Transitioning from Argatroban to Warfarin in Heparin-Induced Thrombocytopenia: An Analysis of Outcomes in Patients with Elevated International Normalized Ratio (INR)
Background: Heparin-induced thrombocytopenia (HIT) can lead to catastrophic thromboembolic complications and requires treatment with an alternative, rapidly active anticoagulant, such as a direct thrombin inhibitor (DTI), either to prevent or treat these complications. Switching to oral warfarin after initial treatment with a DTI is necessary in most patients. Most references related to warfarin suggest that an increased risk for bleeding will occur with elevated international normalized ratios (INRs) > 4.6. In patients receiving argatroban, it is not uncommon to achieve an INR > 4 during this transition.
Because the clinical outcomes in patients achieving an INR > 4 during combined argatroban/warfarin therapies for HIT are not well described, we evaluated the clinical outcomes of 111 patients with this phenomenon.
Methods: We identified patients from the prospective studies of argatroban anticoagulation, Argatroban-911 and Argatroban–915. Data collected from these studies included death from all causes, amputation, new thrombosis, major bleeding, INR values, argatroban doses, aPTT values, platelet counts, and duration of therapy.
Results: Patients were on argatroban monotherapy for a median of 2.8 (0.1–8.1) days, and on cotherapy for a median of 3.7 (0.9–12.8) days. The median platelet count was 70.9 (18–325) × 109/L at the time of HIT diagnosis and increased to 94 (30–324) × 109/L by the time warfarin was initiated. At a median argatroban dose of 1.4 (0.2–2.0) mcg/kg/min, the maximum INR ranged from 4.1 to 21.2 (median 6.4, n = 111) and the corresponding aPTT ranged from 48.1 to 105 (median 71, n = 93) seconds. After argatroban cessation, the first recorded INR within 4 to 24 hours ranged from 1.5 to 12.5 (median 2.9, n = 58). Adverse clinical outcomes occurred in 9 (8.1%) patients during cotherapy and in 12 (10.8%) patients after argatroban anticoagulation was discontinued. Adverse clinical outcomes included 7 cases of new thrombosis, 3 amputations, 12 deaths and 1 major bleed. Eleven of 12 (91.7%) patients died due to causes other than thrombosis, and most deaths (83%) occurred following cotherapy. Five (4.5%) patients developed new thrombosis during argatroban/warfarin cotherapy despite an INR > 4. In contrast only 1 (0.9%) patient experienced major bleeding.
Conclusion: In patients receiving argatroban/warfarin cotherapy and with an elevated INR > 4, the risk for thrombosis exceeds the risk of bleeding. Traditional paradigms concerning elevated INRs and warfarin may need to be redesigned for the patient population on cotherapy with direct thrombin inhibitors.
Abbreviated Abstract. The clinical outcomes of 111 patients with INRs > 4 while on combined argatroban (dose ≤ 2 mcg/kg/min) and warfarin were evaluated. Adverse clinical outcomes (7 new thrombosis, 3 amputations, 12 deaths and 1 major bleed) occurred in 21 patients. Eleven deaths were due to causes other than thrombosis. Five patients developed new thrombosis while only 1 had major bleeding. The risk for thrombosis exceeds the risk of bleeding in patients with HIT despite an INR > 4.
Key Wordsargatroban warfarin international normalized ratio (INR) heparin-induced thrombocytopenia
Warkentin TE, Sheppard JI, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood
Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med
Hirsh J, Heddle N, Kelton JG. Treatment of heparin induced thrombocytopenia: A critical review. Arch Int Med
Nand S, Wong W, Yuen B, Yetter A, Schmulbach E, Gross Fisher S. Heparin-induced thrombocytopenia with thrombosis: Incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol
Warkentin TE. Heparin-induced thrombocytopenia: Pathogenesis and management. Br J Haematol
Messmore H, Jeske W, Wehrmacher W, Walenga J. Benefit-risk assessment of treatments for heparin-induced thrombocytopenia. Drug Safety
Greinacher A, Volpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: A prospective study. Circulation
Greinacher A, Janssens U, Berg G, et al. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Heparin-Associated Thrombocytopenia Study (HAT) investigators. Circulation
Lewis BE, Wallis DE, Berkowitz SD, et al. ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation
Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG. Argatroban-915 Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med
Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med
Warkentin TE, Sikov WM, Lillicrap DP. Multicentric warfarin-induced skin necrosis complicating heparin-induced thrombocytopenia. Am J Hematol
Warkentin TE, Whitlock RP, Teoh KH. Warfarin-associated multiple digital necrosis complicating heparin-induced thrombocytopenia and Raynaud’s phenomenon after aortic valve replacement for adenocarcinoma-associated thrombotic endocarditis. Am J Hematol
Srinivasan AF, Rice L, Bartholomew JR. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Int Med
Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: Recognition, treatment, and prevention. Chest
Hursting MJ, Zehnder JL, Joffrion, JL, et al. The International Normalized Ratio during concurrent warfarin and argatroban anticoagulation: Differential contributions of each agent and effects of the choice of thromboplastin used. Clin Chem
. 1999;45:409–412.PubMedGoogle Scholar
Sheth SB, DiCicco RA, Hursting MJ, et al. Interpreting the international normalized ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost
Mattson C, Menschiek-Lundin A, Wahlander K, et al. Effect of melagatran on prothrombin time assays depends on the sensitivity of the thromboplastin and the final dilution of the plasma sample. Thromb Haemost
Fenyvesi T, Joerg I, Harenberg J. Influence of lepirudin, argatroban, and melagatran on prothrombin time and additional effect of oral anticoagulation. Clin Chem
Product Information. Argatroban. GlaxoSmithKline Research Triangle Park, NC November 2003.Google Scholar
Fihn SD, McDonell M, Martin D. Risk factors for complications of chronic anticoagulation: A multicenter study. Ann Intern Med
Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med
Hursting MJ, Lewis BE, MacFarlane DE. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemostas
2004, in press.Google Scholar
Brown PM, Hursting MJ. Lack of pharmacokinetic interactions between argatroban and warfarin. Am J Health-Syst Pharm
Hoppensteadt DA, Kahn S, Fareed J. Factor X values as a means to assess the extent of oral anticoagulation in patients receiving antithrombin drugs. Clin Chem
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