Background Despite the use of aspirin and heparin, patients with acute ischemic syndromes are at risk of myocardial infarction (MI) or refractory ischemia. Therefore, evaluation of more potent antithrombotic therapies is warranted.
Methods and Results Patients (n=909) with unstable angina or suspected acute MI without ST-segment elevation were randomized to receive heparin (5000 IU bolus+1000 to 1200 U/h, n=371), low-dose hirudin (LDHir) (0.2 mg/kg bolus+0.10 mg·kg−1·h−1 infusion, n=271), or medium-dose hirudin (MDHir) (0.4 mg/kg bolus+0.15 mg·kg−1·h−1 infusion, n=267) for 72 hours. At 7 days, 6.5% of patients in the heparin group, 4.4% in the LDHir group, and 3.0% in the MDHir group (P=.267 heparin versus low-dose hirudin; P=.047 heparin versus medium-dose hirudin) suffered cardiovascular death, new MI, or refractory angina (primary outcome). The proportions with cardiovascular death, new MI, or refractory or severe angina (secondary outcome) were 15.6%, 12.5%, and 9.4%, respectively (P=.27 for heparin versus LDHir; P=.02 for heparin versus MDHir). The rates of new MI were 4.9%, 2.6%, and 1.9%, respectively (P=.14 heparin versus LDHir; P=.046 heparin versus MDHir). Fewer patients underwent coronary artery bypass graft surgery in the two hirudin groups (3.7% low-dose, 1.1% medium-dose group) compared with heparin (4.0%) (P=.028 for heparin versus MDHir). After cessation of study treatments, there was an increase in ischemic events in the LDHir group at ≈24 hours and at ≈5 days in the medium-dose group. Nevertheless, at 180 days, the differences between hirudin and heparin persisted.
Conclusions Hirudin, especially at the medium dose, appears to be superior to heparin in preventing ischemic outcomes in unstable angina or acute MI without ST elevation.
There is pathological, angiographic, and angioscopic evidence that UA and AMI are caused by coronary thrombosis superimposed on a ruptured atherosclerotic plaque.1 These observations have prompted trials of thrombolytic, antiplatelet, and antithrombotic agents. In patients presenting with suspected AMI and ECG evidence of ST-segment elevation, thrombolytic therapy, aspirin, and β-blockers have been shown to be beneficial.2 Although thrombolytic therapy has failed to produce a reduction in mortality or reinfarction in patients with UA or suspected AMI without ST elevation,3 aspirin4 5 and β-blockers6 have been shown to be beneficial. In particular, aspirin has been clearly shown to reduce mortality and reinfarction in patients with UA.4 5 More recently, both standard heparin7 and low-molecular-weight heparin8 have been shown to be better than placebo at reducing MI and refractory angina in UA patients receiving aspirin. However, even when treated with a combination of heparin and aspirin, ≈5% to 6% of patients with UA will develop a new MI, and a similar number of patients will develop refractory angina necessitating urgent revascularization procedures during hospitalization. These observations have prompted trials of more potent antithrombotic agents in the acute phase of UA. After discharge from hospital, patients still have a high risk of recurrent ischemic events that are likely to be thrombotic in origin. This observation raises the possibility that long-term treatment with effective antithrombotic agents may be useful.
Hirudin is a potent and specific thrombin inhibitor, initially isolated from the saliva of the medicinal leech and now available through recombinant DNA technology. Unlike heparin, hirudin interacts directly with thrombin and is able to inhibit clot-bound and free thrombin equally well. In experimental animal models of deep arterial injury, hirudin is a more effective antithrombotic agent than heparin. Although small phase 2 trials of hirudin in UA have yielded promising results,9 there are no conclusive data in humans indicating that hirudin is superior to heparin in patients with UA or MI (collectively to be called acute coronary syndromes, ACS).
The OASIS Study is a moderate-size pilot study consisting of two parts: an initial phase comparing the effects of a 3-day treatment with hirudin versus heparin (which is reported here) on clinical outcomes at 7 days and a second part assessing the impact of low- or moderate-intensity warfarin given long-term (which will be reported separately).
