Anticoagulants Evaluated for Treatment of HIT

Current treatment of HIT focuses on agents that rapidly control thrombin generation (Fig. 2) (see Chapters 13-17). Table 2 lists the available evidence on efficacy for three such agents: danaparoid, lepirudin, and argatroban (listed in the order the drugs became available), which are approved for use in HIT in various countries. Danaparoid is an indirect (antithrombin-dependent) inhibitor of factor Xa and, to a lesser extent, thrombin, whereas lepirudin and argatroban inhibit thrombin directly and without the need for a cofactor, i.e., they are classified as direct thrombin inhibitors (DTIs). Only one RCT for the management of HIT has been performed. This study compared danaparoid with dextran 70 for the treatment of HIT-associated thrombosis (Chong et al., 2001) (see Chapter 13). As the study was small and open-label, we have listed it as supporting a level 1B recommendation.

Hit Fibrin

FIGURE 2 Thrombin generation and fibrin formation in acute HIT. (A) Thrombin generation, as assessed by TAT complexes, is markedly increased in acute HIT (mean, 55 ng/mL; normal, <4.1 ng/mL). Whereas danaparoid reduces thrombin generation in these patients, the defibrinogen-ating snake venom, ancrod, does not. (B) Levels of cross-linked fibrin degradation products (D-dimer) are increased in patients with acute HIT (mean, 4-5mg/mL; normal, <0.5mg/mL). Whereas danaparoid reduces D-dimer levels, ancrod increases their levels. Baseline (B) samples were obtained at diagnosis of HIT and before treatment with danaparoid or ancrod; subsequent values are shown for day 1 (D1, 1-24 h postinitiation of treatment), day 2 (D2, 25-48 h), and day 3 (D3, 49-72 h). *p < 0.001, **p < 0.002. Abbreviations: HIT, heparin-induced thrombocytopenia; TAT, thrombin-antithrombin. Source: From Warkentin, 1998.

FIGURE 2 Thrombin generation and fibrin formation in acute HIT. (A) Thrombin generation, as assessed by TAT complexes, is markedly increased in acute HIT (mean, 55 ng/mL; normal, <4.1 ng/mL). Whereas danaparoid reduces thrombin generation in these patients, the defibrinogen-ating snake venom, ancrod, does not. (B) Levels of cross-linked fibrin degradation products (D-dimer) are increased in patients with acute HIT (mean, 4-5mg/mL; normal, <0.5mg/mL). Whereas danaparoid reduces D-dimer levels, ancrod increases their levels. Baseline (B) samples were obtained at diagnosis of HIT and before treatment with danaparoid or ancrod; subsequent values are shown for day 1 (D1, 1-24 h postinitiation of treatment), day 2 (D2, 25-48 h), and day 3 (D3, 49-72 h). *p < 0.001, **p < 0.002. Abbreviations: HIT, heparin-induced thrombocytopenia; TAT, thrombin-antithrombin. Source: From Warkentin, 1998.

TABLE 2 Rapidly Acting Anticoagulants for the Treatment of HIT: Main Studies

Supporting Efficacy

Drug Studies

Danaparoid Randomized controlled trial comparing danaparoid + warfarin vs. dextran 70 + warfarin (Chong et al., 2001) Retrospective comparison of danaparoid vs. lepirudin (Farner et al., 2001) Retrospective comparison of danaparoid vs. ancrod and/or coumarin

(Lubenow et al., 2006) Compassionate release program (Magnani, 1993, 1997; Magnani and Gallus, 2006)

Lepirudin HAT-1: prospective cohort study with historical controls (Greinacher et al., 1999a)

HAT-2: prospective cohort study with historical controls (Greinacher et al., 1999b) Meta-analysis of HAT-1 and -2 studies (Greinacher et al., 2000) HAT-3: prospective cohort study with historical controls (Lubenow et al., 2005) Meta-analysis of HAT-1, -2, and -3 studies (Lubenow et al., 2005) Retrospective comparison of lepirudin (prospective cohort) and danaparoid

(contemporaneous controls) (Farner et al., 2001) Post-marketing surveillance (Lubenow et al., 2002a)

Argatroban Arg-911: prospective cohort study with historical controls (Lewis et al., 2001) Arg-915: prospective cohort study with historical controls (Lewis et al., 2003) Meta-analysis of Arg-911, -915 and -915X studies, including use of "thrombotic endpoint" (Lewis et al., 2006) Argatroban substudies (data from Arg-911, -915, and -915X studies) Argatroban dose adjustments (Verme-Gibboney and Hursting, 2003) Patients with thrombotic stroke (LaMonte et al., 2004) Patients with a history of HIT (Matthai et al., 2005) Patients with venous thromboembolism (Begelman et al., 2005) Patients undergoing argatroban/warfarin overlap (Bartholomew and Hursting,

2005; Hursting et al., 2005) Patients undergoing renal replacement therapy (Reddy et al., 2005) Patients with renal dysfunction (Guzzi et al., 2006) Patients with hepatic dysfunction (Levine et al., 2006) Patients who are critically ill (Gray et al., 2007) Patients with coronary artery disease (Jang et al., 2007) Cost-effectiveness analysis (Arnold et al., 2006)

Abbreviations: HAT, heparin-associated thrombocytopenia; HIT, heparin-induced thrombocytopenia.

Recommendation. Therapeutic-dose anticoagulation with a rapidly acting anticoagulant, e.g., danaparoid (grade 1B), lepirudin (grade 1C), or argatroban (grade 1C), should be given to a patient with thrombosis complicating acute HIT. Treatment should not be delayed pending laboratory confirmation in a patient strongly suspected (or confirmed) to have HIT.

Availability of anticoagulants varies in different countries. Although currently not available in the U.S., danaparoid is the alternative anticoagulant agent available in most countries worldwide. Bivalirudin and fondaparinux are also potential options for managing some patients with HIT, but current information is still too preliminary to allow for broad recommendations (see Chapters 16 and 17).

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