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European Heart Journal 2000 21(17):1473-1481; doi:10.1053/euhj.1999.2005
Copyright © 2000 by the European Society of Cardiology.
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Reactivation of coagulation after stopping infusions of recombinant hirudin and unfractionated heparin in unstable angina and myocardial infarction without ST elevation: results of a randomized trial

M.D Flathera,b,c,f1, J.I Weitza, S Yusufa,b, J Poguea,d, B Sussexe, J Campeauf, J Gillg, R Schuldh, C.D Joyneri, A.L Morrisj, C Laik, P Thérouxl, J.F Marquism, Y.K Chann, G Venkatesho and A Jesselp

a Hamilton Health Sciences Corporation Research Centre, Hamilton, Ontario, Canada
b Division of Cardiology, McMaster University, Hamilton, Ontario, Canada
c Clinical Trials and Evaluation Unit, Royal Brompton Hospital, London, U.K.
d Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
e St. John's Health Sciences Centre, St. John's, Newfoundland, Canada
f Centre Hospitalier de la Region de l'Amiante, Thetford Mines, Quebec, Canada
g Hamilton General Hospital, Hamilton, Ontario, Canada
h Lethbridge Regional Hospital, Lethbridge, Alberta, Canada
i Sunnybrooke Health Sciences Centre, Toronto, Ontario, Canada
j St Boniface General Hospital, Winnipeg, Manitoba, Canada
k General Hospital and St. Joseph's Hospital, Thunder Bay, Ontario, Canada
l Montreal Heart Institute, Montreal, Quebec, Canada
m Ottawa Heart Institute, Ottawa, Ontario, Canada
n Greater Niagara General Hospital, Niagara Falls, Ontario, Canada
o Welland General Hospital, Welland, Ontario, Canada
p Hoechst Marion Roussel, Marburg, Germany, Bridgewater, PA, U.S.A.

revised November 10, 1999; accepted November 17, 1999

Abstract

Aims To compare effects of heparin and hirudin on biochemical markers of coagulation.

Methods and Results Patients (n=395) with unstable angina or myocardial infarction without ST elevation were randomized to a 72-h infusion of one of three regimens: unfractionated heparin (bolus of 5000IU followed by an infusion of 1200IU.h–1), low-dose hirudin (HBW 023; 0·2mg.kg–1bolus followed by 0·10mg.kg–1.h–1) or medium-dose hirudin (0·4mg.kg–1bolus followed by 0·15mg.kg–1.h–1). Infusions were adjusted to maintain an activated partial thromboplastin time of between 60–100s. Activated partial thromboplastin time, prothrombin fragment 1.2 (F1.2), thrombin antithrombin III complex and D-dimer were measured before, during and after the infusion. Median activated partial thromboplastin time was similar in the two groups early on, but was significantly lower in the heparin group than in the combined hirudin group 48h after starting the infusion (53s and 75s, respectively;P<0·001), and 6h after stopping (31s and 46s, respectively;P<0·001). Median F1.2 levels were not significantly different between the groups during the infusion. Median thrombin antithrombin III levels in the heparin and hirudin groups were 2·8µg.l–1and 2·3µg.l–1, respectively, at 6h (P<0·001), and 3·0µg.l–1and 2·3µg.l–1, respectively, at 48h (P<0·001). Median D-dimer levels were 320ng.ml–1and 260ng.ml–148h after starting the infusion in the heparin and hirudin groups, respectively (P<0·001), and 415ng.ml–1and 280ng.ml–1, respectively (P<0·001) 6h after stopping. D-dimer levels were significantly elevated above baseline values in both groups 24–48h after stopping the infusions.

Conclusions The greater reduction of thrombin antithrombin III and D-dimer during the hirudin infusion supports the hypothesis that hirudin is a more potent antithrombin agent than heparin. Increased D-dimer levels after stopping heparin or hirudin suggest that there is an ongoing pro-coagulant state. These results point to the greater efficacy of hirudin in preventing early clinical events (death, myocardial infarction and refractory ischaemia) compared with heparin that have been observed in large randomized trials. Persistent activation of coagulation afterstopping infusions in our study suggests that a longer course of antithrombotic treatment may be needed to pacify the thrombus.

Key Words: Angina, anticoagulants, heparin, myocardial infarction, randomized trial, thrombosis, thrombin

f1 Correspondence: Marcus D. Flather, MBBS, MRCP, Clinical Trials and Evaluation Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, U.K.

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