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Peripheral artery disease is a major clinical co-morbidity that can significantly affect quality of life, especially in the presence of diabetes mellitus and older age. The focus of this literature review is on medical management, through anti-platelet and anti-coagulation, of peripheral artery disease prior to undergoing surgical or endovascular management. Extensive electronic literature search performed in four major databases (PubMed, SCOPUD, Embase and Ovid) to identify the published randomized and non-randomized studies that compared and discussed the management of peripheral artery disease with different anti-thrombotic agents. A total of 17 studies were identified to meet the inclusion criteria of this review. Among them, 4 were systematic review and meta-analyses, 1 was observational study and 12 were randomized controlled trials. The reported outcomes in each study are summarized and reported separately within this review. Peripheral artery disease is a complex and multifactorial clinical condition. The use of dual anti-platelets, such as aspirin and clopidogrel, are the key in preventing major cardiovascular events as well as stroke and death. Utilization of anti-coagulation such as direct oral anti-coagulants’ as additional parameters for the prevention of disease progression, is paramount. Eventually, the choice of either dual-antiplatelet therapy or combined anti-coagulation with anti-platelets should be carefully considered, particularly following the most recent published debatable studies