Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial.
OBJECTIVE
The purpose of this study was to compare recombinant hirudin and heparin as adjuncts to streptokinase thrombolysis in patients with acute myocardial infarction (AMI).


BACKGROUND
Experimental studies and previous small clinical trials suggest that specific thrombin inhibition improves early patency rates and clinical outcome in patients treated with streptokinase.


METHODS
In a randomized double-blind, multicenter trial, 1,208 patients with AMI < or =6 h were treated with aspirin and streptokinase and randomized to receive recombinant hirudin (lepirudin, i.v. bolus of 0.2 mg/kg, followed by subcutaneous (s.c.) injections of 0.5 mg/kg b.i.d. for 5 to 7 days) or heparin (i.v. placebo bolus, followed by s.c. injections of 12,500 IU b.i.d. for 5 to 7 days). A total of 447 patients were included in the angiographic substudy in which the primary end point, 90-min Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 of the infarct-related artery, was evaluated, while the other two-thirds served as "safety group" in which only clinical end points were evaluated. As an additional efficacy parameter the ST-segment resolution at 90 and 180 min was measured in all patients.


RESULTS
TIMI flow grade 3 was observed in 40.7% in the lepirudin and in 33.5% in the heparin group (p = 0.16), respectively. In the entire study population the proportion of patients with complete ST resolution at 90 min (28% vs. 22%, p = 0.05) and at 180 min (52% vs. 48%, p = 0.18) after start of therapy tended to be higher in the lepirudin group. There was no significant difference in the incidence of hemorrhagic stroke (0.2% vs. 0.3%) or total stroke (1.2% vs. 1.5%), reinfarction rate (4.6% vs. 5.1%) and total mortality rate (6.8% vs. 6.4%) at 30 days, as well as the combined end point of death, nonfatal stroke, nonfatal reinfarction, rescue-percutaneous transluminal coronary angioplasty and refractory angina (22.7 vs. 24.3%) were not statistically different between the two groups.


CONCLUSIONS
Lepirudin as adjunct to thrombolysis with streptokinase did not significantly improve restoration of blood flow in the infarct vessel as assessed by angiography, but was associated with an accelerated ST resolution. There was no increase in the risk of major bleedings with lepirudin compared to heparin.
Neuhaus
K L
KL
Städtische Kliniken, Medizinische Klinik II, Kassel, Germany.
Molhoek
G P
GP
Zeymer
U
U
Tebbe
U
U
Wegscheider
K
K
Schröder
R
R
Camez
A
A
Laarman
G J
GJ
Grollier
G M
GM
Lok
D J
DJ
Kuckuck
H
H
Lazarus
P
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006493:Heparin / Q000009:adverse effects / Q000627:therapeutic use; D024764:Hirudin Therapy; D006629:Hirudins / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012008:Recurrence; D013300:Streptokinase / Q000009:adverse effects / Q000627:therapeutic use*; D015996:Survival Rate; D015912:Thrombolytic Therapy; D016896:Treatment Outcome
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; D006493:Heparin; D013300:Streptokinase; C083544:lepirudin