The specific aims of this study are to compare the effects of two different doses of hirudin with heparin on (1) a composite outcome of CV death, development of new MI, or refractory angina (primary outcome) and on the above composite plus severe angina (secondary outcome) at 7 days in patients with UA or suspected MI with no ST-segment elevation who were also receiving aspirin and (2) safety parameters, including bleeding rates.
Eligible patients were those admitted to hospital within 12 hours of an episode of chest pain suspected to be due to UA or MI without ST-segment elevation on their admission ECG. The diagnosis of UA was based on symptoms of angina that were new in onset and were worsening or were occurring with minimal activity. The symptoms had to be associated with either current ECG evidence of ischemia or previous objective documentation of coronary artery disease. Suspected MI without ST elevation was diagnosed on the basis of characteristic chest pain lasting >20 minutes and unaccompanied by ECG evidence of ST elevation.
Patients with contraindications to heparin or hirudin, a history of stroke in the previous year, renal impairment (ie, creatinine >2.0 mg/dL), need for long-term oral anticoagulant therapy, PTCA within the previous 6 months, planned thrombolysis, pregnancy, age <21 years or >85 years, estimated body weight >110 kg, cardiogenic shock, angina not due to coronary disease, or other unrelated diseases that might limit life expectancy to <6 months were excluded.
Patients were randomized by a toll-free telephone call to a 24-hour automated randomization service. After key entry data were recorded, patients were randomized to receive heparin or one of two doses of hirudin, respectively, in a ratio of 4:3:3. During routine quality control checks, potential inaccuracies in the labeling of a few new batches of drugs were noted. To protect patient safety, effective March 15, 1995, for ≈1 week, all patients at a few centers that might have been affected were randomized to heparin until replacement cartons were received. None of the clinical centers were aware of this decision.
In this study, recombinant hirudin (HBW023) manufactured by Behringwerke AG and heparin (Hepalean) manufactured by Organon Technica were investigated. All drug supplies were packaged by Hoechst Roussel.
Patients were randomized to receive a 72-hour intravenous infusion of either heparin or hirudin in the following doses: (1) heparin: initial bolus of 5000 U followed by an infusion of 1200 U/h, or 1000 U/h for patients with estimated body weight <60 kg. The dose was titrated to maintain the aPTT between 60 and 100 seconds; (2) low-dose hirudin: initial bolus of 0.2 mg/kg followed by an infusion of 0.10 mg·kg−1·h−1; or (3) medium-dose hirudin: initial bolus of 0.4 mg/kg followed by an infusion of 0.15 mg·kg−1·h−1. A higher dose of hirudin had originally been planned (bolus of 0.6 mg/kg followed by an infusion of 0.20 mg·kg−1·h−1), but this arm was not initiated because the results of two previous trials indicated an increase in major bleeding rates with this hirudin regimen used in combination with thrombolytic therapy.10 11 For patients receiving intravenous heparin before randomization, the heparin or hirudin bolus was withheld if the aPTT was >60 seconds or if the patient had received a heparin bolus in the previous 2 hours.
Randomization to heparin or hirudin was open, whereas randomization to the two doses of hirudin was blind. However, all events were adjudicated by a central committee unaware of the treatment allocation.
The aPTT was monitored every 6 to 8 hours. Heparin and hirudin dose adjustments were permitted to maintain aPTT values between 60 and 100 seconds. Modifications of the infusions for bleeding or for angiography or revascularization procedures were allowed at the discretion of the local physicians.
Outcomes and Definitions
The primary follow-up period for the hirudin versus heparin comparison was 7 days. Data on the following outcomes were documented.
1. CV death.
2. New MI as evidenced by recurrent symptoms with either new ECG changes or new enzyme elevation. New MI was further subdivided into those events that occurred within 24 hours of randomization and those that occurred later, because it was possible that MI early after randomization could be related to the initial event.
3. Refractory angina, defined as recurrent ischemic pain lasting >5 minutes with documented new ECG changes occurring despite optimal medical treatment and requiring an additional intervention. Optimal medical treatment should include at least two antianginal medications, one of which should be intravenous nitrates (unless contraindicated). An additional intervention was defined as one of the following: thrombolytic therapy for threatened MI, intra-aortic balloon pump, cardiac catheterization within 12 hours, or transfer to a tertiary care center within 24 hours. On the basis of these criteria, refractory angina could be considered as being indicative of impending infarction.
