Role of New Antiplatelet Agents as Adjunctive Therapies in Thrombolysis James T. Willerson, MD, Paolo Golino, MD, Janice McNatt, John Eidt, MD, Sheng-Kun Yao, MD, and L. Maximilian Buja, MD
Coronary thrombolysis is the treatment of choice for patients with acute Q-wave myocardial jnfarcts who have no contrainditions to such therapy. However, the time required for thrombolysis and the possibility of reocclusion of the infarct-related artery remain problematic. Herein are described experimental animal studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that, when coupled with available thrombolytic interventions, might shorten the time to thrombolysis and delay or prevent reocclusion. From the studiis conducted to date, it is clear that a combined thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shorten the time to thrombolysis and delay or prevent coronary artery reocelusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein Ilb/llla receptor coupled with tissue plasminogen activator (t-PA) and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. Thrombin inhibitors, including heparin and synthetic inhibitors, given with t-PA and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models. Aspirin coupled with intravenous streptokinase reduces mortality in patients with presumed acute myocardial infarction, and a combination of heparin and t-PA results in infarct-artery patency more frequently than t-PA without heparin. Data from these studies are encouraging with regard to the posslbility of developlng effective and relatively safe thrombolytic regimens that shorten the time to thrombolysis and delay or prevent coronary artery reocclusion. (Am J Cardiol 1991;67:12A-18A)
oronary thrombolysis has been evaluated extensively as a meansto prevent or attenuate pathophysiologic eventsoccurring with acute myocardial infarction. Studies in experimental animals and patients show that the administration of thrombolytic agentsearly in the courseof myocardial infarction reducesinfarct sizeand preservesventricular function.1-3However, the time required for thrombolysis with currently available agentsremainslonger than desirable,and there is an important risk of coronary artery reocclusionafter successfulthrombolytic therapy. Thus, it should be useful to identify adjunctive therapy that shortensthe time to thrombolysis and prevents coronary artery reocclusion following thrombolytic therapy. Platelets are activated in responseto a variety of substances.Studies from our laboratory as well as others have demonstratedthat thromboxane A2 and serotonin are important mediatorsof intracoronary platelet activation in experimental preparations of concentrically stenosedcanine coronary arteries with endothelial injury.4-s Others haveshownthat the platelet glycoprotein IIb/IIIa platelet receptors are important in platelet binding to fibrin and the developmentof a thrombus; a monoclonal antibody directed against the platelet glycoprotein IIb/ IIIa receptorsenhancesthrombolysis in experimental animal models.9JoIn addition, clinical studiesin which aspirin has been combined with selectedthrombolytic interventions suggest enhanced thrombolytic protection.” This review summarizescurrent information related to experimental animal and clinical studies that have been performed in an attempt to alter platelet activation and shorten the time to thrombolysis and prevent or delay coronary artery reocclusion after thrombolytic therapy.
