Transitioning from Argatroban to Warfarin Therapy in Patients with Heparin-induced Thrombocytopenia

Abstract

Argatroban, a direct thrombin inhibitor used for thromboprophylaxis or treatment in heparin-induced thrombocytopenia (HIT), is routinely monitored using the activated partial thromboplastin time (aPTT) yet also prolongs the international normalized ratio (INR). Peritransitional INRs, aPTTs, anticoagulant dosing patterns, and outcomes were evaluated in 165 HIT patients who were transitioned, without guidelines, from argatroban to warfarin therapy. Argatroban (median doses: 1.5-2.0 mcg/kg/min) and warfarin (median dose: 5 mg initially with 3.8 mg/day thereafter) overlapped a median 4 days. Median (5-95th percentile) aPTTs (in seconds) and INRs, respectively, were 59.8 (38.8-82.9) and 3.2 (1.7-7.0) during argatroban monotherapy, 68.6 (44.5-104) and 5.3 (2.4-16) maximally during cotherapy, 59.9 (38.7-92.2) and 4.0 (2.2-11.6) immediately before argatroban cessation during cotherapy, and 36.0 (25.6-60.2) and 2.3 (1.3-7.3) within a median 10-12 hours after argatroban cessation. Major bleeding occurred in 1 (0.6%) patient pretransitionally and no patient during or after cotherapy. Eighteen (10.9%) patients experienced 19 peritransitional adverse outcomes (one death, two amputations, 16 new thromboses); these patients had more severe HIT than event-free patients (median baseline platelet count, 39 vs. 83 x 10(9)/L). Of 108 patients with post-transitional INR data, 43 achieved a therapeutic INR (prospectively defined as 1.9-3.5), 34 were subtherapeutic, and 31 were supratherapeutic, with no across-group trend in new thrombosis. Hence in the absence of guidelines, physicians transfer patients from argatroban to warfarin therapy with acceptably low complication rates in HIT, without systematically over- or under-dosing warfarin. Furthermore, INRs greater than 5 commonly occur in HIT patients during argatroban monotherapy and argatroban/warfarin cotherapy, without major bleeding.

Treatment and Prevention of Heparin-Induced Thrombocytopenia

“…There are, however, data suggesting that premature discontinuation of the thrombin or factor Xa inhibitor may result in an increased risk of recurrent thrombosis. Hursting et al 115 found that seven out of 16 new episodes of thrombosis occurred on the day after argatroban was discontinued in a subgroup of patients who received argatroban and warfarin. Of the patients who had an adverse event during the transition to warfarin, 70% had received , 5 days of treatment with argatroban (5 days is the accepted minimum length of time necessary for warfarin to reduce prothrombin levels to those commonly associated with effective anticoagulation).…”

Transitioning from Argatroban to Warfarin in Heparin-Induced Thrombocytopenia: An Analysis of Outcomes in Patients with Elevated International Normalized Ratio (INR)

“…The combined use of argatroban and warfarin increases the INR greater than that observed with warfarin alone, and a cotherapy INR > 4 (if the argatroban dose is ≤ 2 mcg/kg/min) generally reflects a therapeutic INR on warfarin alone [21]. Although INRs greater than 4.6 on warfarin alone are associated with a significantly greater risk of hemorrhage [22], this paradigm does not apply to healthy subjects [17] or patients with HIT [23] receiving argatroban and warfarin therapy. Our analysis provides additional information on the clinical outcomes, including bleeding, of 111 patients with HIT transitioned from argatroban to warfarin during two prospective trials.…”

“…The INR should then be repeated 4 to 6 hours later, when the anticoagulant effects of argatroban would be expected to be negligible, to ensure a therapeutic value on warfarin alone [20]. Although INRs >4 while on warfarin are historically associated with a significantly increased risk of bleeding [21,22], INRs >7 while on argatroban and warfarin cotherapy have been reported to occur without bleeding in both healthy subjects [17] and HIT patients [23]. However, the clinical outcomes in HIT patients achieving an INR >4 during combined argatroban ≤2 mcg/kg/min and warfarin therapies are not well described.…”

Erratum

“…112,113 The VKAs should be initiated when platelet counts have normalized to a steady state, then brought on underbridged with a DTI. [114][115][116] There is emerging evidence that the newly developed small molecule anticoagulants including apixaban, dabigatran, edoxaban, otamixaban, and rivaroxaban may become new immediate and long-term treatment options for thrombosis in patients with HIT. 109 …”