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(Circulation. 1995;91:2132-2139.)
© 1995 American Heart Association, Inc.

Articles

Randomized Double-Blind Comparison of Two Doses of Hirulog With Heparin as Adjunctive Therapy to Streptokinase to Promote Early Patency of the Infarct-Related Artery in Acute Myocardial Infarction

Pierre Théroux, MD; Félix Pérez-Villa, MD; David Waters, MD; Jacques Lespérance, MD; Faryala Shabani, MD; Raoul Bonan, MD

From the Department of Medicine, Montreal Heart Institute (Canada).

Correspondence to Pierre Théroux, MD, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, H1T 1C8, Canada.

	Abstract

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Background An improved survival rate is a consequence of successful reperfusion of the infarct-related artery. This double- blind, randomized trial investigated the potential of Hirulog, a direct thrombin inhibitor, to improve the early patency rates obtained with streptokinase and aspirin.

Methods and Results Angiographic patency of the culprit coronary artery lesion was assessed 90 and 120 minutes after the initiation of streptokinase and aspirin and again after 4±2 days in 68 patients with acute myocardial infarction. Patients were randomized to Hirulog 0.5 mg/kg per hour for 12 hours followed by 0.1 mg/kg per hour (low dose), Hirulog 1.0 mg/kg per hour for 12 hours followed by placebo (high dose), or to heparin 5000 U bolus followed by 1000 U/h titrated to an activated partial thromboplastin time (aPTT) 2 to 2.5 times control after 12 hours. At 90 minutes, TIMI flow grade 2 or 3 was observed in 96% of patients treated with the low dose of Hirulog, in 79% with the high dose, and in 46% with heparin (P=.006) and TIMI flow grade 3 was observed in 85%, 61%, and 31% of patients, respectively (P=.008). At 120 minutes, these figures were 100%, 82%, and 62% for TIMI flow grades 2 and 3 (P=.046) and 92%, 68%, and 46% for TIMI flow grade 3 (P=.014). At 90 minutes, the relative risk for restoring TIMI flow grade 3 was 2.77 with Hirulog 0.5 mg/kg per hour compared with heparin (95% confidence limits, 1.21 to 6.35; P<.001) and 1.4 compared with Hirulog 1.0 mg/kg per minute (95% confidence limits, 1.00 to 1.51; P=.04). Patients who received a placebo infusion after 12 hours experienced more clinical events and reocclusion during the following 4 days than patients in the other two groups.

Conclusion Hirulog yields higher early patency rates in the culprit coronary artery than heparin when used as adjunctive therapy to streptokinase and aspirin in the early phase of acute myocardial infarction. High doses are not required and may be less effective than lower doses, which suggests that too much thrombin inhibition may be harmful.

Key Words: angiography • heparin • streptokinase • antithrombins

	Introduction

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The gain derived from thrombolytic therapy in acute myocardial infarction is enhanced as time to treatment is shortened¹ and effective reperfusion is achieved earlier.² Documented results of the GUSTO angiographic trial showed that more rapid and more complete restoration of coronary blood flow was an important determinant of myocardial salvage and of reduction in mortality.² Accordingly, measures are recommended to minimize the time elapsed between onset of pain and administration of the thrombolytic agent,^{1 3} and therapeutic strategies aimed at achieving earlier and more complete clot lysis are being investigated intensively.

The new direct thrombin inhibitors may help restore early effective flow. Experimental studies have shown that recombinant hirudin^{4 5} and related peptides, such as Hirulog,^{6 7} can facilitate thrombolysis and prevent reocclusion better than heparin when used with tissue-type plasminogen activator^{4 6 7} or streptokinase.⁵ One recent study⁸ in humans has suggested that recombinant hirudin combined with front-loaded tissue-type plasminogen activator could prevent reocclusion after successful reperfusion. However, major trials in which this agent was used during thrombolysis were recently interrupted by complications from excess bleeding.^{9 10 11} A pilot angiographic study of Hirulog with streptokinase and aspirin has suggested better early patency with this direct antithrombin infused at 0.5 mg/kg per hour for 12 hours followed by 0.1 mg/kg per hour.¹² The present study was designed to reproduce this observation and to investigate whether administration of a higher dose for a shorter period of time would yield better results. Two different doses of Hirulog were compared with heparin in consecutive patients with acute myocardial infarction treated with streptokinase and aspirin in a randomized, double-blind trial, with angiographic patency as the end point.

