HIT-4 - HIT-4


The goal of this study was to compare the safety and efficacy of recombinant hirudin (lepirudin) and unfractionated heparin (UFH) when used in conjunction with streptokinase in the treatment of patients with acute ST-segment elevation myocardial infarction (STEMI).


Hirudin, a specific thrombin inhibitor, when used in conjunction with streptokinase for acute STEMI, would lead to increased myocardial reperfusion at 90 minutes when compared to the combination of UFH and streptokinase.

Study Design

Study Design:

Patients Enrolled: 1,208
Mean Follow Up: 30 days
Mean Patient Age: 30-92
Female: 24

Patient Populations:

Patients aged 18-75 years with a time interval between symptom onset and start of therapy of <6 hours and an ST-segment elevation ≥0.2 mV in at least two precordial leads or ST-segment elevation ≥0.1 mV in at least two limb leads were eligible.


Contraindications to thrombolysis, streptokinase therapy during the last year, heparin therapy within two hours before study medications, and known renal insufficiency (serum creatinine >2.0 mg/dl or 1.77 mmol/l)

Primary Endpoints:

The primary endpoint was TIMI 3 flow in the infarct-related artery 90 minutes after start of study medication.

Secondary Endpoints:

The combined and individual incidences of death, nonfatal stroke, nonfatal reinfarction, rescue PTCA, or refractory angina pectoris within 30 days after randomization; the individual incidences of hemorrhagic and nonhemorrhagic strokes; the proportion of patients with complete resolution of ST-segment elevation at 90 and 180 minutes; and one-year mortality

Drug/Procedures Used:

Eligible patients were randomized to receive either an IV bolus of lepirudin (0.2 mg/kg body weight) or placebo prior to streptokinase (1.5 million units IV given over six minutes). Subsequently, patients in the lepirudin arm received subcutaneous injections (0.5 mg/kg) every 12 hours and those in the heparin arm received subcutaneous injections of 12,500 IE every 12 hours. Both groups had dosing adjusted to a target activated partial thromboplastin time of two times normal for 5-7 days.

Concomitant Medications:

A loading dose of 300 mg aspirin followed by 100-200 mg daily thereafter

Principal Findings:

At 90-minute angiography, there was no significant difference in the percentage of patients attaining TIMI 3 flow between the lepirudin group and the heparin group (40.7% vs. 33.5%, p=0.16). There was a significantly higher percentage of patients who achieved complete ST-segment resolution at 90 minutes in the lepirudin group compared to the heparin group (28% vs. 22%, p=0.05). However, the difference was no longer significant at 180 minutes (52% vs. 48%, p=0.18).

There was no statistically significant difference in the incidence of hemorrhagic stroke (0.2% vs. 0.3%), total stroke (1.2% vs. 1.5%), rate of reinfarction (4.6% vs. 5.1%), or total mortality rate (6.8% vs. 6.4%) at 30 days. Similarly, the combined endpoint of death, nonfatal stroke, nonfatal reinfarction, rescue percutaneous transluminal coronary angioplasty (PTCA), and refractory angina (22.7 vs. 24.3%) was not statistically different between the two groups.


Among patients with STEMI, lepirudin, in combination with streptokinase, did not significantly improve the incidence of TIMI 3 blood flow at 90 minutes when compared to the standard therapy of heparin and streptokinase. Those treated with lepirudin had a higher incidence of ST-segment resolution at 90 minutes, but the difference between the two groups was not significant at 180 minutes. Additionally, the rates of major bleeding complications and major adverse cardiac events were similar in the two groups.

These findings suggest that the combination of lepirudin and streptokinase may accelerate reperfusion in STEMI. However, this did not translate into an improvement in clinical outcomes.


Neuhaus KL, Molhoek GP, Zeymer U, et al. Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial. J Am Coll Cardiol 1999;34:966-73.

Clinical Topics: Anticoagulation Management, Invasive Cardiovascular Angiography and Intervention

Keywords: Stroke, Myocardial Infarction, Body Weight, Heparin, Fibrinolytic Agents, Angioplasty, Balloon, Coronary, Hirudins, Streptokinase, Partial Thromboplastin Time, Recombinant Proteins, Myocardial Reperfusion

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