Which strategy is “best” after myocardial infarction? the beta-blocker strategy plus implantable cardioverter defibrillator trial: rationale and study design1


      The Beta-blocker Strategy plus Implantable Cardioverter Defibrillator (BEST–ICD) Trial is a multicenter prospective randomized trial that started in June 1998, in 95 centers in Italy and Germany. The trial will test the hypothesis whether, in high-risk post myocardial infarction (MI) patients already treated with β blockers, electrophysiologic study (EPS)-guided therapy (including the prophylactic implantation of implantable cardioverter defibrillator [ICD] in inducible patients) will improve survival compared with conventional therapy. Patients eligible for the study are survivors of recent MI (≥5 and ≤21 days), aged ≤80 years, with left ventricular ejection fraction ≤35% and ≥1 of the following additional risk factors: (1) ventricular premature beats ≥10/hour; (2) decreased heart rate variability (standard deviation of unusual RR intervals <70 msec); and (3) presence of ventricular late potentials. Furthermore, all enrolled patients must be able to tolerate at least 25 mg of metoprolol per day. These patients constitute about 9% of all patients with recent MI and are expected to have a 2-year all-cause mortality >25% of which 50% is anticipated to be from sudden death. The main criteria of exclusion from the study are (1) a history of sustained ventricular arrhythmia; (2) documentation of nonsustained ventricular tachycardia during the screening phase; and (3) the need for myocardial revascularization and contraindications or intolerance to β-blocker therapy. Eligible patients will be randomized to 2 different therapeutic strategies: conventional strategy or EPS/ICD strategy. Patients allocated to the EPS/ICD strategy will undergo further risk stratification, and electrophysiologically inducible patients (∼35%) will receive prophylactic ICDs, in addition to the conventional therapy, whereas noninducible patients will be only conventionally treated. The primary endpoint of the study will be death from all causes. By hypothesizing a 30% reduction in the 2-year mortality (from 20% to 14%) in the EPS/ICD group compared with conventionally treated patients, 1,200 patients will have to be included. A triangular, 2-sided sequential design with preset boundaries, for a 5% significance level and 90% power to detect a reduction in 2-year mortality from 20% to 14%, will be used to permit early termination of the trial if the strategy is found to be efficacious, no difference, or inefficacious.
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        • Califf R.M
        • White H.D
        • Van de Werf F
        • Sadowski Z
        • Armstrong P.W
        • Vahanian A
        • Simoons M.L
        • Simes R.J
        • Lee K.L
        • Topol E.J
        One-year results from the global utilization of streptokinase and TPA for occluded coronary arteries (GUSTO I) trial.
        Circulation. 1996; 94: 1233-1238
        • Rouleau J.L
        • Talajic M
        • Sussex B
        • Potvin L
        • Warnica W
        • Davies R.F
        • Gardner M
        • Stewart D
        • Plante S
        • Dupuis R
        • Lauzon C
        • Ferguson J
        • Mikes E
        • Balnozan V
        • Savard P
        Myocardial infarction patients in the 1990s—their risk factors, stratification and survival in Canada.
        J Am Coll Cardiol. 1996; 27: 1119-1127
        • Volpi A
        • De Vita C
        • Franzosi M.G
        • Geraci E
        • Maggioni A.P
        • Mauri F
        • Negri E
        • Santoro E
        • Tavazzi L
        • Tognoni G
        Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis. Results of the GISSI-2 data base.
        Circulation. 1993; 88: 416-429
        • Antiplatelet Trialists Collaboration
        Secondary prevention of vascular disease by prolonged antiplatelet treatment.
        Br Med J. 1988; 296: 320-331
        • Yusuf S
        • Peto R
        • Lewis J
        • Collins R
        • Sleight P
        Beta blockade during and after myocardial infarction.
        Prog Cardiovasc Dis. 1985; 27: 335-371
        • Latini R
        • Maggioni A.P
        • Flather M
        • Sleight P
        • Tognoni G
        ACE inhibitor use in patients with myocardial infarction. Summary of evidence from clinical trials.