	Methods

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Study Population
All patients admitted to the Montreal Heart Institute for acute myocardial infarction during the study period were screened for participation in the trial. The entry criteria included onset of chest pain within the previous 6 hours and the presence of ST-segment elevation in two adjacent ECG leads or left bundle branch block. The exclusion criteria consisted of age >81 years old and contraindications to the use of a thrombolytic or anticoagulant agent. During the study period, from January to November 1993, 180 patients were admitted with a diagnosis of acute myocardial infarction and 70 were enrolled in the trial. One hundred ten patients were excluded because of the absence of ECG criteria (29 patients), of the presence of cardiogenic shock or acute pulmonary edema at admission (13 patients), of chest pain of more than 6 hours' duration (14 patients), of current treatment with intravenous heparin or Coumadin when the infarct was recognized (19 patients), of thrombolytic therapy initiated in another hospital (10 patients), of streptokinase administered in the previous 2 years (6 patients), of recent stroke or trauma or active peptic ulcer (10 patients), of other associated diseases (2 patients), or of patient or doctor refusal (7 patients). The study design was approved by the Institutional Review Board, and all patients signed the informed consent form before the initiation of the study.

Study Design
Aspirin 325 mg was first administered orally to all patients with suspected myocardial infarction. Eligible patients were randomized in a double-blind manner in one of three parallel study groups to receive Hirulog 0.5 mg/kg per hour (low dose), Hirulog 1.0 mg/kg per hour (high dose), or heparin 1000 U/h during the first 12 hours. An initial bolus of placebo was given to patients randomized to Hirulog, and a bolus of 5000 U heparin was given to patients randomized to heparin. Randomization was unbalanced to allow more patients to be given Hirulog than heparin. In this phase 2 trial, the underlying rationale was to maximize the statistical power of the findings in the experimental groups while showing that the results observed with heparin did not deviate from the previously well documented and reproducible angiographic findings of other studies.^{2 12 13 14 15 16} Two patients were randomized to each dose of Hirulog per each patient randomized to heparin. The study drugs were prepared in advance and left at the emergency room to accelerate initiation of treatment. In a double-dummy technique, one bag contained Hirulog at one of two dosage levels or placebo, and the other contained heparin or placebo. Infusion of one or the other of the two bags was initiated a few minutes before streptokinase 1.5 million U was administered over 45 to 60 minutes. After 12 hours, the infusion bag of Hirulog was changed; the initial dose of 0.5 mg/kg per hour was reduced to 0.1 mg/kg per hour, and the dose of 1.0 mg/kg per minute was replaced by a placebo; these doses were infused at a fixed rate throughout the rest of the study for 4 to 6 days, until the second angiography. Starting at 12 hours, the infusion rate of heparin was titrated to an activated partial thromboplastin time (aPTT) two to three times control values. The results of the aPTT were communicated only to the unblinded pharmacist for adjustment of the infusion rate according to a predefined algorithm. The infusion of the placebo-heparin bag was also titrated to maintain the blinding. The study drugs were discontinued 30 minutes before the second angiogram.

Cardiac Catheterization
An attempt was made to perform coronary angiography 60 and 90 minutes after the start of the streptokinase; all patients had the 90-minute injection. A percutaneous femoral approach was used. The suspected coronary artery was injected to determine the TIMI flow grade.¹³ The injections were repeated every 10 minutes until TIMI flow grade 3 was observed or to a maximal time of 120 minutes after the initiation of streptokinase. Coronary angioplasty was attempted after 120 minutes if TIMI grade 2 or 3 flow was not reached. In the interim, the opposite coronary artery was fully opacified, and a left ventriculogram was obtained in the 30° right anterior oblique position before the end of the procedure. The femoral sheath was removed 6 to 12 hours later, after interruption of the study-drug infusions for 1 to 2 hours; the infusions were restarted after application of the compressing bandage. The median total interruption time was 135 minutes for each of the Hirulog-treated groups and 140 minutes for the heparin-treated group (P=NS). Difficulty in achieving local hemostasis led to a prolonged 7-hour interruption in 1 patient who received the low dose of Hirulog. Sixty-five of 68 patients were recatheterized 4 to 6 days later. The second angiogram was performed in all cases except in the event of death. After recatheterization, the patency of the culprit coronary artery lesion was verified and the left ventriculogram was repeated. Coronary angioplasty was performed at that time if clinically indicated.

