Selecting between direct oral anticoagulants (DOACs) and warfarin requires understanding their distinct mechanisms, pharmacokinetics, monitoring requirements, and clinical evidence by indication. Warfarin (Coumadin): A vitamin K antagonist that inhibits vitamin K epoxide reductase (VKORC1), depleting the active (carboxylated) forms of factors II, VII, IX, and X, plus proteins C and S. Onset is delayed (3-5 days for full anticoagulant effect because existing carboxylated factors must be cleared). Requires frequent INR monitoring (target 2.0-3.0 for most indications; 2.5-3.5 for mechanical heart valves). Highly influenced by CYP2C9/VKORC1 pharmacogenomics, diet (vitamin K intake), drug interactions (CYP2C9/3A4/1A2 inhibitors and inducers), and alcohol. Reversed by vitamin K (24-48 hours), 4F-PCC (immediate), or FFP. DOACs: Target a single coagulation factor — either thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban). Predictable pharmacokinetics with fixed dosing; no routine monitoring required. Rapid onset (1-4 hours). Shorter half-lives (5-17 hours vs. warfarin's 20-60 hours). Fewer food and drug interactions. Specific reversal agents available. Evidence-based selection by indication: - Atrial fibrillation (NVAF): DOACs are PREFERRED over warfarin based on large RCTs (RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF-TIMI 48) — DOACs showed...