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Shouki Bazarbashi,1 Heba Mohamed El Zawahry,2 Tarek Owaidah,3 Mohammad A AlBader,4 Ashraf Warsi,5– 7 Mahmoud Marashi,8,9 Emad Dawoud,10 Hassan Jaafar,11 Sherif M Sholkamy,12 Fady Haddad,13 Alexander T Cohen14 1Section of Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia; 2Department of Medical Oncology, The National Cancer Institute, Cairo University, Cairo, Egypt; 3Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia; 4Hematology Unit, Al Sabah Hospital, South Surra, Kuwait; 5Department of Adult Hematology, Princess Noorah Oncology Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs–Western Region, Jeddah, Saudi Arabia; 6College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs–Western Region, Jeddah, Saudi Arabia; 7King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs-Western Region, Jeddah, Saudi Arabia; 8Hematology Department, Dubai Hospital, Dubai, United Arab Emirates; 9Department of Hematology, Mediclinic City Hospital, Dubai, United Arab Emirates; 10Department of Oncology, Tawam Hospital, Al Ain, United Arab Emirates; 11Department of Oncology, Sheikh Khalifa Specialty Hospital, Ras Al-Khaimah, United Arab Emirates; 12Department of Vascular Surgery, Ain Shams University, Cairo, Egypt; 13Vascular and Endovascular Surgery, American University of Beirut Medical Center, Beirut, Lebanon; 14Department of Haematological Medicine, Guy’s and St Thomas’ Hospitals NHS Foundation Trust, King’s College London, London, UKCorrespondence: Shouki Bazarbashi, Section of Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Center, Alfaisal University, 1 Alzahrawi Street, Riyadh, 11211, Saudi Arabia, Tel +966 505443546, Email bazarbashi@gmail.comAbstract: Venous thromboembolism is a leading cause of morbidity and mortality in patients with active cancer who require anticoagulation treatment. Choice of anticoagulant is based on careful balancing of the risks and benefits of available classes of treatment: vitamin K antagonists, low-molecular-weight heparin (LMWH), and direct oral anticoagulants (DOACs). Results from randomized controlled trials have shown the consistent efficacy of DOACs versus LMWH in the treatment of cancer-associated venous thromboembolism (VTE). However, increased major gastrointestinal bleeding was observed for edoxaban and rivaroxaban, but not apixaban, compared with LMWH dalteparin. Most guidelines recommend DOACs for the treatment of cancer-associated VTE in patients without gastrointestinal or genitourinary cancer, and with considerations for renal impairment and drug–drug interactions. These updates represent a major paradigm shift for clinicians in the Middle East and North Africa. The decision to prescribe a DOAC for a patient with cancer is not always straightforward, particularly in challenging subgroups of patients with an increased risk of bleeding. In patients with gastrointestinal malignancies who are at high risk of major gastrointestinal bleeds, apixaban may be the preferred DOAC; however, caution should be exercised if patients have upper or unresected lower gastrointestinal tumors. In patients with gastrointestinal malignancies and upper or unresected lower gastrointestinal tumors, LMWH may be preferred. Vitamin K antagonists should be used only when DOACs and LMWH are unavailable or unsuitable. In this review, we discuss the overall evidence for DOACs in the treatment of cancer-associated VTE and provide treatment suggestions for challenging subgroups of patients with cancer associated VTE.Plain Language Summary: Patients with cancer are at risk of blood clots forming in their veins, which can cause illness and death. To prevent such blood clots, most patients with cancer need anticoagulant therapy. There are three types of anticoagulants available for the treatment of cancer-associated blood clots in a vein, namely, vitamin K antagonists, low-molecular-weight heparin (LMWH), and direct oral anticoagulants (DOACs). Drug trials have shown that DOACs are more effective than LMWH; however, DOACs can have a greater risk of causing major gastrointestinal bleeding. Among DOACs, edoxaban and rivaroxaban are drugs associated with higher rates of gastrointestinal bleeding. Recently updated guidelines for doctors recommend that DOACs be used as the first treatment for patients with cancer at risk of blood clot formation in a vein. For doctors in the Middle East and North Africa, this new approach differs from existing practices. Notably, choosing a treatment also depends on the type of cancer, because gastrointestinal cancers and cancers of the genitals and urinary system have an especially high risk of gastrointestinal bleeding. The choice also depends on the presence of kidney problems, drug–drug interactions, and access to the drugs. Apixaban may be the preferred DOAC in patients with gastrointestinal cancer, but this drug should be used with care in patients with upper or unresected lower gastrointestinal tumors. For patients with upper or unresected lower gastrointestinal tumors, treatment with LMWH may be preferred. Vitamin K antagonists should be used only when DOACs and LMWH are unavailable or unsuitable.Keywords: anticoagulation, apixaban, cancer, vitamin K antagonist, low-molecular-weight heparin

Thrombosis is a common complication in patients with cancer and it is estimated that about 20% of patients with cancer experience venous thromboembolism (VTE). This complication is associated with high rate of morbidity and mortality and is sometimes the first manifestation of an occult cancer. The risk profiles and markers involved in cancerassociated thrombosis share similarities with inflammation-induced atherosclerosis and thrombosis. The type of cancer, chemotherapy, surgery, central venous catheters, pre-chemotherapy platelet and leukocyte count are associated with high risk of VTE in cancer patients. Landmark studies demonstrated that effective prophylaxis and treatment of VTE reduced morbidity and increased survival. Low-molecular-weight heparin (LMWH) is preferred as an effective and safe means for prophylaxis and treatment of VTE. It has largely replaced unfractionated heparin and vitamin K antagonists. The advantages of LMWH include increased survival and quality of life, decreased rate of VTE, low incidence of thrombocytopenia. New guidelines for prophylaxis and treatment are now available and prophylaxis is recommended in hospitalized cancer patients and patients undergoing major surgery. Treatment with LMWH should be considered as the first line of therapy for established VTE and to prevent recurrent thrombosis in patients with cancer.