Influence of Diabetes on 5-Year Mortality and Morbidity in a Randomized Trial Comparing CABG and PTCA in Patients With Multivessel Disease
The Bypass Angioplasty Revascularization Investigation (BARI)
Background Patients with diabetes mellitus have increased morbidity and mortality after coronary revascularization. The Bypass Angioplasty Revascularization Investigation (BARI), a trial of percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass graft surgery (CABG) in patients with multivessel disease, reported a 5-year survival advantage of CABG over PTCA in patients with treated diabetes mellitus (TDM). This report examines these findings in more detail.
Methods and Results Eighteen clinical centers randomly assigned 1829 patients with multivessel coronary disease to undergo initial CABG or PTCA. Patients were followed an average of 5.4 years. TDM was defined as a history of diabetes with use of oral hypoglycemic agents or insulin at study entry. Nineteen percent of the randomized population (353 patients) met these criteria. TDM patients had more unfavorable baseline characteristics than other patients, but among TDM patients, these characteristics were similar between the CABG and PTCA groups. Better average 5.4-year survival with CABG was due to reduced cardiac mortality (5.8% versus 20.6%, P=.0003), which was confined to those receiving at least one internal mammary artery graft.
Conclusions Patients with TDM assigned to an initial strategy of CABG have a striking reduction in cardiac mortality compared with PTCA. Long-term internal mammary artery graft patency may contribute to this improved outcome by reducing the fatality of follow-up myocardial infarction.
Patients with diabetes mellitus have a greater incidence of atherosclerotic cardiovascular disease, which, when present, is associated with increased mortality and morbidity compared with nondiabetic patients with cardiovascular disease.1 2 3 4 5 6 Diabetes is an independent risk factor for lesion progression, graft occlusion, and cardiac mortality after CABG.7 8 9 10 11 In two recent studies, a history of diabetes was associated with a twofold increase in mortality over 5 to 8 years after PTCA compared with patients without diabetes.12 13 In addition, diabetes mellitus has been identified as an independent risk factor for the development of restenosis after balloon angioplasty or stent placement.14 15
In 1987, the NHLBI initiated the BARI, a randomized trial to compare the efficacy of CABG and PTCA in patients with multivessel disease.16 17 18 19 20 The primary hypothesis was that an initial revascularization strategy of PTCA did not compromise clinical outcome over a 5-year period compared with an initial strategy of CABG. BARI recently reported no significant difference in survival over a 5-year period between the two strategies.21 Four baseline patient characteristics (clinical presentation, number of coronary vessels diseased, left ventricular function, and American College of Cardiology/American Heart Association lesion type) were prespecified for subgroup analysis. On the basis of findings of an earlier trial,22 the Safety and Data Monitoring Board recommended that diabetes also be monitored. Among patients with TDM, defined as diabetes mellitus treated with oral hypoglycemic agents or insulin at study entry, all-cause mortality was significantly lower in those assigned to CABG than in those assigned to PTCA (19% versus 35%, P=.003).21 The present report extends this comparison to cause-specific mortality and examines CABG efficacy by use of IMA grafts versus SVGs only.
The trial protocol, including a detailed description of study aims, patient selection, exclusion criteria, procedure guidelines, definitions, and administrative structure, has been published.16 17 18 19 20 Briefly, patients were eligible for BARI if they had angiographically documented multivessel coronary artery disease with either clinically severe angina or objective evidence of marked myocardial ischemia requiring revascularization and were suitable for both PTCA and CABG. Between August 1988 and August 1991, 1829 patients from 18 clinical centers were entered into the trial after providing written informed consent. Patients were followed an average 5.4 years, until June 5, 1995, when 67% had 5 years of follow-up. The primary study end point was all-cause mortality at 5 years. Secondary end points included MI and functional and symptomatic status.
