• drugs, originally called novel oral anticoagulants (NOAC), are now more appropriately referred to as direct oral anticoagulants (DOAC)
  • DOACs:
    • are associated with the same or lower incidence of ischemic stroke and bleeding (especially ICH)
      • on top of that, ICH on DOACs has a better prognosis than ICH on warfarin [Inohara, 2018]
    • have standardized dosing with no need for laboratory monitoring of the anticoagulant effect
    • have relatively predictable pharmacokinetics
    • have a rapid onset of action and resolution after discontinuation (⇒ easy switch or periprocedural discontinuation)
  • data from RCTs have been confirmed in routine clinical practice (e.g., GLORIA-AF registry, etc.)
  • specific antidotes are available for both dabigatran (since 2016 – idarucizumab) and factor Xa inhibitors (since 2019 – andexanet alfa)
Direct oral anticoagulants (DOACs)

Indications for the use of direct oral anticoagulants

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Overview of DOACs

Direct thrombin inhibitors

Factor Xa inhibitors

The effect of anticoagulant drugs on coagulation cascade
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Pharmacokinetics and pharmacodynamics

DOACs are the substrate of two efflux pumps, P-gp and BCRP. The activity of both systems determines the bioavailability and the rate of bioelimination. Some DOACs (rivaroxaban, apixaban) are substrates of CYP isoenzymes (mainly CYP3A4), which influence their transformation to inactive metabolites. Inhibition of P-gp in particular increases bioavailability and slows elimination into the bile; blockade of CYP3A4 slows inactivation and transformation. Many drugs are significant inhibitors of both CYP3A4 and P-gp. Clinically important inhibitors of both systems include azole-type antifungals (ketoconazole, fluconazole, itraconazole, etc.), antiretrovirals (e.g., ritonavir, etc.), and the macrolides clarithromycin and erythromycin.

Dabigatran Rivaroxaban Apixaban Edoxaban
mechanism of action
direct thrombin inhibitor
factor Xa inhibitor
factor Xa inhibitor
factor Xa inhibitor
time to peak
1.5h
2-4h
2-4h
1-2h
bioavailability 3-7% 66%-100%
(with food)
> 50% 62%
prodrug yes no no no
clearance extrarenal/renal 20/80% 65/35% 72/28% 50/50%
CYP3/A4 no yes (elimination) yes (elimination) minimal
plasma protein binding
35% 92-96% 90% 55%
half-life 12-17h 5-9 h (younger)
11-13h (older)
12h 10-14h
pharmacokinetic interactions
P-gp
PPIs
CYP 3A4
P-gp
CYP 3A4
P-gp
P-gp (reduce dose by 50%)
reversal
idarucizumab (specific) andexanet
4F-PCC (nonspecific)
andexanet
4F-PCC (nonspecific)
andexanet
4F-PCC (nonspecific)
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Interactions

Pharmacodynamic interactions
  • other anticoagulants / antiplatelet drugs / NSAIDs ⇒ ↑ risk of bleeding
  • carefully assess the clinical benefit of these combinations (typical indication DOAC + clopidogrel/ticagrelor after coronary stenting)
  • consider the use of prophylactic PPI
Pharmacokinetic interactions
  • interactions between resorption, transformation, and elimination
  • mainly via CYP3A4 and P-glycoprotein inhibitors (↑ effect up to 50%)
    • azole antifungals (fluconazole, ketoconazole) and antiretrovirals (ritonavir, nelfinavir) are strong CYP3A4 and P-qp inhibitors
    • inhibitors from the group of macrolide antibiotics (clarithromycin and erythromycin)
  • concomitant use of dronedarone and dabigatran is contraindicated, dose reduction is required while taking dabigatran and slow-release verapamil at the same time
  • decreased rivaroxaban levels with concomitant use of levetiracetam have been reported → see here
  • except for dabigatran, there is no significant interaction between DOACs and antacids/PPIs [Bolek, 2017]