The TIMI flow grade was determined by consensus decision between an experienced radiologist and a cardiologist not involved in patient care.¹⁴ The culprit coronary artery lesions showing TIMI flow grade 2 or 3 at 90 and 120 minutes were quantified by the Coronary Artery Analysis System¹⁷ in the incidence best showing the lesion. This analysis was repeated in the same incidence on the late angiogram.

Bleeding
All bleeding was carefully evaluated and recorded. Serious bleeding was defined as a drop of 5 g/L in blood hemoglobin, intracranial hemorrhage, or the administration of a blood transfusion. These were further subdivided as either spontaneous or related to an interventional procedure.

Laboratory Analyses
Activated partial thromboplastin times were determined at baseline, before the dose modifications of the study drugs at 12 hours, and daily thereafter until the second angiogram. Thromboplastin IL-aPTT (Coulter Electronics) was used; the values reported by our laboratory had a ceiling value of 150 seconds. Plasma levels of Hirulog were assessed by enzyme immunoassay 90 minutes and 12 hours after initiation of treatment.

Statistics
The primary end points of the study were TIMI flow grades 2 and 3 and TIMI flow grade 3, 90 and 120 minutes after the initiation of streptokinase. Secondary end points included differences in angiographic patency between the two dose regimens of Hirulog, death, reinfarction, hemodynamic deterioration, recurrent ischemia, and reocclusion at late angiography.

On the basis of the results of our pilot study with streptokinase and Hirulog¹² and on previously published angiographic data with streptokinase and heparin,^{2 13 14 15 16} failure rates were assumed of 30% to restore TIMI flow grade 3 with Hirulog and of 70% with heparin. A sample size of 85 patients would allow detection of this improvement with =.05 and a power of 80% in a 4:1 comparison of Hirulog with heparin, assuming an even event rate with the two doses of Hirulog. It was recognized that this sample size would permit only limited power to detect differences in the secondary end points between the three study groups. Thus, 68 patients randomized to one of two doses of Hirulog would allow a 70% power to detect an 80% risk reduction in failing to restore effective coronary blood flow with the high dose. The study was stopped prematurely after enrollment of 70 patients because of local administrative problems unrelated to the trial. No interim look at the data was performed.

Two randomized patients were not included in the primary data analysis; this decision was made before unblinding the study. One patient randomized to Hirulog 0.5 mg/kg per minute did not receive the study drug because cardiogenic shock rapidly developed; this patient was immediately catheterized but died before any coronary injection could be made to assess angiographic patency. The other patient was randomized on the basis of the criteria of atypical chest pain and a left bundle branch block but had a completely normal coronary angiogram; the bundle branch block subsequently was documented to be rate dependent. The study drug was rapidly discontinued in this patient. An intention-to-treat analysis including these 2 patients, provided in "Results," does not modify the primary analysis.

All clinical and angiographic data were analyzed locally by the study investigators and classified before unblinding the study. Baseline characteristics of the study groups were compared by ² analysis for discrete variables and by ANOVA for continuous variables. The end-point events in the three study groups were first compared by logistic ANOVA by use of the CATMOD procedure in the SAS/STAT software; when P<.05, the intergroup differences were tested by contrast analysis with P<.05/3 considered significant. Significant levels for other data were set at P=.05. The relative risks of a patent coronary artery and 95% confidence limits were calculated by the Taylor series. aPTT results were analyzed by the Mann-Whitney rank sum test and are presented as median and 25th and 75th percentiles. Other data are mean±SD.

	Results

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Patient Characteristics
Table 1 describes the characteristics of the study population. These did not differ statistically significantly among the patients in any of the three groups. Mean age of the study population was 61 years, and 82% were men. The time from onset of pain to hospital arrival was 98±75 minutes and to streptokinase administration, 142±88 minutes. The total dose of streptokinase could be administered to all patients within a mean of 53±16 minutes. All patients received concomitant aspirin therapy and most received morphine, nitrates, a ß-blocker, and a calcium antagonist. Except for aspirin and morphine, however, these drugs usually were started only after the first angiogram. The myocardial infarction involved the anterior wall in 32% of patients and the inferior wall in 68%. Slightly more patients in the group receiving the high dose of Hirulog had an inferior infarction with involvement of the right coronary artery; the time from onset of pain to streptokinase administration was also a little longer in this group compared with the other two.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patients in the Various Study Groups

