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direct oral anticoagulant; novel oral anticoagulant (DOAC, NOAC)

A term applied collectively to newer oral anticoagulants developed to replace warfarin Indications: - prophylaxis for venous thromboembolism - more effective for preventing venous thromboembolism in elderly & in patients with cancer than warfarin [1] - no more or less effective in the prevention of recurrent venous thromboembolism than warfarin [6] - treatment of venous thromboembolism - direct oral anticoagulants comparable to warfarin in patients with cancer-related venous thromboembolism [3] - apixaban more effective with less major bleeding than rivaroxaban [27] - short-term rates of recurrence of thromboembolism & major bleeding similar with rivaroxaban vs apixaban [30] - cancer-related VTE recurrence & major bleeding are similar in apixaban, rivaroxaban, & enoxaparin [31] - rivaroxaban is associated with higher bleeding but lower mortality compared to apixaban & enoxaparin [31] - atrial fibrillation - prevention of embolic stroke - efficacy similar to warfarin [7,10] - efficacy equal or greater than warfarin [8] - safe & effective alternatives to warfarin in a routine care setting [1] - reduced all-cause mortality relative to warfarin [20] - apixaban appears to be direct oral anticoagulant of choice [20] - apixaban with 5-fold higher risk of stroke when underdosed [15] - apixaban 5 mg PO BID may not increase risk of hemorrhagic stroke [24] - dabigatran & rivaroxaban not associated with higher risk of stroke when underdosed [15] - reduces all-cause mortality relative to warfarin [2] - risks of death, any bleeding, or major bleeding lower for apixaban & dabigatran compared with warfarin [10] - use within 7 days of ischemic stroke appears safe [12] - better than warfarin for preventing stroke & systemic embolism in patients with atrial fibrillation & early-stage renal failure [29] - treatment of acute heparin-induced thrombocytopenia [16] - ST segment elevation myocardial infarction (STEMI) [22] as add-on to antiplatelet therapy Contraindications: - creatinine clearance < 30 ml/min, ESRD [5] - of no benefit for NSTEMI [22] - valvular heart disease, valvular atrial fibrillation due to rheumatic heart disease [5] - morbid obesity (BMI >40 mg/kg) [42] - high-risk antiphospholipid antibody syndrome * questionable - pregnancy - osteoporosis (GRS11: due to increased fracture risk relative to warfarin) [42] - ref [41] concludes decreased fracture risk relative to warfarin - end-stage renal disease - apixaban may be used because warfarin is ineffective - left ventricular thrombus, catheter-associated deep venous thrombosis, splanchnic vein thrombosis, cerebral venous thrombosis [45] Benefit/risk: - STEMI: NNT= 63 to prevent one cardiovascular event; NNH = 96 to cause one major bleeding event [22] - NSTEMI: NNT= 130 to prevent one cardiovascular event; NNH = 137 to cause one major bleeding event [22] Dosage: - renal dosing underprescribed 43% of time [15] - stop 24-36 hours prior to standard-risk surgery* & 2-4 days prior to high-risk surgery in patients with normal renal function [5] - stop 24 hours prior to GI endoscopy & resume 24 hours after for low risk procedures & 48 hours later for high risk procedures in patients with atrial fibrillation [44] * includes colonoscopy or other endoscopic procedure during which biopsy may occur [5] (also see perioperative anticoagulation) Pharmacokinetics: - 1/2 life varies 7-20 hours - betrixaban with longest 1/2 life of 20 hours - rivaroxaban with shortest 1/2 life of 7-11 hours - renal clearance varies from 80% for dabigatran vs 5% for betrixaban (apixaban 25%, edoxaban 35%, rivaroxaban 66%) [5] Adverse effects: - major bleeding, including intracranial hemorrhage, & fatal hemorrhage ~40% less frequent than with warfarin [1] - no more or less major bleeding than warfarin [6,19] - major bleeding less frequent in elderly & in patients with renal insufficiency than with warfarin [1] - risk of intracranial hemorrhage less than warfarin (RR=0.42) [1,2,9,21,23] - 15-20 mg QD of rivaroxaban associated with increased risk of intracranial hemorrhage; smaller daily doses of rivaroxaban or apixaban are not [24] - risk of bleeding similar to warfarin [6,7,8] - risk of GI bleeding less than warfarin (RR=0.25) [14] - apixaban with lowest risk of GI bleed [13,23, 43] - lowest risk of GI bleed in patients > 75 years - risk < 1/2 that with rivaroxaban (highest risk) [37] - rates of ischemic stroke, systemic embolism, intracranial hemorrhage & all-cause mortality similar for apixaban, dabigatran, edoxaban, & rivaroxaban for patients with atrial fibrillationincluding for patients >= 80 years & those with chronic kidney disease [43] - among Medicare recipients with atrial fibrillation >= 65 years, apixaban is associated with lower risk of major ischemic events & major hemorrhage than rivaroxaban [39] - coadministration of proton pump inhibitor - may decrease risk of upper GI bleed [26] - does not decrease risk of upper GI bleed [32] - decreases risk of subtherapeutic DOAC levels in frail elderly* - no bleeding complications with joint aspiration or joint injection [17] - risk of new-onset osteoporosis less than that of warfarin [40] - risk of bone fracture less than warfarin [41] - risk of death in nursing home residents less than warfarin - increased risk of bleeding with untreated respiratory tract infections [38] - 55% of frail elderly have either subtherapeutic or supratherapeutic levels* [46] - 40% with supratherapeutic levels, 14% with subtherapeutic levels - rivaroxaban associated with higher risk of supratherapeutic levels (RR=1.8) - chronic renal failure stage 4 associated with higher risk of supratherapeutic levels (RR=2.4) - proton pump inhibitor use associated with lower risk of subtherapeutic levels (RR=0.09) * frail elderly admitted with acute illness [46] Drug interactions: - may interact with amiodarone, fluconazole, rifampin, & phenytoin in Haan Chinese [18] - concurrent uses of DOAC & aspirin associated with increased bleeding & hospitalizations but similar rate of thrombosis [35] - concurrent use of macrolides may increase risk of bleeding [38] Note: - recommened checklist for patients on direct oral anticoagulants [4] - idarucizumab for dabigatran reversal [28] - andexanet alfa for apixaban & rivaroxaban reversal [28] - non-specific prohemostatic agents such as prothrombin complex concentrate have also been used for DOAC reversal [28] * DOAC reversal agents associated with an effective hemostasis rate of 78.5% [36] * failure to achieve hemostasis with reversal agent(s) predicts mortality after severe DOAC-relating bleeds (RR=3.63) [36]

Interactions

drug interactions drug adverse effects (more general classes)

Specific

apixaban (Eliquis) asundexian dabigatran (Pradaxa) edoxaban (Savaysa) rivaroxaban (Xarelto)

General

pharmaceutical anticoagulant

References

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