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Original ArticleFree PreviewArchive

Comparison of Invasive and Conservative Strategies after Treatment with Intravenous Tissue Plasminogen Activator in Acute Myocardial Infarction

List of authors.
  • The TIMI Study Group*

Abstract

We treated 3262 patients with intravenous recombinant tissue plasminogen activator (rt-PA) within four hours of the onset of chest pain thought to be caused by myocardial infarction. Of these patients, 1636 were then randomly assigned to treatment according to an invasive strategy consisting of coronary arteriography 18 to 48 hours after the administration of rt-PA, followed by prophylactic percutaneous transluminal coronary angioplasty (PTCA) if arteriography demonstrated suitable anatomy; 1626 patients were randomly assigned to treatment according to a conservative strategy, as part of which arteriography and PTCA were to be performed only in patients with spontaneous or exercise-induced ischemia.

In the group assigned to the invasive strategy, PTCA was attempted in 928 of the 1636 patients (56.7 percent); the procedure was anatomically successful in 93.3 percent. In the group assigned to the conservative strategy, 216 patients (13.3 percent) underwent clinically indicated PTCA within 14 days of the onset of symptoms. Reinfarction or death within 42 days, the primary end point, occurred in 10.9 percent of the group assigned to the invasive strategy and in 9.7 percent of those assigned to the conservative strategy (P not significant). There were no significant differences between the two groups in the ejection fraction at rest or during exercise, either at hospital discharge or six weeks after randomization. Eleven of 582 patients (1.9 percent) who received 150 mg of rt-PA and 15 of 2952 patients (0.5 percent) who received 100 mg of rt-PA had intracranial hemorrhage.

A subgroup of 1390 patients who were eligible for short-term intravenous beta-blockade were randomly assigned to receive 15 mg of intravenous metoprolol immediately, followed by oral metoprolol, or oral metoprolol begun on day 6. The ejection fraction and the incidence of death in the two groups were similar during the hospital period. Total mortality within the first 6 days and at 42 days was also similar. However, in the group that received intravenous metoprolol, 16 patients had nonfatal reinfarctions and 107 patients had recurrent ischemic episodes by six days after entry into the study, as compared with 31 and 147 patients, respectively, among those randomly assigned to deferred oral beta-blockade (P = 0.02 and P = 0.005, respectively); the latter comparison was considered statistically significant according to the study criteria.

Thus, in patients with acute myocardial infarction who were treated with rt-PA and with heparin followed by aspirin, an invasive strategy of coronary arteriography 18 to 48 hours after the onset of symptoms, followed by prophylactic PTCA, offered no advantage in terms of reductions in mortality or reinfarction over a more conservative strategy, according to which these procedures were provided only to patients with recurrent ischemia; the latter strategy was less complex and less costly. Early intravenous beta-blockade, when used in addition to rt-PA, appears to be of benefit in reducing recurrent infarction and ischemia. (N Engl J Med 1989; 320:618–27.)

Funding and Disclosures

Address reprint requests to the Maryland Medical Research Institute, 600 Wyndhurst Ave., Baltimore, MD 21210.

Supported by research contracts from the National Heart, Lung, and Blood Institute.

After recruitment for the TIMI trial ended, the principal investigators at the clinical centers and central units completed voluntary statements of financial interests to cover the entire period of support for TIMI II (March 1986 through September 1988) and submitted these statements to the coordinating center. Reports were received from all 34 of the principal investigators participating in TIMI. Twenty-six investigators reported that they had not served as consultants to Genentech and that neither they nor their close relatives bought, sold, or held Genentech stock or stock options. One reported serving as a consultant. Six reported that they had bought, sold, or held Genentech stock and stock options, and one reported serving as a consultant and having bought, sold, or held Genentech stock or stock options.

The members of the TIMI Operations Committee and the members of the TIMI Safety and Data-Monitoring Committee were responsible for monitoring study performance and treatment effects during the course of the trial. None of these persons served as a consultant to Genentech, and none bought, sold, or held Genentech stock or stock options.