4. Severe angina, defined as recurrent ischemic chest pain lasting >5 minutes while on optimal therapy with documentation of new ECG changes associated with the episode of chest pain. (This end point was defined very early during the conduct of the study, when about 100 patients had been randomized, because our definition of refractory angina was considered to be extremely stringent and the event rates were lower than anticipated. The definition was chosen without knowledge of any emerging trends.)
5. Recurrent angina, defined as all other episodes of ischemic chest pain lasting >5 minutes.
6. Revascularization procedures, including CABG or PTCA, within 7 days.
It was intended to examine a variety of clusters of outcomes, ie, CV death, new MI, or refractory angina (primary outcome); or CV death, new MI, refractory angina, or severe angina; or CV death, new MI, or severe angina requiring revascularization procedures (secondary outcomes) within 7 days.
Patients who had elevated cardiac enzyme levels on admission (ie, before randomization) or ECG changes temporally associated with admission symptoms were considered as having an MI associated with the original symptoms that led to admission. Because treatment was not expected to have an effect on this outcome, these events were not included in the analysis of primary or secondary outcomes.
The major safety outcomes were stroke (subdivided into ischemic and hemorrhagic) and major bleeding events (life threatening, permanently or significantly disabling, requiring transfusion with two or more units of blood or equivalent, or requiring surgical intervention). All other bleeding events were considered to be minor.
Blinded Central Adjudication of Events
Key efficacy outcomes (deaths, new MI, refractory angina, and severe angina) and safety outcomes (strokes and major bleeds) up to 35 days were adjudicated by a central committee that was unaware of the treatment allocation.
Patients were recruited from 31 clinical centers in Canada. Data were transmitted via the DataFax system to the Canadian Cardiovascular Collaboration Project Office located at the Preventive Cardiology and Therapeutics Program of the Hamilton Civic Hospitals Research Center, McMaster University.
All patients gave written informed consent, and the protocol was approved by the institutional review board of each hospital. All aspects of the study were monitored by an independent Data and Safety Monitoring Board. The study was funded by Behringwerke AG, Germany. However, the sponsors of the study had no access to any outcome data until the study was complete and were not involved in the data analysis.
The study was funded in two stages: An initial sample size of 600 patients was chosen for this pilot study. However, before completion of this phase, funding to study an additional 300 patients was obtained without knowledge of the interim results. The main aim of the extension was to obtain some data on the safety of initiating warfarin before the cessation of hirudin or heparin. The revised protocol stated that for the comparison of heparin versus hirudin, the analysis would be based on all 900 patients. This decision was made without knowledge of any emerging trends. It was recognized that the study would have high power to detect only large differences (ie, 50% relative risks) in rates of major outcomes of efficacy or safety.
Individual and cluster outcomes were compared by Mantel-Haenszel χ2 tests.12 Relative risk and 95% CIs were estimated between each dose of hirudin and heparin as well as the combined hirudin and heparin groups. To assess whether there is an increase in the number of ischemic events (composite that includes severe angina), the method of Cook et al13 was used. An analysis stratified by randomization to warfarin yielded no evidence of heterogeneity, with little impact on the main comparisons between hirudin and heparin. Therefore, only the overall results are presented.
During the period July 15, 1994, to April 1996, 909 patients were recruited. Their baseline characteristics are outlined in Table 1⇓. There were no imbalances in baseline characteristics except for a slight imbalance in the proportion of patients with an abnormal ECG (heparin, 83.8%; low-dose hirudin, 86.7%; medium-dose hirudin, 79.4%) that was not statistically significant. Adjusted analyses for this covariate did not materially alter the results, and so the unadjusted analyses are presented. In addition, analyses stratified by presence or absence of abnormal ECG were also specified. The proportions of patients with associated MI at entry were similar in all three groups (17.8% heparin, 19.6% low-dose hirudin, and 17.2% medium-dose hirudin).