Angiographic Results
The culprit coronary artery could be injected at 60 minutes in 37 patients and at 90 minutes in all 68 patients. Fig 1 illustrates the TIMI flow grades 2 and 3 and the TIMI flow grade 3 observed at 60, 90, and 120 minutes in the various study groups. For the purpose of this analysis, TIMI flow grade 3 observed at an early time was considered to persist until 120 minutes. None of the patients had a clinical evolution that suggested that this was not the case. Coronary angioplasty was attempted in the 10 patients with persisting TIMI flow grade 0 or 1 at 120 minutes and successfully restored TIMI flow grade 3 in 7 patients; the immediate mean residual percent luminal diameter reduction in these patients was 39.6±13%.

View larger version (43K): [in this window] [in a new window]   Figure 1. Bar diagram showing the number of patients with TIMI flow grades 2 and 3 (open bars) and TIMI flow grade 3 (shaded bars) observed in three study groups 60, 90, and 120 minutes after the initiation of streptokinase. P values were calculated by ANOVA; the P values at the right of the bars correspond to TIMI flow grades 2 and 3 and TIMI flow grade 3. P values corresponding to post hoc intergroup comparisons are shown at the bottom of the bars in a similar fashion when appropriate.

Early Angiographic Results
The logistic ANOVA of early angiographic patency rates showed statistically significant differences between the three study groups. The gain with Hirulog 0.5 mg/kg per hour versus heparin accounted for this difference (Fig 1). With this low dose of Hirulog, TIMI flow grade 2 or 3 was achieved in 87%, 96%, and 100% of patients at 60, 90, and 120 minutes, respectively, after the onset of streptokinase, and TIMI flow grade 3 was achieved in 69%, 85%, and 92% respectively, during these times. For heparin, TIMI flow grade 2 or 3 was achieved in 43%, 46%, and 62% and TIMI flow grade 3 was achieved in 29%, 31%, and 46% of patients at 60, 90, and 120 minutes, respectively. An analysis by intention-to-treat, which assumed that the excluded patient randomized to Hirulog 0.5 mg/kg per hour failed reperfusion and that the patient randomized to heparin succeeded did not affect the significance of the results for TIMI flow grade 3 at 90 minutes in 23 of 28 patients randomized to Hirulog 0.5 mg/kg per hour (82%) and in 5 of 14 patients randomized to heparin (36%, P=.004).

Patients given the higher dose of Hirulog (1.0 mg/kg per hour) had patent arteries more frequently than those given heparin but less frequently than those given the low dose of Hirulog (0.5 mg/kg per hour). TIMI flow grade 2 or 3 was present in 79% (P=.044 versus heparin and P=.079 versus Hirulog 0.5 mg/kg per hour) and 82% of patients given Hirulog 1.0 mg/kg per hour at 90 and 120 minutes, respectively. TIMI flow grade 3 was present in 61% of patients given Hirulog 1.0 mg/kg per hour at 90 minutes (P=.081 versus heparin and P=.048 versus Hirulog 0.05 mg/kg per hour) and in 68% of patients given this dose of Hirulog at 120 minutes (Fig 1).

The relative risks (RRs) for achieving TIMI flow grade 2 or 3 with Hirulog at either dose compared with heparin were RR=1.87 (95% CI, 0.78 to 4.47, P=.07) at 60 minutes, RR=1.89 (95% CI, 1.04 to 3.43; P=.02) at 90 minutes, and RR=1.59 (95% CI, 1.00 to 2.52; P=.006) at 120 minutes. For TIMI flow grade 3, RR=2.22 (95% CI, 0.67 to 7.38; P=.1), RR=2.36 (95% CI, 1.03 to 5.43; P=.006), and RR=1.73 (95% CI, 0.95 to 3.16; P=.02) for 60, 90, and 120 minutes, respectively. The RRs for restoring TIMI grade 3 flow with the lower dose versus the higher dose of Hirulog were 1.40 (95% CI, 1.00 to 1.97; P=.04) and 1.36 (95% CI, 1.04 to 1.8; P=.02) at 90 and 120 minutes, respectively.

