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Tissue-type plasminogen activator. A review of its pharmacology and therapeutic use as a thrombolytic agent
D Collen1, H R Lijnen, P A Todd
1Centre for Thrombosis and Vascular Research, Campus Gasthuisberg, Leuven, Belgium.
Insights
Recombinant tissue-type plasminogen activator (rt-PA) effectively recanalizes coronary arteries in acute myocardial infarction, salvaging heart function and reducing mortality. Further trials are needed to compare its long-term clinical efficacy against other thrombolytic agents.
Area of Science:
- Cardiovascular Medicine
- Biotechnology
- Pharmacology
Background:
- Coronary arterial thrombolysis is a key treatment for acute myocardial infarction (heart attack).
- Early intervention with thrombolytic agents can restore blood flow, preserve heart muscle, and decrease mortality.
- Established thrombolytic agents include streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC), and recombinant tissue-type plasminogen activator (rt-PA).
Purpose of the Study:
- To evaluate the properties and efficacy of recombinant tissue-type plasminogen activator (rt-PA) in treating acute myocardial infarction.
- To compare rt-PA with other thrombolytic agents like streptokinase and urokinase.
- To assess the contribution of rt-PA, a product of recombinant DNA technology, to managing thromboembolic diseases.
Main Methods:
- Review of non-comparative, placebo-controlled, and comparative clinical trials involving rt-PA.
- Biochemical analysis of rt-PA's properties, including its similarity to endogenous plasminogen activator and fibrin specificity.
- Meta-analysis of available comparative trials to assess recanalization rates, left ventricular function, and mortality.
Main Results:
- rt-PA demonstrates attractive biochemical properties, being similar to physiological plasminogen activator and highly fibrin-specific.
- Recanalization rates for rt-PA range from 60-80% in various trials.
- rt-PA showed comparable efficacy to urokinase and appeared more effective than streptokinase for early arterial recanalization in meta-analyses.
Conclusions:
- rt-PA is a significant advancement from recombinant DNA technology for treating acute myocardial infarction and thromboembolic disease.
- While rt-PA shows promise, further large-scale comparative trials are necessary to definitively establish its relative clinical efficacy and impact on morbidity and mortality compared to other agents.
- The agent's effects on left ventricular function require additional investigation.
Abstract:
Coronary arterial thrombolysis is becoming an established treatment of acute myocardial infarction. If given early enough, it recanalises occluded coronary arteries, salvages myocardial function and reduces mortality. A reduction of mortality in patients with acute myocardial infarction has now been demonstrated for streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC; anistreplase) and recombinant tissue-type plasminogen activator (rt-PA). From the biochemical point of view, rt-PA has several attractive properties. It is similar to or identical with the physiological plasminogen activator in blood, it does not induce an antibody response, and it is more fibrin-specific than most or all other currently known thrombolytic agents. The rate of recanalisation of occluded coronary arteries with rt-PA is about 60 to 80% in non-comparative and placebo-controlled trials. rt-PA was similar in efficacy to urokinase in the only trial to compare the 2 agents. In 2 comparative trials evaluated by meta-analysis, rt-PA appeared more effective than streptokinase for the early recanalisation of occluded arteries. Both agents were comparable in their effects on left ventricular function in 2 comparative trials, but further study is needed to conclusively evaluate this parameter. Moreover, both agents reduce inhospital mortality, but much larger direct comparative trials are required before scientifically valid statements can be made on the relative clinical efficacy of available thrombolytic agents in terms of their effects on both morbidity and mortality. Thus, rt-PA constitutes a notable contribution of recombinant DNA technology to the treatment of thromboembolic disease, the main cause of death and disability in Western societies.