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(Circulation. 1997;96:2118-2120.)
© 1997 American Heart Association, Inc.

Articles

Direct Thrombin Inhibition Superior to Heparin During and After Thrombolysis

Dose, Duration, and Drug

James H. Chesebro, MD

From the Cardiovascular Institute, Mount Sinai Medical Center, New York, NY.

Correspondence to James H. Chesebro, MD, Cardiovascular Institute, Box 1030, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029-6574.

Key Words: Editorials • heparin • thrombolysis • thrombosis

	Introduction

Top Introduction Dose of Antithrombotic Therapy Duration of Therapy Drug References

 
Thrombosis and thrombolysis are dynamic, simultaneous, and opposing processes. Blocking one opposing process will enhance the other. The more potent the antithrombotic drug, the more rapid and thorough the thrombolysis.¹ Enhancing thrombolysis reduces the residual mass of mural thrombus and thus the residual stenosis, local shear force, and propensity for platelet deposition and reocclusion. The immediate increase in thrombin generation and activity with thrombolysis necessitates the simultaneous administration of an antithrombotic drug with the lytic agent to maximize the extent of thrombolysis.^{1 2}

Recombinant hirudin, a 65–amino acid peptide that nearly encircles the thrombin molecule, is the prototype and gold standard of direct thrombin inhibitors.³ It is the tightest-binding (K_i=10^-13) thrombin inhibitor and can be detected as the hirudin-thrombin complex at least 18 hours after r-hirudin administration is stopped.⁴ When administered to humans intravenously to prolong the aPTT ratio to only 1.7x to 2.2x control levels, its potency for blocking growth of thrombus on aortic tunica media during ex vivo perfusion at moderate shear force is similar in quantitative antithrombotic potency to c7E3.^4A Other direct thrombin inhibitors with lower binding affinities (K_i=10^-11 and K_i=10^-9) experimentally have proved to be less potent antithrombotics against thrombosis than r-hirudin in porcine carotid and coronary arteries after deep arterial injury by angioplasty.⁵ Two other direct anti-thrombins, Inogatran (K_i=10^-9) and Efegatran, a tripeptide (LY 294468), have low binding affinities and were clinically no better than heparin during studies in patients with unstable angina^{6 7} and acute myocardial infarction,^{6 7} respectively. Although effectiveness may be improved by increasing the dose of antithrombins with low binding affinities, previous studies of thrombolysis combined with heparin or direct thrombin inhibition with hirudin in humans suggest that high aPTTs signal a high risk of hemorrhagic stroke.^{8 9}

Hirulog is a 20–amino acid synthetic peptide that combines a fragment of the C-terminus of hirudin (interacts with the anion-binding exosite of thrombin) with an N-terminus fragment that interacts with the catalytic site of thrombin (K_d=2.3x10^-9). In a study reported in this issue of Circulation,¹⁰ comparisons of safety and ability to achieve early and complete flow of the infarct-related artery at 90 to 120 minutes of treatment were made between hirulog and heparin among patients with acute myocardial infarction receiving streptokinase and aspirin. The higher incidence of TIMI 3 flow at 90 to 120 minutes (primary end point; 46% for low-dose hirulog, 48% for high-dose hirulog, and 35% for heparin) and the lesser need for rescue angioplasty in the hirulog groups (13 patients receiving heparin, 4 receiving low-dose hirulog, and 6 receiving high-dose hirulog) document the angiographic superiority of hirulog over heparin in patients receiving streptokinase and aspirin for acute myocardial infarction.

In this study, there were no differences between groups in creatine kinase peak levels, ejection fraction, end-systolic volume, wall-motion score, and number of abnormal chords at 2 to 3 days. This suggests that infarct size may be no different between therapies. Other measurements to consider to avoid the problem of myocardial stunning, which may be present at 2 to 3 days after infarction, might be area under the curve for creatine kinase and change in repeat left ventricular function parameters from baseline to a later angiogram, but even more sensitive would be short-term and postreperfusion quantitative myocardial salvage determined by ^99mTc-sestamibi by single-photon emission computed tomographic imaging.¹¹ This probably would be the most sensitive measure of myocardial salvage for future studies.

	Dose of Antithrombotic Therapy

Top Introduction Dose of Antithrombotic Therapy Duration of Therapy Drug References

 
The best antithrombotic dose of hirulog remains uncertain. The incidence of TIMI 3 flow would suggest that the short-term low (0.25 mg · kg^-1 · h^-1) and high (0.5 mg · kg^-1 · h^-1) doses have equal effectiveness. However, the angiographic incidences of reocclusion (from TIMI grade 2 or 3 flow to grade 0 or 1 flow) of 7%, 4.6%, and 1.3% in the heparin, low-dose hirulog group (infusion dose reduced by 50% to 0.125 mg · kg^-1 · h^-1 after 12 hours and continued at least until repeat angiography), and high-dose hirulog group (infusion reduced by 50% to 0.25 mg · kg^-1 · h^-1 after 12 hours), respectively, suggest that high-dose hirulog (or more specifically, 0.25 mg · kg^-1 · h^-1 as discussed below) is the best antithrombotic dose. However, the number of patients is too small to say for certain that 0.25 mg · kg^-1 · h^-1 is the best antithrombotic dose.

