Articles
15 August 1991

Hemorrhagic Events during Therapy with Recombinant Tissue-Type Plasminogen Activator, Heparin, and Aspirin for Acute Myocardial Infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial

Publication: Annals of Internal Medicine
Volume 115, Number 4

Abstract

Objectives: To assess the effects of invasive procedures, hemostatic and clinical variables, the timing of beta-blocker therapy, and the doses of recombinant plasminogen activator (rt-PA) on hemorrhagic events.
Design: A multicenter, randomized, controlled trial.
Setting: Hospitals participating in the Thrombolysis in Myocardial Infarction, Phase II trial (TIMI II).
Interventions: Patients received rt-PA, heparin, and aspirin. The total dose of rt-PA was 150 mg for the first 520 patients and 100 mg for the remaining 2819 patients. Patients were randomly assigned to an invasive strategy (coronary arteriography with percutaneous angioplasty [if feasible] done routinely 18 to 48 hours after the start of thrombolytic therapy) or to a conservative strategy (coronary arteriography done for recurrent spontaneous or exercise-induced ischemia). Eligible patients were also randomly assigned to either immediate intravenous or deferred beta-blocker therapy.
Measurements: Patients were monitored for hemorrhagic events during hospitalization.
Main Results: In patients on the 100-mg rt-PA regimen, major and minor hemorrhagic events were more common among those assigned to the invasive than among those assigned to the conservative strategy (18.5% versus 12.8%, P < 0.001). Major or minor hemorrhagic events were associated with the extent of fibrinogen breakdown, peak rt-PA levels, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70 kg or less, female gender, and physical signs of cardiac decompensation. Immediate intravenous beta-blocker therapy had no important effect on hemorrhagic events when compared with delayed beta-blocker therapy. Intracranial hemorrhages were more frequent among patients treated with the 150-mg rt-PA dose than with the 100-mg rt-PA dose (2.1% versus 0.5%, P < 0.001). The extent of the plasmin-mediated hemostatic defect was also greater in patients receiving the 150-mg dose.
Conclusions: Increased morbidity due to hemorrhagic complications is associated with an invasive management strategy in patients with acute myocardial infarction. Our findings show the complex interaction of several factors in the occurrence of hemorrhagic events during thrombolytic therapy.

