(Circulation. 1996;94:863-865.)
© 1996 American Heart Association, Inc.
Articles |
Thrombin Inhibitors in Fibrinolysis
A Hobson's Choice of Alternatives
Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, Mass.
Correspondence to Dr Joseph Loscalzo, Boston University Medical Center Hospital, 88 E Newton St, Boston, MA 02118-2394.
Key Words: Editorials • thrombolysis • thrombosis • coronary disease
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Where to elect there is but one Take Hobson's choice-take that or none. -England's Reformation. Chapter IV, p 326.
Legend holds that Tobias Hobson, the first Englishman to rent horses for hackney use, offered potential customers one of two choices: take the horse nearest the door of his establishment or take none at all. More often than not, the horse offered was surpassed in appearance and quality by others further down the line, and the nature of the purchaser's dilemma has since become a metaphor for anyone given a difficult choice between two suboptimal alternatives. Adjunctive anticoagulant use in patients treated with fibrinolytic therapy for acute coronary syndromes presents a Hobsonian choice to cardiologists: administering them increases the risk of significant bleeding, yet withholding them increases the risk of acute rethrombosis.
The adjunctive use of thrombin inhibitors with thrombolytic therapy for the treatment of acute Q-wave myocardial infarction is predicated on activation of the coagulation system during fibrinolysis.1 Both plasmin-mediated platelet activation2 and plasmin-mediated prothrombinase activity3 lead to the generation of thrombin during fibrinolytic therapy and, thereby, to the conversion of fibrinogen to fibrin.4
Preclinical studies confirmed the view that thrombin inhibitors administered with plasminogen activators potentiate fibrinolysis.5 6 The use of heparin as an adjunct to thrombolytic therapy in patients with acute Q-wave myocardial infarction is not, however, universally accepted. Hemorrhagic risk is believed to be excessive, especially when heparin is used in conjunction with streptokinase; thus, current guidelines suggest that heparin be administered with tissue plasminogen activator but that its use in patients treated with streptokinase be delayed after infusion of the thrombolytic agent. While clinically judicious, this recommendation overlooks the important mechanistic fact that activation of the clotting system peaks approximately 1 hour after the infusion of tissue plasminogen activator or streptokinase.4 6 Thus, delaying the early administration of a thrombin inhibitor may theoretically limit the extent to which thrombin elaboration can be suppressed during fibrinolytic therapy.
In recent years, direct thrombin inhibitors have been heralded as a significant improvement over heparin for the treatment of prothrombotic disorders. Hirudin7 and its congeners represent the family of these agents most extensively studied to date. Early data suggested that hirudin and its congener bivalirudin are more potent than heparin,8 enhance the rate of thrombolysis by tissue plasminogen activator more than heparin,6 and provide more uniform anticoagulation than heparin,9 all without the many other unwanted side effects of heparin.
Owing to these unique properties and pharmacological profile, hirudin was first compared with heparin as an adjunct to thrombolytic therapy in the Thrombolysis In Myocardial Infarction (TIMI) 5 trial.10 This trial was a pilot, dose-ranging study designed to test the efficacy and safety of hirudin as an adjunct to thrombolysis with tissue plasminogen activator. The results of the trial were encouraging and showed that hirudin was at least as efficacious as heparin and perhaps somewhat better as adjunctive therapy for thrombolysis with no greater hemorrhagic risk. Similar results were obtained in the TIMI 6 dose-ranging pilot trial in which the efficacy and safety of hirudin as an adjunct to thrombolysis with streptokinase were compared with those of heparin.11 Again, these pilot results were encouraging and supported the development of a larger, definitive, prospective, blinded comparison of adjunctive hirudin and heparin in patients with acute Q-wave myocardial infarction.
Two trials were established to address this timely and important issue: the TIMI 9 and Global Utilization of Strategies to Open Occluded Coronary Arteries (GUSTO) II trials. A single dose of heparin was compared with a single dose of hirudin in both of these trials, and, importantly, the initial doses used were comparatively high: the highest dose of hirudin used in TIMI 5 was chosen for TIMI 9 and GUSTO II (0.6 mg/kg bolus followed by 0.2 mg/kg per hour), and heparin dosing was weight-adjusted (5000 U bolus followed by 1300 U/h for patients 
80 kg or 1000 U/h for patients <80 kg). By December 1994, both trials-now known as TIMI 9A and GUSTO IIa-were prematurely terminated by recommendation of their respective data and safety monitoring committees because of an unacceptable and unexpectedly high rate of intracerebral hemorrhage; importantly, this increased hemorrhagic rate was observed in both the hirudin and heparin treatment arms of both trials.12 13 Rather than terminate these trials, the investigators reasoned that they should continue them both using lower doses of hirudin (0.1 mg/kg bolus followed by 0.1 mg/kg per hour) and heparin (5000 U bolus followed by 1000 U/h) and did so in what became known as the TIMI 9B and GUSTO IIb trials, respectively.
