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From the experimental myocardial infarction to the clinical acute myocardial infarction: limitations of thrombolytic therapy
International
Journal of
CARDIOLOGY
ELSEVIER
International Journal of Cardiology 49 (Suppl.) (1995) S71-S75
From the experimental myocardial infarction to the clinical acute myocardial infarction: limitations of thrombolytic therapy Mario Marzilli University ofPisa Medical School; Instituteof Clinical Physiology CNR, Via Saoi; 8 56100PISA. Italy
Abstract Early administration of thrombolytic agents in acute myocardial infarction lowers mortality and preserves left ventricular function. Currently, only one third of infarct patients receive this treatment, the vast majority being excluded because of restrictive criteria and delayed hospital admission. When correctly administered, thrombolytic therapy achieves reperfusion in 50-85% of occluded vessels. Five to 15% of these initially recanalized vessels eventually reocclude. Possible mechanisms of failure of thrombolytic therapy to induce stable coronary reperfusion include thrombus formation during thrombolysis, platelet activation by thrombolysis, fibrin deposition during thrombolysis, and resistance to thrombolysis. Bleeding complications including intracranial haemorrhage remain a major complication. New therapeutic regimens, new thrombolytic agents and more effective anti-thrombotic drugs, together with intervention strategies that anticipate the time of treatment, promise a significant increase of the overall benefits obtainable with thrombolysis in acute myocardial infarction.
Keywords: Acute myocardial infarction; Thrombolysis; Pre-hospital treatment
1. Introduction Following evidence from many large-scale ran• domized trials, administration of thrombolytic agents is regarded as the crucial moment in phar• macologic treatment of acute myocardial infarc• tion. Thrombolysis is supposed to limit infarct size, preserve structure and function of the left ventricle, and reduce mortality and morbidity [1,2]. However, the clinical impact of thrombolytic therapy remains much more limited than one would reasonably expect from experimental re• sults. In fact, despite the great number of studies
and papers on this subject and the sustained effort of pharmaceutical companies in promoting thrombolytic therapy, only 15-30% of patients with myocardial infarction are being treated with thrombolytic agents, even in most recent reports [3,4]. Several factors contribute to these disap• pointing results, including restrictive criteria of enrolment and delayed hospital admission. In most of the larger trials, EeG evidence of ST segment elevation was required to include the patients, and this is a limiting factor because this pattern is present, at the time of hospital admis• sion, only in 60-70% of the patients eventually
0167-5273/95/$09.50 (C) 1995 Elsevier Science Ireland Ltd, All rights reserved SSDI 0167 -5273(95) 02341-S
S72
M. Marzilli /Intemationalloumal ofCardiology49 (SuppL) (/995) S71-S75
discharged with ~ diagnosis of myocardial infarc• tion. The second relevant limiting factor is the ex• cessive time delay between pain onset and hospi• tal admission, in the majority of patients, it ex• ceeds 6 h. Most studies have concluded that the beneficial effects of this treatment are most evi• dent if it is administered very early after symp• toms begin [5,6] and patients arriving later than 6 h are generally excluded. Other frequent exclu• sion criteria are recent cerebrovascular episodes, severe hypertension, bleeding peptic ulcer, etc. In many centres, age over 70 is also an exclusion criteria, despite evidence from several studies suggesting greater risk and greater reduction in mortality in older patients [7]. Coronary reperfusion is achieved in 50-85% of treated patients. Reperfusion rate is influenced by the choice of the thrombolytic drug, by the route and modality of administration, and by the time of angiography. Most investigators agree that patients with failed thrombolysis have a worse prognosis and that this worse prognosis is not reverted by adjuntive mechanical recanalization by PTCA [8,9]. Angiographic studies have demonstrated that a sizable portion of the vessel, initially recanalized from 5 to 15%, eventually re-occludes, despite anti-thrombotic therapy with heparin and/or as• pirin. Re-occlusion usually occurs 48-72 h after treatment and is associated with a loss of the beneficial effect of reperfusion [to]. 2. Possible mechanisms of the failure of thrombolytic therapy
2.1. Thrombus formation during thrombolysis
Before and during thrombolytic therapy, both spontaneous thrombus lysis and thrombus forma• tion have been observed [11-16]. According to recent studies, thrombolysis itself appears to sti• mulate thrombus formation through a variety of pathways. Variable intensity and time course of this thrombotic reaction can explain the failure of thrombolysis, its variable time course, late re-oc• elusion, etc, depending on the unstable and un• predictable balance between thrombus formation and lysis. Major stimuli to thrombus formation
during thrombolytic therapy appear to be platelet activation and thrombin-mediated fibrin deposi• tion.