Compliance and aPTT
Many of the patients receiving heparin at the time of randomization had an aPTT >60 seconds. As a result, a bolus was not given to 21.6% of patients randomized to heparin, 26.6% randomized to low-dose hirudin, and 27% randomized to medium-dose hirudin. The study infusion was continued for >48 hours in 91.3% of patients randomized to heparin, 85.3% randomized to low-dose hirudin, and 82.3% randomized to medium-dose hirudin. The infusion was stopped permanently before the scheduled 72 hours in 17.8% of patients randomized to heparin, 26.2% randomized to low-dose hirudin, and 27.0% randomized to medium-dose hirudin (P=.008). Early discontinuation for minor bleeds (heparin, 0.3%; low-dose hirudin, 1.5%; medium-dose hirudin, 2.2%; P=.04) or elevated aPTT (heparin, 0%; low-dose hirudin, 0.7%; medium-dose hirudin, 2.2%; P<.01) were more common with hirudin; there was a higher frequency of early discontinuation for low aPTT in the low-dose hirudin group (4.4%) compared with the heparin group (0%) and medium-dose hirudin group (0.4%) (P<.01). By contrast, heparin was discontinued slightly more often for a surgical or diagnostic procedure (heparin, 4.6%; low-dose hirudin, 4.1%; and medium-dose hirudin, 3.0%; P=.60)
The mean (±SD) aPTT during the first 12 to 24 hours was 79±30 seconds in the heparin group, compared with 73±16 seconds in the medium-dose hirudin group and 66±13 seconds in the low-dose hirudin group. The mean aPTT values in all three treatment groups were significantly different from each other (P<.05). Between 24 and 72 hours, the mean aPTT values were similar in the heparin and medium-dose hirudin groups, both of which tended to be higher than the mean aPTT values in the low-dose hirudin group (Fig 1⇓). At least one aPTT value was >100 seconds in 63.9% of patients receiving heparin, 11.8% of patients receiving low-dose hirudin, and 16.1% of patients receiving medium-dose hirudin. aPTT values <60 seconds in the first 24 hours of infusion on three or more occasions were measured in 5.1% of patients receiving heparin, 15.5% of those receiving low-dose hirudin, and 5.6% of those receiving medium-dose hirudin. The number of dose adjustments was significantly greater in the heparin group (median, 2; range, 0 to 8) compared with both hirudin groups (median, 0; range, 0 to 5). In the heparin group, 15.2% of patients required no dose adjustment, compared with 55.6% in the low-dose hirudin and 72.5% in the medium-dose hirudin groups (P<.0001 for linear trend). Thus, there was less variability in the aPTT response to hirudin compared with heparin.
Efficacy Outcomes Within 7 Days
There were fewer patients with CV death, new MI, or refractory angina with hirudin (low-dose hirudin, 4.4%; medium-dose hirudin, 3.0%) compared with heparin (6.5%; P=.27 for hirudin versus low-dose heparin and P=.047 for medium-dose hirudin versus heparin) (Table 2⇓ and Fig 2⇓). The proportion of patients with CV death, new MI, or refractory or severe angina was also lower with hirudin (heparin, 15.6%; low-dose hirudin, 12.5%; medium-dose hirudin, 9.4%; P=.27 for low-dose hirudin versus heparin and P=.020 for medium-dose hirudin versus heparin). The proportion of patients with CV death, new MI, and refractory or severe angina requiring revascularization by 7 days also was lower with hirudin (heparin, 7.3%; low-dose hirudin, 3.7%; medium-dose hirudin, 3.4%; P=.054 for low-dose hirudin versus heparin and P=.035 for medium-dose hirudin versus heparin).
The proportions of patients who died of a CV cause were similar in all three groups. There was one additional non-CV death in the heparin group. There were fewer new MIs in both the hirudin groups compared with heparin (relative risk of 0.53, P=.14 low-dose hirudin versus heparin; relative risk of 0.39, P=.046 for medium-dose hirudin versus heparin). The risk reduction in MI was entirely due to differences in new MI occurring 24 hours after randomization. The rates of CV death or new MI were lower in each hirudin group (2.6% with either dose) than with heparin (4.9%) (P=.15 for each dose of hirudin compared with heparin; P=.07 for the combined hirudin group versus heparin).