Author Affiliations

*The investigators and centers participating in the TIMI II trial are listed in the Appendix.

Appendix

Participants in the TIMI Phase II Trial were as follows:

Study Chairman: E. Braunwald, M.D., Harvard University, Boston. Coordinating Center: Maryland Medical Research Institute, Baltimore (Principal Investigator: G.L. Knatterud, Ph.D.; Coinvestigators: M.L. Terrin, M.D., M.P.H., S. Forman, M.A., D.T. Harris, R. Ross, M.Sc., P.C. Wilkins, B.S., M. Bryant, Ph.D., P.L. Canner, Ph.D., M. Carroll, J. Depkin, B.S., J. Dotson, C. Fiery, M. Johnson, C. Kelly, P. Noble, B.S., B. Thompson, Ph.D., W.R. Bell, M.D., and L. Scherlis, M.D.). Radiographic Core Laboratory: University of Washington, Seattle (Principal Investigator: H.T. Dodge, M.D.; Coinvestigators: B.G. Brown, M.D., Ph.D., J.W. Kennedy, M.D., F.H. Sheehan, M.D., B. Bisson, and E. Bolson, M.S.). Radionuclide Core Laboratory: Yale University, New Haven, Conn. (Principal Investigator: B. Zaret, M.D.; Coinvestigator: F. Wackers, M.D., D.S. Kayden, M.D., K. Davis, R.T.N.M., and R. Green, R.T.N.M.). Coagulation Core Laboratory: University of Vermont, Burlington, Vt. (Principal Investigator: K. Mann, Ph.D.; Coinvestigators: D. Stump, M.D., D. Collen, M.D., E. Bovill, M.D., and R. Tracy, Ph.D.). Electrocardiographic Core Laboratory for Qualifying Electrocardiograms: George Washington University, Washington, D.C. (Principal Investigator: A.M. Ross, M.D.; Coinvestigators: G.B. Bren, M.D., and A.G. Wasserman, M.D.). Electrocardiographic Core Laboratory for Exercise Electrocardiograms: St. Louis University, St. Louis (Principal Investigator: B.R. Chaitman, M.D.; Coinvestigators: R.D. Wiens, M.D., L. Shaw, M.S., M. Haueisen, B.S., and L.T. Younis, M.D., Ph.D.). National Heart, Lung, and Blood Institute Program Office: National Institutes of Health, Bethesda, Md. (Principal Investigator: E.R. Passamani, M.D.; Coinvestigators: T.L. Robertson, M.D., G. Lan, Ph.D., R. Solomon, M.H.S., and G. Sopko, M.D.). Pathology Core Laboratory: National Institutes of Health, the Clinical Center, Bethesda, Md. (Principal Investigator: W.C. Roberts, M.D.; Coinvestigator: J. Kalan, M.D.). Percutaneous Transluminal Coronary Angioplasty Quality-Control Laboratory: Brown University, Providence (Principal Investigator: D.O. Williams, M.D.; Coinvestigators: R. Riley, M.D., H. White, M.D., B. Sharaf, M.D., F. Fedele, M.D., E. Thomas, M.D., T. Drew, M.D., J. Joelson, M.D., and D. Hardink, R.N.). Drug-Distribution Center: Cooperative Studies Program, Veterans Administration Medical Research Service, Albuquerque, N.M. (Principal Investigator: C. Colling, R.Ph., M.S.; Coinvestigators: C. Haakenson, R.Ph., M.S., and M. Sather, R.Ph., M.S.).

