TNK-tissue plasminogen activator in acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 10a dose-ranging trial

Christopher P. Cannon, Carolyn H. McCabe, C. Michael Gibson, Magdi Ghali, Rafael F. Sequeira, George R. McKendall, Judy Breed, Nishit B. Modi, Norma Lynn Fox, Russell P. Tracy, Ted W. Love, Eugene Braunwald

Research output: Contribution to journalArticle

214 Citations (Scopus)

Abstract

Background: TNK-tissue plasminogen activator (TNK-TPA) is a genetically engineered variant of TPA, which in experimental models has a slower plasma clearance and greater fibrin specificity and is 80-fold more resistant to plasminogen activator inhibitor-1 than alteplase TPA. Methods and Results: The Thrombolysis in Myocardial Infarction (TIMI) 10A trial was a Phase 1, dose-ranging pilot trial designed to evaluate the pharmacokinetics, safety, and efficacy of TNK-TPA in patients with acute myocardial infarction. One hundred thirteen patients with acute ST-segment elevation myocardial infarction presenting within 12 hours and without contraindications to thrombolysis were enrolled and treated with a single bolus of TNK-TPA over 5 to 10 seconds with doses ranging from 5 to 50 mg. TNK-TPA demonstrated a plasma clearance of 151±55 mL/min and a half-life of 17±7 minutes. Comparable values for wild-type TPA are 572±132 mL/min and 3.5±1.4 minutes, respectively. Systemic fibrinogen and plasminogen levels fell by only 3% and 13%, respectively, at 1 hour after TNK-TPA administration. TIMI grade 3 flow at 90 minutes was achieved in 57% to 64% of patients at the 30- to 50-mg doses. Seven patients (6.2%) experienced a major hemorrhage, which occurred at a vascular access site in six patients. Conclusions: TNK-TPA has a prolonged half-life so it can be administered as a single bolus. TNK-TPA appears to be very fibrin specific, and the initial patency and safety profiles are encouraging. Further study of this new thrombolytic agent is ongoing.

Original languageEnglish
Pages (from-to)351-356
Number of pages6
JournalCirculation
Volume95
Issue number2
StatePublished - Feb 11 1997
Externally publishedYes

Fingerprint

Myocardial Infarction
Fibrin
Half-Life
Safety
Fibrinolytic Agents
Plasminogen
Plasminogen Activator Inhibitor 1
Tissue Plasminogen Activator
TNK-tissue plasminogen activator
Fibrinogen
Blood Vessels
Theoretical Models
Pharmacokinetics
Hemorrhage

Keywords

  • myocardial infarction
  • plasminogen activators
  • reperfusion
  • thrombolysis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Cannon, C. P., McCabe, C. H., Michael Gibson, C., Ghali, M., Sequeira, R. F., McKendall, G. R., ... Braunwald, E. (1997). TNK-tissue plasminogen activator in acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 10a dose-ranging trial. Circulation, 95(2), 351-356.

TNK-tissue plasminogen activator in acute myocardial infarction : Results of the thrombolysis in myocardial infarction (TIMI) 10a dose-ranging trial. / Cannon, Christopher P.; McCabe, Carolyn H.; Michael Gibson, C.; Ghali, Magdi; Sequeira, Rafael F.; McKendall, George R.; Breed, Judy; Modi, Nishit B.; Fox, Norma Lynn; Tracy, Russell P.; Love, Ted W.; Braunwald, Eugene.

In: Circulation, Vol. 95, No. 2, 11.02.1997, p. 351-356.

