Apixaban Therapy For Asian Patients With Cancer-related Venous Thromboembolism: A Short Communication

Yoshinori Imamura^*
*Correspondence: Yoshinori Imamura, Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, Japan, Tel: +81-78-382-5820, Email:

About the Study

Venous Thromboembolism (VTE) is the most common type of thromboembolism and is a severe and potentially fatal condition among patients with cancer [1,2]. While anticoagulant therapy is the recommended standard of care for cancer-associated VTE, it is complicated by both an elevated risk of recurrent VTE and bleeding events [3]. Over the past few years, several randomized control trials have been reported [4-8]. And numerous guidelines now recommend direct oral anticoagulants in addition to low molecular weight heparins as the new standard treatment for this disease without high risk of gastrointestinal or genitourinary bleeding [9-11]. However, few Asian patients were included in these pivotal trials, and no Asianspecific information is available.

Against this background, we conducted a phase II trial to evaluate the safety and efficacy of a standard dose of apixaban in Japanese patients with cancer-associated VTE (UMIN000028447). Despite having similar eligibility criteria to previous phase III trials [6,7,12,13], the study was terminated due to safety concerns after only 27 patients had been enrolled [14]. International Society on Thrombosis and Haemostasis-defined major and Clinically Relevant Non-Major (CRNM) bleeding occurred in five (19%) and two patients (7%), respectively, giving the primary endpoint of major/CRNM bleeding occurred in 26% (95% CI, 11-46). All major bleeding episodes observed during the maintenance phase (11-145 days). Although no recurrent VTE or VTE-related death was observed, the incidence of major bleeding events in this study was unexpectedly high.

This high incidence of bleeding among Japanese patients with cancer-associated VTE treated with apixaban may be explained by pharmacokinetic and pharmacodynamic considerations. Simulations based on a population pharmacokinetic model of apixaban demonstrated that Cmax and AUC were approximately 42% and 50% higher, respectively, in typical Japanese VTE subjects than typical non-Asian VTE subjects [15]. In addition, cancer patients tend to have more bleeding risk factors applicable to the dose adjustment criteria for apixaban in the prevention of stroke in atrial fibrillation, such as advanced age, low body weight, and renal dysfunction [16].

Furthermore, East Asian patients have a reduced anti-ischemic effect and increased risk of bleeding during antithrombotic therapies compared to Caucasian patients [17]. A representative practical example is cardioembolic stroke prevention with warfarin: a major difference is found in the lower prothrombin time-international normalized ratio target in Japanese subjects aged >70 years (1.6-2.6) versus those in Europeans (2.0-3.0) [18]. Unlike for the prevention of stroke in atrial fibrillation, dose reduction of apixaban is not recommended for VTE; nevertheless, apixaban at the standard dose may be an overdose for Japanese patients with cancer-associated VTE [19].

In this regard, we are now conducting another open-label, nonrandomized, multicenter phase II trial to assess the safety and efficacy of a reduced dose of apixaban in Japanese patients with cancer-associated VTE, using almost the same eligibility criteria and endpoints as in our previous study (jRCTs051220095). Apixaban treatment will be initiated at 10 mg (standard dosage) twice daily for 1 week, followed by 2.5 mg (half of standard dosage) twice daily for 23 weeks. These doses were selected for the following reasons:

▪ AUC of apixaban in Japanese patients with cancer-associated VTE is estimated to be approximately twice that of non-Asian patients with noncancer VTE [15,19,20].

▪ Extended anticoagulation with apixaban (2.5 mg twice daily) in Western patients reduced risk of recurrent VTE without increasing the rate of major bleeding [21].

▪ Prophylactic apixaban (2.5 mg twice daily) in Western patients also reduced risk of cancer-associated VTE [22].

▪ Fatal pulmonary embolism in patients with VTE increases until day 7, after which the risk of fatal bleeding is higher [23].

▪ Without initial intensifying therapy, the rate of initial VTE recurrence was elevated [24,25].

▪ No recurrent VTE or VTE-related death was observed, and all major bleeding was observed during the maintenance phase in our previous study [14].

Through this ongoing study, we aim to complement the evidence for apixaban in Asian patients and develop a novel anticoagulation strategy with a better risk-benefit balance for patients at high risk of bleeding, such as those with intact gastrointestinal disease.

Conclusion

In conclusion, Asian patients may have a higher risk of bleeding during apixaban therapy than Western patients due to pharmacokinetic and pharmacodynamic reasons. Although the pivotal phase III trials have been provided the concrete evidence of apixaban for Western patients with cancer-associated VTE, Asian-specific data are still warranted. Our ongoing phase II trial of a reduced dose of apixaban in Japanese patients with cancer-associated VTE could be a clue for a more balanced anti-coagulant therapy for patients with a high risk of bleeding.

Conflict of Interest

Yoshinori Imamura has received speaker bureau/honoraria from Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, and Pfizer.

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