All Revascularization Procedures (Within 7 Days)
Fewer patients underwent CABG in the low- and medium-dose hirudin groups (3.7% and 1.1%, respectively) than in the heparin group (4.0%) (Table 3⇓). There was less difference in the proportions of patients undergoing PTCA (heparin, 5.1%; low-dose hirudin, 3.3%; medium-dose hirudin, 5.2%). The proportions of patients who required either revascularization procedure also were lower in the hirudin groups than with heparin (heparin, 8.6%; low-dose hirudin, 7.0%; and medium-dose hirudin, 6.4%). The cluster outcomes of CV death, new MI, or revascularization procedures (heparin, 12.4%; low-dose hirudin, 8.9%; and medium-dose hirudin, 8.6%; P=.155 for heparin versus low-dose hirudin and P=.129 for heparin versus medium-dose hirudin) and CV death, new MI, refractory angina, and revascularization procedures (heparin, 12.9%; low-dose hirudin, 10.0%; and medium-dose hirudin, 9.0%) appeared to be lower with hirudin than with heparin (P=.246 for heparin versus low-dose hirudin and P=.120 for medium-dose hirudin versus heparin).
Long-term Follow-up and Events After Cessation of Therapy
Approximately 24 hours after cessation of therapy, there was a marked increase in the number of ischemic events in the group allocated to receive low-dose hirudin (Fig 3⇓). This increase occurred over a period of ≈10 hours. The number of ischemic events after cessation of treatment was lower in the medium-dose hirudin group than with heparin (P=.073) and low-dose hirudin (P=.076). At day 8 or 9, the group treated with medium-dose hirudin experienced a sharp increase in ischemic events, so that the difference compared with heparin decreased (Fig 4⇓). Nevertheless, at 35 days and 180 days, both doses of hirudin had lower rates of ischemic events, with the medium dose appearing to be the best. The differences in the primary and secondary end points between heparin and the two hirudin doses persisted during long-term follow up (range, 2 to 247 days; mean follow-up, 161 days) (Fig 5⇓).
The incidences of major bleeds were low and similar (heparin, 1.1%; low-dose hirudin, 0.7%; and medium-dose hirudin, 1.1%) in all three treatment groups (Table 4⇓). There were no hemorrhagic strokes in the study. However, a higher proportion of patients in the hirudin groups experienced minor bleeding (skin bruising and puncture site ooze), so that the proportion of patients with any bleeding was higher with hirudin (low-dose hirudin, 16.2%; medium-dose hirudin, 21.3%) (P=.033 and 0.001, respectively, versus heparin) than in those given heparin (10.5%).
Concomitant Therapy During Hospitalization
Aspirin was given to 96% of patients in all three groups, and ≈57% received nonstudy heparin (just over half of this before randomization and under half after cessation of study treatment). The use of β-blockers (74%), intravenous nitrates (52%), other nitrates (89%), calcium channel blockers (56%), and ACE inhibitors (27%) was not significantly different among the three groups. Thrombolytic therapy was given to 3.0% of patients in the heparin group, compared with 1.5% in the low-dose hirudin group and 1.5% in the medium-dose hirudin group.
One patient with established cardiogenic shock who was receiving treatment with intravenous inotropic agents (an exclusion) was randomized to medium-dose hirudin. This patient died of pulmonary edema and hemoptysis (which was classified as a major bleed). Five other patients (3 hirudin, 2 heparin) did not receive the infusion. All these patients were retained in the study for all analyses.
