- Email: [email protected]
Anti-Thrombotic, anti-platelet and fibrinolytic therapy: Current management of acute myocardial infarction
Anti-Thrombotic, Anti-Platelet and Fibrinolytic Therapy: Current Management of Acute Myocardial Infarction Gérard Helft, MD, PhD1 and Stephen G. Worthley, MB BS, PhD, FRACP2 1Clinique
Cardiologique-Adultes, Hùpital Necker, Assistance Publique, Paris, France and 2Cardiovascular Research Centre, Monash Medical Centre, Clayton, Victoria, Australia
Significant advances in the treatment of patients with acute myocardial infarction (MI) have been obtained in recent times. In particular, thrombolytic therapy has been shown to preserve ventricular function and improve survival in patients with acute MI. Therapies now include third-generation thrombolytic agents, percutaneous transluminal coronary angioplasty (PTCA) and intracoronary stenting, and new anti-thrombotic therapies including anti-platelet treatment with glycoprotein (GP) IIb/IIIa inhibition and direct anti-thrombin agents. This review will focus on the use of GP IIb/IIIa antagonists and thrombin inhibitors as adjunctive therapies to thrombolytic treatment of patients with acute MI. (Heart, Lung and Circulation 2001; 10: 68–74) Key words: anti-thrombotic therapy, myocardial infarction, thrombosis.
Pathophysiology of Acute Myocardial Infarction Thrombus formation on a disrupted plaque is the major cause of acute coronary syndromes (ACS),1,2 and platelet and fibrin deposition begins immediately after plaque rupture. The magnitude and stability of the acute thrombotic occlusion will modulate the severity of the ACS. If the thrombus is large and fixed, an acute MI may develop. Angiographic analysis of coronary arteries during thrombolytic therapy after MI revealed that in 85% of patients the responsible lesion had less than 70% stenosis (Fig. 1).3 Unless the thrombus is rapidly lysed and the blood flow is re-established, the result is myocardial injury and necrosis of myocytes. Even with reperfusion, there is a risk of recurrent thrombosis at the site of plaque rupture, which is dependent on a number of local and systemic factors (Table 1). In patients with MI, the infarct-related artery is
Correspondence: Stephen G. Worthley, Cardiovascular Research Centre, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Email: [email protected]
occluded and the main goal is to re-open the vessel and achieve reperfusion as rapidly as possible. Prompt and complete reperfusion has been shown to reduce mortality and morbidity rates.4 After establishing patency, however, the vessel must also be kept open to maintain the benefits of treatment. However, fibrinolytic agents have shown prothrombotic response as indicated by the high incidence of re-occlusion observed in patients undergoing thrombolysis.5 One of the postulated mechanisms to explain the paradoxical phenomenon is that the thrombus undergoing lysis exposes clot-bound thrombin and activates the coagulation cascade. In addition, the thrombolytic agent may successfully lyse the existent thrombus but is inactive on the initial thrombogenic stimulus that triggered the formation of the initial thrombus. This explains the need for adjunctive antithrombotic therapies. This need also exists with percutaneous interventional strategies in which adequate anti-platelet therapy post stent is essential.
Standard Thrombolytic Therapy Rapid dissolution of the occlusive intracoronary thrombus by fibrinolytic agents has been evaluated in several
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large clinical studies. This intravenous thrombolytic approach leads to a 20% relative decrease in 30-day mortality rates when compared to no thrombolytic therapy.4,6 However, thrombolysis is hampered by some critical limitations. First, adequate coronary patency (Thrombolysis in Myocardial Infarction [TIMI]-3 flow) at 90 min is only obtained in half of patients. Second, angiographic re-occlusion occurs in 10–20% of cases. Third, major haemorrhagic complications and, in particular, intracerebral haemorrhages are dramatic and occur in about 0.5–1% of patients. Furthermore, these
Figure 1. Meta-analysis of studies showing the association between stenosis severity and associated risk of coronary occlusion and myocardial infarction (MI). Percentage coronary stenosis: , <50%; , 50–70%; , >70%. Table 1.
Factors modulating atherothrombosis
Local fluid dynamics Shear stress Tensile stress Nature of the exposed substrate Degree of injury (mild versus severe arterial injury) Composition of atherosclerotic plaque Residual mural thrombus Systemic thrombogenic factors Hypercholesterolaemia Catecholamines (including cocaine) Smoking Diabetes Homocysteine Lipoprotein (a) Infective agents Chlamydia pneumoniae Helicobacter pylori Cytomegalovirus Hypercoagulable states Fibrinogen von Willebrand factor Tissue factor Defective fibrinolytic states Plasminogen activator inhibitor-1 Tissue plasminogen activator Tissue activable fibrinolysis inhibitor
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complications have slightly increased in recent trials, but this may relate to an older patient population and greater comorbidity in these recent studies.
