factor Xa inhibitor

**Mechanism** - Direct, reversible inhibitors of free and clot-bound factor Xa, which sits at the start of the common pathway where the intrinsic and extrinsic pathways converge. - Blocking Xa decreases thrombin generation, so less fibrinogen is converted to fibrin. Each Xa molecule normally generates many thrombin molecules, so inhibiting Xa has an amplified effect. - They act independent of antithrombin. This differs from heparin, LMWH, and fondaparinux, which are indirect inhibitors and need antithrombin III.

**Drugs (the "-xaban" suffix)** - Rivaroxaban: once or twice daily depending on indication, and should be taken with food (15 and 20 mg doses) for absorption. - Apixaban: twice daily, with the least renal clearance (~27%) and generally the lowest bleeding risk. - Edoxaban: once daily, with reduced efficacy in patients with CrCl >95 mL/min in AFib. - Betrixaban: discontinued.

**Indications** - Stroke and systemic embolism prevention in nonvalvular atrial fibrillation. - Treatment and secondary prevention of DVT/PE. - DVT prophylaxis after hip or knee replacement. - Rivaroxaban at low dose, with aspirin, is also used in stable CAD or PAD.

**Advantages over warfarin** - Rapid onset and offset, with no bridging needed. - Predictable pharmacokinetics, with no routine INR monitoring. - Few drug and food interactions (no vitamin K diet issues). - Lower rates of intracranial hemorrhage.

**Adverse effects** - Bleeding is the major one, especially GI bleeding (higher with rivaroxaban). - Epidural or spinal hematoma after neuraxial anesthesia or lumbar puncture. - Premature discontinuation increases thrombotic risk, which is a boxed warning.

**Metabolism and interactions** - Metabolized by CYP3A4 and transported by P-gp. Strong dual inhibitors (ketoconazole, ritonavir) raise levels. Strong dual inducers (rifampin, carbamazepine, phenytoin, St. John's wort) lower levels. - Renally cleared to varying degrees, so dose adjust in renal impairment.

**Lab findings** - PT may be mildly prolonged (more with rivaroxaban), and aPTT may be mildly prolonged. - These tests are unreliable for monitoring. If needed, use an anti-Xa assay calibrated to the specific drug.

**Contraindications and cautions** - Active pathological bleeding. - Mechanical heart valves, where warfarin is preferred (dabigatran was inferior in RE-ALIGN). - Moderate-to-severe mitral stenosis. - Antiphospholipid syndrome, especially triple-positive, where warfarin is preferred (DOACs are associated with more thrombotic events). - Pregnancy: avoid. Use LMWH instead. - Extreme body weight and severe renal or hepatic impairment need caution.

**Reversal** - Andexanet alfa is a recombinant, catalytically inactive decoy factor Xa that binds and sequesters the inhibitor. - 4-factor prothrombin complex concentrate (PCC) is an alternative. - Activated charcoal if the ingestion was recent. - Contrast with dabigatran (direct thrombin inhibitor), which is reversed by idarucizumab.

**High-yield comparisons** - Fondaparinux is an indirect Xa inhibitor (via antithrombin), given SC, and has a very low HIT risk. - Heparin and LMWH inhibit Xa and thrombin (heparin) via antithrombin. LMWH has predominantly anti-Xa activity. - Dabigatran is a direct thrombin (IIa) inhibitor. - Warfarin inhibits vitamin K epoxide reductase (VKORC1), which reduces factors II, VII, IX, and X plus proteins C and S.