Angiographic reperfusion was achieved in 22 of 23 patients (96%) who received Hirulog 0.5 mg/kg per hour within 4 hours after onset of pain and in all 4 patients (100%) who received this dose regimen more than 4 hours after the onset of pain; reperfusion was achieved in 20 of 26 patients (77%) with Hirulog 1.0 mg/kg per hour within 4 hours and in 2 of 2 patients treated after 4 hours (100%). Reperfusion was achieved in 4 of 10 patients given heparin within 4 hours after the onset of pain (40%) and 2 of 3 (66%) given heparin more than 4 hours after the onset of pain. The site of the infarction did not influence the results of this study with TIMI flow grade 2 or 3 at 90 minutes in 16 of 17 patients (94%) with an inferior myocardial infarction treated with Hirulog 0.5 mg/kg per hour, in 16 of 20 (80%) treated with Hirulog 1.0 mg/kg per hour, and in 4 of 9 (44%) treated with heparin.

Late Angiographic Results and Quantitative Coronary Angiography
Coronary angiography repeated after 4 to 6 days in all but 3 patients showed TIMI flow grade 3 in 25 of 26 patients (96%) in the group that received the low dose of Hirulog, in 22 of 27 (81%) that received the high dose of Hirulog, and in 10 of 12 (83%) in the heparin-treated group. Angiographic reocclusion occurred in 5 patients; 4 had received the placebo infusion after the 12-hour infusion of Hirulog and 1 had received the 0.1 mg/kg per hour infusion of Hirulog.

Quantitative coronary angiography of the culprit coronary artery lesions, with TIMI flow grade 2 or 3 obtained spontaneously during the infusion and with no coronary angioplasty, showed similar minimal diameters in the three study groups at 90 minutes, 120 minutes, and 5 days. At 90 minutes, minimal diameter was 0.99±0.32 mm in patients who received the low dose of Hirulog, 1.11±1.15 mm in those who received the high dose of Hirulog, and 0.95±0.59 mm in those who received heparin. At 120 minutes, these minimal diameter measurements were 1.02±0.29, 1.15±0.38, and 1.06±0.50 mm, respectively. Significant improvement at 5 days was observed only in the heparin-treated group (from 1.06±0.50 mm at 120 minutes to 1.3±0.52 mm, P<.05). Measurements were not significantly different in the groups that received the low (1.09±0.40 mm) and the high doses of Hirulog (1.35±0.75 mm).

Fig 2 illustrates the serial changes in minimal diameter for each patient and also includes the 7 patients with successful angioplasty at 120 minutes. Whereas minimal diameter increased at 5 days in patients with drug-induced reperfusion, it decreased from 2.42±0.85 to 1.54±1.16 mm (P<.02) in patients with mechanical reperfusion, corresponding to luminal diameter reductions of 39.6±14% and 62.5±21.5%, respectively (P<.02).

View larger version (26K): [in this window] [in a new window]   Figure 2. Graph of individual minimal diameters of culprit coronary artery lesions showing TIMI flow grades 2 and 3 at the initial angiogram. Measures were obtained by quantitative coronary angiography. illustrates patients with spontaneous reperfusion during study drug infusion; , patients reperfused by balloon angioplasty after 120 minutes. The improvement in minimal diameter between 120 minutes and 5 days was statistically significant in the heparin-treated group. Lesion diameter decreased in all patients treated with early angioplasty. More reocclusion occurred in patients who received placebo after the 12-hour infusion of Hirulog 1 mg/kg per hour was discontinued.

Clinical Results
Clinical outcomes are summarized in Table 2. Ischemia during the temporary discontinuation of the study drug to remove the femoral sheath was observed in only 1 patient, in whom the chest pain was accompanied by transient ST-segment elevation. This patient was receiving Hirulog 0.5 mg/kg per hour. Overall, recurrent ischemia and recurrent myocardial infarction occurred less frequently in patients treated with the low dose of Hirulog (7%) than in those treated with the high dose modified to placebo after 12 hours (18%) or with heparin (23%). One patient in the group treated with the low dose of Hirulog died because of cardiac rupture, and 1 in each of the two other groups died of cardiogenic shock. Baseline ejection fraction was similar in all three study groups and patients in the group treated with the low dose of Hirulog showed greater improvement at the second angiogram. Serious bleeding complications were observed in 22% of patients treated with the low dose of Hirulog, 18% of those treated with the high dose of Hirulog, and 31% of those treated with heparin. Two thirds of the serious bleeding cases were related to the catheter at the femoral arterial puncture site in the group treated with Hirulog, and one third were spontaneous and unrelated to an intervention; in the group treated with heparin, half were spontaneous and half catheter-related. Blood transfusion was administered in 5% of the Hirulog-treated patients and 31% of the heparin-treated patients (P<.02). No intracranial bleeding or stroke occurred in the study.

