Thrombolytic, Antiplatelet, and Antithrombotic Agents Cindy L. Grines,
The reiative effk~cy and safety of indiiual thromboiytic agents, administered akne and with antiplateiet and antithrombotic drugs, in the treatment of acute myocardiil infarction are presented. The clink1 benefits and risks of treatment chokes are diissed in reiatkm to the mechanisms of the formatkm and prevention of thrombus and thromboiysii. it is concluded that streptokinase, tissue piasmhwgen activator (tPA), and anisoyiated piasminogen-streptokinase activator complex (APSAC) signifi~ntiy reduce mortality and improve ieft ventricular function equally, despite dtiferences in the rate at whkh they achieve vascular patency, their durations of actiin, and the extent to whM their use is associated with adverse events. The questions of how best to minimize reocciusion/reinfarctlon, bieeding, and stroke are diissed, with pattialar focus on the beneficial use of aspirin and the unresolved issue of how best to use heparin. (Am J Cardioi 1992;7O:l8 I-26 I)
From the Cardiac Catheterization Laboratory, William Beaumont Hospital, Royal Oak, Michigan. Address for reprints: Cindy L. Grines, MD, Director, Cardiac Catheterization Laboratory, Division of Cardiovascular Diseases, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48073. 18 I
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
MD
T
he mechanism of acute myocardial infarction (MI) is a ruptured atherosclerotic plaque, exposing collagen fibers that bind platelets and initiate the coagulation cascade.’ Platelets contain multiple receptors for various proteins that cause further platelet aggregation and adhesion (Figure 1).2 Platelet membranes also bind coagulation Factors V and X, which potentiate conversion of prothrombin to thrombin. Thrombin, in turn, catalyzes the conversion of fibrinogen to fibrin, resulting in a stable fibrin matrix. Additionally, the platelet receptor glycoprotein (GP) IIb/ IIIa binds with fibrinogen, resulting in further platelet aggregation and subsequent occlusive coronary thrombus. An understanding of the contribution of these substances to the development of thrombus has led to wide clinical investigation of fibrinolytic, antithrombin, and antiplatelet drugs as therapeutic agents in patients with acute ischemic syndromes. All thrombolytic agents exert their effects by activating the enzyme plasminogen and converting it to plasmin. Plasmin is capable of digesting fibrinogen, a major component of clots. The 3 thrombolytic agents currently approved for intravenous use in acute MI are streptokinase, anisoylated plasminogen-streptokinase activator complex (anistreplase, or APSAC), and tissue plasminogen activator (t-PA). Streptokinase: Streptokinase works by joining to plasminogen in a complex that converts neighboring plasminogen to plasmin, a proteolytic enzyme capable of lysing fibrin clots3 Streptokinase activates fibrin-bound and circulating plasminogen equally and thus lacks significant fibrin specificity. The breakdown of circulating fibrinogen into fibrin degradation products results in antiplatelet and anticoagulant effects as well as reducing serum viscosity.67 Since streptokinase is a product of P-hemolytic streptococci, it is antigenic and may produce allergic reactions in patients with recent streptococcal infections. Allergic reactions consisting of pruritus, rash, or fevers occur in 5% of patients, are usually quite mild, and are easily treated with antihistamines or antipyretic agents. DECEMBER 21, 1992
The incidence of anaphylaxis is approximately 0.1%.3 Although the pharmacologic half-life of streptokinase is 30 minutes, depletion of fibrinogen usually lasts for 24 hours.8 Antibodies develop approximately 5 days after streptokinase therapy and persist for 6 months to 1 year; therefore, it is recommended that patients not be re-treated with streptokinase (or its derivative, APSAC) during that time interval. Hypotension, due to vasodilation, occurs in approximately lo-15% of patients given streptokinase. Patients who exhibit hypotension can be treated easily by temporarily stopping or decreasing the infusion rate of streptokinase and administering intravenous fluids. The advantages of streptokinase, with or without the additive effect of aspirin9 include its proven track record in tens of thousands of patients, its cost savings at $100-300 per dose, and its ability to improve left ventricular function and save lives. Disadvantages of streptokinase include the potential for allergic reactions and hypotension (although some believe that afterload reduction is beneficial after an MI). Although coronary reperfusion occurs more slowly with streptokinase than