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References

1.
. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1:397-402.
2.
. A prospective trial of intravenous strep-tokinase in acute myocardial infarction (I.S.A.M.). Mortality, morbidity, and infarct size at 21 days. N Engl J Med. 1986;314:1465-71.
3.
Kennedy JMartin GDavis KMaynard CStadius M, and Sheehan F. The Western Washington intravenous streptokinase in acute myocardial infarction randomized trial. Circulation. 1988;77:345-52.
4.
White HNorris RBrown MTakayama MMaslowski A, and Bass N. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med. 1987;317:850-5.
5.
. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349-60.
6.
Van de Werf F and Arnold A. Intravenous tissue plasminogen activator and size of infarct, left ventricular function, and survival in acute myocardial infarction. Br Med J. 1988;297:1374-9.
7.
Wilcox Rvon der Lippe GOlsson CJensen GSkene A, and Hampton J. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet. 1988;2:525-30.
8.
. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet. 1988;1:545-9.
9.
Rao APratt CBerke AJaffe AOckene I, and Schreiber T. Thrombolysis in Myocardial Infarction (TIMI) trial—phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol. 1988;11:1-11.
10.
Califf RTopol EGeorge BBoswick JAbbottsmith C, and Sigmon K. Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of acute myocardial infarction. Am J Med. 1988;85:353-9.
11.
Anderson JRothbard RHackworthy RSorensen SFitzpatrick P, and Dahl C. Multicenter reperfusion trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: controlled comparison with intracoronary streptokinase. J Am Coll Cardiol. 1988;11:1153-63.
12.
. GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Lancet. 1990;336:65-71.
13.
Collen DBounameaux HDe Cock FLijnen H, and Verstraete M. Analysis of coagulation and fibrinolysis during intravenous infusion of recombinant human tissue-type plasminogen activator in patients with acute myocardial infarction. Circulation. 1986;73:511-7.
14.
Bovill EStump DTracy RCollen DRobertson T, and Terrin M. Dose-response relationship of rt-PA infusion to induction of systemic fibrino(geno)lysis in the thrombolysis in myocardial infarction (TIMI) trial [Abstract]. Blood. 1987;760(Suppl 1): 1323a.
15.
. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) phase II trial. N Engl J Med. 1989;320:618-27.
16.
Rogers WBairn DGore JBrown BRoberts R, and Williams D. Comparison of immediate invasive, delayed invasive, and conservative strategies after tissue type plasminogen activator: results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II-A Trial. Circulation. 1990;81:1457-76.
17.
Roberts RRogers WMueller HLambrew CDiver D, and Smith H. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study. Circulation. 1991;83:422-37.
18.
Braunwald EKnatterud G, and Passamani E. Announcement of protocol change in thrombolysis in myocardial infarction trial [Letter]. J Am Coll Cardiol. 1987;9:467.
19.
Braunwald EKnatterud GPassamani ERobertson T, and Solomon R. Update from the thrombolysis in myocardial infarction trial. J Am Coll Cardiol. 1987;10:970.
20.
Jan KChien S, and Bigger J. Observations on blood viscosity changes after acute myocardial infarction. Circulation. 1975;51:1079-84.
21.
Tracy RBovill EStump DLin TGomol T, and Collen D. Reduction of in vitro artifact during blood collection in the Thrombolysis in Myocardial Infarction Trial, Phase II [Abstract]. Blood. 1988;72:1415.
22.
Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol. 1957;17:237-46.
23.
Stump DTopol EChen AHopkins A, and Collen D. Monitoring of hemostasis parameters during coronary thrombolysis with recombinant tissue-type plasminogen activator. Thromb Haemost. 1988;59:133-7.
24.
Merskey CLalezari P, and Johnson A. A rapid, simple, sensitive method for measuring fibrinolytic split products in human serum. Proc Soc Exp Biol Med. 1969;131:871-5.
25.
Holvoet PCleemput H, and Collen D. Assay of human tissue-type plasminogen activator (t-PA) with an enzyme-linked immunosorbent assay (ELISA) based on three murine monoclonal antibodies to t-PA. Thromb Haemost. 1985;54:684-7.
26.
Fleiss J. Statistical Methods for Rates and Proportions. 2d edition. New York: John Wiley & Sons; 1981:19-32, 56-82.
27.
Snedecor G and Cochran W. Statistical Methods. 6th edition. Ames, Iowa: Iowa State University Press; 1967;91-116, 317-321.
28.
. 1985 SAS Users Guide, Basic Statistics. Version 5. Cary, North Carolina: SAS Institute Incorporated; 1985.
29.
Hosmer D and Lemeshow S. Applied Logistic Regression. New York: John Wiley & Sons 1989;25-37, 106-8.
30.
Dixon W, ed. BMDP Statistical Software Manual. Berkeley, California: University of California Press; 1985.
31.
Kalbfleisch J and Prentice P. The Statistical Analysis of Failure Time Data. New York, New York: John Wiley & Sons; 1980:122-7.
32.
Chaitman BThompson BWittry MStump DHamilton W, and Hillis L. The use of tissue-type plasminogen activator for acute myocardial infarction in the activator for acute myocardial infarction in the elderly: results from TIMI phase I, open label studies and the TIMI-II pilot study. J Am Coll Cardiol. 1990;114:1159-65.
33.
Stump DCaliff RTopol ESigmon KThornton D, and Masek R. Pharmacodynamics of thrombolysis with recombinant tissue type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. Circulation. 1989;80:1222-30.
34.
Mueller HRao A, and Forman S. Thrombolysis in myocardial infarction (TIMI): comparative studies of coronary reperfusion and systemic fibrinogenolysis with two forms of recombinant tissue-type plasminogen activator. J Am Coll Cardiol. 1987;10:479-90.
35.
Gore JSloan MPrice TRandall ABovill E, and Collen D. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma following acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction (TIMI) Study. Thrombolysis in Myocardial Infarction, Phase II Pilot and Clinical Trial. Circulation. 1991;83:448-59.
36.
Garabedian HGold HLeinbach RYasuda TJohns J, and Collen D. Dose-dependent thrombolysis, pharmacokinetics and hemostatic effects of recombinant human tissue-type plasminogen activator for coronary thrombosis. Am J Cardiol. 1986;58:673-9.
37.
Kelton J and Warkentin T. Heparin-induced thrombocytopenia. In: Coller BS, ed. Progress in Hemostasis and Thrombosis. Philadelphia: W.B. Saunders; 1991;10:1-34.

Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 115Number 415 August 1991
Pages: 256 - 265

History

Published in issue: 15 August 1991
Published online: 1 December 2008

Keywords

Authors

Affiliations

Michael L. Terrin, MD, MPH
Margaret Frederick, PhD
Costas T. Lambrew, MD
George Sopko, MD, MPH
Russell P. Tracy, PhD
James H. Chesebro, MD
From the University of Vermont College of Medicine, Burlington, Vermont; Maryland Medical Research Institute, Baltimore, Maryland; Columbia University and New York University, New York, New York; University of Massachusetts Medical School, Worcester, Massachusetts; University of Texas Southwestern Medical Center, Dallas, Texas; Maine Medical Center, Portland, Maine; George Washington University, Washington, DC; Harvard Medical School, Boston, Massachusetts; Baylor College of Medicine, Houston, Texas; University of Minnesota, Minneapolis, Minnesota; National Heart, Lung, and Blood Institute, Bethesda, MD; and Mayo Clinic, Rochester, Minnesota. For current author addresses, see end of text.
*
For a listing of the investigators and centers participating in the TIMI II trial, see reference 15.

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Edwin G. Bovill, Michael L. Terrin, David C. Stump, et al. Hemorrhagic Events during Therapy with Recombinant Tissue-Type Plasminogen Activator, Heparin, and Aspirin for Acute Myocardial Infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med.1991;115:256-265. doi:10.7326/0003-4819-115-4-256

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