Treatment Of Isolated

Isolated HIT refers to HIT diagnosed on the basis of thrombocytopenia alone, rather than because of HIT-associated thrombosis. Often, the initial reason for administering heparin includes routine postoperative prophylaxis or a medical indication such as acute stroke or myocardial infarction. Until the early 2000s, the standard approach upon suspecting HIT in such patients was discontinuation of heparin, sometimes with substitution of oral anticoagulants.

A. Natural History of Isolated HIT

During the mid-1990s, new data indicated a high risk for venous thrombosis in postoperative orthopedic patients who developed HIT, particularly for pulmonary embolism (Warkentin et al., 1995) (see Chapter 2). Thus, HIT came to be viewed as a dramatic, albeit transient, prothrombotic state, even when the original indication for heparin was routine antithrombotic prophylaxis.

In July 1992, the author became aware of a 68-yr-old patient whose platelet count fell from 151 to 51 X 109/L between days 5 and 8 following coronary artery bypass surgery, during routine postoperative heparin antithrombotic prophylaxis. The heparin was stopped, and laboratory testing confirmed HIT. The platelet count recovered, and the patient was discharged to home on postoperative day 12. Three days later, the patient complained of dyspnea, and then died suddenly. Postmortem examination showed massive pulmonary embolism. This tragic outcome prompted the question: Is mere cessation of heparin sufficient for a patient with isolated HIT?

To address this problem, the author performed a study of the natural history of HIT (Warkentin and Kelton, 1996). From a database of patients with serologi-cally proven HIT, a 62-patient cohort with isolated HIT was identified: the cumulative 30-day thrombotic event rate was 52.8% (see Fig. 2 in Chapter 3). The rate of thrombosis was similarly high whether heparin was simply stopped or substituted with warfarin.

Similar findings were reported later by Wallis and colleagues (1999) from Loyola University. These investigators also found a high frequency of subsequent thrombosis (43 of 113, or 38%) in patients with isolated HIT managed by discontinuation of heparin. Surprisingly, a trend was observed for the highest risk of thrombosis in those patients in whom heparin was stopped most promptly (see Table 7 in Chapter 3).

Further evidence supporting an unfavorable natural history of untreated HIT was provided by a prospective cohort study (Greinacher et al., 2000). These investigators found that the thrombotic event rate was 6.1% per day during the mean 1.7-day interval between diagnosis of HIT (and cessation of heparin) and initiation of lepirudin therapy. This event rate corresponded closely to the 10% rate of thrombosis observed in the Hamilton study in the first 48 h following diagnosis of isolated HIT (Warkentin and Kelton, 1996).

B. Argatroban

A synthetic small-molecule thrombin inhibitor derived from L-arginine, now known as argatroban, was used in Japan during the 1980s as a treatment for chronic arterial occlusion (Tanabe, 1986). During this time, argatroban also underwent investigation as treatment for HIT in Japan, particularly in the setting of hemodialysis (Matsuo et al., 1988). In 1993, exclusive rights to the compound for the United States and Canada were acquired from Mitsubishi-Tokyo Pharmaceuticals, Inc. by Texas Biotechnology Corporation (TBC) of Houston. In 1995, clinical evaluation of this agent for HIT began in the United States, using a prospective, multicenter, open-label design with historical controls, the ARG-911 study (Lewis et al., 2001) (see Chapter 15). Two groups of patients were studied: HIT without thrombosis (i.e., isolated HIT) and HIT complicated by thrombosis (heparin-induced thrombocytopenia/thrombosis syndrome [HITTS]). Eligibility was based on clinical suspicion of HIT, and serological confirmation of the diagnosis, therefore, was not required. Both patient groups received the identical therapeutic-dose regimen of argatroban (initially, 2 mg/kg/min, then adjusted by activated partial thromboplastin time [aPTT]). The favorable results of the ARG-911 and subsequent studies (ARG-915, ARG-915X) led to the approval of argatroban on June 30, 2000, by the U.S. Food and Drug Administration (FDA) as "anticoagulant for prophylaxis or treatment of thrombosis in patients with HIT" (Table 1). Thus, for the first time in the United States, a drug was approved for the novel indication of prevention of thrombosis in isolated HIT. A marketing partnership between TBC (now, Encysive) and SmithKline Beecham (now, GlaxoSmithKline) commenced in August 1997. Marketing of argatroban began on November 13, 2000. More recently (April, 2002) argatroban received approval for anticoagulation in patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI).