In this edition of Circulation, the results of the completed TIMI 9B trial are presented.14 The data show that heparin and hirudin are equally effective as adjunctive therapies for tissue-type plasminogen activator or streptokinase in preventing unsatisfactory thrombotic outcomes and do so without a significant difference in major bleeding events.
Upon review of the results of this trial, two questions immediately come to mind: (1) Why were these results different from those predicted by the TIMI 5 trial? (2) What are the implications of these results for the future use of direct thrombin inhibitors in acute coronary syndromes? To attempt to shed some light on these difficult questions, we must first turn to a discussion of the mechanisms of action of hirudin and heparin.
Hirudin is a direct thrombin inhibitor that binds with high affinity to thrombin and prevents the expression of the catalytic activity of the enzyme. Heparin, in contrast, indirectly inhibits thrombin by catalyzing enzyme inhibition by the naturally occurring serine protease inhibitors (serpins) antithrombin III and heparin cofactor II. Importantly, the former serpin inhibits not only thrombin but also other coagulation proteases, including factors IXa, Xa, XIa, and XIIa. The ability of heparin to catalyze the inhibition of thrombin as well as coagulation proteases that lead to the production of thrombin gives it a distinctive antithrombotic profile in contrast to hirudin: heparin inhibits thrombin generation and activity, whereas hirudin inhibits thrombin activity alone.
Notwithstanding the comparative potency of hirudin as a thrombin inhibitor, its inability to prevent activation of procoagulants that generate thrombin can have important adverse consequences for its overall antithrombotic efficacy. During thrombolytic therapy, the coagulation system elaborates thrombin, which, in turn, is efficiently inhibited by hirudin; however, small amounts of thrombin may be generated in local microenvironments transiently or may be relatively unavailable to hirudin transiently, which could lead to fibrin production, platelet activation, and thrombus formation. The autoamplifying nature of pathways for thrombin generation and platelet activation implies that even modest degrees of uninhibited activity can ultimately have important prothrombotic effects.
In support of this mechanism, recent data suggest that tissue factor expression by endothelial cells in tissue culture is heterogeneous and can achieve sufficiently high local concentrations that local deposition of fibrin occurs even in the presence of concentrations of hirudin sufficient to inhibit thrombin in the fluid phase.15 In addition, activation of platelets by 
-thrombin is not as effectively inhibited by hirudin as is the procoagulant activity of thrombin and requires a 10-fold molar excess of inhibitor over enzyme,16 suggesting that platelet activation by thrombin may be less susceptible to inhibition by currently accepted doses of hirudin than is fibrin formation. That heparin is more effective than hirudin in preventing prothrombin activation and free thrombin generation after platelet activation in plasma17 supports the implications of these observations. Hirudin is more effective than heparin at inactivating thrombin; however, once thrombin inhibitory capacity is exceeded, an explosive generation of free thrombin occurs that far exceeds that observed in the presence of heparin.17
The results of TIMI 9B can be interpreted to suggest that the mechanistic differences between heparin and hirudin essentially offset one another, rendering these antithrombotic agents at the doses used in this study clinically indistinguishable from one another: hirudin is more potent than heparin as a thrombin inhibitor, yet heparin can inhibit procoagulant activation and thrombin generation. Studies of plasma markers of thrombin activity (fibrinopeptide A) and prothrombin activation (prothrombin fragment I.II) support the view that heparin is more efficient at inhibiting thrombin generation than hirudin and does so at equivalent levels of thrombin activity.18 19
The potential benefits of hirudin in the TIMI 9 trial were initially offset by the hemorrhagic risks of the high dose used. Reducing the dose to a far lower dose clearly improved the hemorrhagic risk; yet, no clear benefit of the agent over heparin was realized under these conditions. This Hobsonian experience is thoroughly illustrative of a most important point for trials of antithrombotic therapies in acute coronary syndromes: antithrombotic agents have narrow therapeutic indices. The doses chosen of hirudin and heparin for TIMI 9A were predicated on the preliminary data from an earlier pilot trial, and the doses chosen for TIMI 9B were predicated on the adverse results of TIMI 9A. An instructive example of this important point is the recently published trial of heparin versus bivalirudin for patients undergoing percutaneous transluminal coronary angioplasty for unstable or postinfarction angina.20 In this trial, a conservatively low dose of bivalirudin was chosen that showed a clear benefit over heparin in terms of hemorrhagic complications, reducing them by 61%; however, this safety benefit was unaccompanied by any improvement in efficacy.