        Circulation. 1995; 92: 3132-3137
        • Scandinavian Simvastatin Survival Study Group
        Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease.
        Lancet. 1994; 344: 1383-1389
        • Sacks M.F
        • Pfeffer M.A
        • Moye L.A
        • Rouleau J.L
        • Rutherford J.D
        • Cole T.G
        • Brown L
        • Warnica W
        • Arnold J.M.O
        • Wun C.C
        • Davis B.R
        • Braunwald E
        The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.
        N Engl J Med. 1996; 335: 1001-1009
        • Michels K.B
        • Yusuf S
        Does PTCA in acute myocardial infarction affect mortality and reinfarction rates? A quantitative overview (meta-analysis) of the randomized clinical trials.
        Circulation. 1995; 91: 476-485
        • Raviele A
        • Bonso A
        • Gasparini G
        • Themistoclakis S
        Prophylactic implantation of implantable cardioverter/defibrillator in post-myocardial infarction patients.
        in: Vardas P.E Cardiac Arrhythmias, Pacing and Electrophysiology. Kluger Academic Publishers, Dordrecht1998: 305-310
      1. ACC/AHA practice guidelines for the management of patients with acute myocardial infarction.
        J Am Coll Cardiol. 1996; 28: 1328-1428
        • Feruglio G.A
        • Vanuzzo D
        La cardiopatia ischemica in Italia.
        G Ital Cardiol. 1989; 19: 754-762
        • Uretsky B.F
        • Sheahan R.G
        Primary prevention of sudden cardiac death in heart failure.
        J Am Coll Cardiol. 1997; 30: 1589-1597
        • Pratt C.M
        • Waldo A.L
        • Camm A.J
        Can antiarrhythmic drugs survive survival trials?.
        Am J Cardiol. 1998; 81: 24D-34D
        • Bigger J.T
        • Fleiss J.L
        • Kleiger R
        • Miller J.P
        • Rolnitzky L.M
        The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction.
        Circulation. 1984; 69: 250-258
        • Mukharji J
        • Rude R.E
        • Poole W.K
        • Gustafson N
        • Thomas L.J
        • Strauss H.W
        • Jaffe A.S
        • Muller J.E
        • Roberts R
        • Raabe D.S
        • Croft C.H
        • Passamani E
        • Braunwald E
        • Willerson J.T
        Risk factors for sudden death after acute myocardial infarction.
        Am J Cardiol. 1984; 54: 31-36
        • Kostis J.B
        • Byington R
        • Friedman L.M
        • Goldstein S
        • Furberg C
        Prognostic significance of ventricular ectopic activity in survivors of acute myocardial infarction.
        J Am Coll Cardiol. 1987; 10: 231-242
        • Maggioni A.P
        • Zuanetti G
        • Franzosi M.G
        • Rovelli F
        • Santoro E
        • Staszewsky L
        • Tavazzi L
        • Tognoni G
        Prevalence and prognostic significance of ventricular arrhythmias after acute myocardial infarction in the fibrinolytic era. GISSI-2 results.
        Circulation. 1993; 87: 312-322
        • Denniss A.R
        • Richards D.A
        • Cody D.V
        • Russel P.A
        • Young A.A
        • Cooper M.J
        • Ross D.L
        • Uther J.B
        Prognostic significance of ventricular tachycardia and fibrillation induced at programmed stimulation and delayed potentials detected on the signal-averaged electrocardiograms of survivors of acute myocardial infarction.
        Circulation. 1986; 74: 731-745
        • McClements B.M
        • Adgey A.A.J
        Value of signal-averaged electrocardiography, radionuclide ventriculography, Holter monitoring and clinical variables for prediction of arrhythmic events in survivors of acute myocardial infarction in the thrombolytic era.
        J Am Coll Cardiol. 1993; 21: 1419-1427
        • Cain M.E
        • Anderson J.L
        • Arnsdorf M.F
        • Mason J.W
        • Scheinman M.M
        • Waldo A.L
        ACC expert consensus document. Signal-averaged electrocardiography.