Research output: Contribution to journalArticle

Cannon, CP, McCabe, CH, Michael Gibson, C, Ghali, M, Sequeira, RF, McKendall, GR, Breed, J, Modi, NB, Fox, NL, Tracy, RP, Love, TW & Braunwald, E 1997, 'TNK-tissue plasminogen activator in acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 10a dose-ranging trial', Circulation, vol. 95, no. 2, pp. 351-356.
Cannon CP, McCabe CH, Michael Gibson C, Ghali M, Sequeira RF, McKendall GR et al. TNK-tissue plasminogen activator in acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 10a dose-ranging trial. Circulation. 1997 Feb 11;95(2):351-356.
Cannon, Christopher P. ; McCabe, Carolyn H. ; Michael Gibson, C. ; Ghali, Magdi ; Sequeira, Rafael F. ; McKendall, George R. ; Breed, Judy ; Modi, Nishit B. ; Fox, Norma Lynn ; Tracy, Russell P. ; Love, Ted W. ; Braunwald, Eugene. / TNK-tissue plasminogen activator in acute myocardial infarction : Results of the thrombolysis in myocardial infarction (TIMI) 10a dose-ranging trial. In: Circulation. 1997 ; Vol. 95, No. 2. pp. 351-356.
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abstract = "Background: TNK-tissue plasminogen activator (TNK-TPA) is a genetically engineered variant of TPA, which in experimental models has a slower plasma clearance and greater fibrin specificity and is 80-fold more resistant to plasminogen activator inhibitor-1 than alteplase TPA. Methods and Results: The Thrombolysis in Myocardial Infarction (TIMI) 10A trial was a Phase 1, dose-ranging pilot trial designed to evaluate the pharmacokinetics, safety, and efficacy of TNK-TPA in patients with acute myocardial infarction. One hundred thirteen patients with acute ST-segment elevation myocardial infarction presenting within 12 hours and without contraindications to thrombolysis were enrolled and treated with a single bolus of TNK-TPA over 5 to 10 seconds with doses ranging from 5 to 50 mg. TNK-TPA demonstrated a plasma clearance of 151±55 mL/min and a half-life of 17±7 minutes. Comparable values for wild-type TPA are 572±132 mL/min and 3.5±1.4 minutes, respectively. Systemic fibrinogen and plasminogen levels fell by only 3{\%} and 13{\%}, respectively, at 1 hour after TNK-TPA administration. TIMI grade 3 flow at 90 minutes was achieved in 57{\%} to 64{\%} of patients at the 30- to 50-mg doses. Seven patients (6.2{\%}) experienced a major hemorrhage, which occurred at a vascular access site in six patients. Conclusions: TNK-TPA has a prolonged half-life so it can be administered as a single bolus. TNK-TPA appears to be very fibrin specific, and the initial patency and safety profiles are encouraging. Further study of this new thrombolytic agent is ongoing.",
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AU - Michael Gibson, C.

AU - Ghali, Magdi

AU - Sequeira, Rafael F.

AU - McKendall, George R.

AU - Breed, Judy

AU - Modi, Nishit B.

AU - Fox, Norma Lynn

AU - Tracy, Russell P.

AU - Love, Ted W.

AU - Braunwald, Eugene

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N2 - Background: TNK-tissue plasminogen activator (TNK-TPA) is a genetically engineered variant of TPA, which in experimental models has a slower plasma clearance and greater fibrin specificity and is 80-fold more resistant to plasminogen activator inhibitor-1 than alteplase TPA. Methods and Results: The Thrombolysis in Myocardial Infarction (TIMI) 10A trial was a Phase 1, dose-ranging pilot trial designed to evaluate the pharmacokinetics, safety, and efficacy of TNK-TPA in patients with acute myocardial infarction. One hundred thirteen patients with acute ST-segment elevation myocardial infarction presenting within 12 hours and without contraindications to thrombolysis were enrolled and treated with a single bolus of TNK-TPA over 5 to 10 seconds with doses ranging from 5 to 50 mg. TNK-TPA demonstrated a plasma clearance of 151±55 mL/min and a half-life of 17±7 minutes. Comparable values for wild-type TPA are 572±132 mL/min and 3.5±1.4 minutes, respectively. Systemic fibrinogen and plasminogen levels fell by only 3% and 13%, respectively, at 1 hour after TNK-TPA administration. TIMI grade 3 flow at 90 minutes was achieved in 57% to 64% of patients at the 30- to 50-mg doses. Seven patients (6.2%) experienced a major hemorrhage, which occurred at a vascular access site in six patients. Conclusions: TNK-TPA has a prolonged half-life so it can be administered as a single bolus. TNK-TPA appears to be very fibrin specific, and the initial patency and safety profiles are encouraging. Further study of this new thrombolytic agent is ongoing.

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