Cause of Death
Cause of death was classified by an independent Mortality and Morbidity Classification Committee as cardiac, noncardiac but related to atherosclerotic disease, other noncardiac medical causes (eg, cancer, pulmonary disease), trauma, suicide, and other or unknown causes.16 Cardiac death was defined as death <1 hour after onset of cardiac symptoms, within 30 days after documented or probable MI, or due to intractable CHF, cardiogenic shock, or other documented cardiac causes. A cardiac cause was defined as contributory when cardiac malfunction was involved but other direct causes of death could not be ruled out (eg, chronic CHF with pulmonary embolism). Documents used for classification included death certificate; coroner’s report if available; report from the clinical center’s principal investigator; surgical and catheterization laboratory reports if death occurred within 30 days of a procedure; ECG and enzyme data if measured within 24 hours of death; and the patient’s baseline, procedure, and hospital study data. Each case was reviewed independently by two committee members, with disagreements resolved by full committee consensus.
Q-wave MI was determined by central laboratory analysis of ECGs requiring a two-step worsening of the Minnesota Q-wave code23 24 or a new left bundle-branch block associated with a twofold increase in total creatine phosphokinase with a positive MB fraction. Non–Q-wave MI was diagnosed when cardiac enzymes were elevated with chest pain for >20 minutes or with the appearance of new ECG changes. Cardiac enzymes were not used to define an MI within 96 hours after coronary revascularization.
Initial Revascularization Procedures
Left ventricular and coronary arteriographic findings were analyzed by a central laboratory using a quantitative arteriographic coding system.25 A successful dilatation was defined as (1) reduction in luminal diameter narrowing of ≥20%, (2) final lumen diameter narrowing of <50%, and (3) TIMI grade 3 flow. The details of surgical revascularization were collected prospectively.
Patient group differences were evaluated with the χ2 test (or Fisher’s exact test) for categorical data and the Wilcoxon test for continuous or count data. Crude cause-specific mortality rates for an average 5.4 years of follow-up were computed as a percentage of the number of patients at baseline. The Kaplan-Meier estimate26 was used to calculate cardiac survival (freedom from cardiac mortality) under the assumption that censoring for incomplete follow-up or noncardiac death was noninformative. The log-rank statistic, stratified according to clinical center, was used to compare cardiac survival curves between treatment groups. A Cox regression model27 was used to compare cardiac mortality rates, adjusted for baseline differences, in patients with TDM after PTCA, after CABG with an IMA graft, and after all other CABG procedures (SVG only). In the Cox model, baseline differences between the three treatment groups were summarized by a score that estimated each patient’s likelihood of receiving an IMA graft. The score function was obtained from a logistic regression model using symptomatic and ischemic status, race, sex, age ≥65 years, right-dominant coronary artery system, four or more significant lesions, significant lesion in the left anterior descending coronary artery, CHF, and body mass index to predict which CABG patients received an IMA graft. To assess the influence of MI on mortality, cardiac mortality rates were computed for patients with a diagnosed MI and for those without a diagnosed MI in each of three groups (PTCA, CABG with IMA, and CABG with SVG only).
At study entry, 447 patients (24% of the randomized population) had a history of diabetes and 353 (19%) had TDM as defined above. The 94 patients with a history of diabetes but not receiving oral hypoglycemic agents or insulin were included in the 1476 patients classified as not having TDM or “all other” BARI patients.
BARI patients with and without TDM differed substantially (Table 1⇓). Patients with TDM were more often women and blacks and had a lower formal educational level than other patients. A higher proportion of those with TDM had a history of CHF, hypertension, chronic renal failure, and peripheral vascular disease. In addition, TDM patients had higher triglyceride levels and body mass indexes. The severity of angina at the time of randomization was similar, but TDM patients were more likely to report an inactive lifestyle and a lower quality of life. The extent of coronary disease was also greater in the TDM group, as reflected by the presence of three-vessel disease and more distal lesions. Left ventricular ejection fraction was lower among treated diabetics.
Among TDM patients, baseline characteristics were equally distributed between treatment arms, with the exception that PTCA patients had higher mean LDL cholesterol.
Initial Revascularization Procedure
Table 2⇓ presents characteristics of the initial intervention for patients receiving their assigned treatment. For patients assigned to CABG with and without TDM, 96% and 98%, respectively, received their assigned procedures. TDM patients had a higher mean number of significant lesions and distal sites and a lower proportion with all intended vessels grafted. IMA grafting, whose use (81% to 82% of all CABGs) did not differ by TDM status, was usually performed in conjunction with SVGs. There was a greater use of sequential grafts in the TDM patients.