View this table: [in this window] [in a new window]   Table 2. Secondary End-Point Events

Table 3 shows the median aPTT values observed at various times during the study; these were significantly more prolonged at 12 hours in patients treated with the high dose of Hirulog compared with those treated with the low dose of Hirulog or with heparin. The aPTT measurements reached the ceiling value of 150 seconds in 75% of the patients treated with the high dose of Hirulog, compared with 21% of those treated with the low dose of Hirulog and 50% of those treated with heparin. The values subsequently decreased to normal once patients were treated with placebo and to similar values between 40 and 50 seconds with Hirulog 0.5 mg/kg per hour and with heparin. Plasma levels of Hirulog in patients treated with the lower dose of Hirulog were 1526±108 ng/mL at 90 minutes and 2064±36 ng/mL at 12 hours. Significantly higher values were observed in patients treated with the high dose of Hirulog: 2628±1370 and 3924±2456 ng/mL at 90 minutes and 12 hours, respectively (P<.002).

View this table: [in this window] [in a new window]   Table 3. Median and 25th and 75th Percentile Values of Activated Partial Thromboplastin Time in the Three Study Groups

	Discussion

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Hirulog Versus Heparin
This randomized, double-blinded study reinforces the observation of our pilot study¹² and shows that Hirulog added to streptokinase promotes early patency of the infarct-related artery better than heparin. More importantly, the results provide further information on the modalities for the benefit by documenting that the potentiation of clot lysis by Hirulog is an early phenomenon observed as soon as 60 minutes after injection and that larger doses are not necessarily required to reap the benefits of injection. This could be important, considering the excessive serious bleeding complications recently reported with the combination of recombinant hirudin and tissue-type plasminogen activator.^{10 11} Other pilot studies of direct thrombin inhibitors in the setting of thrombolysis have used recombinant hirudin to show a nonsignificant trend toward better early flow restoration and significantly less reocclusion^{8 9} ; however, in these studies, front-loaded tissue-type plasminogen activator was used as the thrombolytic agent, which reduced the power to detect an effect because of higher reperfusion rates achieved with this agent than with streptokinase. The benefits observed with Hirulog and streptokinase, if confirmed in a larger study, could have considerable clinical effects, considering the extensive worldwide use of streptokinase based on favorable results of major trials^{18 19} and on its low cost. Indeed, the patency rates observed in this study with the combination are better than those reported with the more effective therapeutic regimen now used: the combination of heparin and front-loaded tissue-type plasminogen activator.²

Hirudin and Hirulog should theoretically lead to similar benefits, since the two drugs share similar mechanisms of action.²⁰ Both agents interact with the anion-binding exosite and the catalytic site of thrombin and form stoichiometric complexes with the enzyme. Unlike heparin, the direct thrombin inhibitors are not neutralized by components of the platelet-release reaction, such as platelet factor 4.²¹ In addition, the direct thrombin inhibitors inactivate fluid-phase and clot-bound thrombin equally well, whereas heparin is limited in its ability to inhibit clot-bound thrombin.²²

In experimental models of thrombosis, both Hirulog and hirudin accelerate thrombolysis and prevent reocclusion.⁶ Hirudin is a potent and specific inhibitor isolated from the saliva of the medicinal leech.²¹ In contrast, Hirulog is a synthetic bivalent peptide that contains the [D]Phe-Pro-Arg-Pro catalytic site inhibitor and the carboxy-terminal portion of hirudin residues 53 to 64 that interacts with the anion-binding exosite of thrombin, with a polyglycyl link.²⁰ Thus, unlike hirudin, Hirulog is cleaved by thrombin so that active site inhibition is lost. Hirulog has a half-life of 36 minutes, whereas the half-life of hirudin is 2 to 3 hours; elimination of Hirulog is primarily by protease digestion, with only 20% eliminated by the kidneys; hirudin is excreted entirely through the kidneys. As a result, Hirulog may have a different risk-to-benefit ratio than hirudin when used with a thrombolytic agent.