C
STUDIES IN EXPERIMENTAL ANIMAL MODELS
We evaluatedwhether single or simultaneousadministration of thromboxane and serotonin receptor antagonists combinedwith tissue plasminogenactivator (t-PA) and heparin shortenthe time to thrombolysis and prevent or delay coronary artery reocclusion after thrombolytic therapy.i2J3 In thesestudies,coronary thrombi were induced in 26 anesthetized,open-chestdogsby inserting a copper coil into the left anterior descending coronary From the Departmentsof Internal Medicine and Pathology,University of Texas Medical School,Texas Heart Institute, Houston,Texas. This artery (LAD) (Fig. 1). Coronary artery blood flow velocistudy was supported in part by Specialized Center of Research in ty was monitored throughout the experiment with a Ischemic Heart Disease,Grant HL17669 from the National Heart, Doppler flow probe placed proximally to the coil. The Lung, and Blood Institute, Bethesda,Maryland. Address for reprints: James T. WilIerson, MD, Cardiology Re- presenceof a thrombus was documentedfor 30 minutes. search,1-191,Texas Heart Institute, P.O. Box 20345,Houston,Texas Dogs were assignedto 1 of 4 groups: group 1 (n = 8) 77225. served as control subjects,receiving a bolus of heparin
12A
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67
Aortic Pressure (mmHg)
LAD Phasic Flow (KHZ)
4
0 LAD Mean FIOW (KHZ)
FIGURE 1. ReprewnM ve tracing of hendynamic data obtained frem a dog treated with heparin, tissue plasminogen activator and thremboxane remptor antagonist SQ29548 and serotonin receptar antagonisl LY53857 in combination. A, bassline mea~~~,25mmh).B,attarplacementofthecoppercoilintothekft~derrcen&lg C--Y artary WW and Uuumbus fonnath (paper speed, 25 nnn/min). C, administration of tissue pbminogen activator caused lysis of ths ttwomkuMd~~ltknofMoodflawthat~weda~a~aml~ntpattsrnthrwghart fhe experimentel period WP- wed, WithpenniSSiOllOftlWAmerican 25 mm/min). (See text for details.) (Repro&cd Heart Aswxlation, Cimutation.lz)
(200 U/kg) and of t-PA (80 pg/kg), followed by a continuous infusion (8 pg/kgmin) for 190 minutes or until reperfusion was achieved. Group 2 (n = 10) received, immediately before heparin and t-PA, an intravenous bolusof 0.4 mg/kg of a thromboxane receptorantagonist (SQ29548, Squibb Pharmaceuticals, Princeton, New Jersey) and 0.2 mg/kg of a serotonin receptor antagonist (LY 53857,Eli Lilly Pharmaceuticals,Indianapolis, Indiana). Group 3 (n = 7) received,beforeheparin and t-PA, an intravenous bolus of the thromboxane receptor antagonist alone (0.4 mg/kg). Group 4 (n = 7) received,before heparin and t-PA, an intravenous bolus of the serotonin receptor antagonist alone (0.2 mg/kg). After thrombolysis, all dogs were monitored for 90 minutes or until a persistent reocclusion occurred. Treatment with a combination of the thromboxane and serotonin receptor antagonists markedly shortened the time required to lyse coronary artery thrombi, from 46 f 7 to 15 f 3 minutes in groups 1 and 2 animals, respectively (p
Coronary thrombolysis is the treatment of choice for patients with acute Q-wave myocardial jnfarcts who have no contrainditions to such therapy. However, the time required for thrombolysis and the possibility of reocclusion of the infarct-related artery remain problematic. Herein are described experimental animal studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that, when coupled with available thrombolytic interventions, might shorten the time to thrombolysis and delay or prevent reocclusion. From the studiis conducted to date, it is clear that a combined thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shorten the time to thrombolysis and delay or prevent coronary artery reocelusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein Ilb/llla receptor coupled with tissue plasminogen activator (t-PA) and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. Thrombin inhibitors, including heparin and synthetic inhibitors, given with t-PA and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models. Aspirin coupled with intravenous streptokinase reduces mortality in patients with presumed acute myocardial infarction, and a combination of heparin and t-PA results in infarct-artery patency more frequently than t-PA without heparin. Data from these studies are encouraging with regard to the posslbility of developlng effective and relatively safe thrombolytic regimens that shorten the time to thrombolysis and delay or prevent coronary artery reocclusion. (Am J Cardiol 1991;67:12A-18A)
oronary thrombolysis has been evaluated extensively as a meansto prevent or attenuate pathophysiologic eventsoccurring with acute myocardial infarction. Studies in experimental animals and patients show that the administration of thrombolytic agentsearly in the courseof myocardial infarction reducesinfarct sizeand preservesventricular function.1-3However, the time required for thrombolysis with currently available agentsremainslonger than desirable,and there is an important risk of coronary artery reocclusionafter successfulthrombolytic therapy. Thus, it should be useful to identify adjunctive therapy that shortensthe time to thrombolysis and prevents coronary artery reocclusion following thrombolytic therapy. Platelets are activated in responseto a variety of substances.Studies from our laboratory as well as others have demonstratedthat thromboxane A2 and serotonin are important mediatorsof intracoronary platelet activation in experimental preparations of concentrically stenosedcanine coronary arteries with endothelial injury.4-s Others haveshownthat the platelet glycoprotein IIb/IIIa platelet receptors are important in platelet binding to fibrin and the developmentof a thrombus; a monoclonal antibody directed against the platelet glycoprotein IIb/ IIIa receptorsenhancesthrombolysis in experimental animal models.9JoIn addition, clinical studiesin which aspirin has been combined with selectedthrombolytic interventions suggest enhanced thrombolytic protection.” This review summarizescurrent information related to experimental animal and clinical studies that have been performed in an attempt to alter platelet activation and shorten the time to thrombolysis and prevent or delay coronary artery reocclusion after thrombolytic therapy.