2.2. Platelet activation by thrombolysis
Platelets can be activated during thrombolytic therapy through a plasmin-mediated mechanism, by a thrombin-mediated mechanism from the thrombin exposed on the clot, or by a collagen• mediated mechanism from the collagen exposed at ulcerated atherosclerotic plaques. Moreover, partial clot lysis results in changes of 'shear rate' in the presence of a significant residual stenosis with additional platelet activation and deposition on the arterial wall [17-19]. Platelet activation contributes to reformation of the coronary thrombus, to heparin resistance by release of factor 4 and thrombospondin and to inhibition of tissue plasminogen activator through release of the plasminogen activator inhibitor PAI·I. Platelets can also contribute to coronary re-occlusion by stimulating arterial vasoconstric• tion through release of thromboxane-A2. In ani• mal models platelet-rich clots bind less tissue plasminogen activator and are more resistent to its lytic action [20].
2.3. Fibrin deposition during thrombolysis
Due to increased thrombin activity, fibrin depo• sition is observed during thrombolytic therapy. This is a consequence of exposure of fibrin-bound thrombin in partially dissolved clots, of circulating fibrin-degradation products, and of new thrombin formation from prothrombin [21,22]. Thrombin bound to fibrin, to fibrin-degradation products, and to extracellular matrix is less sensi• tive to inhibition from heparin-antithrombin com• plex but is still active in inducing fibrin deposition and platelet aggregation [23]. Higher circulating levels of fibrinopeptide A and other thrombin• activation markers, that are found during throm• bolytic therapy in patients with failed reperfusion and re-occlusion, are consistent with this hy• pothesis [24].
2.4. Resistance to thrombolysis
Resistance to thrombolytic agents can also be the consequence of previous exposure to the drug
M. Marzilli /IntemationalJoumal of Cardiology 49 (5upplJ (1995) 571-575
resulting in sensitization and elevated levels of circulating antibodies; can be caused by certain characteristics of the clot such as age, structure and size limiting penetration of the drug; can result from elevated circulating level of plasmino• gen-activator inhibitor released from platelets and from the liver; and even from elevated level of lipoprotein A [25,26]. Apoprotein A, a key component of lipoprotein A, has a structure similar to plasminogen and can compete with plasminogen at surface receptors in many cell types. Elevated circulating levels of lipoprotein A could limit the number of cell re• ceptors available for thrombolysis [26].
2.5. Bleeding complications
Thrombolytic therapy in acute myocardial in• farction is associated with a 0.3-1.5% incidence of intracranial haemorrhage, despite the efforts to exclude patients undergoing this therapy at risk from this dramatic complication [27]. This compli• cation is common to all thrombolytic agents tested in large scale trials and represents a major prob• lem. The mechanisms that cause intracranial bleeding in patients without overt predisposing factors such as elevated distolic pressure or previ• ous history of intracranial bleeding or intracranial aneurisms remain unknown. It has been hypothe• sized that bleeding results from lysis of asympto• matic old clots present inside brain vessels or as a direct effect of the lytic agent on intracranial vascular permeability. So far no major progress has been reported in the understanding and/or prevention of this phenomenon. 3. Future perspectives The overall impact of thrombolytic treatment in acute myocardial infarction could be signifi• cantly increased if a greater percentage of patients were treated immediately following the onset of chest pain and if more effective and safer agents were available.
