Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial
Topic: Anticoagulation in acute coronary syndrome (direct thrombin inhibitors)
Aim:
- Compare recombinant hirudin and heparin as adjuncts to streptokinase thrombolysis in patients with acute myocardial infarction (MI).
Design:
- Multi-centered, double blinded, randomized clinical trial
Treatment:
- Lepirudin (0.2 mg/kg IV bolus before streptokinase, followed by 0.5 mg/kg subcutaneous, first dose within 30 minutes of streptokinase, and then every 12 hours) over 5-7 days.
Control:
- Unfractionated heparin (IV placebo bolus, followed by 12,500 U subcutaneous, first dose 30 minutes after streptokinase, and then every 12 hours) over 5-7 days.
Cohort:
- 1,208 patients
Inclusion criteria:
- Acute MI (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; <6 hours) treated with aspirin (300 mg loading, then 100-200 mg daily) and streptokinase (1.5 million units IV infusion over 60 minutes).
- 18-75 years of age
Exclusion criteria:
- Contraindication to thrombolysis
- Streptokinase therapy during the last year
- Heparin therapy within 2 hours before study medications
- Known renal insufficiency (serum creatinine 2.0 mg/dl or 1.77 mmol/liter)
Follow up:
- 30 days
Primary endpoint:
- Early and complete patency defined as the proportion of patients with TIMI-3 flow in the infarct-related artery 90 min after start of study medication.
Secondary endpoint:
- Combined and individual incidences of death, MI, or disability from stroke, death, nonfatal stroke, nonfatal reinfarction, rescue PTCA or refractory angina within 30 days after randomization; hemorrhagic and non-hemorrhagic strokes; the proportion of patients with complete resolution of ST-segment elevation at 90 (70 to 110) and 180 (120 to 240) minutes and one-year mortality.
Main results:
- Mean age 61 years; 76% of the patients were men. Infarct territories were similar between groups.
- TIMI 3 flow of infarct related artery was observed in 40.7% (85/209, CI 33.9%-47.7%) of the lepirudin treated patients and 33.5% (70/209, CI 27.1%-40.3%) of the heparin treated patients (p=0.16).
- Analysis of patients treated per protocol (n=342) revealed more TIMI 3 flow in lepirudin versus heparin at 90 min (43.4%, CI 36-51.1%; vs 32.3%, CI 25.3%-40.0%, p=0.045).
- The reinfarction rate during the five days of study treatment was lower in the lepirudin group (1% vs. 2.5%, p=0.048) but similar at 30 days.
- The combined incidences of death or nonfatal reinfarction at 30 days were similar between groups (10.4% vs 11% in lepirudin- and heparin-treated patients, respectively).
- The incidences of major and minor bleedings were similar in both treatment groups.
TAKE AWAY: Specific thrombin inhibition with lepirudin tends to accelerate infarct vessel patency induced by streptokinase, without an increase in major bleeding complications.