For patients assigned to PTCA, 98% with TDM and 95% without TDM underwent their assigned procedure. TDM patients had more significant stenoses and more distal lesions but a similar number of attempted lesions (2.4 versus 2.3). Among significant attempted lesions, TDM patients had a lower mean reference diameter before and after PTCA, as well as lower mean minimum lumen diameter after PTCA (P<.01 for each comparison).
Within each treatment arm, in-hospital event rates were similar among patients with and without TDM (Table 3⇓). Among those with TDM, the in-hospital mortality was 1.2% for CABG and 0.6% for PTCA, and the incidence of Q-wave MI was threefold greater after CABG compared with PTCA. Among the TDM patients receiving PTCA, 7.1% required emergency CABG and 2.9% underwent nonemergency CABG during the initial hospitalization, and 2.4% required emergency PTCA. Other minor complications were similar between the CABG and PTCA groups.
All-Cause Mortality During Follow-up
The 5-year survival of TDM patients was significantly worse than for other patients (73.1% versus 91.3%, P<.0001 for the log-rank test). For the 94 patients with untreated diabetes at baseline, the 5-year survival was 93.3% compared with 91.1% for the 1382 patients without a history of diabetes. When the patients with TDM were analyzed by treatment assignment, the cumulative survival rates were significantly higher for patients assigned to CABG on the basis of a stringent prespecified .005 level of significance (80.6 for CABG, 65.5 for PTCA, P=.003 for the log-rank test). This treatment difference did not vary significantly by clinical centers (P=.90).
Cause-specific mortality after an average of 5.4 years of follow-up is shown in Table 4⇓ for patients who underwent their assigned revascularization procedure. Cardiac mortality rates were 20.6% and 5.8% for PTCA and CABG, respectively, among patients with TDM, compared with 4.8% and 4.7%, respectively, for other BARI patients. Rates of noncardiac death related to atherosclerosis and of death attributed to other medical causes, while considerably higher for patients with TDM, were comparable by assigned treatment within both TDM and non-TDM patients. Thus, among patients with TDM, the excess mortality observed in the PTCA group in comparison with the CABG group was cardiac and not due to other causes (P<.01 by Fisher’s exact test). As seen in the Figure⇓, the cardiac survival curves between TDM and non-TDM patients diverge steadily beginning in the first year of follow-up, as do the survival curves within the TDM group by assigned treatment.
Impact of IMA Use on Cardiac Events
The relation of the presence of an IMA graft to cardiac mortality was particularly striking (Table 5⇓). Cardiac mortality with TDM was 2.9% when at least one IMA was used and 18.2% when only SVG conduits were used. The latter rate was similar to that of patients receiving PTCA (20.6%). Because patients were not assigned at random to use of IMA graft, this survival advantage could potentially be due to factors related to patient suitability for IMA grafts rather than the conduit itself. However, after adjustment for the selection factors (likelihood of receiving IMA grafts), cardiac mortality in TDM patients not treated with IMA grafts remained excessive, with an 8.1 risk ratio for cardiac death with PTCA and a 7.4 risk ratio for SVG alone compared with patients receiving at least one IMA graft (P<.005 for each comparison). Among patients without TDM, cardiac mortality rates were similar across the three treatment groups.
Postrandomization MI rates were also analyzed among TDM patients. Although the cardiac death rate in those receiving IMA grafts was substantially reduced compared with the other two groups, postrandomization MI rates were comparable for all three groups. However, when cardiac mortality and MI are cross-classified in the final two columns of Table 5⇑, however, it is apparent that IMA use in diabetic patients was associated with sharply decreased cardiac mortality with or without MI.
Patients without TDM had nearly identical cardiac mortality and MI rates regardless of treatment or conduit. However, IMA use was once again associated with lower post-MI cardiac mortality. This finding in both nondiabetics and TDM patients suggests that an IMA graft protected patients from high cardiac mortality when an intervening MI was sustained. In the large majority of patients without TDM and without intercurrent MI, cardiac mortality was remarkably similar between CABG and PTCA.
The BARI Investigators recently reported that patients with TDM at the time of randomization to an initial strategy of PTCA experienced higher mortality over a period of 5 years compared with treated diabetics assigned to CABG.21 To elucidate the mechanisms potentially involved in this observed differential mortality, this report details clinical and angiographic characteristics and specific causes of death of patients with and without TDM.