3.1. Delay of treatment
Most large scale trials have consistently shown that thrombolytic therapy is more beneficial the earlier it is performed, but, at the same time, that
S73
the percentage of patients treated within 1 h is less than 10%. The majority of patients with acute myocardial infarction are admitted to the hospital after such a long delay that the benefit of thrombolysis is limited or it is just too late for thrombolysis. Many factors contribute to the on• set-admission delay, including patient-related fac• tors and logistic factors. All possible interventions aimed to shorten this delay and to increase the percentage of patients treated at the time of maximum efficacy of thrombolysis should be con• sidered and, if possible, realized. Patient education, especially in high-risk groups, to identify infarct symptoms and to imme• diately search for help could significantly shorten the patient-related delay that still averages 70-80 min [28]. Changes in the organization of out-of• hospital emergency medicine could allow to antic• ipate the administration of the thrombolytic agent at home, in the ambulance or in the emergency room, transforming part of the transport and admission time into therapeutic time.
3.2. Thrombolytic agents
With the available drugs, greater efficacy of the thrombolytic treatment could be achieved with new therapeutic strategies such as faster injec• tion, starting with a loading dose or with a double bolus, or combining different agents. A major benefit would derive from prevention of late re-occlusion of recanilazed vessels. So far, even the regimens that include association of aspirin and heparin, do not consistently prevent delayed lysis, failure of lysis or early re-occlu• sions. Aspirin inhibits cyclo-oxygenase-dependent platelet activation, but several alternative mecha• nisms of activation are not affected by aspirin; heparin is not so effective in inhibiting clot-bound thrombin, as with circulating thrombin, it requires the presence of anti-thrombin to be active, and can be antagonized by platelet-derived factor 4 and by thrombospondin, and in the same patient paradoxically stimulates, directly, platelet activa• tion. Several new anti-platelet agents are being released for clinical use that, in experimental models of platelet-rich thrombi, have been shown
S74
M Marzilli I International Journalof Cardiology 49 (Suppl] (1995) S71-S75
to accelerate clot lysis and to prevent re-occlu• sion. The final step of platelet aggregation includes activation of the glicoprotein receptor lIb lIlIa, belonging to the receptor family denominated integrins. Several adhesive molecules, including fibrinogen, fibrolectin, and von Willebrand factor, bind to the receptor and start platelet aggrega• tion. These adhesive molecules share a sequence of amino-acids containing arginin-glicin-aspartate (ROD). Two types of compounds that block these receptors are currently under clinical evaluation: a monoclonal antibody and several peptides with an ROO sequence (disintegrines) obtained from snake venom or by synthetic processes. These compounds, by blocking the lIb IlIla receptor, prevent platelet aggregation, accelerate clot lysis and prevent re-occlusion in experimental models. Inhibitors of prostaglandin and of serotonin, antagonists of von Willebrabd factor, and inhibi• tors of protein C kinase are also under evalua• tion. New anti-thrombin agents that do not need anti-thrombin III (as heparin) to inhibit thrombin and are equally effective on circulating and fibrin-bound thrombin should soon become avail• able [29]. In animal models of thrombosis, these new direct anti-thrombin agents significantly in• crease the reperfusion rate following rTPA, and limit re-occlusion. 4. Conclusions Overall benefits from thrombolytic therapy in acute myocardial infaction are markedly limited by the excessive delay between the onset of the symptoms and hospital admission that excludes too many patients from this treatment, and by the limited efficacy and severe side effects of avail• able agents. New therapeutic regimens, new thrombolytic agents and more effective anti-thrombotic drugs promise a significant improvement in the overall results in the near future, provided the ongoing studies demonstrate that the greater lytic action is not associated with greater haemorragic risk. In the mean time, every effort should be made to reach more patients earlier. EMIP, MITI, and GREAT have consistently demonstrated the fea-