We are only beginning to understand the intricacies of the mechanism(s) of action of direct thrombin inhibitors and their clinical application in acute coronary syndromes. Clearly, heparin is not an ideal drug, but it is the anticoagulant with which we have the greatest experience. Direct thrombin inhibitors offer at the very least ease of use with stable anticoagulant activity, lack of direct effects on platelet function, and uniformity of pharmacological composition and activity. As with heparin, however, they have very narrow therapeutic indices that must be defined for each specific patient population before dosage schedules can be recommended. The need to define the therapeutic index is particularly critical in patients with acute coronary syndromes who are typically treated with other antithrombotic and fibrinolytic agents that can increase the hemorrhagic risk significantly. In addition, alternative adjunctive therapies that limit the tissue factor-dependent and platelet-dependent generation of thrombin may enhance the benefits of direct thrombin inhibitors without increasing their hemorrhagic risk.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Eisenberg PR, Sherman LA, Jaffe AS. Paradoxic elevation of fibrinopeptide A after streptokinase: evidence for continued thrombosis despite intense thrombolysis. J Am Coll Cardiol. 1987;10:527-529.[Abstract]
2.
Rudd MA. Amarante P, Smick D, George D, Loscalzo J. Temporal effects of tissue plasminogen activator infusion in rabbits on platelet aggregation ex vivo. Circ Res. 1990;67:1175-1181.
3. Eisenberg PR, Sobel BE, Jaffe AS. Activation of prothrombin accompanying thrombolysis with recombinant tissue-type plasminogen activator. J Am Coll Cardiol. 1992;19:1065-1069.[Abstract]
4.
Owen J, Friedman BA, Wilkins C, Berke AD, Powers ER. Thrombolytic therapy with tissue plasminogen activator or streptokinase induces transient thrombin activity. Blood. 1988;72:616-620.
5.
Haskel EJ, Prager NA, Sobel BE, Abendschein DR. Relative efficacy of antithrombin compared with antiplatelet agents in accelerating coronary thrombolysis and preventing early reocclusion. Circulation. 1991;83:1048-1056.
6.
Rudd MA, George D, Johnstone MJ, Moore RT, Collins L, Rabbani L, Loscalzo J. Effect of thrombin inhibition on the dynamics of thrombolysis and platelet function during thrombolytic therapy. Circ Res. 1992;70:829-834.
7. Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res. 1994;74:1-23.[Medline] [Order article via Infotrieve]
8.
Heras M, Chesebro JH, Webster MWI, Mruk JS, Grill DE, Penny WJ, Bowie EJW, Badimon L, Fuster V. Hirudin, heparin, and placebo during deep arterial injury in the pig: the in vivo role of thrombin in platelet-mediated thrombosis. Circulation. 1990;82:1476-1482.
9. Sharma GVRK, Lapsley D, Vita JA, Sharma S, Coccio E, Adelman B, Loscalzo J. Safety and efficacy of hirulog, a direct thrombin inhibitor, in unstable angina. Am J Cardiol. 1993;72:1357-1360.[Medline] [Order article via Infotrieve]
10. Cannon CP, McCabe CH, Henry TD, Schweiger MJ, Gibson RS, Mueller HS, Becker RC, Kleiman NS, Haugland JM, Anderson JL, Sharaf BL, Edwards SJ, Rogers WJ, Williams DO, Braunwald E, for the TIMI Investigators. A pilot trial of recombinant desulfatohirudin compared to heparin in conjunction with tissue plasminogen activator and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 5 Trial. J Am Coll Cardiol. 1994;23:993-1003.[Abstract]
11. Lee LV. 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.[Medline] [Order article via Infotrieve]
12.
Antman EM, for the TIMI 9A Investigators. Hirudin in acute myocardial infarction: safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial. Circulation. 1994;90:1624-1630.
13.
Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation. 1994;90:1631-1637.
14.
Antman EM, for the TIMI 9B Investigators. Hirudin in acute myocardial infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B Trial. Circulation. 1996;94:911-921.
15. Kirchhofer D, Tschopp TB, Hadvary P, Baumgartner HR. Endothelial cells stimulated with tumor necrosis factor-alpha express varying amounts of tissue factor resulting in inhomogeneous fibrin deposition in a native blood flow system: effects of thrombin inhibitors. J Clin Invest. 1994;93:2073-2083.
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17. Gallistl S, Muntean W, Leis HJ. Effects of heparin and hirudin on thrombin generation and platelet aggregation after intrinsic activation of platelet-rich plasma. Thromb Haemost. 1995;74:1163-1168.[Medline] [Order article via Infotrieve]
18. Zoldhelyi P, Janssens S, Lefevre G, Collen D, van de Werf F, for the GUSTO 2a Investigators. Effects of heparin and hirudin (CGP 39393) on thrombin generation during thrombolysis for acute myocardial infarction. Circulation. 1995;92(suppl I):I-740. Abstract.
19. Scharfstein JS, Abendschein DR, Eisenberg PR, George D, Cannon CP, Becker RC, Sobel B, Cupples LA, Braunwald E, Loscalzo J, for the TIMI-5 Investigators. Usefulness of fibrinogenolytic and procoagulant markers during thrombolytic therapy in predicting clinical outcomes in acute myocardial infarction. Am J Cardiol. In press.
20.
Bittl JA, Strony J, Brinker JA, Ahmed WH, Meckel CR, Chaitman BR, Maraganore J, Deutsch E, Adelman B, for the Hirulog Angioplasty Study Investigators. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med. 1995;333:764-769.
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