Clinical Centers: Albert Einstein College of Medicine–Montefiore Medical Center, New York (Principal Investigator: H.S. Mueller, M.D.; Coinvestigators: M.A. Greenberg, M.D., R. Grose, M.D., G. Gordon, M.D., J.D. Goldfischer, M.D., M. Bensman, M.D., J. Cooper, M.D., B. Ventura, R.N., K. Hemingway, R.N., M. Stein, R.N., P. Michaud-Edelstein, R.N., L. Henson, R.N., J. Durkin, R.N., and P. Murphy, R.N.); Baylor College of Medicine, Houston (Principal Investigator: R. Roberts, M.D.; Coinvestigators: P. Nelson, R.N., S. Minor, M.D., C. Pratt, M.D., A. Raizner, M.D., W.L. Winters, M.D., M.S. Verani, M.D., J.M. Lewis, M.D., J. Heibig, M.D., N. Kleiman, M.D., and M.K. VanderMolen, R.N.); Baystate Medical Center, Springfield, Mass. (Principal Investigator: M.J. Schweiger, M.D.; Coinvestigators: R.E. Gianelly, M.D., T. Marantz, M.D., M. Porway, M.D., E. Brickman, R.N., F. Blank, R.N., and J. Mitchell, R.N.); Boston University Medical Center, Boston (Principal Investigator: TJ. Ryan, M.D.; Coinvestigators: C.S. Apstein, M.D., J.B. Cadigan, III, M.D., D.P. Faxon, M.D., A.K. Jacobs, MD., M.A. Kellett, Jr., M.D., B.J. Polansky, M.D., N.A. Ruocco, M.D., T.A. Sanborn, M.D., T. Varricchione, R.R.T., D.A. Weiner, M.D., N. Battinelli, R.N., and B. Hankin, R.N.); Bridgeport Hospital, Bridgeport, Conn. (Principal Investigator: J.D. Babb, M.D.; Coinvestigators: Z.A. Adefuin, M.D., M. Driesman, M.D., J. Meizlish, M.D., and D. Yasick, R.N.); Brown University, Providence (Principal Investigator: D.O. Williams, M.D.; Coinvestigators: T.M. Drew, M.D., R.S. Riley, M.D., H.J. White, M.D., D. Shefcyk, M.D., J. Joelson, M.D., E. Thomas, M.D., B. Sharaf, M.D., F. Fedele, M.D., M. Nathanson, M.D., G. McKendall, M.D., D. Becker, M.D., D.L. Hardink, R.N., M. Macedo, R.N., G. Weeks, M.D., R. Mich, M.D., and E. Berger, M.D.); Columbia University, New York (Principal Investigator: E. Powers, M.D.; Coinvestigators: A. Berke, M.D., L. Johnson, M.D., A.B. Nichols, M.D., D.S. Reison, M.D., A. Schwartz, M.D., R. Watson, M.D., E. Escala, R.N., H.S. Wasserman, M.D., and M. Apfelbaum, M.D.); Cornell Medical Center, New York (Principal Investigators: J.S. Borer, M.D., and T.L. Schreiber, M.D.; Coinvestigators: D.H. Miller, M.D., J.W. Moses, M.D., I. Tamari, M.D., B. Charash, M.D., B. Gerling, M.D., D.A. Silvasi, R.N., and A. McNulty, R.N.); George Washington University, Washington, D.C. (Principal Investigator: A.M. Ross, M.D.; Coinvestigators: G.B. Bren, M.D., R.I. Katz, M.D., R.H. Leiboff M.D., P.J. Varghese, M.D., A.G. Wasserman, M.D., M. Magee, R.N., G. Cavallo, R.N., J. Mendelson, R.N.); Harvard University, Boston (Principal Investigator: D.S. Baim, M.D.; Coinvestigators: D. Diver, M.D., S. Herson, M.D., J.E. Markis, M.D., R.G. McKay, M.D., B. Lorell, M.D., C. (Brewer) Senerchia, R.N., M.S., G.A. Carey, R.N., and J. Schweiger, R.N.); Maine Medical Center, Portland, Me. (Principal Investigator: C.T. Lambrew, M.D.; Coinvestigators: W.D. Alpern, M.D., R.A. Anderson, M.D., D.J. Cutler, M.D., J.P. Driscoll, M.D., M. Kellett, M.D., J.C. Love, M.D., P.R. Minton, M.D., R.L. Morse, M.D., P.K. Shaw, M.D., P.W. Sweeney, M.D., S. Vermilya, R.N., P. Birmingham, R.N., and N. McIntire, R.N.); Mayo Foundation, Rochester, Minn. (Principal Investigator: J.H. Chesebro, M.D.; Coinvestigators: D.R. Bresnahan, M.D., B.J. Gersh, M.D., F.A. Miller, M.D., M.B. Mock, M.D., H.C. Smith, M.D., R. Frye, M.D., D.L. Hayes, M.D., I. Clements, M.D., W.K. Freeman, M.D., J.A. Rumberger, M.D., R. Gibbons, M.D., R. Nishimura, M.D., R. Rodeheffer, M.D., R. Click, M.D., J. Oh, M.D., L. Sinak, M.D., D. Klees, L.P.N., L. Meyers, L.P.N., R. Vlietstra, M.D., J. Bresnahan, M.D., D. Holmes, Jr., M.D., and