Circulation, Vol 90, 1638-1642, Copyright © 1994 by American Heart Association
KL Neuhaus, R von Essen, U Tebbe, A Jessel, H Heinrichs, W Maurer, W Doring, D Harmjanz, V Kotter and E Kalhammer
BACKGROUND: Adjunctive therapy for thrombolysis in acute myocardial
infarction consists of platelet inhibition with aspirin and thrombin
inhibition with heparin. Thrombin inhibition may be improved by the use of
hirudin as indicated by experimental and phase II clinical studies. The
randomized, double-blind phase III r-Hirudin for Improvement of
Thrombolysis study (HIT III) compared a recombinant hirudin (HBW 023) with
heparin. The primary end point was the incidence of death or reinfarction.
METHODS AND RESULTS: Seven thousand patients with acute myocardial
infarction and a duration of symptoms of less than 6 hours were to be
randomized to receive intravenous heparin (70 IU/kg body wt bolus and 15
IU.kg-1.h-1) or hirudin (0.4 mg/kg body wt bolus and 0.15 mg.kg-1.h-1)
infused over 48 to 72 hours and adjusted to an activated partial
thromboplastin time of 2 to 3.5 times baseline values. In a pilot phase,
1000 patients receiving front-loaded alteplase for thrombolysis were to be
recruited by 93 German centers. After enrollment of 302 patients, the trial
was stopped after an increased rate of intracranial bleeding was observed
in the hirudin group (5 of 148, 3.4%) compared with the heparin group (0 of
154). The overall stroke rate was 3.4% in the hirudin group and 1.3% in the
heparin group. Other major bleeding occurred in five versus three patients
and ventricular rupture occurred in three versus one patient in the hirudin
and heparin groups, respectively. There were 19 in-hospital deaths, with 13
of them from the hirudin group. CONCLUSIONS: Although the number of
patients was too small for a definite benefit-risk assessment, at the
dosage tested, hirudin in combination with front- loaded alteplase and
aspirin may be associated with an increased rate of intracranial
hemorrhage. Our findings are consistent with the observations of the
GUSTO-II and TIMI-9 trials, where higher doses of another recombinant
hirudin were used. Therefore, the therapeutic range of hirudin as an
adjunct to thrombolysis may be smaller than previously thought, and
reappraisal of dose finding should be considered.
ARTICLES
Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausarzte (ALKK)
Stadtische Kliniken Kassel, Medizinische Klinik II, Germany.
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