Mechanisms of Failure of Thrombolysis The mechanisms responsible for failure of thrombolysis and/or recurrent thrombosis after coronary thrombolysis are complex and numerous. They are not fully understood but include increased procoagulant activity induced by pharmacological activation of plasminogen, local expression of procoagulant activity when the vessel is reperfused, presence of high shear forces that promote platelet deposition, and attenuation of physiological fibrinolytic activity after pharmacological thrombolysis.7 Thus, recurrent thrombosis after coronary thrombolysis depends on a complex interaction between procoagulant factors associated with the atherosclerotic plaque, procoagulant activity induced by the residual thrombus, and paradoxical procoagulant activity which is promoted by pharmacological thrombolysis. 8,9 The interaction between thrombus-bound thrombin and circulating blood may not only exert a prothrombotic stimulus through the activation of factor V but also by reducing endogenous thrombolytic potential via the induction of thrombin activatable fibrinolysis inhibitor (TAFI). TAFI is converted to a carboxypeptidase that inhibits fibrinolysis when exposed to the thrombin–thrombomodulin complex.10 The relationship of thrombolysis and platelet activation is complex and still debated.7 Multiple and counterbalancing effects come into play. These include platelet secretion of both fibrinolytic and anti-fibrinolytic components, assembly of fibrinolytic components on the platelet surface, and the influence of plasmin on platelet function. However, although plasmin has been shown to directly induce platelet activation in some systems,11 the concentrations of plasmin used are higher than during pharmacological thrombolysis. Nonetheless, there is marked platelet activation after pharmacological coronary thrombolysis.12 One potential mechanism for platelet activation is the formation of thrombin, which is the most potent platelet agonist. When using streptokinase, there is still perhaps another mechanism of platelet activation involving anti-streptokinase antibody. A plasminogen–streptokinase–anti-streptokinase antibody ternary complex seems to induce platelet aggregation.13
Alternatives to Standard Thrombolytic Therapy The significant incidence of resistance to thrombolytics and re-occlusion after successful reperfusion explain the
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search for new and more potent thrombolytics, so-called ‘third-generation’ thrombolytic agents. TIMI-3 flow is achieved in only half of the patients despite using the best therapy currently available with recombinant tissuetype plasminogen activator (rt-PA). The emphasis has shifted to producing a mutant form of rt-PA that is more potent and selective.14–16 This intensive research has led to the discovery of many mutants, three of which have achieved good results in clinical trials: reteplase, lanoteplase and TNK-t-PA. Unfortunately, initial observations have not been corroborated and recent trials with these new thrombolytics have shown equivalence to17 but not superiority over other thrombolytics. Other thrombolytics such as staphylokinase are under investigation.18 However, it is difficult to imagine that these thrombolytics alone will permit major advances in terms of reperfusion. Primary percutaneous transluminal coronary angioplasty (PTCA) was developed as an effective reperfusion intervention in MI. 19,20 Substantial debate has surrounded the relative merits of thrombolysis and conventional primary PTCA. However, a mortality benefit at 30 days for primary PTCA compared with early generation thrombolytic agents has been demonstrated in a meta-analysis of the data from all randomised trials.19–25 However, it is uncertain whether this result could be obtained in the majority of hospitals.
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intracerebral haemorrhage (0.2% on average), led to hope that these agents may be beneficial in conjunction with thrombolytic agents. These GP IIb/IIIa inhibitors have several beneficial effects when combined with thrombolytic therapy. They can reduce the amount of thrombus through a ‘dethrombotic’ action based on the ability to displace the fibrinogen already bound to the GP IIb/IIIa receptor as the affinity of the blocking agent is greater than that of fibrinogen for the receptor. They also decrease the activity of factor XIII, critical for fibrin stabilisation and subsequent clot retraction and decrease the activity of plasminogen activator inhibitor released by the activated platelets. The first available GP IIb/IIIa inhibitor was a chimeric antibody fragment directed against the receptor (abciximab). Subsequently, cyclic peptide inhibitors (eptafibatide), smaller synthetic non-peptide molecules mainly for parenteral short-term infusion (tirofiban, lamifiban) and, recently, oral agents, have been developed. Studies in animal models (mainly the dog) have demonstrated that the combination of thrombolytic agents with abciximab is beneficial in acute MI.28–30 This combination allows more rapid, complete and sustained coronary perfusion. Interestingly, these effects were obtained even with half the thrombolytic dose. Therefore, a reduced number of haemorrhagic complications due to the thrombolytic therapy could be expected in humans, if such a strategy was adopted.
