Research Article: Role of Factor Xa Inhibitors in Cancer-Associated Thrombosis: Any New Data?

Date Published: October 15, 2011

Publisher: Hindawi Publishing Corporation

Author(s): Ali Zalpour, Michael H. Kroll, Vahid Afshar-Kharghan, Syed Wamique Yusuf, Carmen Escalante.


The association between cancer and venous thromboembolism (VTE) has been well documented in the literature. Prevention and treatment of VTE in cancer patients is imperative. Typically, the mainstay regimen for VTE prevention and treatment has been anticoagulation therapy, unless contraindicated. This therapy consists of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), factor Xa inhibitor, or vitamin K antagonist (VKA). Current guidelines recommend LMWH over VKA for the treatment of VTE in cancer patients. Factor-specific anticoagulants have been proven safe and effective, and recently factor Xa inhibitors have emerged as a treatment alternative to heparins and VKA. Currently, three factor Xa inhibitors have been identified: fondaparinux (the only one approved so far by the US Food and Drug Administration), idraparinux (in clinical trials), and idrabiotaparinux (in clinical trials). This paper will examine the role of these agents, focusing on fondaparinux, for the prevention and treatment of VTE in cancer patients.

Partial Text

The association between cancer and venous thromboembolism (VTE) has been well recognized and established [1]. Cancer patients have a 4-fold higher risk of developing VTE than do patients without cancer, and chemotherapy increases that risk to 6-fold [2]. In cancer patients undergoing surgical procedures, rates of postoperative VTE can increase 2-fold greater than rates of postoperative VTE in patients without cancer [3]. Frequency of VTE has increased by up to 28% in years 1995 to 2003 in hospitalized cancer patients and with the higher mortality rates compared to those hospitalized cancer patients without VTE (16.3% versus 6.3%, P < 0.0001) [4]. Idraparinux, another long-acting factor Xa inhibitor (2.5 mg SQ weekly dose), currently is being investigated in clinical trial for the prevention and treatment of VTE. Idraparinux has a longer t1/2 (up to 60 days) and has no antidote (Table 2) [17, 18]. The van Gogh trial showed noninferiority of idraparinux versus standard of care (UFH with VKA) for VTE treatment (2.9% versus 3.0%;OR: 0.98, 95% CI: 0.63% to 1.50%). Major bleeding events in the idraparinux group versus standard-of-care group were 4.5% versus 7.0% (P = 0.004). In the PE arm of the study, the rate of recurrent PE in the idraparinux versus standard of care was 3.5% versus 1.6% (OR: 2.14, 95% CI: 1.21% to 3.78%), which did not meet the noninferiority criteria [71]. Recurrent VTE in six-month subgroup analysis of cancer patients enrolled in of the van Gogh trial was 2.5% in the idraparinux group compared to 6.4% in the standard of care group (hazard ration 0.39, 95%CI: 0.14–1.11). The rate of bleeding was comparable (OR 0.89, 95% CI: 0.50–1.59) [72]. These results need further investigation in forthcoming idraparinux trials. Currently, one case report of successful reversal of idraparinux with rVIIa (30 μg/kg) exists in the literature [73]. The role of idraparinux in cancer patients undergoing surgical procedures also needs to be investigated. Shorter acting anticoagulants such as heparins should be used in surgical settings where epidurals are indicated. Idrabiotaparinux is another long-acting factor Xa inhibitor (3.0 mg SQ weekly dose) that has a t1/2 of up to 60 days and has no antidote (Table 2). Addition of a biotin moiety to the molecule of idraparinux has been shown in animal studies to be neutralized by avidin (egg protein), an antidote in bleeding cases. A recent study of treatment of VTE (cancer patients comprised ∼5%) comparing idrabiotaparinux (3.0 mg SQ weekly) versus idraparinux (2.5 mg SQ weekly) for 180 days showed equal factor Xa inhibition, recurrent VTE of 2.3% versus 3.2% (difference of −0.9%, 95% CI: −3.2% to −1.4%), clinically relevant bleeding of 5.2% versus 7.3% (difference of −2.1%, 95% CI: −5.6% to −1.4%, P = 0.29), and a mortality rate of 1.6% versus 3.2% (difference of 1.7%, 95% CI: −3.9% to −0.5%). Three patients in the idrabiotaparinux group required avidin for planned procedures with favorable outcomes [74]. Overall results showed the comparative efficacy and safety of idrabiotaparinux to idraparinux. Further trials are needed to assess safety and efficacy of this agent in cancer patients. More targeted anticoagulants such as factor Xa inhibitors are being investigated. To date, fondaparinux has received FDA approval for the prevention and treatment of VTE. Such long-acting agents provide feasibility and better compliance than VKA or heparins. Evidence suggests that fondaparinux should be used in the acute phase of VTE treatment, but evidence of the efficacy and safety for long-term treatment is lacking, especially in cancer patients. Monitoring patients for bleeding, especially those at high risk for bleeding, is necessary owing to the fact that long-acting agent reversal is partially possible. Evidence of the newer, longer acting factor Xa inhibitors such as idraparinux and idrabiotaparinux is clearly lacking at present.   Source: