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Argatroban-915 - ARG-915
Description:
The goal of the study was to evaluate treatment with argatroban, a direct thrombin inhibitor, compared with historical controls among patients with heparin-induced thrombocytopenia (HIT).
Study Design
Study Design:
Patients Enrolled: 418
Mean Follow Up: 37 days
Mean Patient Age: Mean age 64 years
Female: 50
Patient Populations:
Presence of thrombocytopenia, defined as a platelet count <100 x 10^9/L, or a 50% reduction in count after heparin therapy with HIT as the only explanation.
Exclusions:
Unexplained aPTT >2 times control at baseline, documented coagulation disorder or bleeding diathesis unrelated to HIT, a lumbar puncture within the past 7 days, or a history of previous aneurysm, hemorrhagic stroke, or recent (within 6 months) thrombotic stroke unrelated to HIT with thrombosis, known bleeding site (unless the risk of thrombosis outweighed potential bleeding risk), terminal illness with life expectancy <2 weeks.
Primary Endpoints:
Composite of all-cause death, all-cause amputation, or new thrombosis.
Secondary Endpoints:
Individual components of the composite endpoint and death caused by thrombosis.
Drug/Procedures Used:
Patients with HIT (n=189) or HIT with thrombosis (HITTS) (n=229) were treated with argatroban 2 µg/kg/min intravenous infusion to maintain an activated partial thromboplastin time (aPTT) of 1.5 to 3. Data were compared to historical controls with HIT (n=139) or with HITTS (n=46).
Principal Findings:
Median platelet count at baseline was 84 x 10^9/L in the argatroban-treated HIT patients and 88 x 10^9/L in the argatroban-treated HITTS patients, lower than the historical controls (123 and 106 x 10^9/L, respectively). The mean duration of therapy with argatroban was 5.1 days in HIT patients and 7.1 days in HITTS patients, with 76% completing the protocol specified duration of therapy.
Compared with the historical control group, the primary composite endpoint of death, amputation, or new thrombosis in argatroban-treated HIT patients was significantly lower (28.0% vs 38.8%, p=0.04). In HITTS patients, the primary composite endpoint trended lower with argatroban compared with historical controls but did not reach statistical significance (41.5% vs 56.5%, p=0.07). Among the components of the composite, in HIT patients argatroban was associated with a reduction in new thrombosis (5.8% vs 23.0%, p<0.001) with no difference in death (19.0% vs 20.9%, p=0.78) or amputation (4.2% vs 2.9%, p=0.57) compared with historical control. In HITTS patients, new thrombosis occurred less frequently in argatroban-treated patients compared with historical controls (13.1% vs 34.8%, p<0.001) but there was no difference in death (23.1% vs 28.3%, p=0.45) or amputation (14.8% vs 10.9%, p=0.64). There was no difference in major bleeding for argatroban-treated patients compared with historic controls (HIT: 5.3% vs 8.6%, p=0.27; HITTS: 6.1% vs 2.2%, p=0.48).
Interpretation:
Among patients with heparin-induced thrombocytopenia, treatment with the direct thrombin inhibitor argatroban was associated with a reduction in the primary composite endpoint of death, amputation, or new thrombosis compared with historical controls, without an increase in bleeding.
One limitation of the study was the historical control design, which the authors noted was selected since they felt it was unethical to use placebo and not use any anticoagulation. Despite the lack of active control, argatroban is one of the few approved treatments for HIT. Results were very similar to the Argatroban-911 study by the same group, which also compared patients treated with argatroban for HIT to the same historical controls.
References:
Lewis BE, et al. Argatroban Anticoagulant in Patients With Heparin-Induced Thrombocytopenia. Arch Intern Med. 2003;163:1849-1856.
Keywords: Pipecolic Acids, Platelet Count, Thrombosis, Partial Thromboplastin Time, Heparin, Hemorrhage, Thrombocytopenia
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