Is there a role yet for new direct oral anticoagulants in cancer patients?

Malignancy and its associated management have long been recognised as significant risk factors for venous thromboembolism (VTE). The risk of VTE in cancer patients is increased by seven-fold, with approximately 5–20% of all cancer patients will develop VTE. Complex aetiology involving prothrombotic state of underlying tumour cells and the haemostatic sideeffects of oncological treatments including cytotoxic drugs, hormonal therapy, radiotherapy and surgery lead to difficulties in defining optimal VTE prevention and management in cancer patients. Nonetheless, the consequential morbidity and mortality dictate that its amelioration must remain a priority for clinicians. Currently, low-molecular weight heparins (LMWHs) are the preferred anticoagulants for the prophylaxis and treatment of VTE in cancer patients. Meanwhile, vitamin K antagonists (VKA) such as warfarin are advocated where high cost or poor renal function precludes the use of LMWHs in the treatment of VTE. Considering long-term treatment, LMWH demonstrates superior efficacy to warfarin. Recent meta-analysis by the Cochrane Collaboration on seven randomised controlled trials (RCTs) comparing LMWHs with VKAs found a statistically significant reduction in VTE (hazard ratio 0.47; 95% confidence interval, CI 0.32 to 0.71), but no significant difference in survival benefit, bleeding and thrombocytopenia. In addition, LMWHs hold a myriad of practical advantages over VKAs including fewer drug interactions, avoidance of frequent venepuncture and predictable effect especially in those with risk of gastrointestinal tract disturbance such as nausea, vomiting, diarrhoea and malabsorption. However, disadvantages include bruising and pain from daily injection, potential cost associated with requirement for district nurses and increased risk of thrombocytopenia and osteoporosis. The main advantages of VKAs are that they are effective in preventing recurrent VTE and are time proven. However, cancer patients have numerous complicating factors such that achieving and maintaining a therapeutic international normalised ratio is challenging; frequent venepuncture becomes unavoidable. Over recent years, several novel direct oral anticoagulant (DOAC) agents have emerged which specifically target key molecules within the coagulation cascade. These mainly include factor Xa inhibitors (e.g. rivaroxaban, apixaban and edoxaban) and direct thrombin inhibitors (e.g. dabigatran). Results emerging from phase three trials for both classes appear promising in the treatment of VTE. Both the EINSTEIN-DVT and EINSTEIN-PE RCTs demonstrated noninferiority of rivaroxaban when compared with standard treatment (enoxaparin for 5–10 days followed by an oral VKA) in preventing recurrent VTE. In a subgroup analysis of 207 (6%) and 223 (4.6%) cancer patients enrolled in the EINSTEIN-DVT and EINSTEIN-PE, respectively, similar results were found. Moreover, in the EINSTEIN-Ext trial, the superiority of rivaroxaban over placebo in long-term prevention of recurrent VTE was reported. Similar non-inferiority of apixaban and edoxaban when compared with standard treatment was reported in the AMPLIFY and HOKUSAI trials, respectively. The bleeding risk with the factor Xa inhibitors does not appear significantly different compared with LMWHs and warfarin. With regard to dabigatran, the RE-COVER and RE-MEDY trials demonstrated it to be non-inferior to warfarin in the prevention of recurrent VTE and VTE-related death in acute and long term, respectively. Similar conclusions were drawn from the subgroup analysis of 121 (4.7%) cancer patients in the RE-COVER study. Dabigatran was shown to have similar safety profile including bleeding although with more adverse events leading to drug discontinuation and dyspepsia when compared with warfarin in the RE-COVER study. Meanwhile, in the RE-MEDY study, dabigatran demonstrated a trend toward a lower risk of bleeding but significantly more acute coronary syndrome when compared to warfarin. A recent meta-analysis performed subgroup