C. Therapeutic-Dose Anticoagulation for Isolated HIT

The approval by the FDA of identical therapeutic-dose regimens of argatroban for both prophylaxis and treatment of HIT highlighted the emerging view that HIT is a high-risk prothrombotic state. This contrasted with the earlier concept that HIT was generally benign, provided that thrombocytopenia was promptly recognized and heparin discontinued. Further support for the new view included studies showing HIT to be a profound hypercoagulable state (markedly elevated molecular markers of in vivo thrombin generation) (Warkentin et al., 1997; Greinacher et al., 2000) and recognition that many patients already have subclini-cal deep vein thrombosis at the time that isolated HIT is first recognized (Tardy et al., 1999).

Indeed, therapeutic doses of an alternative anticoagulant might be generally applicable for treatment of most patients with isolated HIT (Farner et al., 2001) (see Chapters 12-15). For example, although the prophylactic-dose regimen of lepi-rudin for HIT is initially lower than the therapeutic-dose regimen (0.10mg/kg/h, rather than 0.15 mg/kg/h, and without an initial lepirudin bolus), subsequent dose adjustments are made using the aPTT; thus, the eventual infusion rate approaches the one given using the therapeutic regimen (see Chapters 12 and 14 for current recommendations regarding dosing of lepirudin). A high success rate (91.4%) was observed using such "prophylactic" doses of lepirudin for isolated HIT (Farner et al., 2001).

In contrast, the prophylactic-dose regimen using danaparoid (750 U bid or tid) may be somewhat less effective than therapeutic-dose danaparoid (usually, 150200 U/h after an initial bolus) for preventing new thromboembolic complications in acute HIT: 81.4% versus 91.6% (Farner et al., 2001) (see Chapter 13). If this difference is real, it could be explained by greater efficacy of the therapeutic-dose regimen, in which at least twice as much danaparoid is usually given (3600-4800 vs. 1500-2250 U/24h). The implication of Farner's study is that the approved prophylactic-dose regimen of danaparoid may not be optimal, either when used for its approved indication in Europe (i.e., prevention of HIT-associated thrombosis) or for the corresponding "off-label" use for HIT elsewhere (Warkentin, 2001) (see Chapter 12).

D. Bivalirudin

The 20-amino acid hirudin analog, bivalirudin (Angiomax, formerly, Hirulog), was first used over 10 yr ago in the United States on a compassionate use basis for the treatment of four patients with HIT (Nand, 1993; Reid and Alving, l994; Chamberlin et al., 1995). Since then, it has undergone limited off-label use for the treatment of HIT (Francis et al., 2003), often in patients with both renal and hepatic compromise (see Chapter 16). In contrast to its limited use in managing HIT, bivalirudin is widely used for anticoagulation in the setting of percutaneous transluminal coronary angioplasty (PTCA) as well as other types of PCI (Warkentin and Koster, 2005). Indeed, bivalirudin is the only direct thrombin inhibitor that is approved for an indication beyond that involving HIT (Table 1). In November 2005, approval was also granted for use of bivalirudin for anticoagulation of patients with (or at risk of) HIT (or HIT-associated thrombosis) undergoing PCI (Table 1).