High Dose Versus Low Dose of Hirulog
Experimental studies in pigs have shown less platelet and fibrinogen deposition at sites of deep arterial injury with higher doses of recombinant hirudin, prolonging the aPTT to two to four times control compared with lower doses, with which aPTT was prolonged to 1.7 times control. In these studies, prolonged aPTT correlated inversely with quantitative platelet and fibrinogen deposition, suggesting a dose-antithrombotic response.²³ Accordingly, this study included a group treated with a higher dose of Hirulog, which prolonged the aPTT to more than four times control. An unexpected finding, however, was that the lower dose was more effective resulting in TIMI flow grade 2 or 3 in 18% and 14% more patients, respectively, than with the high dose of Hirulog. The difference could be a chance effect because of the small number of patients studied; this lower dose, however, improved flow in a statistically significant manner compared with heparin, which suggests that, at a minimum, higher doses are not definitively better than lower doses. This finding implies that too much thrombin inhibition could be harmful compared with moderate inhibition. This point has not been emphasized previously, although many dose-ranging studies have failed to show better benefits with higher doses of recombinant hirudin compared with lower doses.^{8 9 24 25} Thus, in the TIMI 5 study, early TIMI flow grade 3 was 67% with lower doses and 55% with a higher dose.⁸ Further, in the TIMI 6 study, the reduction in mortality and in serious cardiac events was not better with the low dose of hirudin compared with higher doses.²⁴ Finally, a multicenter angiographic trial of unstable angina suggested less improvement in the cross-sectional area of the culprit lesion and less TIMI flow grade improvement with the highest dose compared with lower doses.²⁵ As in our study, these pilot studies contain small numbers of patients, and differences in baseline characteristics could have influenced the results. These differences may not be measurable and, even when not statistically different, they may add together to create a group difference in patient characteristics. In our study, there were slightly more smokers in the group given the high dose of Hirulog, which could have favored more successful thrombolysis.²⁶ In this group, time from onset of pain to onset of streptokinase was slightly longer and 3 more patients had an inferior myocardial infarction, two factors with a possible small negative effect on the success of treatment.¹⁴ Subanalyses of patients by time to treatment, <4 or 4 hours after onset of pain, and site of myocardial infarction, however, have shown no influence of these factors on the results.

The explanation for a potential deleterious effect of excess thrombin inhibition is unclear. One possibility is that at high doses, the direct thrombin inhibitors block the protein C anticoagulant pathway. Thus, by interacting with thrombin, these agents can prevent the formation of the thrombin-thrombomodulin complex that activates protein C.²¹ Since activated protein C is a potent anticoagulant because it proteolytically degrades activated factors V and VIII, key factors in the coagulation pathways,²⁷ a decrease in the levels of activated protein C will compromise the hemostatic balance.²⁸ Further studies are needed to test this new hypothesis.

Results of the present study also showed that prolonged aPTT does not indicate better success. In this study, the aPTT values observed with Hirulog 0.5 mg/kg per hour were not higher at any time than values observed with heparin. Higher aPTTs may not be required and may increase the risk of bleeding.¹⁰

Clinical Results
An excess of clinical events and of angiographic reocclusion occurred after the very acute phase in the group of patients treated by infusion with Hirulog followed by placebo. Recurrent ischemia supervened in 3 patients, recurrent infarction in 2, and reocclusion in 4; these events were less frequent in the group that maintained the infusion of 0.1 mg/kg per hour of Hirulog. This supports the findings of TIMI 5 of a beneficial effect of the antithrombotic agent in the days after thrombolysis.⁸ The differences between groups were not significant, but the small number of events precludes firm conclusions. The same limitation applies to other secondary end points of the study and to the bleeding complications. It is, however, encouraging to see that bleeding complications were not more frequent with Hirulog. This remains to be carefully tested in a larger study, considering the recently reported excess bleeding risk with recombinant hirudin.^{9 10 11}

The results of the present study, which show improved thrombolysis with a conservative dose of Hirulog, should be confirmed by a larger trial and by documentation of associated clinical benefits. If confirmed, however, this new adjunctive therapy could be effective for promoting the thrombolytic efficacy of streptokinase beyond that of the best thrombolytic regimen now available.

	Acknowledgments

 
The authors want to acknowledge the enthusiastic collaboration of the cardiologists of the coronary care units and of the cardiac catheterization laboratory who made this research work possible. They also acknowledge Luce Bégin for superb secretarial work and Dr Jeffrey J. Weitz for useful comments on the manuscript.

Received October 26, 1994; accepted November 11, 1994.

	References

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