Rationale of Anti-Platelet Therapy The rationale behind anti-platelet therapy relates to two major factors: (i) thrombin-mediated platelet activation is one of the major prothrombotic mechanisms; and (ii) thrombus-bound thrombin is protected from the plasma inhibitor and thus is still active upon thrombus re-canalisation. The potential of using anti-platelet therapy was first suggested by the results of the second International Study of Infarct Survival (ISIS-2) study.26 In this study, in patients randomly assigned to receive 160 mg aspirin per day, mortality rate was reduced by 23% at 35 days, a result that was similar to that obtained with streptokinase (25% reduction). The combination of the two drugs showed an additive effect, with a further decrease in mortality rate (42% reduction). The potential of decreasing the thrombolytic dosing in conjunction with anti-platelet therapy is interesting. By limiting the thrombolytic-induced prothrombotic effect, the regimen of reduced dose thrombolytic and anti-platelet therapy may in fact further improve coronary patency rates in acute MI. Recently, the success of potent inhibitors of platelet aggregation, glycoprotein (GP) IIb/IIIa antagonists, in acute coronary syndromes,27 combined with a low rate of
Preliminary Data: Thrombolytics and IIb/IIIa Inhibitors Three small pilot clinical studies have evaluated the combination of thrombolytics with IIb/IIIa inhibitors.15,31,32
Thrombolysis and Angioplasty in Myocardial Infarction This was a dose-ranging trial combining thrombolytic therapy (rt-PA) with a murine-derived monoclonal antibody 7E3 Fab.15 Sixty patients with acute MI receiving rt-PA, aspirin and heparin were randomised to escalating doses of this GP IIb/IIIa inhibitor or placebo. This safety study showed that the bleeding rate was not higher in the experimental group than in the control patients, and indicated a coronary patency rate (TIMI grade 2 and 3) of about 90% with the combination of the GP IIb/IIIa inhibitor and rt-PA.
IMPACT AMI (Integrilin to Manage Platelet Aggregation to Combat Thrombosis After Myocardial Infarction) This randomised, placebo-controlled dose-ranging trial tested six doses of eptafibatide (Integrilin) and compared
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the highest Integrilin dose against placebo in patients with acute MI receiving a full dose of rt-PA. 31 All patients received aspirin and intravenous heparin infusion. With the highest Integrilin dose, TIMI grade 3 was achieved at 90 min in 66% of patients compared with 39% of patients receiving placebo. Composite clinical end-points of death, re-infarction, stroke, percutaneous or surgical coronary re-vascularisation, or new inhospital heart failure or pulmonary oedema were similar in both groups.
PARADIGM (The Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction) This dose-ranging study compared patients with acute MI treated with either alteplase or streptokinase and randomly assigned with lamifiban.32 Despite a higher angiographic patency of the infarct-related artery with lamifiban, the clinical outcomes in the lamifiban and placebo groups were not significantly different.
Clinical Trials with Thrombolytics and IIb/IIIa Inhibitors Strategies for Patency Enhancement in the Emergency Department (SPEED) or the Global Use of Strategies To Open Occluded coronary arteries ( (GUSTO-IV) Pilot Study The surrogate end-point in this trial was TIMI flow at 60 min obtained with abciximab and reteplase (r-PA).33 All patients were given aspirin. Patients were randomised to either standard-dose abciximab alone or standard-dose abciximab with low-dose reteplase, with or without low-dose heparin. The preliminary results demonstrated that combination therapy with half-dose (or greater) reteplase led to TIMI-3 flow rates at least equivalent to full-dose fibrinolytic therapy. No excess bleeding was observed. Early (60 min) and complete reperfusion without an excess of haemorrhage appeared possible by combining abciximab and reduced-dose reteplase.
Thrombolysis in Myocardial Infarction (TIMI-14) This complex, large (888 patients) randomised trial was designed to evaluate the combination of thrombolytic agents and abciximab.34 The results were striking and showed that the most promising regimen tested was 50 mg of alteplase (15 mg bolus plus an infusion of 35 mg over 60 min) in combination with abciximab. Compared with full-dose alteplase alone, the 50 mg alteplase regimen produced substantial significant increases in the rates of TIMI-3 flow (76 vs 57%) and infarct-related artery patency (TIMI-2 and -3 flow; 93 vs
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78%) at 90 min. Although the implications of the marked increase in TIMI-3 flow when abciximab is combined with half the usual dose of alteplase in this trial are exciting, it must be remembered that this is only a phase II trial. Therefore, the phase III TIMI-14 and GUSTO-IV AMI trials are now being conducted, with predefined clinical end-points. The new drug combinations will be tested against standard thrombolytic therapy to confirm the preliminary results.
IIb/IIIa Inhibitors and Percutaneous Coronary Interventions The preliminary results of another large-scale trial (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications; CADILLAC) were recently presented at the Scientific Sessions of the American Heart Association (AHA) in 1999. In this trial, patients with acute MI were randomised to percutaneous revascularisation with either stenting (Multilink) or PTCA. In a 2 × 2 factorial design, these initial groups were further randomised to either abciximab or placebo. The combination of stenting and abciximab led to the best results, the global mortality in this subgroup being very low (1.4%). Abciximab has improved the rate of recurrent ischaemia when combined with stenting or PTCA.
Anticoagulant Agents Unfractionated and Low Molecular Weight Heparins The use of heparin in patients with MI provides a probable benefit with a relative reduction in mortality rate of approximately 20%.35 However, these results are from the prethrombolytic area and the control groups in these trials did not receive aspirin, the benefit of which is now clearly established. The rationale for systemic anticoagulation as adjunctive therapy to non-fibrin-specific thrombolytic agents is weak, because these thrombolytics have an anticoagulant effect through the generation of fibrinogen degradation products. Consistent with this is the absence of a significant effect with heparin on coronary patency in patients treated with streptokinase or anistreplase. However, the results with heparin as an adjunct to thrombolysis with rt-PA are unequivocal. Presently, intravenous heparin is recommended in patients treated with rt-PA, according to the GUSTO strategy.36 It is well known that low molecular weight heparins (LMWH) have several potential advantages over unfractionated heparin, including better availability and a more predictable anticoagulant effect which explains the less need for monitoring.37 Although these agents have been successfully tested in unstable angina and nonQ-wave MI,38,39 they are yet to be studied in Q-wave MI.