sibility and safety of pre-hospital thrombolysis and confirmed that the benefits obtainable from this treatment are inversely related to the time interval between onset of pain and treatment. Based upon these studies, new intervention strategies should be defined in order to anticipate therapy in acute infarction. References [I] Tiefenbrunn AJ, Sobel BE. The impact of coronary thrombolysis on myocardial infarction. Fibrinolysis 1989: 3: 1-15. [2] Sobel BE. Coronary thrombolysis: Editorial overview. Coronary Artery Dis 1990; 1: 3-7. [3] Lee ill, Weisberg MC, Brand DA et al. Candidates for thrombolysis among emergency room patients with acute chest pain. Ann Intern Med 1989; 110: 957-962. [4] Jagger JD, Murray RG, Davies MK et al. Eligibility for thrombolytic therapy in acute myocardial infarction. Lancet 1987: 1: 34-35. [5] Gruppo Italiano per 10 Studio della Streptochinasi nell' Infarto Miocardico (GISSI). Long-term effects of intra• venous thrombolysis in acute myocardial infarction: Fi• nal report of the GISSI study. Lancet 1987: 2: 871-874. [6] ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17, 187 cases of suspected acute myocardial infarction: ISIS• 2 Lancet 1988: 2: 349-360. [7] 0' Connor CM, Califf RM. Aggressive therapy of acute MI in the elderly. Hosp Pract 1992; 59-76. [8] Ellis SG, Debowey D, Bates ER, Topol EJ. Treatment of recurrent ischemia after thrombolysis and successful reperfusion for acute myocardial infarction: Effect on in-hospital mortality and left ventricular function. J Am Coli Cardio11991: 17: 752-757. [9] Califf RM, Topol EJ, George BS et al. Characteristics and outcome of patients in whom reperfusion with intra• venous tissue-type plasminogen activator fails: Results of the thrombolysis and angioplasty in myocardial in• farction (TAMI) I trial. Circulation 1988: 77: 5 1090-1099. [10] Ohman EM, Califf RM, Topol EJ et al. Consequences of reocclusion following successful reperfusion therapy in acute myocardial infarction. Circulation 1990; 82: 781-791. [11] Owen J, Friedman KD, Grossman BA et al. Thrombo• lytic therapy with tissue plasminogen activator or strep• tokinase induces transient thrombin activity. Blood 1988; 72: 616-620. [I21 Fitzgerald OJ, Catella F, Roy 1., Fitzgerald GA Market platelet activation in vivo after intravenous streptoki• nase in patients with acute myocardial infarction. Circu• lation 1988; 77: 142-150.
M Marzilli / International Journal of Cardiology 49 ISuppl} (1995)S71-S75 [13] Eisenberg PR, Sherman lA, Jaffe AS. Paradoxic eleva• tion of fibrinopeptide A: Evidence for continued throm• bosis despite intensive fibrinolysis. J Am Coli Cardiol 1987; 10: 527-529. [14] Owen J, Friedman KD, Grossman BA et al. Thrombo• lytic therapy with tissue plasminogen activator or strep• tokinase induces transient thrombin activity. Blood 1988; 72: 616-620. [15] Eisenberg PRo Miletich JP. Induction of marked throm• bin activity by pharmacologic concentrations of plasminigen activators in non-anticoagulated whole blood. Thromb Res 1989; 55: 635-643. [16] Gulba DC, Barthels M, Westhoff-Bleck M et at. In• creased thrombin levels during thrombolytic therapy in acute myocardial infarction. Circulation 1991; 83: 937-944. [17] Ohlstein EH, Storer B, Fujita T, Shebuski RJ. Tissue• type plasminogen activator and streptokinase induce platelet hyperaggregability in the rabbit. Thromb Res 1987; 46: 575-585. [18] Golino