhD, StephenS. Gottlieb, MD, and Philip Lavori, PhD. APPENDIX BEST steering committee: Jeffrey L. Anderson, MD, University of Utah; Barry Greenberg, MD. University of California, San Diego: William Boden, MD, VA Medical Center, Boston: Heidi Krause-Steinrauf, MS (Study Biostatistician), VA Medical Center, Palo Alto; Michael R. Bristow. MD, University of Colorado: Robert Zelis, MD. Penn State University Medical Center; Peter Carson, MD, VA Medical Center, Washington, DC.: Philip W. La&, PhD, VA Medical Center, Palo Alto. (Coordinating Center Principal Investigator); Cindy Coiling, RPh, MS, VA Medical Center. Albuquerque; JoAnn Lindenfeld, MD, University of Colorado: Michael J. Domanski, MD (NHLBI Co-Chairman of BEST), National Heat. Lung. and Blood Institute, Bethesda, Maryland; Daniel Deykin. MD (ex offcioJ, VA Cooperative Studies Program; Eric J. Eicbbom, MD (VA Co-Chairman of BEST), VA Medical Center, Dallas.
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