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The Fraxiparin Anticoagulant Therapy in Myocardial Infarction Study Amsterdam (FATIMA) study40 was a small trial showing that nadroparine is beneficial as an adjunct to rt-PA, with no major complications. A recent trial presented at the Scientific Sessions of the American College of Cardiology (ACC) in 2000, the second Heparins and Reperfusion Therapy (HART II) Study, comparing heparin and enoxaparin in combination with rt-PA, has shown equivalency in terms of infarct-related artery patency. Other ongoing trials testing the combination of thrombolytics and LWMH are presently being conducted: Acute Myocardial Infarction with Streptokinase (AMI SK), ENoxaparin and TNK-t-PA with or without GP IIb/IIIa Inhibitor as Reperfusion strategy in ST elevation MI (ENTIRE) and the third Assessment of the Safety of a New Thrombolytic (ASSENT-3).
for this phenomenon is that early reperfusion occurs less often with the former, leaving more room for improvement by better adjunctive therapy. To confirm this, the HERO-2 trial is being conducted, involving 17 000 patients with MI randomised to receive either intravenous heparin or bivalirudin prior to streptokinase administration. Another thrombin inhibitor, argatroban, was compared to heparin in the Myocardial Infarction with Novastan and TPA (MINT) study. 4 7 Argatroban appeared to enhance reperfusion with rt-PA in patients with MI, although the results were not significantly different. However, the incidence of major bleeding was lower in the patients receiving argatroban.
Direct Anti-Thrombin Agents
In acute MI, the challenge associated with pharmacological reperfusion strategies lies not only in the improvement of the 90-min coronary blood flow but also in sustaining the patency of the artery. Thus, new strategies, including the use of GP IIb/IIIa inhibitors and new thrombin inhibitors, have been tested. There is a clear rationale, both pathophysiological and clinical, for combining the GP IIb/IIIa inhibitors with thrombolytics. The combination of stenting with GP IIb/IIIa is also an attractive strategy. Presently, the most promising strategy seems to be the combination of half-dose thrombolytics and GP IIb/IIIa inhibitors. In particular, abciximab associated with half the usual dose of rt-PA has enhanced the rate of successful thrombolysis, producing earlier TIMI-3 flow. If these results are confirmed by the ongoing phase III trials, this will be a major advance in the management of acute MI.
As discussed above, thrombin plays a pivotal role in the balance between the coagulation and fibrinolytic systems. For this reason, a significant interest in thrombin inhibitors has emerged. Starting with hirudin, many specific inhibitors have been produced and tested in different settings. In acute MI, hirudin and hirulog have been studied in clinical trials. After two initial promising small trials (TIMI-5 testing hirudin with rt-PA41 and TIMI-6 testing hirudin with streptokinase42) two largescale studies, TIMI-9A43 and GUSTO-IIa,36 failed because of an excess of intracerebral haemorrhages. Therefore, lower doses of anticoagulation (i.e. hirudin and heparin) were evaluated in subsequent studies, TIMI-9B and GUSTO-IIb.44 However, in these trials, there was not a significant difference between heparin and hirudin in the composite primary end-point of 30-day death or new MI. Using hirulog, the Hirulog and Early Reperfusion / Occlusion (HERO) trial45 found this compound to be more effective than heparin in terms of TIMI-3 flow at 90 min in patients receiving streptokinase and aspirin. However, this trial was not intended to evaluate clinical end-points. The results of the Hirudin for Improvement of Thrombolysis (HIT)-4 trial46 found that lepirudin (recombinant hirudin) as an adjunct to thrombolysis with streptokinase was associated with an accelerated ST resolution when compared to heparin, although this was not associated with a significant improvement in coronary blood flow. Interestingly, a post hoc analysis of the GUSTO IIb trial has shown that patients receiving streptokinase and hirudin had a better outcome when compared to patients receiving streptokinase and heparin. These results suggest that direct thrombin inhibition could be more useful with fibrin-non-specific fibrinolytic agents such as streptokinase, than with fibrin-specific fibrinolytic agents such as rt-PA. A potential explanation
Conclusions
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non-Q-wave MI: a double blind, randomized parallel group multicenter study comparing enoxaparin and intravenous unfractionated heparin: methods and design. J. Thromb. Thrombolysis 1997; 4: 271–4. Turpie AG. Management of acute coronary syndromes with low molecular weight heparin: TIMI-11A and 11B. Can. J. Cardiol. 1998; 14 (Suppl E): 20–23. Chamuleau S, de Winter R, Levi M et al. on behalf of the Fraxiparin Anticoagulant Therapy in Myocardial Infarction Study Amsterdam (FATIMA) Study group. Low molecular weight heparin as an adjunct to thrombolysis for acute myocardial infarction: the FATIMA Study. Heart 1998; 80: 35–9. Cannon C, McCabe C, Henry T. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial. J. Am. Coll. Cardiol. 1994; 23: 993–1003. Lee L. Initial experience with hirudin and streptokinase in acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 6 trial. Am. J. Cardiol. 1995; 75: 7–13.
