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Argatroban-911 - ARG-911
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: 304
Mean Follow Up: 37 days
Mean Patient Age: Mean age 61 years
Female: 54
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; or documented history of positive HIT antibody (ie, latent disease) and required anticoagulation in the absence of thrombocytopenia or heparin challenge.
Exclusions:
Unexplained aPTT >2 times control at baseline, documented coagulation disorder or bleeding diathesis unrelated to HIT with thrombosis, 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.
Primary Endpoints:
Composite of all-cause death, all-cause amputation, or new thrombosis.
Secondary Endpoints:
Individual components of the composite endpoint, death caused by thrombosis, achievement of adequate anticoagulation, defined as aPTT ≥1.5 times baseline, and resolution of thrombocytopenia.
Drug/Procedures Used:
Patients with HIT with isolated thrombocytopenia (n=160) or HIT with thrombosis syndrome (HITTS) (n=144) 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=147) or with HITTS (n=46).
Principal Findings:
Median platelet count at baseline was 82 x 10^9/L in the argatroban-treated HIT patients and 66 x 10^9/L in the argatroban-treated HITTS patients, lower than the historical controls (111 and 94 x 10^9/L, respectively). The majority of the patients had active HIT, with only 10% classified as latent HIT but with a positive HIT antibody test and requiring anticoagulation. The mean duration of therapy with argatroban was 5.3 days in HIT patients and 5.9 days in HITTS patients, with 83% 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 (25.6% vs 38.8%, p=0.014). In HITTS patients, the primary composite endpoint trended lower with argatroban compared with historical controls but did not reach statistical significance (43.8% vs 56.5%, p=0.13). Among the components of the composite, in HIT patients argatroban was associated with a reduction in new thrombosis (6.9% vs 15.0%, p=0.027) with no difference in death (16.9% vs 21.8%, p=0.311) or amputation (1.9% vs 2.0%, p=1.0) compared with historical control. In HITTS patients, none of the individual components of the composite differed between argatroban treated patients and historical controls: new thrombosis (14.6% v s 19.6%, p=0.486), death (18.1% vs 28.3%, p=0.146), amputation (11.1% vs 8.7%, p=0.787). Thrombocytopenia was resolved more frequently in the argatroban-treated patients compared with historic controls (HIT: 81% vs 41%; HITTS: 69% vs 50%). There was no difference in major bleeding for argatroban-treated patients compared with historic controls (HIT: 3.1% vs 8.2%, p=0.078; HITTS: 11.1% vs 2.2%, p=0.077).
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.
References:
Lewis BE, et al. Argatroban Anticoagulant Therapy in Patients With Heparin-Induced Thrombocytopenia. Circulation. 2001;103:1838-1843.
Keywords: Pipecolic Acids, Platelet Count, Thrombosis, Partial Thromboplastin Time, Heparin, Hemorrhage, Thrombocytopenia
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