The hazards of subgroup analysis without a priori defined hypotheses and sufficient sample size to achieve the desired power are well recognized, as is the influence of multiple analyses of the data. We established wide, 99.5% CIs for within-subgroup treatment comparisons, corresponding to a stringent .005 level of significance. Additional support for our findings comes from a recent report from another large multicenter randomized trial, the Coronary Angioplasty versus Bypass Revascularization Investigation (CABRI).28 In contrast, the Emory Angioplasty versus Surgery Trial (EAST) failed to show a survival advantage for CABG.29 The survival rate in the small group of diabetic patients in that study, however, was uncharacteristically similar to the nondiabetic patients.
Investigation of cause-specific mortality rates was critical to our understanding of the significant mortality difference observed between treatment groups in TDM patients. Cardiac mortality was more than three times higher in TDM patients initially revascularized with PTCA, whereas other cause-specific noncardiac death rates, although higher in TDM patients, remained remarkably similar by treatment group. Although patients with TDM are known to have a significantly higher incidence of restenosis and progression of coronary artery disease,1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 we hypothesize that PTCA, rather than leading to increased mortality, may simply fail to alter the natural clinical course in TDM patients with coronary artery disease.
The survival benefit of CABG was limited to use of IMA grafts, and it was particularly striking after postrandomization MI in patients with and without TDM. Although postrandomization MI rates were comparable by assigned treatment and conduit type, the subsequent cardiac mortality was lowest with the placement of IMA grafts. This observation was similar to the substantially lower postinfarction mortality rates reported by Peduzzi et al30 and Alderman31 in the VA study for patients initially randomized to CABG instead of medical treatment. We hypothesize that IMA grafts, being less susceptible to disease progression (accelerated in TDM), may provide better alternative sources of perfusion to maintain ventricular function in regions of hypoperfusion resulting from coronary occlusion.
It is well documented that diabetic patients have a greater incidence of mortality post-MI than nondiabetic patients.32 33 34 35 36 37 38 Among diabetic patients, MIs can more often be painless or atypical, manifesting and diagnosed as sudden CHF, cardiac shock, arrhythmia, or sudden death.39 40 Several basic mechanisms might explain the increased mortality of acute MI in diabetics. The benefits of preconditioning of the myocardium may be inhibited by the influence of hypoglycemic drugs that inhibit the ATPase-sensitive potassium channels.41 A hyperpolarizing mechanism present in endothelial cells of normal arteries may be impaired in diabetics, which may compromise endothelial cell function.42 Insulin resistance may contribute to abnormalities in coronary flow.43 Microvascular abnormalities may lead to myocardial ischemia in diabetics even without epicardial coronary artery disease.44 A higher incidence of silent ischemia, plaque disruption, and thrombosis in diabetic patients may help explain the increased rate of acute coronary syndromes and MI observed in diabetics.35 36 37 38 39 40 41 42 43 44 45 Diabetics have a higher incidence of lipid abnormalities and hypertension, which further increases their risk for coronary artery disease.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
The results of two recent prospective studies have clearly documented the importance of glycemic control in reducing cardiovascular mortality and morbidity in diabetics.46 47 One-year mortality was also reduced in a randomized trial of diabetics with aggressive insulin and glucose therapy early after MI.48 It has been estimated that in diabetic men, aggressive medical therapy and risk factor modification could reduce mortality from coronary artery disease, which is between three and five times greater than among nondiabetics.49 The importance of control of diabetes cannot be overemphasized.
Limitations and Clinical Implications of the Study
The number of BARI patients with TDM was relatively small (353), although larger than in other recently reported trials comparing CABG and PTCA.28 29 Because diabetes was not the original focus of the BARI trial, we collected no detailed information as to the type, degree, and duration of diabetes. The BARI diabetic classification, also used in the diabetes substudy of the MRFIT trial and the Joslin Clinic follow-up study,6 32 was based on patient history, strengthened by the objective evidence of insulin or oral hypoglycemic use. Because BARI was not specifically designed to evaluate TDM, the adequacy of glucose control is unknown, and differential adherence to medical therapy cannot be ruled out.