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43. Antman E. Hirudin in acute myocardial infarction: safety report from the Thrombolysis and Thrombin inhibition In Myocardial Infarction (TIMI) 9A trial. Circulation 1994; 90: 1624–30. 44. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N. Engl. J. Med. 1996; 335: 775–82. 45. White H, Aylward P, Frey M. Randomized double blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO): Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigation. Circulation 1997; 96: 2155–61. 46. Neuhaus K, Molhoek P, Zeymer U et al. for the HIT-4 Investigators. Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction. J. Am. Coll. Cardiol. 1999; 34: 966–73. 47. Jang I, Brown D, Guigliano R et al. A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study. J. Am. Coll. Cardiol. 1999; 33: 1879–85.
Cardiologique-Adultes, Hùpital Necker, Assistance Publique, Paris, France and 2Cardiovascular Research Centre, Monash Medical Centre, Clayton, Victoria, Australia
Significant advances in the treatment of patients with acute myocardial infarction (MI) have been obtained in recent times. In particular, thrombolytic therapy has been shown to preserve ventricular function and improve survival in patients with acute MI. Therapies now include third-generation thrombolytic agents, percutaneous transluminal coronary angioplasty (PTCA) and intracoronary stenting, and new anti-thrombotic therapies including anti-platelet treatment with glycoprotein (GP) IIb/IIIa inhibition and direct anti-thrombin agents. This review will focus on the use of GP IIb/IIIa antagonists and thrombin inhibitors as adjunctive therapies to thrombolytic treatment of patients with acute MI. (Heart, Lung and Circulation 2001; 10: 68–74) Key words: anti-thrombotic therapy, myocardial infarction, thrombosis.
Pathophysiology of Acute Myocardial Infarction Thrombus formation on a disrupted plaque is the major cause of acute coronary syndromes (ACS),1,2 and platelet and fibrin deposition begins immediately after plaque rupture. The magnitude and stability of the acute thrombotic occlusion will modulate the severity of the ACS. If the thrombus is large and fixed, an acute MI may develop. Angiographic analysis of coronary arteries during thrombolytic therapy after MI revealed that in 85% of patients the responsible lesion had less than 70% stenosis (Fig. 1).3 Unless the thrombus is rapidly lysed and the blood flow is re-established, the result is myocardial injury and necrosis of myocytes. Even with reperfusion, there is a risk of recurrent thrombosis at the site of plaque rupture, which is dependent on a number of local and systemic factors (Table 1). In patients with MI, the infarct-related artery is
Correspondence: Stephen G. Worthley, Cardiovascular Research Centre, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Email: [email protected]
occluded and the main goal is to re-open the vessel and achieve reperfusion as rapidly as possible. Prompt and complete reperfusion has been shown to reduce mortality and morbidity rates.4 After establishing patency, however, the vessel must also be kept open to maintain the benefits of treatment. However, fibrinolytic agents have shown prothrombotic response as indicated by the high incidence of re-occlusion observed in patients undergoing thrombolysis.5 One of the postulated mechanisms to explain the paradoxical phenomenon is that the thrombus undergoing lysis exposes clot-bound thrombin and activates the coagulation cascade. In addition, the thrombolytic agent may successfully lyse the existent thrombus but is inactive on the initial thrombogenic stimulus that triggered the formation of the initial thrombus. This explains the need for adjunctive antithrombotic therapies. This need also exists with percutaneous interventional strategies in which adequate anti-platelet therapy post stent is essential.
Standard Thrombolytic Therapy Rapid dissolution of the occlusive intracoronary thrombus by fibrinolytic agents has been evaluated in several
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large clinical studies. This intravenous thrombolytic approach leads to a 20% relative decrease in 30-day mortality rates when compared to no thrombolytic therapy.4,6 However, thrombolysis is hampered by some critical limitations. First, adequate coronary patency (Thrombolysis in Myocardial Infarction [TIMI]-3 flow) at 90 min is only obtained in half of patients. Second, angiographic re-occlusion occurs in 10–20% of cases. Third, major haemorrhagic complications and, in particular, intracerebral haemorrhages are dramatic and occur in about 0.5–1% of patients. Furthermore, these
Figure 1. Meta-analysis of studies showing the association between stenosis severity and associated risk of coronary occlusion and myocardial infarction (MI). Percentage coronary stenosis: , <50%; , 50–70%; , >70%. Table 1.
Factors modulating atherothrombosis
Local fluid dynamics Shear stress Tensile stress Nature of the exposed substrate Degree of injury (mild versus severe arterial injury) Composition of atherosclerotic plaque Residual mural thrombus Systemic thrombogenic factors Hypercholesterolaemia Catecholamines (including cocaine) Smoking Diabetes Homocysteine Lipoprotein (a) Infective agents Chlamydia pneumoniae Helicobacter pylori Cytomegalovirus Hypercoagulable states Fibrinogen von Willebrand factor Tissue factor Defective fibrinolytic states Plasminogen activator inhibitor-1 Tissue plasminogen activator Tissue activable fibrinolysis inhibitor
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complications have slightly increased in recent trials, but this may relate to an older patient population and greater comorbidity in these recent studies.
