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

Introduction

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
  • no more or less effective in the prevention of recurrent venous thromboembolism than warfarin
• treatment of venous thromboembolism
  • direct oral anticoagulants comparable to warfarin in patients with cancer-related venous thromboembolism
  • apixaban more effective with less major bleeding than rivaroxaban
  • short-term rates of recurrence of thromboembolism & major bleeding similar with rivaroxaban vs apixaban
  • cancer-related VTE recurrence & major bleeding are similar in apixaban, rivaroxaban, & enoxaparin
    • rivaroxaban is associated with higher bleeding but lower mortality compared to apixaban & enoxaparin
• atrial fibrillation
  • prevention of embolic stroke
    • efficacy similar to warfarin
    • efficacy equal or greater than warfarin
    • safe & effective alternatives to warfarin in a routine care setting
    • reduced all-cause mortality relative to warfarin
    • apixaban appears to be direct oral anticoagulant of choice
      • apixaban with 5-fold higher risk of stroke when underdosed
      • apixaban 5 mg PO BID may not increase risk of hemorrhagic stroke
      • dabigatran & rivaroxaban not associated with higher risk of stroke when underdosed
  • reduces all-cause mortality relative to warfarin
  • risks of death, any bleeding, or major bleeding lower for apixaban & dabigatran compared with warfarin
  • use within 7 days of ischemic stroke appears safe
• better than warfarin for preventing stroke & systemic embolism in patients with atrial fibrillation & early-stage renal failure
• treatment of acute heparin-induced thrombocytopenia
• ST segment elevation myocardial infarction (STEMI) as add-on to antiplatelet therapy

Contraindications

• creatinine clearance < 30 ml/min, ESRD
• of no benefit for NSTEMI
• valvular heart disease, valvular atrial fibrillation due to rheumatic heart disease
• morbid obesity (BMI >40 mg/kg)
• high-risk antiphospholipid antibody syndrome

* questionable

• pregnancy
• osteoporosis (GRS11: due to increased fracture risk relative to warfarin)
  • ref 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

Benefit/risk

• STEMI: NNT= 63 to prevent one cardiovascular event; NNH = 96 to cause one major bleeding event
• NSTEMI: NNT= 130 to prevent one cardiovascular event; NNH = 137 to cause one major bleeding event

Dosage

• renal dosing underprescribed 43% of time

• stop 24-36 hours prior to standard-risk surgery* & 2-4 days prior to high-risk surgery in patients with normal renal function
• 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

* includes colonoscopy or other endoscopic procedure during which biopsy may occur (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%)

Adverse effects

• major bleeding, including intracranial hemorrhage, & fatal hemorrhage ~40% less frequent than with warfarin
  • no more or less major bleeding than warfarin
  • major bleeding less frequent in elderly & in patients with renal insufficiency than with warfarin
  • risk of intracranial hemorrhage less than warfarin (RR=0.42)
  • 15-20 mg QD of rivaroxaban associated with increased risk of intracranial hemorrhage; smaller daily doses of rivaroxaban or apixaban are not
  • risk of bleeding similar to warfarin
  • risk of GI bleeding less than warfarin (RR=0.25)
  • 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)
    • 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
  • among Medicare recipients with atrial fibrillation >= 65 years, apixaban is associated with lower risk of major ischemic events & major hemorrhage than rivaroxaban
  • coadministration of proton pump inhibitor
    • may decrease risk of upper GI bleed
    • does not decrease risk of upper GI bleed
    • decreases risk of subtherapeutic DOAC levels in frail elderly*
  • no bleeding complications with joint aspiration or joint injection
• risk of new-onset osteoporosis less than that of warfarin
  • risk of bone fracture less than warfarin
• risk of death in nursing home residents less than warfarin
• increased risk of bleeding with untreated respiratory tract infections
• 55% of frail elderly have either subtherapeutic or supratherapeutic levels*
  • 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

• drug adverse effects of direct oral anticoagulants
• drug adverse effects of antithrombotic agent(s)

Drug interactions

• may interact with amiodarone, fluconazole, rifampin, & phenytoin in Haan Chinese
• concurrent uses of DOAC & aspirin associated with increased bleeding & hospitalizations but similar rate of thrombosis
• concurrent use of macrolides may increase risk of bleeding

• drug interaction(s) of direct oral anticoagulants (DOAC) with NSAIDs
• drug interaction(s) of oral anticoagulants with selective serotonin reuptake inhibitor (SSRI)
• drug interaction(s) of aspirin, P2Y12 inhibitors & anticoagulants

Notes

• recommened checklist for patients on direct oral anticoagulants
• idarucizumab for dabigatran reversal
• andexanet alfa for apixaban & rivaroxaban reversal
• non-specific prohemostatic agents such as prothrombin complex concentrate have also been used for DOAC reversal

* DOAC reversal agents associated with an effective hemostasis rate of 78.5%

* failure to achieve hemostasis with reversal agent(s) predicts mortality after severe DOAC-relating bleeds (RR=3.63)

More general terms

• pharmaceutical anticoagulant

More specific terms

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