G. Reeder, M.D.); New York Medical College, Valhalla, N.Y. (Principal Investigator: M.V. Herman, M.D.; Coinvestigators: M.B. Weiss, M.D., M. Cohen, M.D., J. Levy, M.D., M. Feld, M.D., R. Grief, M.D., R. Wallach, M.D., A.M. Kanakaraj, R.N., V. Rosal-Greif, R.N., and Y. Sait, P.A.); New York University, New York (Principal Investigator: F. Feit, M.D.; Coinvestigators: J.N. Slater, M.D., A. Simon, R.N., J. Breed, R.N., M.S. Nachamie, M.D., W.J. Cole, M.D., I.C. Schulman, M.D., M.J. Rey, M.D., M. Attubato, M.D., and S. Shapiro, R.N.); North Shore University, Manhasset, N.Y. (Principal Investigator: J. Morrison, M.D.; Coinvestigators: V. Padmanabhan, M.D., P. Reiser, M.D., L. Ong, M.D., S. Green, M.D., A. Tortolani, M.D., M.L. Andresen, R.N., T. Imhof, R.N., L. Genovese, R.N., and M. Ward, R.N.); Northwestern University, Evanston, Ill. (Principal Investigator: R. Davison, M.D.; Coinvestigators: T. McDonough, M.D., B. Kramer, M.D., S. Meyers, M.D., P. Niemyski, R.N., M. Parker, R.N., K. Kaplan, M.D., D. Fintel, M.D., M. Salinger, M.D., D.C. Hueter, M.D., G. Wilner, M.D., C. Berkowitz, M.D., and K. Duun, R.N.); St. Louis University, St. Louis (Principal Investigator: B.R. Chaitman, M.D.; Coinvestigators: M.G. Vandormael, M.D., M.J. Kern, M.D., W.P. Hamilton, M.D., J.G. Dwyer, M.D., T. Thornton, R.N., J. Anthony, R.N., K. Galan, R.N., M. Major, R.N., and G. Huber, R.N); University of Alabama, Birmingham, Ala. (Principal Investigator: W.J. Rogers, M.D.; Coinvestigators: J.G. Arciniegas, M.D., W.A. Baxley, M.D., R.C. Bourge, M.D., T.M. Bulle, M.D., T.B. Cooper, M.D., L.S. Dean, M.D., R. Hess, D.O., W.A.H. MacLean, M.D., S.E. Papapietro, M.D., C. Saenz, M.D., A.W.H. Stanley, M.D., M.T. Simpson, M.D., K. Bynum, R.N., T. Eubanks, R.N., and L. Maske, R.N.); University of Massachusetts, Worcester, Mass. (Principal Investigator: J. Gore, M.D., Coinvestigators: J.S. Alpert, M.D., J.R. Benotti, M.D., J. Leppo, M.D., I.S. Ockene, M.D., J.F. Rippe, M.D., B.H. Weiner, M.D., J. Dalen, M.D., J.M.J. Gaca, M.D., S.P. Ball, R.N., J. Corrao, R.N., and C. Mahan, R.N.); University of Minnesota, Minneapolis, Minn. (Principal Investigator: M. Hodges, M.D.; Coinvestigators: W.T. Hession, M.D., S.W. Sharkey, M.D., D. Wysham, M.D., I. Goldenberg, M.D., A. Adicoff, M.D., R. Brandenburg, Jr., M.D., F.L. Gobel, M.D., L. Nordstrom, M.D., R. Van Tassel, M.D., C. White, M.D., R. Wilson, M.D., A. Ettinger, R.N., L. Palmquist, R.N., C. Siebold, R.N., N. Carruthers, R.N., and C. Farmer, R.N.); University of Texas, Dallas (Principal Investigator: J. Willerson, M.D.; Coinvestigators: L.D. Hillis, M.D., G.J. Dehmer, M.D., D.L. Brown, M.D., M. Winniford, M.D., B.G. Firth, M.D., M.M. Carry, M.D., B. Toates, R.N., S. Cochran, R.N., P. Surratt, R.N., and J. Moore, R.N., M.S.N.); Washington University, St. Louis (Principal Investigator: P.A. Ludbrook, M.D.; Coinvestigators: A.J. Tiefenbrunn, M.D., N.A. Ricciotti, R.N., M.S.N., A.S. Jaffe, M.D., and B.E. Sobel, M.D.); William Beaumont Hospital, Royal Oak, Mich. (Principal Investigator: R. Ramos, M.D.; Coinvestigators: G. Timmis, M.D., V. Gangadharan, M.D., S. Gordon, M.D., C. Tollis, R.N., and E. Worden, R.N.); Yale University, New Haven, Conn. (Principal Investigator: L.S. Cohen, M.D.; Coinvestigators: C.K. Francis, M.D., J. Alexander, M.D., D. Copen, M.D., M. Cleman, M.D., H. Cabin, M.D., M. Remetz, M.D., L. Decklebaum, M.D., J. Gerard-Amatruda, R.N., D. Penn, R.N., A. Miller, R.N., and C. Piselli, R.N.).