Mechanisms of Failure of Thrombolysis The mechanisms responsible for failure of thrombolysis and/or recurrent thrombosis after coronary thrombolysis are complex and numerous. They are not fully understood but include increased procoagulant activity induced by pharmacological activation of plasminogen, local expression of procoagulant activity when the vessel is reperfused, presence of high shear forces that promote platelet deposition, and attenuation of physiological fibrinolytic activity after pharmacological thrombolysis.7 Thus, recurrent thrombosis after coronary thrombolysis depends on a complex interaction between procoagulant factors associated with the atherosclerotic plaque, procoagulant activity induced by the residual thrombus, and paradoxical procoagulant activity which is promoted by pharmacological thrombolysis. 8,9 The interaction between thrombus-bound thrombin and circulating blood may not only exert a prothrombotic stimulus through the activation of factor V but also by reducing endogenous thrombolytic potential via the induction of thrombin activatable fibrinolysis inhibitor (TAFI). TAFI is converted to a carboxypeptidase that inhibits fibrinolysis when exposed to the thrombin–thrombomodulin complex.10 The relationship of thrombolysis and platelet activation is complex and still debated.7 Multiple and counterbalancing effects come into play. These include platelet secretion of both fibrinolytic and anti-fibrinolytic components, assembly of fibrinolytic components on the platelet surface, and the influence of plasmin on platelet function. However, although plasmin has been shown to directly induce platelet activation in some systems,11 the concentrations of plasmin used are higher than during pharmacological thrombolysis. Nonetheless, there is marked platelet activation after pharmacological coronary thrombolysis.12 One potential mechanism for platelet activation is the formation of thrombin, which is the most potent platelet agonist. When using streptokinase, there is still perhaps another mechanism of platelet activation involving anti-streptokinase antibody. A plasminogen–streptokinase–anti-streptokinase antibody ternary complex seems to induce platelet aggregation.13
Alternatives to Standard Thrombolytic Therapy The significant incidence of resistance to thrombolytics and re-occlusion after successful reperfusion explain the
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search for new and more potent thrombolytics, so-called ‘third-generation’ thrombolytic agents. TIMI-3 flow is achieved in only half of the patients despite using the best therapy currently available with recombinant tissuetype plasminogen activator (rt-PA). The emphasis has shifted to producing a mutant form of rt-PA that is more potent and selective.14–16 This intensive research has led to the discovery of many mutants, three of which have achieved good results in clinical trials: reteplase, lanoteplase and TNK-t-PA. Unfortunately, initial observations have not been corroborated and recent trials with these new thrombolytics have shown equivalence to17 but not superiority over other thrombolytics. Other thrombolytics such as staphylokinase are under investigation.18 However, it is difficult to imagine that these thrombolytics alone will permit major advances in terms of reperfusion. Primary percutaneous transluminal coronary angioplasty (PTCA) was developed as an effective reperfusion intervention in MI. 19,20 Substantial debate has surrounded the relative merits of thrombolysis and conventional primary PTCA. However, a mortality benefit at 30 days for primary PTCA compared with early generation thrombolytic agents has been demonstrated in a meta-analysis of the data from all randomised trials.19–25 However, it is uncertain whether this result could be obtained in the majority of hospitals.
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intracerebral haemorrhage (0.2% on average), led to hope that these agents may be beneficial in conjunction with thrombolytic agents. These GP IIb/IIIa inhibitors have several beneficial effects when combined with thrombolytic therapy. They can reduce the amount of thrombus through a ‘dethrombotic’ action based on the ability to displace the fibrinogen already bound to the GP IIb/IIIa receptor as the affinity of the blocking agent is greater than that of fibrinogen for the receptor. They also decrease the activity of factor XIII, critical for fibrin stabilisation and subsequent clot retraction and decrease the activity of plasminogen activator inhibitor released by the activated platelets. The first available GP IIb/IIIa inhibitor was a chimeric antibody fragment directed against the receptor (abciximab). Subsequently, cyclic peptide inhibitors (eptafibatide), smaller synthetic non-peptide molecules mainly for parenteral short-term infusion (tirofiban, lamifiban) and, recently, oral agents, have been developed. Studies in animal models (mainly the dog) have demonstrated that the combination of thrombolytic agents with abciximab is beneficial in acute MI.28–30 This combination allows more rapid, complete and sustained coronary perfusion. Interestingly, these effects were obtained even with half the thrombolytic dose. Therefore, a reduced number of haemorrhagic complications due to the thrombolytic therapy could be expected in humans, if such a strategy was adopted.