P, Ashton JH, Glas-Greenwait P et a1. Media• tion of reocclusion by thromboxane A2 and serotonin after thrombolysis with tissue-type plasminogen activa• tor in a canine preparation of coronal)' thrombosis . Circulation 1988; 77: 678-684. [19] Badimon 1., Lassila R, Badimon J et a1. Residual throm• bus is more thrombogenic than severely damaged vessel wall (Abstract). Circulation 1988; 78 (Suppl 11): ii-119. [20] Jang IK, Gold HZ, Ziskind AA et al, Differential sensi• tivity of erythrocyte-rich and platelet-rich arterial thrombi to lysis with recombinant tissue-type plasmino• gen activator: A possible explanation for resistance to coronary thrombolysis. Circulation 1989; 79: 920-928. [21] Francis CW, Marcham RE Jr, Barlow GH et a1. Throm• bin activity of fibrin thrombi and soluble plasmic deriva• tives. J Lab ain Med 1983; 102: 220-230. [22] Weitz Jl, Hudoba M, Massel D et a1. Clot-bound throm-
[23]
[24]
[25]
[26] [27]
[28]
[29]
[30]
S75
bin is protected frpm inhibition by heparin-antithrombin III-independent inhibitors. J CIin Invest 1990; 86: 385-391. Bar-Shavit R, Eldor A, V10davsky I. Binding of throm• bin to subendothelial extracellular matrix protection and expression of functional properties. J Clin Invest 1989; 84: 1096-1104. Eisenberg PRo Sobel BE, Jaffe AS. Activation of pro• thrombin accompanying thrombolysis with recombinant tissue-type plasminogen activator. J Am Coli Cardiol 1992; 19: 1065-1069. Lew AS, Neer T, Rodriguez L et al. Clinical failure of streptokinase due to an unsuspected high titer of anti• streptokinase antibody. J Am Coli Cardiol 1984; 4: 183-185. Miles lA, Fless GM, Levin EG et al. A potential basis for the thromnotic risks associated with lipoproteinta), Nature 1989;339-401. Gore JM, Sloan M, Price TR et al. Intracerebral hae• morrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic ther• aphy in the thrombolysis in myocardial infarction study. Circulation 1991; 83: 448-459. Weaver WO, Eisenberg MS, Martin JS et al. Myocardial infarction triage and intervention project-phase 1: Patient characteristics and feasibility of pre-hospital ini• tiation of thrombolytic therapy. J Am Coli Cardiol 1990; 15: 925-931. Heras M, Chesebro JH, Penny WJ et al. Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs. Heparin versus recombinant hirudin, a specific thrombin inhibitor . Circulation 1989; 79: 657-665. Maraganore JM, Chao B, Joseph ML et al. Anticoagu• lant activity of synthetic hirud in peptides. J Bioi Chem 1989; 25: 8692-8698.
Journal of
CARDIOLOGY
ELSEVIER
International Journal of Cardiology 49 (Suppl.) (1995) S71-S75
From the experimental myocardial infarction to the clinical acute myocardial infarction: limitations of thrombolytic therapy Mario Marzilli University ofPisa Medical School; Instituteof Clinical Physiology CNR, Via Saoi; 8 56100PISA. Italy
Abstract Early administration of thrombolytic agents in acute myocardial infarction lowers mortality and preserves left ventricular function. Currently, only one third of infarct patients receive this treatment, the vast majority being excluded because of restrictive criteria and delayed hospital admission. When correctly administered, thrombolytic therapy achieves reperfusion in 50-85% of occluded vessels. Five to 15% of these initially recanalized vessels eventually reocclude. Possible mechanisms of failure of thrombolytic therapy to induce stable coronary reperfusion include thrombus formation during thrombolysis, platelet activation by thrombolysis, fibrin deposition during thrombolysis, and resistance to thrombolysis. Bleeding complications including intracranial haemorrhage remain a major complication. New therapeutic regimens, new thrombolytic agents and more effective anti-thrombotic drugs, together with intervention strategies that anticipate the time of treatment, promise a significant increase of the overall benefits obtainable with thrombolysis in acute myocardial infarction.