The changing doses over time in the hirulog groups (reducing the infusion doses by 50%) make it difficult to evaluate the dose-response relationship using the incidence of reocclusion. However, the optimal antithrombotic infusion dose suggested by both the TIMI 3 flow (achieved at 90 to 120 minutes with 0.25 mg · kg^-1 · h^-1) and the lowest incidence of reocclusion at 2 to 3 days achieved in the high-dose group, in which hirulog infusion at 0.25 mg · kg^-1 · h^-1 was continued beyond 12 hours, suggests that an infusion no greater than 0.25 mg · kg^-1 · h^-1 would be sufficient therapy. The aPTT after 11 hours on this dose (96±30 seconds) and after 24 hours on this dose after streptokinase therapy (83±23 seconds) also suggests that this would probably be a safe dose.

Safety needs to be evaluated in establishing the dosage for any antithrombotic drug because if given in too high a dose, such drugs may cause serious bleeding. In the GUSTO IIa study, in which bleeding resulted within both the hirudin and heparin groups in association with thrombolysis, the mean±SD aPTT at 12 hours after thrombolytic therapy was 110±46 seconds for heparin or hirudin patients with hemorrhagic stroke and 87±36 seconds for patients with no hemorrhagic stroke.⁸ Similar observations were made in the TIMI 9A study.⁹ These studies suggest that aPTTs during therapy should not exceed 85 to 90 seconds or 2.5x to 3.0x control. The aPTT at 11 hours after streptokinase plus the hirulog infusion of 0.25 mg · kg^-1 · h^-1 was begun was 96±30 seconds, and it was 117±35 seconds for the hirulog infusion of 0.50 mg · kg^-1 · h^-1. The high aPTT and the presence of a hemorrhagic stroke in the latter group suggest that 0.50 mg · kg^-1 · h^-1 would probably not be a safe dose of hirulog to use with a thrombolytic agent.

Dose–antithrombotic response considerations are different for direct-thrombin inhibitors (with r-hirudin being the prototype) than for heparin. The direct thrombin inhibitor hirudin exhibits a threshold dose–antithrombotic response that appears to occur at aPTTs of 1.8x to 2.0x control as measured from quantification of thrombus growth in vivo and ex vivo in the pig.^{12 13} The effectiveness of intravenous hirudin at similar aPTTs in humans in reducing quantitative growth of thrombus with no greater antithrombotic effect at higher doses during direct ex vivo perfusion of deeply injured artery suggests a similar threshold level in humans and pigs.^{4A 13} Heparin, on the other hand, has a direct, progressive, and ever-increasing dose–antithrombotic response relationship in pigs.¹⁴ In humans, the highest and probably most effective dose (300 U/kg, as used during cardiopulmonary bypass surgery) was used as a bolus dose in the HEAP pilot study without lytic therapy in lytic-therapy–eligible patients (chest pain and ST-segment elevation) and led to TIMI 3 flow in 36% of patients 90 minutes after the start of treatment (similar to the 29% to 32% incidence of TIMI 3 flow found at 90 minutes for streptokinase in GUSTO IIb).^{15 16} This dose of heparin, which appears to cause acute "dethrombosis,"¹⁶ would, of course, be too high to administer with a lytic agent or to administer long-term. Lower doses of direct thrombin inhibition with hirudin^{17 18} or blockage of thrombin generation¹⁷ also cause "dethrombosis" or endogenous thrombolysis. Thus, there is a need for a direct thrombin inhibitor that provides more potent antithrombotic effects than heparin at a lower (and presumably safer) aPTT. Hirulog may fulfill this need.

It appears that it is critical to define the threshold antithrombotic dose for a direct thrombin inhibitor by quantitatively measuring thrombus growth (ideally in vivo, but ex vivo quantitation in the Badimon chamber appears consistent with results in vivo).^{12 13} Measurement of short-term incidence of progression from patency to arterial occlusion is helpful but not nearly as sensitive as measuring quantitative growth of intra-arterial thrombus to quantify thrombus burden. For example, experimental evaluation of heparin, aspirin, and r-hirudin shows that each prevents short-term arterial occlusion. However, there is an 8-fold to 10-fold lower amount of mural thrombus after 2 hours of therapy with hirudin (quantified by ¹¹¹In-labeled platelet deposition) than after therapy with heparin or aspirin.¹⁹ This determination of intra-arterial thrombus burden rather than waiting for occlusion requires fewer animals or patients, is safer and more sensitive, reduces research expenses, and will probably play a major role in determining future dosing of antithrombotic therapies.