Rationale of Anti-Platelet Therapy The rationale behind anti-platelet therapy relates to two major factors: (i) thrombin-mediated platelet activation is one of the major prothrombotic mechanisms; and (ii) thrombus-bound thrombin is protected from the plasma inhibitor and thus is still active upon thrombus re-canalisation. The potential of using anti-platelet therapy was first suggested by the results of the second International Study of Infarct Survival (ISIS-2) study.26 In this study, in patients randomly assigned to receive 160 mg aspirin per day, mortality rate was reduced by 23% at 35 days, a result that was similar to that obtained with streptokinase (25% reduction). The combination of the two drugs showed an additive effect, with a further decrease in mortality rate (42% reduction). The potential of decreasing the thrombolytic dosing in conjunction with anti-platelet therapy is interesting. By limiting the thrombolytic-induced prothrombotic effect, the regimen of reduced dose thrombolytic and anti-platelet therapy may in fact further improve coronary patency rates in acute MI. Recently, the success of potent inhibitors of platelet aggregation, glycoprotein (GP) IIb/IIIa antagonists, in acute coronary syndromes,27 combined with a low rate of
Preliminary Data: Thrombolytics and IIb/IIIa Inhibitors Three small pilot clinical studies have evaluated the combination of thrombolytics with IIb/IIIa inhibitors.15,31,32
Thrombolysis and Angioplasty in Myocardial Infarction This was a dose-ranging trial combining thrombolytic therapy (rt-PA) with a murine-derived monoclonal antibody 7E3 Fab.15 Sixty patients with acute MI receiving rt-PA, aspirin and heparin were randomised to escalating doses of this GP IIb/IIIa inhibitor or placebo. This safety study showed that the bleeding rate was not higher in the experimental group than in the control patients, and indicated a coronary patency rate (TIMI grade 2 and 3) of about 90% with the combination of the GP IIb/IIIa inhibitor and rt-PA.
IMPACT AMI (Integrilin to Manage Platelet Aggregation to Combat Thrombosis After Myocardial Infarction) This randomised, placebo-controlled dose-ranging trial tested six doses of eptafibatide (Integrilin) and compared
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the highest Integrilin dose against placebo in patients with acute MI receiving a full dose of rt-PA. 31 All patients received aspirin and intravenous heparin infusion. With the highest Integrilin dose, TIMI grade 3 was achieved at 90 min in 66% of patients compared with 39% of patients receiving placebo. Composite clinical end-points of death, re-infarction, stroke, percutaneous or surgical coronary re-vascularisation, or new inhospital heart failure or pulmonary oedema were similar in both groups.
PARADIGM (The Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction) This dose-ranging study compared patients with acute MI treated with either alteplase or streptokinase and randomly assigned with lamifiban.32 Despite a higher angiographic patency of the infarct-related artery with lamifiban, the clinical outcomes in the lamifiban and placebo groups were not significantly different.
Clinical Trials with Thrombolytics and IIb/IIIa Inhibitors Strategies for Patency Enhancement in the Emergency Department (SPEED) or the Global Use of Strategies To Open Occluded coronary arteries ( (GUSTO-IV) Pilot Study The surrogate end-point in this trial was TIMI flow at 60 min obtained with abciximab and reteplase (r-PA).33 All patients were given aspirin. Patients were randomised to either standard-dose abciximab alone or standard-dose abciximab with low-dose reteplase, with or without low-dose heparin. The preliminary results demonstrated that combination therapy with half-dose (or greater) reteplase led to TIMI-3 flow rates at least equivalent to full-dose fibrinolytic therapy. No excess bleeding was observed. Early (60 min) and complete reperfusion without an excess of haemorrhage appeared possible by combining abciximab and reduced-dose reteplase.
Thrombolysis in Myocardial Infarction (TIMI-14) This complex, large (888 patients) randomised trial was designed to evaluate the combination of thrombolytic agents and abciximab.34 The results were striking and showed that the most promising regimen tested was 50 mg of alteplase (15 mg bolus plus an infusion of 35 mg over 60 min) in combination with abciximab. Compared with full-dose alteplase alone, the 50 mg alteplase regimen produced substantial significant increases in the rates of TIMI-3 flow (76 vs 57%) and infarct-related artery patency (TIMI-2 and -3 flow; 93 vs
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78%) at 90 min. Although the implications of the marked increase in TIMI-3 flow when abciximab is combined with half the usual dose of alteplase in this trial are exciting, it must be remembered that this is only a phase II trial. Therefore, the phase III TIMI-14 and GUSTO-IV AMI trials are now being conducted, with predefined clinical end-points. The new drug combinations will be tested against standard thrombolytic therapy to confirm the preliminary results.
IIb/IIIa Inhibitors and Percutaneous Coronary Interventions The preliminary results of another large-scale trial (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications; CADILLAC) were recently presented at the Scientific Sessions of the American Heart Association (AHA) in 1999. In this trial, patients with acute MI were randomised to percutaneous revascularisation with either stenting (Multilink) or PTCA. In a 2 × 2 factorial design, these initial groups were further randomised to either abciximab or placebo. The combination of stenting and abciximab led to the best results, the global mortality in this subgroup being very low (1.4%). Abciximab has improved the rate of recurrent ischaemia when combined with stenting or PTCA.