        J Am Coll Cardiol. 1996; 27: 238-249
        • Kleiger R.E
        • Miller J.P
        • Bigger J.T
        • Moss A.J
        Decreased heart rate variability and its association with increased mortality after acute myocardial infarction.
        Am J Cardiol. 1987; 59: 256-262
        • Farrell T.G
        • Bashir Y
        • Cripps T
        • Malik M
        • Poloniecki J
        • Bennett E.D
        • Ward D.E
        • Camm A.J
        Risk stratification for arrhythmic events in postinfarction patients based on heart rate variability, ambulatory electrcardiographic variables and signal-averaged electrocardiogram.
        J Am Coll Cardiol. 1991; 18: 687-697
        • Hartikainen J.E.K
        • Malik M
        • Staunton A
        • Poloniecki J
        • Camm J
        Distinction between arrhythmic and nonarrhythmic death after acute myocardial infarction based on heart rate variability, signal-averaged electrocardiogram, ventricular arrhythmias and left ventricular ejection fraction.
        J Am Coll Cardiol. 1996; 28: 296-304
        • Zuanetti G
        • Neilson J.M.M
        • Latini R
        • Santoro E
        • Maggioni A.P
        • Ewing D.J
        Prognostic significance of heart rate variability in post-myocardial infarction patients in the fibrinolytic era. The GISSI-2 results.
        Circulation. 1996; 94: 432-436
        • La Rovere M.T
        • Bigger J.T
        • Marcus F.I
        • Mortara A
        • Schwartz P.J
        Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction.
        Lancet. 1998; 351: 478-484
        • Schwartz P.J
        • Wolf S
        QT interval prolongation as predictor of sudden death in patients with myocardial infarction.
        Circulation. 1978; 57: 1074-1077
        • Perkiömäki J.S
        • Koistinen J
        • Yli-Mäyri S
        • Huikuri H.V
        Dispersion of QT interval in patients with and without susceptibility to ventricular tachyarrhythmias after previous myocardial infarction.
        J Am Coll Cardiol. 1995; 26: 174-179
        • Rosenbaum D.S
        • Jackson L.E
        • Smith J.M
        Electrical alternans and vulnerability to ventricular arrhythmias.
        N Engl J Med. 1994; 330: 235-241
        • Waspe L.E
        • Seinfeld D
        • Ferrick A
        • Kim S.G
        • Matos J.D
        • Fisher J.D
        Prediction of sudden death and spontaneous ventricular tachycardia in survivors of complicated myocardial infarction.
        J Am Coll Cardiol. 1985; 5: 1292-1301
        • Wilber D.J
        • Olshansky B
        • Moran J.F
        • Scanlon P.J
        Electrophysiologic testing and nonsustained ventricular tachycardia.
        Circulation. 1990; 82: 350-358
        • Bourke J.P
        • Richards D.A
        • Ross D.L
        • Wallace E.M
        • McGuire M.A
        • Uther J.B
        Routine programmed electrical stimulation in survivors of acute myocardial infarction for prediction of spontaneous ventricular tachyarrhythmias during follow-up.
        J Am Coll Cardiol. 1991; 18: 780-788
        • Pedretti R
        • Etro M.D
        • Laporta A
        • Sarzi Braga S
        • Carù B
        Prediction of late arrhythmic events after acute myocardial infarction from combined use of noninvasive prognostic variables and inducibility of sustained monomorphic ventricular tachycardia.
        Am J Cardiol. 1993; 71: 1131-1141
        • Furberg C.D
        Effect of antiarrhythmic drugs on mortality after myocardial infarction.
        Am J Cardiol. 1983; 52: 32C-36C
        • The Cardiac Arrhythmia Suppression Trial (CAST) Investigators
        Preliminary report.
        N Engl J Med. 1989; 321: 406-412
        • The Cardiac Arrhythmia Suppression Trial II Investigators
        Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction.
        N Engl J Med. 1992; 327: 227-233
        • Teo K.K
        • Yusuf S
        • Furberg C.D
        Role of antiarrhytmic prophylaxis in acute myocardial infarction. Review of clinical results.