	Duration of Therapy

Top Introduction Dose of Antithrombotic Therapy Duration of Therapy Drug References

 
Studies in the porcine angioplasty model in our laboratory have documented that doses of the direct thrombin inhibitor r-hirudin that totally block macroscopic mural thrombus formation need to be administered for >48 hours. Cessation of therapy at 48 hours results in an incidence of macroscopic mural thrombosis and quantitative ¹¹¹In-labeled platelet deposition at 72 hours similar to that of placebo therapy (J.H. Chesebro, MD, et al, unpublished data, 1992). Thus, short-term therapy for a long-term thrombogenic surface or diseased artery is insufficient and appears to result in a recurrence of events, as evidenced by the GUSTO IIb study of patients with acute coronary syndromes, including those treated with thrombolysis for acute myocardial infarction. A highly significant reduction of the incidence of death or myocardial infarction occurred at 24 and 48 hours in the direct thrombin inhibition (hirudin) group compared with the heparin group (duration of both therapies was 75±29 hours) but dissipated over time, resulting in a small benefit for direct thrombin inhibition with hirudin at 30 days (P=.06).²⁰ A similar loss of the initial low incidence of death or myocardial infarction achieved while low-molecular-weight heparin plus aspirin was administered compared with aspirin alone was seen in the FRISC study of patients with unstable angina or non–Q-wave myocardial infarction. The decreased benefit occurred when the dose of low-molecular-weight heparin was reduced and administered once daily (instead of twice daily) after hospital dismissal. The discrepancy in the incidence of death or myocardial infarction between the two treatment groups narrowed after hospitalization, especially by 42 days.²¹ In the OASIS pilot study of unstable angina and non–Q-wave myocardial infarction, in which hirudin appeared superior to heparin in the short term, the beneficial effect seemed to be sustained when patients were switched to warfarin therapy (mean INR of 2.2) for at least 3 months (cardiovascular death, myocardial infarction, or refractory angina; 5.1% for warfarin therapy and 12.1% for standard therapy of aspirin alone; P=.08).²²

Thus, it appears that short-term treatment is insufficient for a long-term disease in which healing of a disrupted plaque may take as long as 3 to 6 months, although most events occur within the first month. Direct thrombin inhibition with hirulog or hirudin appears to be more beneficial than treatment with heparin, but strategies must be designed for longer-term antithrombotic therapy after an acute coronary syndrome. This may include subcutaneous therapy or oral therapy such as warfarin (to an INR of 2.0 to 3.0) plus aspirin or a new future direct thrombin inhibitor if it meets criteria for antithrombotic potency, aPTT, and clinical safety. Oral antithrombotics that inhibit the coagulation cascade proximal to thrombin or directly block thrombin with a high binding affinity appear to act predominantly on the platelet are also future possibilities for long-term therapy. The minimum duration for more potent antithrombotic therapy appears to be 30 days, during which time most events are clustered, but the FRISC and OASIS pilot studies suggest that 3 months or more of therapy that is more potent than aspirin is needed.

	Drug

Top Introduction Dose of Antithrombotic Therapy Duration of Therapy Drug References

 
The optimal direct antithrombin therapy would have a potent antithrombotic effect at a low aPTT threshold (such as twice control), block or minimize growth of mural thrombus after deep arterial injury, inhibit both platelet and fibrinogen/fibrin deposition, be effective at both high and low shear forces, block thrombus growth onto preexisting thrombus, promote "dethrombosis" or endogenous lysis, have a rapid onset of action and stable drug blood levels, be easy to monitor, and have a low side-effect profile of bleeding, allergy, or change in blood counts. More is known about r-hirudin experimentally than hirulog.^{1 3 4 5 10 12 13 14} However, both of these medications appear to have many of these properties but require additional strategies and studies to deliver longer-term antithrombotic protection. Neither hirulog, hirudin, or other direct thrombin inhibitors appear to possess a long-lasting local effect against the arterial wall after treatment is stopped. Thus, a longer-acting formulation, such as for subcutaneous administration, is needed. In addition, it appears particularly important to define the lowest aPTT at which direct antithrombin treatment would be effective (the threshold dose–antithrombotic response) to maximize long-term effectiveness, safety, and the cost-benefit ratio of a new, more expensive drug.

	Selected Abbreviations and Acronyms

 

aPTT = activated partial thromboplastin time INR = international normalized ratio r-hirudin = recombinant hirudin TIMI = Thrombolysis In Myocardial Infarction

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction Dose of Antithrombotic Therapy Duration of Therapy Drug References

 

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