with other available agents, this has not translated into worsened clinical outcome. Tissue plasminogen acthtor: t-PA is a naturally occurring human protein that is nonantigenic and may be readministered immediately in the event of reinfarction.3 Derived by recombinant DNA technology, t-PA is fibrin-specific. Therefore, t-PA selectively binds to the fibrin of clots and the resulting complex converts neighboring plasminogen to plasmin, producing more localized thrombolysis. Although this has resulted in lesser depletion of circulating fibrinogen, fibrin specificity has not resulted in a reduced incidence of bleeding complications.8 Further, the short plasma half-life of t-PA (5 minutes) may result in a higher rate of infarct vessel reocclusion and has resulted in the widespread use of concomitant intravenous heparin. The dose of t-PA recommended by the Food and Drug Administration is 100 mg over 3 hours (60 mg, 20 mg, and 20 mg over hours 1, 2, and 3, respectively). Patients with a small body size have been shown to have an increased risk of bleeding complications with t-PA therapy. Therefore, in patients who weigh 4 hours from chest pain onset), but 24-hour patency rates are similar to other available agents. Advantages of APSAC include the ability to administer the entire dose as a bolus over 2-5 minutes, moderate expense, and the ability to open acutely more arteries than is possible with streptokinase therapy. The potential for allergic and hypotensive reactions remains, however, and this agent has not been demonstrated to be superior to streptokinase or t-PA with regard to improvement in ventricular function or reduction in mortality. Clinical endpoints after thrombolytii therapy: In order to select a particular thrombolytic agent, it is important to compare the clinical benefits derived from various thrombolytic drugs. Clinical endpoints after thrombolytic therapy have included infarct vessel patency, left ventricular function, mortality, and complications, i.e., bleeding, reocclusion, or allergic reactions. The first Thrombolysis in Myocardial Infarction (TIMI-1) trial, sponsored by the National Heart, Lung, and Blood Institute, provided some of the earliest data supporting the clinical efficacy of thrombolytic agents. l1 Patients with an occluded infarct vessel documented by pretreatment angiography were randomized to receive intravenous streptokinase or t-PA. In patients treated with streptokinase, 35% of occluded vessels were reperfused by 90 minutes, whereas a 60% reperfusion rate was observed with t-PA treatment. Since that time, t-PA has been-consistently shown to be the fastest of the thrombolytic agents in terms of establishing patency. Streptokinase, which is not fibrin-specific, is slower in effect. APSAC, an agent with only mild fibrin specificity, results in a rate of opening somewhat faster than streptokinase. Streptokinase and APSAC have more gradual reperfusion, referred to as the catch-up phenomenon, and by 24 hours no difference in patency has been observed between t-PA and other agents17(Figure 2). Further, studies utilizing catheterization performed l-3 weeks after treatment demonstrated maintenance of equivalent patency rates with the 3 agents over time. DECEMBER 21, 1992
Before the thrombolytic era, it was well established that left ventricular function was an important predictor of prognosis after acute MI.‘* All thrombolytic drugs have been demonstrated to improve regional and global ventricular function when compared with placebo.‘” Small trials that directly compared streptokinase with t-PA showed that the 2 agents were similar in preserving left ventricular function.20,21 The Gruppo Italian0 per lo Studio della Soprawivenza nell’Infarcto Miocardico (GISSI-2) randomized 12,490 patients to receive either t-PA or streptokinase and found no difference in left ventricular function or incidence of congestive heart failure between the 2 groups.22 The most obvious clinical benefit of thrombolytic therapy is its lifesaving potential. The placebocontrolled trials have demonstrated that the use of streptokinase,y,23-27t-PA,28 or APSACi5 saves lives. Recently, direct comparisons incorporating nearly 70,000 patients demonstrated mortality to be virtually identical in patients treated with available thrombolytic agents. The GISSI-222 plus international extension”” randomized 20,891 patients to receive t-PA versus streptokinase, with a second randomization to subcutaneous heparin 12,500 U twice daily started at hours 12, versus no heparin (Table I). There was no difference in mortality between t-PA- and streptokinase-treated patients (8.9 vs 8.5%, respectively; difference not significant). Major cardiac events, including reinfarction, congestive heart failure, and progression to cardiogenie shock, were similar between the t-PA- and the streptokinase-treated groups. As expected, hypotension and allergic reactions occurred more frequently after streptokinase therapy. Although t-PA was associated with a significantly higher incidence of stroke compared with streptokinase (1.3 vs l.O%), th is was attributed to an inadequate heparin regimen that may have resulted in more embolic strokes. These results, however, were confirmed in the Third International Study on Infarct Survival (ISIS-3) trial.“” This was a multicenter randomized, double-blind trial in which 41,299 patients were randomized to receive t-PA, streptokinase, or APSAC with a second randomization to subcutaneous heparin 12,500 U twice daily started at hour 4, or no heparin (Table I). There was no evidence of any difference in mortality among streptokinase (10.6%) t-PA (10.3%) and APSAC (10.5%) either overall or in the subgroup with ST-segment elevation randomized