Anticoagulant Agents Unfractionated and Low Molecular Weight Heparins The use of heparin in patients with MI provides a probable benefit with a relative reduction in mortality rate of approximately 20%.35 However, these results are from the prethrombolytic area and the control groups in these trials did not receive aspirin, the benefit of which is now clearly established. The rationale for systemic anticoagulation as adjunctive therapy to non-fibrin-specific thrombolytic agents is weak, because these thrombolytics have an anticoagulant effect through the generation of fibrinogen degradation products. Consistent with this is the absence of a significant effect with heparin on coronary patency in patients treated with streptokinase or anistreplase. However, the results with heparin as an adjunct to thrombolysis with rt-PA are unequivocal. Presently, intravenous heparin is recommended in patients treated with rt-PA, according to the GUSTO strategy.36 It is well known that low molecular weight heparins (LMWH) have several potential advantages over unfractionated heparin, including better availability and a more predictable anticoagulant effect which explains the less need for monitoring.37 Although these agents have been successfully tested in unstable angina and nonQ-wave MI,38,39 they are yet to be studied in Q-wave MI.
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The Fraxiparin Anticoagulant Therapy in Myocardial Infarction Study Amsterdam (FATIMA) study40 was a small trial showing that nadroparine is beneficial as an adjunct to rt-PA, with no major complications. A recent trial presented at the Scientific Sessions of the American College of Cardiology (ACC) in 2000, the second Heparins and Reperfusion Therapy (HART II) Study, comparing heparin and enoxaparin in combination with rt-PA, has shown equivalency in terms of infarct-related artery patency. Other ongoing trials testing the combination of thrombolytics and LWMH are presently being conducted: Acute Myocardial Infarction with Streptokinase (AMI SK), ENoxaparin and TNK-t-PA with or without GP IIb/IIIa Inhibitor as Reperfusion strategy in ST elevation MI (ENTIRE) and the third Assessment of the Safety of a New Thrombolytic (ASSENT-3).
for this phenomenon is that early reperfusion occurs less often with the former, leaving more room for improvement by better adjunctive therapy. To confirm this, the HERO-2 trial is being conducted, involving 17 000 patients with MI randomised to receive either intravenous heparin or bivalirudin prior to streptokinase administration. Another thrombin inhibitor, argatroban, was compared to heparin in the Myocardial Infarction with Novastan and TPA (MINT) study. 4 7 Argatroban appeared to enhance reperfusion with rt-PA in patients with MI, although the results were not significantly different. However, the incidence of major bleeding was lower in the patients receiving argatroban.
Direct Anti-Thrombin Agents
In acute MI, the challenge associated with pharmacological reperfusion strategies lies not only in the improvement of the 90-min coronary blood flow but also in sustaining the patency of the artery. Thus, new strategies, including the use of GP IIb/IIIa inhibitors and new thrombin inhibitors, have been tested. There is a clear rationale, both pathophysiological and clinical, for combining the GP IIb/IIIa inhibitors with thrombolytics. The combination of stenting with GP IIb/IIIa is also an attractive strategy. Presently, the most promising strategy seems to be the combination of half-dose thrombolytics and GP IIb/IIIa inhibitors. In particular, abciximab associated with half the usual dose of rt-PA has enhanced the rate of successful thrombolysis, producing earlier TIMI-3 flow. If these results are confirmed by the ongoing phase III trials, this will be a major advance in the management of acute MI.
As discussed above, thrombin plays a pivotal role in the balance between the coagulation and fibrinolytic systems. For this reason, a significant interest in thrombin inhibitors has emerged. Starting with hirudin, many specific inhibitors have been produced and tested in different settings. In acute MI, hirudin and hirulog have been studied in clinical trials. After two initial promising small trials (TIMI-5 testing hirudin with rt-PA41 and TIMI-6 testing hirudin with streptokinase42) two largescale studies, TIMI-9A43 and GUSTO-IIa,36 failed because of an excess of intracerebral haemorrhages. Therefore, lower doses of anticoagulation (i.e. hirudin and heparin) were evaluated in subsequent studies, TIMI-9B and GUSTO-IIb.44 However, in these trials, there was not a significant difference between heparin and hirudin in the composite primary end-point of 30-day death or new MI. Using hirulog, the Hirulog and Early Reperfusion / Occlusion (HERO) trial45 found this compound to be more effective than heparin in terms of TIMI-3 flow at 90 min in patients receiving streptokinase and aspirin. However, this trial was not intended to evaluate clinical end-points. The results of the Hirudin for Improvement of Thrombolysis (HIT)-4 trial46 found that lepirudin (recombinant hirudin) as an adjunct to thrombolysis with streptokinase was associated with an accelerated ST resolution when compared to heparin, although this was not associated with a significant improvement in coronary blood flow. Interestingly, a post hoc analysis of the GUSTO IIb trial has shown that patients receiving streptokinase and hirudin had a better outcome when compared to patients receiving streptokinase and heparin. These results suggest that direct thrombin inhibition could be more useful with fibrin-non-specific fibrinolytic agents such as streptokinase, than with fibrin-specific fibrinolytic agents such as rt-PA. A potential explanation
Conclusions
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