Keywords: Acute myocardial infarction; Thrombolysis; Pre-hospital treatment
1. Introduction Following evidence from many large-scale ran• domized trials, administration of thrombolytic agents is regarded as the crucial moment in phar• macologic treatment of acute myocardial infarc• tion. Thrombolysis is supposed to limit infarct size, preserve structure and function of the left ventricle, and reduce mortality and morbidity [1,2]. However, the clinical impact of thrombolytic therapy remains much more limited than one would reasonably expect from experimental re• sults. In fact, despite the great number of studies
and papers on this subject and the sustained effort of pharmaceutical companies in promoting thrombolytic therapy, only 15-30% of patients with myocardial infarction are being treated with thrombolytic agents, even in most recent reports [3,4]. Several factors contribute to these disap• pointing results, including restrictive criteria of enrolment and delayed hospital admission. In most of the larger trials, EeG evidence of ST segment elevation was required to include the patients, and this is a limiting factor because this pattern is present, at the time of hospital admis• sion, only in 60-70% of the patients eventually
0167-5273/95/$09.50 (C) 1995 Elsevier Science Ireland Ltd, All rights reserved SSDI 0167 -5273(95) 02341-S
S72
M. Marzilli /Intemationalloumal ofCardiology49 (SuppL) (/995) S71-S75
discharged with ~ diagnosis of myocardial infarc• tion. The second relevant limiting factor is the ex• cessive time delay between pain onset and hospi• tal admission, in the majority of patients, it ex• ceeds 6 h. Most studies have concluded that the beneficial effects of this treatment are most evi• dent if it is administered very early after symp• toms begin [5,6] and patients arriving later than 6 h are generally excluded. Other frequent exclu• sion criteria are recent cerebrovascular episodes, severe hypertension, bleeding peptic ulcer, etc. In many centres, age over 70 is also an exclusion criteria, despite evidence from several studies suggesting greater risk and greater reduction in mortality in older patients [7]. Coronary reperfusion is achieved in 50-85% of treated patients. Reperfusion rate is influenced by the choice of the thrombolytic drug, by the route and modality of administration, and by the time of angiography. Most investigators agree that patients with failed thrombolysis have a worse prognosis and that this worse prognosis is not reverted by adjuntive mechanical recanalization by PTCA [8,9]. Angiographic studies have demonstrated that a sizable portion of the vessel, initially recanalized from 5 to 15%, eventually re-occludes, despite anti-thrombotic therapy with heparin and/or as• pirin. Re-occlusion usually occurs 48-72 h after treatment and is associated with a loss of the beneficial effect of reperfusion [to]. 2. Possible mechanisms of the failure of thrombolytic therapy
2.1. Thrombus formation during thrombolysis
Before and during thrombolytic therapy, both spontaneous thrombus lysis and thrombus forma• tion have been observed [11-16]. According to recent studies, thrombolysis itself appears to sti• mulate thrombus formation through a variety of pathways. Variable intensity and time course of this thrombotic reaction can explain the failure of thrombolysis, its variable time course, late re-oc• elusion, etc, depending on the unstable and un• predictable balance between thrombus formation and lysis. Major stimuli to thrombus formation
during thrombolytic therapy appear to be platelet activation and thrombin-mediated fibrin deposi• tion.
2.2. Platelet activation by thrombolysis
Platelets can be activated during thrombolytic therapy through a plasmin-mediated mechanism, by a thrombin-mediated mechanism from the thrombin exposed on the clot, or by a collagen• mediated mechanism from the collagen exposed at ulcerated atherosclerotic plaques. Moreover, partial clot lysis results in changes of 'shear rate' in the presence of a significant residual stenosis with additional platelet activation and deposition on the arterial wall [17-19]. Platelet activation contributes to reformation of the coronary thrombus, to heparin resistance by release of factor 4 and thrombospondin and to inhibition of tissue plasminogen activator through release of the plasminogen activator inhibitor PAI·I. Platelets can also contribute to coronary re-occlusion by stimulating arterial vasoconstric• tion through release of thromboxane-A2. In ani• mal models platelet-rich clots bind less tissue plasminogen activator and are more resistent to its lytic action [20].
2.3. Fibrin deposition during thrombolysis
Due to increased thrombin activity, fibrin depo• sition is observed during thrombolytic therapy. This is a consequence of exposure of fibrin-bound thrombin in partially dissolved clots, of circulating fibrin-degradation products, and of new thrombin formation from prothrombin [21,22]. Thrombin bound to fibrin, to fibrin-degradation products, and to extracellular matrix is less sensi• tive to inhibition from heparin-antithrombin com• plex but is still active in inducing fibrin deposition and platelet aggregation [23]. Higher circulating levels of fibrinopeptide A and other thrombin• activation markers, that are found during throm• bolytic therapy in patients with failed reperfusion and re-occlusion, are consistent with this hy• pothesis [24].