The reiative effk~cy and safety of indiiual thromboiytic agents, administered akne and with antiplateiet and antithrombotic drugs, in the treatment of acute myocardiil infarction are presented. The clink1 benefits and risks of treatment chokes are diissed in reiatkm to the mechanisms of the formatkm and prevention of thrombus and thromboiysii. it is concluded that streptokinase, tissue piasmhwgen activator (tPA), and anisoyiated piasminogen-streptokinase activator complex (APSAC) signifi~ntiy reduce mortality and improve ieft ventricular function equally, despite dtiferences in the rate at whkh they achieve vascular patency, their durations of actiin, and the extent to whM their use is associated with adverse events. The questions of how best to minimize reocciusion/reinfarctlon, bieeding, and stroke are diissed, with pattialar focus on the beneficial use of aspirin and the unresolved issue of how best to use heparin. (Am J Cardioi 1992;7O:l8 I-26 I)
From the Cardiac Catheterization Laboratory, William Beaumont Hospital, Royal Oak, Michigan. Address for reprints: Cindy L. Grines, MD, Director, Cardiac Catheterization Laboratory, Division of Cardiovascular Diseases, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48073. 18 I
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
MD
T
he mechanism of acute myocardial infarction (MI) is a ruptured atherosclerotic plaque, exposing collagen fibers that bind platelets and initiate the coagulation cascade.’ Platelets contain multiple receptors for various proteins that cause further platelet aggregation and adhesion (Figure 1).2 Platelet membranes also bind coagulation Factors V and X, which potentiate conversion of prothrombin to thrombin. Thrombin, in turn, catalyzes the conversion of fibrinogen to fibrin, resulting in a stable fibrin matrix. Additionally, the platelet receptor glycoprotein (GP) IIb/ IIIa binds with fibrinogen, resulting in further platelet aggregation and subsequent occlusive coronary thrombus. An understanding of the contribution of these substances to the development of thrombus has led to wide clinical investigation of fibrinolytic, antithrombin, and antiplatelet drugs as therapeutic agents in patients with acute ischemic syndromes. All thrombolytic agents exert their effects by activating the enzyme plasminogen and converting it to plasmin. Plasmin is capable of digesting fibrinogen, a major component of clots. The 3 thrombolytic agents currently approved for intravenous use in acute MI are streptokinase, anisoylated plasminogen-streptokinase activator complex (anistreplase, or APSAC), and tissue plasminogen activator (t-PA). Streptokinase: Streptokinase works by joining to plasminogen in a complex that converts neighboring plasminogen to plasmin, a proteolytic enzyme capable of lysing fibrin clots3 Streptokinase activates fibrin-bound and circulating plasminogen equally and thus lacks significant fibrin specificity. The breakdown of circulating fibrinogen into fibrin degradation products results in antiplatelet and anticoagulant effects as well as reducing serum viscosity.67 Since streptokinase is a product of P-hemolytic streptococci, it is antigenic and may produce allergic reactions in patients with recent streptococcal infections. Allergic reactions consisting of pruritus, rash, or fevers occur in 5% of patients, are usually quite mild, and are easily treated with antihistamines or antipyretic agents. DECEMBER 21, 1992
The incidence of anaphylaxis is approximately 0.1%.3 Although the pharmacologic half-life of streptokinase is 30 minutes, depletion of fibrinogen usually lasts for 24 hours.8 Antibodies develop approximately 5 days after streptokinase therapy and persist for 6 months to 1 year; therefore, it is recommended that patients not be re-treated with streptokinase (or its derivative, APSAC) during that time interval. Hypotension, due to vasodilation, occurs in approximately lo-15% of patients given streptokinase. Patients who exhibit hypotension can be treated easily by temporarily stopping or decreasing the infusion rate of streptokinase and administering intravenous fluids. The advantages of streptokinase, with or without the additive effect of aspirin9 include its proven track record in tens of thousands of patients, its cost savings at $100-300 per dose, and its ability to improve left ventricular function and save lives. Disadvantages of streptokinase include the potential for allergic reactions and hypotension (although some believe that afterload reduction is beneficial after an MI). Although coronary reperfusion occurs more slowly with streptokinase than