TIMI Phase II Committees: Operations Committee: E. Braunwald, M.D. (Chairman), G. Knatterud, Ph.D., E. Passamani, M.D., T. Robertson, M.D., and R. Solomon, M.H.S.; Executive Committee: E. Braunwald, M.D. (Chairman), B. Chaitman, M.D., J. Chesebro, M.D., H. Dodge, M.D., G. Knatterud, Ph.D., K. Mann, Ph.D., H. Mueller, M.D., E. Passamani, M.D., R. Roberts, M.D., W. Rogers, M.D., B. Sobel, M.D., D. Stump, M.D., D. Williams, M.D., and B. Zaret, M.D.; Hemorrhagic-Event Review Committee: J. Chesebro, M.D. (Chairman), A. Berke, M.D., E. Bovill, M.D., F. Feit, M.D., J. Gore, M.D., L.D. Hillis, M.D., C. Lambrew, M.D., R. Leiboff, M.D., J. Markis, M.D., L. Offen, M.D., C. Pratt, M.D., S. Sharkey, M.D., G. Sopko, M.D., and M. Terrin, M.D.; Mortality and Morbidity Classification Commiitee. M. Weisfeldt, M.D. (Chairman), W. Baker, M.D., M. Cowley, M.D., K. Kent, M.D., E. Lichstein, M.D., T. Robertson, M.D., L. Scherlis, M.D., and M. Terrin, M.D.; Safety and Data-Monitoring Committee: F. Klocke, M.D. (Chairman), J. Bailar, M.D., R. Conti, M.D., D. DeMets, Ph.D., V. Fuster, M.D., T. Killip, M.D., H. Roberts, M.D., L. Walters, Ph.D. Ex-officio Members: E. Braunwald, M.D., G. Knatterud, Ph.D., E. Passamani, M.D., and T. Robertson, M.D.; Steering Committee: The members of the Steering Committee are the study chairman and the principal investigators from the TIMI clinical centers, core laboratories, coordinating center, and National Heart, Lung, and Blood Institute program office.

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