2.4. Resistance to thrombolysis
Resistance to thrombolytic agents can also be the consequence of previous exposure to the drug
M. Marzilli /IntemationalJoumal of Cardiology 49 (5upplJ (1995) 571-575
resulting in sensitization and elevated levels of circulating antibodies; can be caused by certain characteristics of the clot such as age, structure and size limiting penetration of the drug; can result from elevated circulating level of plasmino• gen-activator inhibitor released from platelets and from the liver; and even from elevated level of lipoprotein A [25,26]. Apoprotein A, a key component of lipoprotein A, has a structure similar to plasminogen and can compete with plasminogen at surface receptors in many cell types. Elevated circulating levels of lipoprotein A could limit the number of cell re• ceptors available for thrombolysis [26].
2.5. Bleeding complications
Thrombolytic therapy in acute myocardial in• farction is associated with a 0.3-1.5% incidence of intracranial haemorrhage, despite the efforts to exclude patients undergoing this therapy at risk from this dramatic complication [27]. This compli• cation is common to all thrombolytic agents tested in large scale trials and represents a major prob• lem. The mechanisms that cause intracranial bleeding in patients without overt predisposing factors such as elevated distolic pressure or previ• ous history of intracranial bleeding or intracranial aneurisms remain unknown. It has been hypothe• sized that bleeding results from lysis of asympto• matic old clots present inside brain vessels or as a direct effect of the lytic agent on intracranial vascular permeability. So far no major progress has been reported in the understanding and/or prevention of this phenomenon. 3. Future perspectives The overall impact of thrombolytic treatment in acute myocardial infarction could be signifi• cantly increased if a greater percentage of patients were treated immediately following the onset of chest pain and if more effective and safer agents were available.
3.1. Delay of treatment
Most large scale trials have consistently shown that thrombolytic therapy is more beneficial the earlier it is performed, but, at the same time, that
S73
the percentage of patients treated within 1 h is less than 10%. The majority of patients with acute myocardial infarction are admitted to the hospital after such a long delay that the benefit of thrombolysis is limited or it is just too late for thrombolysis. Many factors contribute to the on• set-admission delay, including patient-related fac• tors and logistic factors. All possible interventions aimed to shorten this delay and to increase the percentage of patients treated at the time of maximum efficacy of thrombolysis should be con• sidered and, if possible, realized. Patient education, especially in high-risk groups, to identify infarct symptoms and to imme• diately search for help could significantly shorten the patient-related delay that still averages 70-80 min [28]. Changes in the organization of out-of• hospital emergency medicine could allow to antic• ipate the administration of the thrombolytic agent at home, in the ambulance or in the emergency room, transforming part of the transport and admission time into therapeutic time.
3.2. Thrombolytic agents
With the available drugs, greater efficacy of the thrombolytic treatment could be achieved with new therapeutic strategies such as faster injec• tion, starting with a loading dose or with a double bolus, or combining different agents. A major benefit would derive from prevention of late re-occlusion of recanilazed vessels. So far, even the regimens that include association of aspirin and heparin, do not consistently prevent delayed lysis, failure of lysis or early re-occlu• sions. Aspirin inhibits cyclo-oxygenase-dependent platelet activation, but several alternative mecha• nisms of activation are not affected by aspirin; heparin is not so effective in inhibiting clot-bound thrombin, as with circulating thrombin, it requires the presence of anti-thrombin to be active, and can be antagonized by platelet-derived factor 4 and by thrombospondin, and in the same patient paradoxically stimulates, directly, platelet activa• tion. Several new anti-platelet agents are being released for clinical use that, in experimental models of platelet-rich thrombi, have been shown
S74
M Marzilli I International Journalof Cardiology 49 (Suppl] (1995) S71-S75