with other available agents, this has not translated into worsened clinical outcome. Tissue plasminogen acthtor: t-PA is a naturally occurring human protein that is nonantigenic and may be readministered immediately in the event of reinfarction.3 Derived by recombinant DNA technology, t-PA is fibrin-specific. Therefore, t-PA selectively binds to the fibrin of clots and the resulting complex converts neighboring plasminogen to plasmin, producing more localized thrombolysis. Although this has resulted in lesser depletion of circulating fibrinogen, fibrin specificity has not resulted in a reduced incidence of bleeding complications.8 Further, the short plasma half-life of t-PA (5 minutes) may result in a higher rate of infarct vessel reocclusion and has resulted in the widespread use of concomitant intravenous heparin. The dose of t-PA recommended by the Food and Drug Administration is 100 mg over 3 hours (60 mg, 20 mg, and 20 mg over hours 1, 2, and 3, respectively). Patients with a small body size have been shown to have an increased risk of bleeding complications with t-PA therapy. Therefore, in patients who weigh 4 hours from chest pain onset), but 24-hour patency rates are similar to other available agents. Advantages of APSAC include the ability to administer the entire dose as a bolus over 2-5 minutes, moderate expense, and the ability to open acutely more arteries than is possible with streptokinase therapy. The potential for allergic and hypotensive reactions remains, however, and this agent has not been demonstrated to be superior to streptokinase or t-PA with regard to improvement in ventricular function or reduction in mortality. Clinical endpoints after thrombolytii therapy: In order to select a particular thrombolytic agent, it is important to compare the clinical benefits derived from various thrombolytic drugs. Clinical endpoints after thrombolytic therapy have included infarct vessel patency, left ventricular function, mortality, and complications, i.e., bleeding, reocclusion, or allergic reactions. The first Thrombolysis in Myocardial Infarction (TIMI-1) trial, sponsored by the National Heart, Lung, and Blood Institute, provided some of the earliest data supporting the clinical efficacy of thrombolytic agents. l1 Patients with an occluded infarct vessel documented by pretreatment angiography were randomized to receive intravenous streptokinase or t-PA. In patients treated with streptokinase, 35% of occluded vessels were reperfused by 90 minutes, whereas a 60% reperfusion rate was observed with t-PA treatment. Since that time, t-PA has been-consistently shown to be the fastest of the thrombolytic agents in terms of establishing patency. Streptokinase, which is not fibrin-specific, is slower in effect. APSAC, an agent with only mild fibrin specificity, results in a rate of opening somewhat faster than streptokinase. Streptokinase and APSAC have more gradual reperfusion, referred to as the catch-up phenomenon, and by 24 hours no difference in patency has been observed between t-PA and other agents17(Figure 2). Further, studies utilizing catheterization performed l-3 weeks after treatment demonstrated maintenance of equivalent patency rates with the 3 agents over time. DECEMBER 21, 1992
Before the thrombolytic era, it was well established that left ventricular function was an important predictor of prognosis after acute MI.‘* All thrombolytic drugs have been demonstrated to improve regional and global ventricular function when compared with placebo.‘” Small trials that directly compared streptokinase with t-PA showed that the 2 agents were similar in preserving left ventricular function.20,21 The Gruppo Italian0 per lo Studio della Soprawivenza nell’Infarcto Miocardico (GISSI-2) randomized 12,490 patients to receive either t-PA or streptokinase and found no difference in left ventricular function or incidence of congestive heart failure between the 2 groups.22 The most obvious clinical benefit of thrombolytic therapy is its lifesaving potential. The placebocontrolled trials have demonstrated that the use of streptokinase,y,23-27t-PA,28 or APSACi5 saves lives. Recently, direct comparisons incorporating nearly 70,000 patients demonstrated mortality to be virtually identical in patients treated with available thrombolytic agents. The GISSI-222 plus international extension”” randomized 20,891 patients to receive t-PA versus streptokinase, with a second randomization to subcutaneous heparin 12,500 U twice daily started at hours 12, versus no heparin (Table I). There was no difference in mortality between t-PA- and streptokinase-treated patients (8.9 vs 8.5%, respectively; difference not significant). Major cardiac events, including reinfarction, congestive heart failure, and progression to cardiogenie shock, were similar between the t-PA- and the streptokinase-treated groups. As expected, hypotension and allergic reactions occurred more frequently after streptokinase therapy. Although t-PA was associated with a significantly higher incidence of stroke compared with streptokinase (1.3 vs l.O%), th is was attributed to an inadequate heparin regimen that may have resulted in more embolic strokes. These results, however, were confirmed in the Third International Study on Infarct Survival (ISIS-3) trial.“” This was a multicenter randomized, double-blind trial in which 41,299 patients were randomized to receive t-PA, streptokinase, or APSAC with a second randomization to subcutaneous heparin 12,500 U twice daily started at hour 4, or no heparin (Table I). There was no evidence of any difference in mortality among streptokinase (10.6%) t-PA (10.3%) and APSAC (10.5%) either overall or in the subgroup with ST-segment elevation randomized
