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. OASIS Pilot Study Investigators. Organization to Assess Strategies for Ischemic++ Syndromes.
OBJECTIVE
To compare effects of heparin and hirudin on biochemical markers of coagulation.


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 5000 IU followed by an infusion of 1200 IU. h(-1)), low-dose hirudin (HBW 023; 0.2 mg. kg(-1)bolus followed by 0.10 mg. kg(-1). h(-1)) or medium-dose hirudin (0.4 mg. kg(-1)bolus followed by 0.15 mg. kg(-1). h(-1)). Infusions were adjusted to maintain an activated partial thromboplastin time of between 60-100 s. 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 48 h after starting the infusion (53 s and 75 s, respectively;P<0.001), and 6 h after stopping (31 s and 46 s, 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 2.8 microg. l(-1)and 2.3 microg. l(-1), respectively, at 6 h (P<0.001), and 3.0 microg. l(-1)and 2.3 microg. l(-1), respectively, at 48 h (P<0.001). Median D-dimer levels were 320 ng. ml(-1)and 260 ng. ml(-1)48 h after starting the infusion in the heparin and hirudin groups, respectively (P<0.001), and 415 ng. ml(-1)and 280 ng. ml(-1), respectively (P<0.001) 6 h after stopping. D-dimer levels were significantly elevated above baseline values in both groups 24-48 h 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.
Flather
M D
MD
Hamilton Health Sciences Corporation Research Centre, Hamilton, Ontario, Canada.
Weitz
J I
JI
Yusuf
S
S
Pogue
J
J
Sussex
B
B
Campeau
J
J
Gill
J
J
Schuld
R
R
Joyner
C D
CD
Morris
A L
AL
Lai
C
C
Théroux
P
P
Marquis
J F
JF
Chan
Y K
YK
Venkatesh
G
G
Jessel
A
A
D000789:Angina, Unstable / Q000517:prevention & control*; D000925:Anticoagulants / Q000008:administration & dosage*; D000990:Antithrombin III / Q000032:analysis; D000991:Antithrombins / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation; D002170:Canada; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006493:Heparin / Q000008:administration & dosage*; D006629:Hirudins / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000517:prevention & control*; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000378:metabolism; D011516:Prothrombin / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage
D000925:Anticoagulants; D000991:Antithrombins; D015415:Biomarkers; D005343:Fibrinolytic Agents; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C045879:prothrombin fragment 1.2; D000990:Antithrombin III; D011516:Prothrombin; D006493:Heparin