to accelerate clot lysis and to prevent re-occlu• sion. The final step of platelet aggregation includes activation of the glicoprotein receptor lIb lIlIa, belonging to the receptor family denominated integrins. Several adhesive molecules, including fibrinogen, fibrolectin, and von Willebrand factor, bind to the receptor and start platelet aggrega• tion. These adhesive molecules share a sequence of amino-acids containing arginin-glicin-aspartate (ROD). Two types of compounds that block these receptors are currently under clinical evaluation: a monoclonal antibody and several peptides with an ROO sequence (disintegrines) obtained from snake venom or by synthetic processes. These compounds, by blocking the lIb IlIla receptor, prevent platelet aggregation, accelerate clot lysis and prevent re-occlusion in experimental models. Inhibitors of prostaglandin and of serotonin, antagonists of von Willebrabd factor, and inhibi• tors of protein C kinase are also under evalua• tion. New anti-thrombin agents that do not need anti-thrombin III (as heparin) to inhibit thrombin and are equally effective on circulating and fibrin-bound thrombin should soon become avail• able [29]. In animal models of thrombosis, these new direct anti-thrombin agents significantly in• crease the reperfusion rate following rTPA, and limit re-occlusion. 4. Conclusions Overall benefits from thrombolytic therapy in acute myocardial infaction are markedly limited by the excessive delay between the onset of the symptoms and hospital admission that excludes too many patients from this treatment, and by the limited efficacy and severe side effects of avail• able agents. New therapeutic regimens, new thrombolytic agents and more effective anti-thrombotic drugs promise a significant improvement in the overall results in the near future, provided the ongoing studies demonstrate that the greater lytic action is not associated with greater haemorragic risk. In the mean time, every effort should be made to reach more patients earlier. EMIP, MITI, and GREAT have consistently demonstrated the fea-
sibility and safety of pre-hospital thrombolysis and confirmed that the benefits obtainable from this treatment are inversely related to the time interval between onset of pain and treatment. Based upon these studies, new intervention strategies should be defined in order to anticipate therapy in acute infarction. References [I] Tiefenbrunn AJ, Sobel BE. The impact of coronary thrombolysis on myocardial infarction. Fibrinolysis 1989: 3: 1-15. [2] Sobel BE. Coronary thrombolysis: Editorial overview. Coronary Artery Dis 1990; 1: 3-7. [3] Lee ill, Weisberg MC, Brand DA et al. Candidates for thrombolysis among emergency room patients with acute chest pain. Ann Intern Med 1989; 110: 957-962. [4] Jagger JD, Murray RG, Davies MK et al. Eligibility for thrombolytic therapy in acute myocardial infarction. Lancet 1987: 1: 34-35. [5] Gruppo Italiano per 10 Studio della Streptochinasi nell' Infarto Miocardico (GISSI). Long-term effects of intra• venous thrombolysis in acute myocardial infarction: Fi• nal report of the GISSI study. Lancet 1987: 2: 871-874. [6] ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17, 187 cases of suspected acute myocardial infarction: ISIS• 2 Lancet 1988: 2: 349-360. [7] 0' Connor CM, Califf RM. Aggressive therapy of acute MI in the elderly. Hosp Pract 1992; 59-76. [8] Ellis SG, Debowey D, Bates ER, Topol EJ. Treatment of recurrent ischemia after thrombolysis and successful reperfusion for acute myocardial infarction: Effect on in-hospital mortality and left ventricular function. J Am Coli Cardio11991: 17: 752-757. [9] Califf RM, Topol EJ, George BS et al. Characteristics and outcome of patients in whom reperfusion with intra• venous tissue-type plasminogen activator fails: Results of the thrombolysis and angioplasty in myocardial in• farction (TAMI) I trial. Circulation 1988: 77: 5 1090-1099. [10] Ohman EM, Califf RM, Topol EJ et al. Consequences of reocclusion following successful reperfusion therapy in acute myocardial infarction. Circulation 1990; 82: 781-791. [11] Owen J, Friedman KD, Grossman BA et al. Thrombo• lytic therapy with tissue plasminogen activator or strep• tokinase induces transient thrombin activity. Blood 1988; 72: 616-620. [I21 Fitzgerald OJ, Catella F, Roy 1., Fitzgerald GA Market platelet activation in vivo after intravenous streptoki• nase in patients with acute myocardial infarction. Circu• lation 1988; 77: 142-150.
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