The results for diabetic patients in BARI do not necessarily apply to all patients with diabetes. Treated diabetics in the BARI Registry who refused randomization were selected for treatment with PTCA without apparent compromise in survival compared with CABG.50 These patients, however, do not share the adverse baseline characteristics of those in the randomized trial. This observation suggests that in certain diabetic patients, angioplasty may be a suitable alternative to bypass surgery. In addition, we did not enroll patients with single-vessel disease, and use of the IMA graft was left to the discretion of the operator rather than assigned at random. Interpretation of BARI results must also take into account the fact that the initial procedure was standard balloon angioplasty. The impact on outcomes among treated diabetics is not known for the new revascularization technologies, including the frequent use of stents.51 52 53
The clinical implications of our observations are several. Among TDM patients with the characteristics of those randomized in BARI, CABG with IMA grafts appears to be the preferred initial treatment strategy. However, if only SVGs are used, cardiac mortality is similar to that with PTCA. The advances in catheter-based techniques, surgery, and medical therapy call for further properly controlled randomized clinical trials to determine the best treatment strategy for patients with diabetes mellitus.
Selected Abbreviations and Acronyms
|BARI||=||Bypass Angioplasty Revascularization Investigation|
|CABG||=||coronary artery bypass graft surgery|
|CHF||=||congestive heart failure|
|IMA||=||internal mammary artery|
|PTCA||=||percutaneous transluminal coronary angioplasty|
|SVG||=||saphenous vein graft|
|TDM||=||treated diabetes mellitus|
This article was prepared by Edwin Alderman, MD, Martial Bourassa, MD, Maria M. Brooks, PhD, Robert Califf, MD, Bernard Chaitman, MD, Katherine Detre, MD, DrPH, David P. Faxon, MD, Frederick Feit, MD, Robert L. Frye, MD, Regina M. Hardison, BS, David Holmes, MD, Richard Holubkov, PhD, Nicholas Kouchoukos, MD, Ronald Krone, MD, William Rogers, MD, Allan D. Rosen, MS, Hartzell Schaff, MD, Leonard Schwartz, MD, Andrea S. Siewers, MPH, George Sopko, MD, MPH, Kim Sutton-Tyrrell, DrPH, and Patrick Whitlow, MD, on behalf of the BARI Investigators. Dr Frye, as study chairman, assumes responsibility for overall content and integrity of this article.
Participants in the BARI Trial
University of Alabama
Principal Investigator: W.J. Rogers. W.A. Baxley, L.S. Dean, G.S. Roubin, J.K. Kirklin, J.W. Kirklin, A. Pacifico, G.L. Zorn, E. Charles, T.D. Paine, S. Brewer, L.C. Carr, G. Duke, L.E. Maske, T.E. Morgan, K. Doss, J.A. Trobaugh, K.W. Anderson, M. Brunner-Scott, D. Bunn, F. Harris. Former participants: T. Bulle, J.B. Cavender, P.J. Garrahy.
Brown University: Rhode Island Hospital
Principal Investigator: D.O. Williams. T.M. Drew, A.K. Singh, G.N. Cooper, B.L. Sharaf, J.L. Wheeler. Former participants: M.E. Grogan, M. Macedo, J. Moran, E.S. Thomas, H. White.
Bellevue Hospital (Satellite to Brown)
Principal Investigators: F. Feit, M.J. Attubato. S.B. Colvin, A.C. Galloway, G. Ribakove, P.F. Pasternack, M. Rey, S. Shapiro.
Principal Investigators: A.K. Jacobs, D.P. Faxon. G.R. Garber, N.A. Ruocco, R.S. Shemin, G.S. Aldea, T.J. Ryan, D.A. Weiner, B.R. Hankin, M.E. Mazur. Former participants: J.W. Currier, R.M. Mills, G. Paone, J.E. Brush, J.D. Fonger, M.A. Bettmann, J.A. Rothendler.
Cleveland Clinic Foundation
Principal Investigator: P.L. Whitlow. S. Ellis, I. Franco, R. Raymond, E. Topol, D. Cosgrove, F. Loop, B. Lytle, R. Stewart, P.C. Taylor, A.P. Dimas, A.M. Lincoff, W. Proudfit, G. Williams, M. Lowrie, K. Comella. Former participants: J. Frierson, F. Grigera, B. Healy, J. Hollman, L. Korcuska, B. Robalino, A. Rogers, S. Senick, J. Tedrick, K. Vaska.