        JAMA. 1993; 270: 1589-1595
        • Waldo A.L
        • Camm A.J
        • deRuyter H
        • Friedman P.L
        • MacNeil D.J
        • Pauls J.F
        • Pitt B
        • Pratt C.M
        • Schwartz P.J
        • Veltri E.P
        Effect of d-l sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction.
        Lancet. 1996; 348: 7-12
        • Julian D.G
        • Camm A.J
        • Frangin G
        • Janse M.J
        • Munoz A
        • Schwartz P.J
        • Simon P
        Randomized trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction.
        Lancet. 1997; 349: 667-674
        • Cairns J.A
        • Connolly S.J
        • Roberts R
        • Gent M
        Randomized trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations.
        Lancet. 1997; 349: 675-682
        • DIAMOND Study Group
        Dofetilide in patients with left ventricular dysfunction and either heart failure or acute myocardial infarction.
        Clin Cardiol. 1997; 20: 704-710
        • Moss A.J
        • Hall W.J
        • Cannom D.S
        • Daubert J.P
        • Higgins S.L
        • Klein H
        • Levine J.H
        • Saksena S
        • Waldo A.L
        • Wilber D
        • Brown M.W
        • Heo M
        Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia.
        N Engl J Med. 1996; 335: 1933-1940
        • GISSI
        Six-month effects of early treatment with lisinopril and transdermal glyceril trinitrate singly and together withdrawn six weeks after acute myocardial infarction.
        J Am Coll Cardiol. 1996; 27: 337-344
        • Bigger J.T
        • CABG Patch Trial Investigators
        Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery.
        N Engl J Med. 1997; 337: 1569-1575
        • Copie X
        • Hnatkova K
        • Staunton A
        • Fei L
        • Camm A.J
        • Malik M
        Predictive power of increased heart rate versus depressed left ventricular ejection fraction and heart rate variability for risk stratification after myocardial infarction. Results of a two-year follow-up study.
        J Am Coll Cardiol. 1996; 27: 270-276
        • Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology
        Heart rate variability. Standards of measurement, physiological interpretation and clinical use.
        Circulation. 1996; 93: 1043-1065
        • The Norwegian Multicenter Study Group
        Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction.
        N Engl J Med. 1981; 304: 801-807
        • Beta-blocker Heart Attack Trial Research Group
        A randomized trial of propranolol in patients with acute myocardial infarction.
        JAMA. 1982; 247: 1707-1714
        • Viskin S
        • Kitzis I
        • Lev E
        • Zak Z
        • Zajarias A
        • Laniado S
        • Belhassen B
        Treatment with beta-adrenergic blocking agents after myocardial infarction.
        J Am Coll Cardiol. 1995; 25: 1327-1332
        • Hjalmarson A
        • Elmfeldt D
        • Herlitz J
        • Holmberg S
        • Malik I
        • Nyberg G
        • Ryden L
        • Swedberg K
        • Vedin A
        • Waagstein F
        • Waldenstrom A
        • Waldenstrom J
        • Wedel H
        • Wilnelmsen L
        • Wilhelmsson C
        Effect on mortality of metoprolol in acute myocardial infarction.
        Lancet. 1981; 2: 823-837
        • Packer M
        • Bristow M
        • Cohn J.N
        • Colucci W.S
        • Fowler M.B
        • Gilbert E.M
        • Shusterman N.H
        The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.
        N Engl J Med. 1996; 334: 1349-1355
        • The MIAMI Trial Research Group
        Metoprolol in acute myocardial infarction (MIAMI). A randomized placebo-controlled international trial.
        Eur Heart J. 1985; 6: 199-226
        • Di Pede F
        • Gasparini G
        • Raviele A
        • Piccolo E
        Studi elettrofisiologici durante la fase acuta dell infarto miocardico. Può essere prognostico?.
        in: Caturelli G Cura Intensiva Cardiologica 1995. CESI, Roma1995: 495-498
        • Whitehead J
        The Design and Analysis of Sequential Clinical Trials. 2nd ed. Ellis Horwood Limited, Chichester1992