Tissue Plasminogen Activator for the Treatment of Acute Pulmonary Embolism

doi:10.1378/chest.97.3.528

Chest

Volume 97, Issue 3, March 1990, Pages 528-533

https://doi.org/10.1378/chest.97.3.528 Get rights and content

Thirteen patients with acute pulmonary embolism were treated in a randomized double-blind fashion either with recombinant tissue plasminogen activator (rt-PA) 40 to 80 mg, usually in combination with heparin, or with placebo plus heparin. The drug was administered intravenously over 40 to 90 minutes. Nine patients received rt-PA, and four received placebo. A lytic effect was observed 1.5 and three hours after the onset of therapy with rt-PA based upon elevated levels of fragment-D dimers. Among the patients who received rt-PA, there was a modest improvement of the total pulmonary resistance 1.5 hours after the start of therapy, but the angiograms showed no significant changes in two hours. After 24 hours, the lung scans showed a trend toward greater improvement with rt-PA, but the rate of improvement in comparison to control subjects was not statistically significant. Massive bleeding occurred in one patient. The observations in this study suggest that rt-PA has little effect in two hours on angiographic clot burden, but may produce some improvement in hemodynamics. The treatment, however, is not without risk.

Section snippets

METHODS

Between Nov 30, 1986, and June 30, 1987 (seven month s), 13 patients were studied; nine received rt-PA and four received heparin but no rt-PA. The protocol and consent forms were approved by institutional review boards at the six participating hospitals, the data and coordinating center and the National Heart, Lung and Blood Institute. Among those who received rt-PA, eight of nine received heparin simultaneously. All patients received either rt-PA or placebo in a randomized double-blind

RESULTS

The presence of fragment-D dimers in the blood at 1.5 and 3 hours after beginning therapy indicated the in vivo occurrence of clot lysis. Higher levels of fragment-D dimers were present 3 hours after the onset of therapy in the blood of patients who received rt-PA than in patients who received heparin alone (40 ± 29 μg/ml vs 4 ± 3 μg/ml) (mean ± SD) (p<0.01). At 3 hours after the start of treatment among patients who received heparin alone, the plasma fibrinogen was 388 ± 126 mg/dl as compared

DISCUSSION

Fibrinolysis occurred within 1.5 hours after receiving rt-PA, based upon the prompt elevation of fragment D-dimers. The assay that was used was specific for fibrin and did not detect fibrinogen degradation products.⁷ The observed reduction of fibrinogen levels in each of three patients receiving 80 mg of rt-PA was consistent, in addition, with a systemic lysis of fibrinogen. In spite of the prompt onset of fibrinolysis, there was only a limited change of the pulmonary vascular resistance and no

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This study was supported by contracts from the National Heart, Lung, ana Blood Institute.

Manuscript received April 19, 1989; revision accepted September 15.

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PIOPED INVESTIGATORS

Publications Committee: Paul D. Stein, M.D., Chairman; Abass Alavi, M.D.; Christos Athanasoulis, M.D.; R. Edward Coleman, M.D.; Jerry W. Froelich, M.D.; Richard H. Greenspan, M.D.; Alexander Gottschalk, M.D.; Herbert A. Saltzman, M.D.; Michael L. Terrin, M.D., M.P.H.; Carol E. Vreim, Ph.D.; John G. Weg, M.D.

Steering Committee: Herbert A. Saltzman, M.D., Chairman; Abass Alavi, M.D.; Christos Athanasoulis, M.D.; Alexander Gottschalk, M.D.; Richard H. Greenspan, M.D.; Charles A. Hales, M.D.; Mark A. Kelley, M.D.; Paul D. Stein, M.D.; Michael Terrin, M.D., M.P.H.; Carol Vreim, Ph.D.; John G. Weg, M.D.

Duke University: Herbert A. Saltzman, M.D., Principal Investigator; R. Edward Coleman, M.D.; N. Reed Dunnick, M.D.; William J. Fulkerson, Jr., M.D.; Carl E. Ravin, M.D.; Russell Blinder, M.D.; Lee Mallatratt, R.N.

Henry Ford Hospital: Paul D. Stein, M.D., Principal Investigator; Jerry W. Froelich, M.D.; John Popovich, Jr., M.D.; P.C. Shetty, M.D.; Matthew Burke, M.D.; Barry A. Lesser, M.D.; Kenneth V. Leeper, M.D.; James H. Thrall, M.D.; Debbie Adams, R.N.

Massachusetts General Hospital: Charles A. Hales, M.D., Principal Investigator; Christos Athanasoulis, M.D.; Kenneth McKusick, M.D.; B. Taylor Thompson, M.D.; Arthur C. Waltman, M.D.; Stuart Geller, M.D.; Deborah Quinn, R.N., M.S.

University of Michigan: John G. Weg, M.D., Principal Investigator; Kyung J. Cho, M.D.; Jack E. Juni, M.D.; David Williams, M.D.; Charles A. Easton, M.D.; Milton D. Gross, M.D.; Jerold Wallis, M.D.; Andrew Flint, M.D.; Grace Ball, R.N., B.S.N.

University of Pennsylvania: Abass Alavi, M.D., Principal Investigator; Dana R. Burke, M.D.; Mark A. Kelley, M.D.; Gordon K. McLean, M.D.; Steven G. Meranze, M.D.; Harold I. Palevsky, M.D.; Margaret Ahearn-Spera, R.N.C., M.S.N.

Yale University: Richard H. Greenspan, M.D., Principal Investigator; Alexander Gottschalk, M.D.; Jacob S. O. Loke, M.D.; Richard A. Matthay, M.D.; Steven S. Morse, M.D.; Dirk Sostman, M.D.; Donald F. Denny, Jr., M.D.; Lee H. Greenwood, M.D.; Felicia Tencza, M.P.H.

Data and Coordinating Center: Michael L. Terrin, M.D., M.P.H., Principal Investigator; Mary C. Burke; Martha K. Canner; Paul L. Canner, Ph.D.; Carol A. Handy; Thomas E. Hobbins, M.D.; Frank J. Hooper, Sc.D.; Christian R. Klimt, M.D., Dr.P.H.; William Krol, Ph.D.; Joseph A. Kufera, M.S.; Gerard Prud'homme, M.A.; Sharon Pruitt; Pauline Raiz; Bruce W. Thompson, Ph.D.

NHLBI: Carol E. Vreim, Ph.D.; Margaret Wu, Ph.D.

Consultants: Charles S. Greenberg, M.D.; Morris Simon, M.D.

Although recombinant tissue plasminogen activator would seem to have great potential for the treatment of acute pulmonary embolism, experience with this agent is limited, and no comparisons to placebo have been published.1, 2, 3, 4 The purpose of the present study, therefore, was preliminarily to evaluate the efficacy of rt-PA, especially in combination with heparin, compared to placebo plus heparin as treatment for patients with acute pulmonary embolism. The thrombolytic effects of rt-PA may be enhanced when administered in combination with heparin because the addition of new fibrin to the thrombus is prevented by heparin during lytic therapy.⁵

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Chest

Clinical InvestigationsTissue Plasminogen Activator for the Treatment of Acute Pulmonary Embolism

Section snippets

METHODS

RESULTS

DISCUSSION

J Am Coll Cardiol

Lancet

Thrombolytic treatment with recombinant tissue-type plasminogen activator in a patient with massive pulmonary embolism

Ann Intern Med

Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism

Circulation

Enhancement of thrombolysis with tissue-type plasminogen activator by pretreatment with heparin

Circulation

Clinical Investigations
Tissue Plasminogen Activator for the Treatment of Acute Pulmonary Embolism