Principal Investigator: R.M. Califf. R.P. Bauman, V.S. Behar, Y. Kong, M.W. Krucoff, K.G. Morris, R.H. Peter, H.R. Phillips, R. Stack, J.E. Tcheng, R.H. Jones, H.N. Oldham, P. Van Tright, W.A. Baker, T. Bashore, D.F. Fortin, K. Lee, E.M. Ohman, L.A. Drew, M.A. Sellers, V.C. Bass. Former participants: B. Bacon, S.G. Burks, S. Caminiti, T. Daniels, D.J. Frid, H. Gessner, E. Hampton, M.J. Miller, D.B. Pryor, P.J. Quigley, J.S. Rankin, J. Richard, L. Santoro, A. N. Tenaglia.
Harvard University: Beth Israel Hospital
Principal Investigator: D. S. Baim. J. Aroesty, B. Lorell, R. Johnson, R. Thurer, R. Weintraub, M. Flatley. Former participants: M. Cunnion, T. DeFeo-Fraulini, D. Diver, R. McKay, C. McCabe, K. Miller, R. Safian, A. Slater.
Maine Medical Center (Satellite to Harvard)
Principal Investigator: M.A. Kellett Jr. W.D. Alpern, R.A. Anderson, D.J. Cutler, P.W. Sweeney, D.J. Donegan, S. Katz, R.S. Kramer, C.A. Lutes, J.R. Morton, E.R. Nowicki, J.F. Tryzelaar, R.L. White, C.T. Lambrew, S. Bosworth-Farrell, J.C. Kane, N. Tooker.
University of Massachusetts
Principal Investigator: B.H. Weiner. J. Moran, O.N. Okike, A. Pezzella, T.J. VanderSalm, M. Borbone, K. Quist. Former participants: J. Benotti, D. Bitran, J. Dalen, J. Gaca, J. Leppo, M. Pasque, M. Shay, P. Wanta, T. Wisnewski.
Principal Investigator: M. Mock. J. Bresnahan, D. Holmes, G.S. Reeder, C. Mullany, T.A. Orszulak, H. Schaff, P.B. Berger, R. Gibbons, S.L. Kopecky, R.S. Schwartz, H.C. Smith, S. Matheson, L. Kelly, L.A. Pierre. Former participants: D. Bresnahan, B. Gersh, F. Nobrega, M. Peterson, R. Vlietstra.
Medical College of Virginia
Principal Investigator: M.J. Cowley. G. Vetrovec, A. Guerraty, D. Salter, A. Wechsler, K. Kelly Hall. Former participants: C.W. Crandall, D. DeBottis, G. DiSciascio, R.R. Lower, A. Maziarz, A. Nath, B. Sechrist, S. Szentpetery.
University of Michigan
Principal Investigator: B. Pitt. E. Bates, D. Muller, S. Bolling, M. Deeb, M. Kirsh, M.M. Stock, J. Corbett, P. Fox, T. Johnson, K. McNeely, S. Pitt. Former participants: L. Belzowski, D. Bondie, K. Burek, S. Ellis, L. Lee, D. Scarpace, M. Schwaiger, H. Shu, M. Stirling, P. Thomasma, E.J. Topol, J. Walton, S. Werns.
Montreal Heart Institute
Principal Investigator: M.G. Bourassa. R. Bonan, G. Cote, J. Crepeau, P. DeGuise, Y. Leclerc, C. Pelletier, J. Gregoire, G. Hudon, J. Lesperance, J. Trudel, C. Faille. Former participants: A. Arseneault, Y. Castonguay, H. Flageol, D.D. Waters, L. Whittom.
Toronto Hospital (Satellite to Montreal)
Principal Investigator: L. Schwartz. H. Aldridge, D. Uden, T. David, C. Feindel, B. Goldman, I. Lipton, L. Mickleborough, R. Weisel, D. Almond, C. Lazzam, M. McLoughlin, L. Zelovitsky, P. Liu, L. Lazzam, K. Mackie.
New York Medical College
Principal Investigator: M.B. Weiss. R. Moggio, R. Pooley, G. Reed, M. Sarabu, R. Steinberg. Former participants: D. Efstathakis, P. Praeger, M.V. Herman, K. Ryman, Y. Sait, E. Somberg, J.H. Stein.