IX. REDUCING THE RISK OF HIT A. Low Molecular Weight Heparin

For over 50 yr, UFH has been used in numerous clinical situations. However, UFH has several limitations, and efforts to develop potentially superior LMWH preparations began during the 1980s. Advantages of LMWH included better pharmacokinetics (e.g., improved bioavailability, predictable and stable dose response obviating the need for monitoring, lower risk of resistance to anticoagulation, longer plasma half-life) and favorable benefit-risk ratios in experimental animals (Hirsh, 1994; Hirsh et al., 2001). Advantages of UFH include its low cost, widely available

TABLE 2 U.S. Approvals for Enoxaparin and Fondaparinux

Date of U.S. approval

Usea

Enoxaparinb

Fondaparinux

Prophylaxis after hip replacement surgery Prophylaxis after knee replacement surgery Prophylaxis after hip fracture surgery Extended prophylaxis after hip replacement surgery Extended prophylaxis after hip fracture surgery Prophylaxis after general (abdominal) surgery Prophylaxis for unstable angina and non-Q wave myocardial infarction (given together with aspirin) Acute deep-vein thrombosis, with or without pulmonary embolism,d,e together with warfarin Prophylaxis in medical patients at risk for deep-vein thrombosis or pulmonary embolism

March 29, 1993 March 9, 1995

January 30, 1998

May 6, 1997 March 27, 1998

December 7, 2001 December 7, 2001 December 7, 2001

June 17, 2003 May 26, 2005 Under regulatory reviewc

December 31, lees May 28, 2004

November 17, 2000

aUse described may not necessarily conform precisely to the wording of the approved indications. bOther LMWH preparations (dalteparin, tinzaparin) have been approved (at later times) for various indications (not shown).

cFondaparinux has been recently studied extensively for treatment of patients with acute coronary syndrome and will undergo FDA review for use in that setting.

dWording of approved indication for enoxaparin Includes "inpatient" treatment of acute deep vein thrombosis with or without pulmonary embolism and "outpatient" treatment of acute deep vein thrombosis without pulmonary embolism.

eWording of approved indication for fondaparinux: "for the treatment of acute deep vein thrombosis when administered in conjunction with warfarin sodium; and the treatment of acute pulmonary embolism when administered in conjunction with warfarin sodium when initial therapy is administered in the hospital".

laboratory monitoring, and potential for neutralization using protamine. But the question remained: Was the risk of HIT lower with LMWH? This was an important and relevant question, particularly as differences in risk of HIT exist even among UFH preparations derived from different animal sources (see Chapter 3). As discussed earlier (Sec. V.B), there is indeed evidence that LMWH has both a lower risk of HIT antibody formation and (more importantly) a lower risk of HIT and HIT-associated thrombosis. Table 2 provides a historical timeline of the introduction of the LMWH enoxaparin in the United States in various clinical situations.

B. Fondaparinux

Fondaparinux (Arixtra®) is a synthetic pentasaccharide modeled after the anti-thrombin-binding site of heparin. It selectively binds to antithrombin, causing rapid and specific inhibition of factor Xa. In contrast to LMWH, HIT antibodies fail to recognize PF4 mixed with fondaparinux, both in platelet activation and PF4-dependent antigen assays (Warkentin et al., 2005).

Interestingly, evidence suggests that although HIT antibody formation occasionally occurs in association with fondaparinux use, such antibodies fail to react in HIT assays in which fondaparinux replaces UFH or LMWH in vitro (Warkentin et al., 2005; Pouplard et al., 2005). Thus, this pentasaccharide anticoagulant seems unlikely to cause an adverse effect resembling HIT. Although no patients developed HIT with either LMWH (enoxaparin) or fondaparinux in the two orthopedic surgery trials reported (Warkentin et al., 2005), the duration of anticoagulant therapy may have been too brief to reveal a true difference in risk of immune thrombocytopenia between LMWH (frequency 0.1-1.0%) and fondaparinux (anticipated negligible frequency). Fondaparinux is approved in the United States, Canada, and the European Union for antithrombotic prophylaxis in orthopedic surgery as well as other clinical situations (Table 2).

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