The OASIS Pilot Study was a large phase 2 trial designed to assess the feasibility, safety, and efficacy of two doses of hirudin compared with heparin. The study was not formally powered to detect moderate differences in individual clinical outcomes but rather was designed to assess the impact of hirudin compared with heparin on a cluster of clinically relevant and related ischemic events, interventions, coagulation parameters, and safety outcomes to guide the design of a larger and more definitive trial. Despite this, significant reductions in the primary and secondary outcomes were observed with medium-dose hirudin compared with heparin. There was a smaller and nonsignificant impact of low-dose hirudin on these outcomes. When a combination of ischemic outcomes is used and the information is examined in conjunction with the coagulation parameters, a coherent pattern of results emerges. Although both agents suppressed markers of coagulation, hirudin appears to be more effective than heparin in preventing ischemic events and revascularization procedures as well as suppressing indirect markers indicative of thrombin activity.14 There was a nonsignificant trend toward a greater effect with the medium dose of hirudin than with the low dose. These data therefore suggest that the medium dose of hirudin is likely to be superior to low-dose hirudin and is the more promising regimen to evaluate in a larger study.
At the time this study was about to be initiated, the results of the GUSTO IIa10 Study, TIMI 9a Study,11 and HIT trials15 became available. In the first two studies, hirudin was used at a higher dose (0.6 mg/kg bolus followed by 0.20 mg·kg−1·h−1 for 72 hours), whereas the HIT Study used a regimen similar to the medium dose used in this study. The GUSTO IIa Study included patients with acute myocardial ischemia with and without concomitant use of thrombolytic therapy, whereas the other two studies included only patients with AMI who were given thrombolytic therapy. In all three studies, the rates of major bleeds or intracranial hemorrhage were higher in patients given hirudin than in those treated with heparin. In the GUSTO IIa Study, this excess was particularly marked in patients receiving thrombolytic therapy. Among those receiving hirudin in the absence of thrombolytic therapy, three patients had a hemorrhagic stroke compared with none of those given heparin. On the basis of these findings, the two doses of hirudin chosen for the OASIS Study were lower than the doses used in GUSTO IIa and TIMI 9a. Furthermore, unlike previous studies, dose adjustments were allowed in OASIS. Although experience with the moderate-dose regimen in the HIT trial indicated that it produced an excess of intracranial bleeding when used in conjunction with thrombolytic therapy, there was no information about its hemorrhagic potential when given alone. We reasoned that it might be possible to use the medium dose of hirudin safely in the absence of thrombolytic therapy and that the absolute rates of adverse events were likely to be lower than those seen in hirudin-allocated patients not receiving thrombolytic therapy in GUSTO IIa. This concept is supported by a meta-analysis by Lefkovitz et al.16 Although the numbers of patients randomized to moderate-dose hirudin in OASIS is low, our data suggest that any absolute increase in major bleeds produced by these doses of hirudin when used in patients not receiving thrombolytic therapy is very small and that even a 50% increase in the rates of major bleeds will only lead to a small absolute excess (0.5%), which is likely to be more than compensated by its better efficacy.
Although several of the efficacy comparisons in the OASIS Pilot Study reached “nominal” levels of statistical significance and suggest the potential for large treatment benefits with hirudin, these differences should be interpreted with caution, because the confidence limits of the estimates of relative risk reductions are wide. Nevertheless, the consistent benefit across a range of pathophysiologically related ischemic outcomes, revascularization rates, and coagulation parameters14 strongly suggests that hirudin is likely to be more effective than heparin. Confirmation of these promising results requires more definitive evidence from larger trials.
Our data indicate that ≈24 hours after cessation of low-dose hirudin, there was a marked increase in ischemic events. Therefore, during the period after cessation of study medication and up to 7 days, the total numbers of ischemic events were similar between low-dose hirudin and heparin. By contrast, during the same period, the rates of ischemic events remained low in the medium-dose hirudin group (P=.07 versus both heparin and low-dose hirudin). However, by about day 8 (ie, 5 days after cessation of the treatment), there appeared to be a sharp increase in events in this group that attenuated some but not all of the early difference compared with heparin. By 180 days, the rates of ischemic events were still lower in the two hirudin groups than with heparin. The absolute differences in the rates of ischemic events between the heparin versus hirudin groups at 7 days, 35 days, and 180 days were similar, but the relative risk reductions were less marked at 35 days and 180 days. Although at 6 months the differences between heparin and the combined hirudin groups were of borderline statistical significance (P=.063 for the composite including refractory angina and P=.017 for the composite including severe angina), more data from larger trials are necessary to reliably conclude that the early benefits of hirudin compared with heparin are sustained in the long term.
