direct oral anticoagulant

**Classification and mechanism** - Direct factor Xa inhibitors (-xaban): rivaroxaban, apixaban, edoxaban, betrixaban. They bind free and clot-bound factor Xa directly, so they don't need antithrombin III. This blocks conversion of prothrombin (II) to thrombin (IIa). - Direct thrombin (IIa) inhibitor: dabigatran (given as the prodrug dabigatran etexilate). It blocks conversion of fibrinogen to fibrin. It also blocks thrombin-mediated activation of factors V, VIII, XI, and XIII and platelet activation.

**Pharmacology** - Rapid onset, with peak effect in about 1–4 hours. Half-life is about 8–15 hours, so dosing is once or twice daily with no bridging. - Fixed dosing, with no routine monitoring. Predictable pharmacokinetics. - Elimination: - Dabigatran is about 80% renal. - Edoxaban is about 50% renal. - Rivaroxaban is about 33% renal. - Apixaban is about 27% renal, which makes it the most favorable in renal impairment. - Dose adjust or avoid in severe CKD. - Metabolism and interactions: Rivaroxaban and apixaban are CYP3A4 and P-glycoprotein (P-gp) substrates. Strong dual inhibitors (ketoconazole, ritonavir) raise levels. Strong inducers (rifampin, carbamazepine, phenytoin, St. John's wort) lower levels and should be avoided. Dabigatran is a P-gp substrate only. - Rivaroxaban should be taken with food, especially the higher doses, for absorption. Dabigatran capsules must not be opened. They may cause dyspepsia, and absorption needs an acidic environment.

**Clinical uses** - Stroke prevention in nonvalvular AF. This means AF without moderate-to-severe mitral stenosis or a mechanical heart valve. - Treatment and secondary prevention of DVT and PE. - VTE prophylaxis after hip or knee arthroplasty. - Some are used in stable CAD/PAD (low-dose rivaroxaban plus aspirin). - DOACs are generally preferred over warfarin for most VTE and nonvalvular AF. Dabigatran and edoxaban require 5–10 days of parenteral anticoagulation first when treating acute VTE. Rivaroxaban and apixaban use a loading phase instead.

**Contraindications and cautions (high-yield)** - Mechanical heart valves: contraindicated. Dabigatran was associated with more thromboembolic events in RE-ALIGN. Use warfarin. - Moderate-to-severe mitral stenosis: use warfarin. - Antiphospholipid syndrome, especially triple-positive: warfarin is superior. DOACs have more arterial thrombotic events. - Pregnancy: avoid. Use LMWH. - Severe renal impairment and active bleeding. - Extremes of body weight: reduced efficacy or limited data in severe obesity. - Spinal or epidural anesthesia: risk of spinal or epidural hematoma, so hold per timing guidelines.

**Adverse effects** - Bleeding is the main one. GI bleeding is more common with dabigatran, rivaroxaban, and high-dose edoxaban than with warfarin. - Intracranial hemorrhage is less frequent than with warfarin. - Dabigatran causes dyspepsia. - Advantages over warfarin: no routine INR monitoring, no vitamin K dietary issues, and no skin necrosis. They do not cause an initial hypercoagulable state from protein C depletion, so no bridging is needed.

**Reversal** - Idarucizumab (Praxbind): a monoclonal antibody fragment that binds dabigatran. - Andexanet alfa: a recombinant, catalytically inactive factor Xa decoy that reverses apixaban and rivaroxaban. Its use has been limited by thrombotic risk and cost. Check current local guidelines. - 4-factor prothrombin complex concentrate (PCC) is an alternative for factor Xa inhibitor reversal when andexanet is unavailable. - Activated charcoal if the ingestion was recent. - Dabigatran is dialyzable. Factor Xa inhibitors are highly protein bound and are not dialyzable. - Vitamin K and protamine are not effective.

**Lab effects** - Dabigatran prolongs aPTT, thrombin time (TT), and ecarin clotting time. A normal TT effectively excludes dabigatran. - Factor Xa inhibitors can prolong PT and aPTT mildly and variably. Anti-Xa levels calibrated to the specific drug are the best test. - Routine PT/INR is not reliable for measuring DOAC activity.

**Comparison with warfarin (board favorite)** - Warfarin inhibits vitamin K epoxide reductase, which reduces synthesis of II, VII, IX, X, protein C, and protein S. It is monitored with INR and is reversed with vitamin K, FFP, or PCC. - DOACs have a rapid onset and a fixed dose, with no monitoring. - Warfarin is preferred in mechanical valves, moderate-to-severe mitral stenosis, and antiphospholipid syndrome. - Heparin and LMWH work indirectly by activating antithrombin III. Fondaparinux is an indirect factor Xa inhibitor. Argatroban and bivalirudin are parenteral direct thrombin inhibitors used in HIT.

**Mnemonic** - "Xa-ban" drugs = factor Xa inhibitors. Dabigatran = thrombin inhibitor ("-gatran").