St Louis University
Principal Investigator: B.R. Chaitman. F.V. Aguirre, M.J. Kern, G. Kaiser, V. Willman, R. Wiens, C. Huffman, T. Stonner, S. Aubuchon, M. Kramer. Former participants: H. Barner, U. Deligonul, J.Fehl, K. Galan, B. Poole, M.G. Vandormael.
Jewish Hospital (Satellite to St Louis)
Principal Investigators: R.J. Krone, N. Kouchoukos. A. Salimi, T.H. Wareing, P. Cole, K. Fischer, R. Kleiger, S. Kovacs, M. Rich, A. Shah, J. Humphrey, C. Benson, D. Bowen, G. Eisenkramer, T. Jones, E. Kelly, L. Kendricks, J. Moore, P. Rice, R. Umstead, J. Waldschmidt, B. Walker, J. Weaver. Former participants: M. Caruso, L. Coulter, L. Spinner.
Institute of Clinical and Experimental Medicine, Prague, Czech Republic
Principal Investigator: V. Staněk. A. Belán, J. Kováč, P. Firt, J. Pirk, V. Kočandrle, M. Želízko, R. Jandová, E. Tchernoster.
Principal Investigator: K. Kent. N.M. Katz, R. Wallace, L. Elliott, C. Green, J. Lavelle, C. Rackely, K. Kelly Hall. Former participant: B. Shriver.
Central ECG and Myocardial Infarction Classification Laboratory
St Louis University Medical Center
Principal Investigator: B.R. Chaitman. P. Bjerregaard, I. Gussak, R.D. Wiens, L.T. Younis, K. Stocke, K. Russell, S. Cannon, C. Homeyer, M. Miller. Former participants: D. Kargl, L. Maitus, L. Shaw, B. Takase, A. Terry, S. Zhou.
Central Radiographic Laboratory
Stanford University Medical Center
Principal Investigator: E.L. Alderman. B. Brown, W. Sanders, L. Wexler, B. Hollak. Former participants: T. Beam, R. Moore, G. Shao-Zhou, M. Stadius.
Study of Economics and Quality of Life
Stanford University School of Medicine (SEQOL)
Principal Investigator: M. Hlatky. C. Winston, D. Boothroyd, I. Johnstone. Former participants: C. Bacon, K. Cavanaugh, N. Clapp-Channing.
University of Pittsburgh (Pa)
Principal Investigators: K.M. Detre, S.F. Kelsey. K. Sutton-Tyrrell, A.D. Rosen, S.W. Crow, K.H. Andrews, M.M. Brooks, R.M. Hardison, G.F. Harger, R. Holubkov, A.E. Siewers, J.P. Martin, J. Greenhouse, A. Sampson, C. Ravotti. Former participants: W.P. Amoroso, L.M. Anderson, H.X. Barnhart, D. Borrebach, J.E. Bost, D.W. Burry, M.A. Carr, M. Cooper, R.L. Hardesty, D.F. Hursh, L. Kamons, J.F. Killinger, T.E. Kuntz, E.A. Maurer, J.E. Melvin, J.A. Metzler, B.L. Naydeck, N.H. Remaley, A. Spadaro, A.R. Steenkiste, B.F. Uretsky, J. Wilson.
Cardiac Diseases Branch, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md
Program Administrator: G. Sopko. D. Follmann, M. Horan. Former participants: M.J. Domanski, L. Offen, T. Robertson, R. Solomon, J. Verter, D. Zucker.
Safety and Data Monitoring Board
Chair: J.D. Bristow. J. Childress, T. Gardner, C. Grines, J.W. Kennedy, G. Knatterud, J. Waldhausen, C. White. Former participants: H. Gold, R. Roberts.
Morbidity and Mortality Classification Committee
Chair: R. Prineas. C. Fisch, H.L. Greene, R.B. Karp, S.B. King III, J. Mason, J.L. Titus.
Office of Study Chair
Mayo Clinic Foundation, Rochester, Minn
R.L. Frye, MD
This study was sponsored by the National Heart, Lung, and Blood Institute.
↵1 Members of the Writing Group are given in the “Appendix.”
- Received February 3, 1997.
- Revision received May 5, 1997.
- Accepted May 15, 1997.
- Copyright © 1997 by American Heart Association
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