Discussion of Prospective Studies of Argatroban in HIT

Consistently in these studies, argatroban therapy, compared with historical controls, produced significant benefits in clinical outcomes in patients having HIT with or without thrombosis. Argatroban, versus control, was effective in reducing the all-cause composite of death, amputation, or new thrombosis as well as the thrombosis-related composite of death due to thrombosis, amputation secondary to HIT-associated thrombosis, or new thrombosis; lowering mortality from thrombosis and preventing new thrombotic events—without increasing bleeding.

Study patients had clinically diagnosed HIT, and laboratory confirmation of HIT was not required for their treatment. This study design simulated the "real world" of managing HIT, wherein guidelines recommend initiating alternative anticoagulation upon strong clinical suspicion, without delay for laboratory confirmation of HIT (Warkentin and Greinacher, 2004). In ARG-911, HIT antibodies were demonstrated in most, but not all, patients. Argatroban therefore is an effective antithrombotic agent in clinically diagnosed, albeit not always laboratory-confirmed, HIT. Argatroban also provided effective anticoagulation in patients with a history of HIT who required acute anticoagulation for a variety of indications.

Across the studies, the overall major bleeding rate was 6% in argatroban-treated patients, similar to that (7%, p = 0.74) in the control (Lewis et al., 2006), and no patient experienced intracranial hemorrhage while on argatroban therapy. By indirect comparison, major bleeding associated with lepirudin therapy in HIT is 17.6% (Lubenow et al., 2005). However, these DTIs remain to be compared directly, and conclusions about their relative safety profiles cannot be reached. Argatroban was well tolerated upon reexposure.

These studies supported the approval of argatroban as an anticoagulant for the prophylaxis or treatment of thrombosis in patients with HIT, with the per-protocol dosing regimen adopted as the recommended dosing schedule. As practical experience with argatroban has increased during the past several years, some refinements to its dosing and monitoring regimen have been suggested, as discussed in the following section, which continue to optimize its safety in this setting.

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