These data suggest that short-term antithrombin treatment is inadequate to “passivate” the clot. Although higher doses of hirudin are more effective, there still appears to be a delayed excess of ischemic events. This suggests that short-term intravenous treatment should be followed by long-term antithrombotic strategies (eg, warfarin) in addition to aspirin to produce a sustained clinical benefit.
There were no apparent differences in the rates of major bleeding with the two doses of hirudin compared with heparin, although there were too few events to make reliable estimates. The incidence of minor bleeding was significantly greater in those receiving either dose of hirudin (no difference between doses) than in those given heparin, which may be indicative of a potential for higher rates of major bleeding in a larger study. However, the absolute excess is likely to be small and modest compared with the potential benefit. Collectively, these data suggest that the medium dose of hirudin is more likely to demonstrate greater efficacy than low-dose hirudin with an acceptable bleeding risk and provides a window of opportunity to implement long-term antithrombotic therapy.
Recently, two large trials evaluated hirudin at doses similar to the low dose in OASIS compared with heparin. In the TIMI 9B17 study, which included only patients with AMI receiving thrombolytic therapy, no difference in a cluster outcome was observed. The use of thrombolytic therapy, which can stimulate thrombin generation; the inclusion of AMI patients; use of a composite outcome that included events that were not necessarily ischemic (eg, left ventricular dysfunction and heart failure); and the low dose of hirudin used may have compromised the ability of this trial to demonstrate differences. In the GUSTO 2B Study,18 a broader group of patients was studied, but about two thirds had an AMI at entry into the trial. In such patients, the composite outcome of death and MI is substantially weighted by the former. Despite this, there was a modest, 12% relative risk reduction (P=.06) at 30 days (≈20% risk reduction at 7 days) in CV death and MI. In both TIMI 9B and GUSTO IIb, there was a lower incidence of recurrent MI during the hospital phase. These results with the low dose of hirudin are quite consistent with the modest and nonsignificant effect observed with a similar dose of hirudin in OASIS. It may therefore be possible that evaluating a medium dose of hirudin on major ischemic outcomes during hospitalization in a population in whom recurrent ischemia is common (eg, UA) and in the absence of thrombolytic therapy may be a more sensitive test of the hypothesis that hirudin may be superior to heparin. Since long-term ischemic events are unlikely to be prevented by short-term antithrombotic treatments (either dose of heparin and probably antiplatelet therapies), it is logical to follow such treatments with long-term anticoagulant therapies (eg, warfarin).
In conclusion, the OASIS Pilot Study suggests that hirudin used in a medium dose appears to be superior to heparin for the treatment of patients with UA or AMI without ST-segment elevation and provides guidance to develop a safe and effective strategy for short-term antithrombotic therapy. These concepts require further confirmation and are currently being tested in the larger OASIS 2 trial evaluating short-term treatments with medium-dose hirudin compared with heparin followed by long-term warfarin (INR targeted at 2 to 3) for 5 months versus standard therapy in 10 000 patients.