C
STUDIES IN EXPERIMENTAL ANIMAL MODELS
We evaluatedwhether single or simultaneousadministration of thromboxane and serotonin receptor antagonists combinedwith tissue plasminogenactivator (t-PA) and heparin shortenthe time to thrombolysis and prevent or delay coronary artery reocclusion after thrombolytic therapy.i2J3 In thesestudies,coronary thrombi were induced in 26 anesthetized,open-chestdogsby inserting a copper coil into the left anterior descending coronary From the Departmentsof Internal Medicine and Pathology,University of Texas Medical School,Texas Heart Institute, Houston,Texas. This artery (LAD) (Fig. 1). Coronary artery blood flow velocistudy was supported in part by Specialized Center of Research in ty was monitored throughout the experiment with a Ischemic Heart Disease,Grant HL17669 from the National Heart, Doppler flow probe placed proximally to the coil. The Lung, and Blood Institute, Bethesda,Maryland. Address for reprints: James T. WilIerson, MD, Cardiology Re- presenceof a thrombus was documentedfor 30 minutes. search,1-191,Texas Heart Institute, P.O. Box 20345,Houston,Texas Dogs were assignedto 1 of 4 groups: group 1 (n = 8) 77225. served as control subjects,receiving a bolus of heparin
12A
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67
Aortic Pressure (mmHg)
LAD Phasic Flow (KHZ)
4
0 LAD Mean FIOW (KHZ)
FIGURE 1. ReprewnM ve tracing of hendynamic data obtained frem a dog treated with heparin, tissue plasminogen activator and thremboxane remptor antagonist SQ29548 and serotonin receptar antagonisl LY53857 in combination. A, bassline mea~~~,25mmh).B,attarplacementofthecoppercoilintothekft~derrcen&lg C--Y artary WW and Uuumbus fonnath (paper speed, 25 nnn/min). C, administration of tissue pbminogen activator caused lysis of ths ttwomkuMd~~ltknofMoodflawthat~weda~a~aml~ntpattsrnthrwghart fhe experimentel period WP- wed, WithpenniSSiOllOftlWAmerican 25 mm/min). (See text for details.) (Repro&cd Heart Aswxlation, Cimutation.lz)
(200 U/kg) and of t-PA (80 pg/kg), followed by a continuous infusion (8 pg/kgmin) for 190 minutes or until reperfusion was achieved. Group 2 (n = 10) received, immediately before heparin and t-PA, an intravenous bolusof 0.4 mg/kg of a thromboxane receptorantagonist (SQ29548, Squibb Pharmaceuticals, Princeton, New Jersey) and 0.2 mg/kg of a serotonin receptor antagonist (LY 53857,Eli Lilly Pharmaceuticals,Indianapolis, Indiana). Group 3 (n = 7) received,beforeheparin and t-PA, an intravenous bolus of the thromboxane receptor antagonist alone (0.4 mg/kg). Group 4 (n = 7) received,before heparin and t-PA, an intravenous bolus of the serotonin receptor antagonist alone (0.2 mg/kg). After thrombolysis, all dogs were monitored for 90 minutes or until a persistent reocclusion occurred. Treatment with a combination of the thromboxane and serotonin receptor antagonists markedly shortened the time required to lyse coronary artery thrombi, from 46 f 7 to 15 f 3 minutes in groups 1 and 2 animals, respectively (p
