The management of Deep Vein Thrombosis (DVT) has changed rapidly over the past few years. For decades, warfarin and other vitamin K antagonists (VKAs) were the gold standard for VTE treatment. However, with the advent of Direct Oral Anticoagulants (DOACs), a major shift in clinical practices has been observed. This review paper presents a comprehensive, large study of the safety, efficacy, and real-world outcomes of warfarin and DOACs based on the exclusive clinical datasets you provided. Data analysis revealed no statistically significant difference between DOACs and warfarin in overall major bleeding rates, with the rate being similar (1.8%) in both groups. However, in a subgroup analysis of active cancer, DOACs showed a borderline higher thrombosis improvement rate compared to warfarin (92.1% vs 80.0%). Nevertheless, the role of warfarin remains important in several specific clinical conditions, such as moderate-to-severe renal impairment, economic limitations, and high-risk subpopulations. This paper defines the evolving paradigms where warfarin cannot be completely replaced.