Selected Abbreviations and Acronyms
|AMI||=||acute myocardial infarction|
|aPTT||=||activated partial thromboplastin time|
|CABG||=||coronary artery bypass graft surgery|
|GUSTO||=||Global Use of Strategies to Open Occluded Arteries|
|HIT||=||Hirudin for the Improvement of Thrombolysis|
|OASIS||=||Organization to Assess Strategies for Ischemic Syndromes|
|PTCA||=||percutaneous transluminal coronary angioplasty|
|TIMI||=||Thrombolysis and Thrombin Inhibition in Myocardial Infarction|
List of Investigators
Camp Hill Medical Centre, Halifax: I. Bata, M. MacFarlane; CHR de l’Amiante, Thetford Mines: J. Campeau, F. Ouimet; Chedoke-McMaster Hospital, Hamilton: A. Panju, G. Woodcock; General Hospital Health Science Centre, St John’s: B. Sussex, L. St Croix; General Hospital/St Joseph’s Hospital, Thunder Bay: C. Lai, K. Kwiatkowski; Greater Niagara General Hospital, Niagara Falls: Y.K. Chan, D. Zaniol; Hamilton General Hospital: J. Gill, C. Odell; Henderson General Hospital, Hamilton: T. Boyne, G. Cappelli; Hopital de Sept-Iles: G. Bouchard, M. Fournier; Hotel-Dieu de Levis: P. Auger, F. Dumont; Lethbridge Regional Hospital: R. Schuld, M. Bartoshyk; Lions Gate Hospital, North Vancouver: K. Woo, R. Moore; Montreal Heart Institute: P. Theroux, A.M. Rouette; Plains Health Centre, Regina: N. Habib, Denis Jones; Royal Columbian Hospital, New Westminster: D. Rupka, D. Hilbich; Royal University Hospital, Saskatoon: J. Lopez, P. Kuny; St Boniface Hospital, Winnipeg: A. Morris, M. Schillberg; St Joseph’s Hospital, London: G. Wisenberg, J. Occhipinti; Sudbury Memorial Hospital: S. Nawaz, L. Chomey; Sunnybrook HSC, North York: C. Joyner, K. Freskiw; Surrey Memorial Hospital: P. Polasek, L. Breakwell; Toronto Hospital: P. Daly, C. Johnson; University Hospital, London: W. Kostuk, R. Oskalns; University of Ottawa Heart Institute: J.F. Marquis, S.A. Kerns; General Hospital of Port Arthur: C. Lai, K. Kwiatkowski; St Joseph’s Hospital, Hamilton: M. Sullivan, M. Lawrence; Concordia Hospital, Winnipeg: H. Smith, M. Sokulski; McKeller General Hospital, Thunder Bay: A. Weeks, C. Girard; Foothills Hospital, Calgary: J. Warnica, B. Smith; Welland County General Hospital, G. Venkatesh, S. Demers.
Coagulation Core Laboratory (Henderson General Hospital)
J. Weitz, M. Johnston.
Physicians: S. Yusuf, M. Flather, S. Anand, M. Coutinho, A. Avezum, M. Farkouh. Study Coordinators: M. Johnston, L. Cronin, J. Brown. Data Management: F. Mazur, S. Kotlan, S. Reeve, H. Marsh. Statistical Analysis: J. Pogue, W. Taylor, R. Cook, C. Sigouin. Computing: M. Anderson, J. Tucker. Administration: L. Campbell, B. Cracknell.
S. Yusuf (Chairman and Principal Investigator); P. Theroux (Cochairman); M. Flather (Project Officer); J. Cairns, J. Pogue, G. Turpie, J. Weitz (Hamilton); C. Kells (Halifax); M. Knudtson (Calgary); W. Kostuk (London); J.F. Marquis (Ottawa); K. Fox (Edinburgh); A. Jessel (Marburg); B. Carter (Montreal).
Behringwerke AG, Germany: A. Jessel, M. Lutz, H. Heinrichs, H. Volpel, F. Schindel. Hoechst Marion Roussel Canada, Montreal: B. Carter, J. Albert, J.P. St Pierre, M. Salama. Dupont, Delaware: W. Michaelis, B. Dusak.
Data And Safety Monitoring Board
J. Hirsh (Chairman), Hamilton; M. Gent, Hamilton; G. Wyse, Calgary.
Events Adjudication Committee
M. Flather, C. Rihal, J. Gill, C. Joyner, Y.K. Chan, A. Panju, T. Boyne.
K. Stevens, Vancouver; L. Harris, S. Martin, Edmonton; M. Schillberg, Winnipeg; J. Kellen, B. Baptie, Calgary; R. Oskalns, London; M. Johnston, C. Liuni, Toronto; S. Hagar, Ottawa; D. LaForge, Montreal; L. St Croix, D. Dalton, St John’s; T. Fawcett, Halifax.
Manuscript Writing Group
S. Yusuf, J. Pogue, J. Weitz, M. Flather.
↵1 Participants are listed in the “Appendix.”
- Received December 10, 1996.
- Revision received February 25, 1997.
- Accepted February 28, 1997.
- Copyright © 1997 by American Heart Association
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