→ PPI and antithrombotic therapy see here

 

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Dosing

  • rivaroxaban should be taken with food; other DOACs have no such limitation
Dabigatran
dabigatran (PRADAXA) stroke prevention VTE prevention and therapy
(LMWH bridging for 5-10 days)
VTE prevention in knee or hip surgery
(THR 30 days, TKR 10 days)
CrCl > 0.83 ml/s (>50 ml/min) 2x 150 mg 2x 150 mg
 110 mg for the first day
(starting within 4h after surgery)
then 220 mg once daily
CrCl 0.5-0.83 ml/s (30-50 ml/min)
2x 110 mg
(or  2x 150 mg in the absence of other risk factors)
2x 110 mg
  • concomitant use of verapamil
  • age > 80y, consider in patients 75-80 y
  • consider with weight < 50kg
  • GER, gastritis, esophagitis, HAS-BLED > 3
2x 110 mg 2x 110 mg
 75 mg for the first day
(starting within 4h after surgery)
then 150 mg (2x75mg)  once daily
Apixaban
apixaban (ELIQUIS) stroke prevention
VTE prevention and therapy
(no LMHW bridging required)
VTE prevention in the knee or hip surgery (TKR, THR)
CrCl > 0.5 ml/s (>30 ml/min) 2x 5 mg daily
2x 10 mg for a week
then  2x 5 mg/d for 3-6 months
continue with 2x 2.5 mg daily, if needed
2x 2.5 mg daily
(first dose  12-24h after surgery)
continue for 35 days for THR and 12 days for TKR
CrCl 0.25-0.5 ml/s (15-30 ml/min)
or ≥ 2 of risk factors:
age ≥ 80 let, creatinine > 133 umol/l,  weight ≤ 60 kg
2x 2.5 mg daily use with caution (dose reduction is not specified) no dose reduction
Rivaroxaban
rivaroxaban (XARELTO) stroke prevention VTE prevention and therapy
(no LMHW bridging required)
VTE prevention in the hip or knee surgery (THR, TKR)
CrCl > 0.83 ml/s (>50 ml/min) 20 mg once daily 2×15 mg for 3 weeks
then 20mg once daily
(after 6 months, continue with 10 mg once daily if needed)
10 mg once daily
CrCl 0.25-0.83 ml/s (15-49 ml/min)
15 mg once daily
2×15 mg for 3 weeks
then 15 mg once daily
Edoxaban
edoxaban (LIXIANA) stroke prevention
VTE prevention and therapy
(LMHW bridging for 5-10 days)
VTE prevention in the hip or knee surgery (THR, TKR)
CrCl > 0.83 mL/s (>50 mL/min)
with no risk factors (low weight, concomitant drugs)
1x 60 mg
1x 60 mg

CrCl 0.25-0.83 mL/s (15-50 mL/min)
or
some of the risk factors:
P-gp inhibitors (cyclosporine, dronedarone, erythromycin, ketoconazole)
 weight ≤ 60 kg
1x 30 mg
1x 30 mg
(after 5 days of LMHW bridging)

with CrCl > 95 mL/min replace edoxaban with another DOAC (FDA 2015) !

CrCl ≥ 50 mL/min
(0.83 mL/s)
30-49 mL/min
(0.5-0.82 mL/s)
15-29 mL/min
(0.25-0.49 mL/s)
< 15mL/min
(0.25 mL/s)
dabigatran
(PRADAXA)
2x 150 mg 2x 110mg

2x 110mg
concomitant use of verapamil
age > 80y, consider in patients 75-80 y
consider with weight < 50kg
GER, gastritis, esophagitis, HAS-BLED > 3

apixaban
(ELIQUIS)
l 2x 5 mg 2x 2.5 mg
2x 2.5mg
if  ≥ 2 of risk factors are present:
age ≥ 80 let, creatinine > 133 umol/l,  weight ≤ 60 kg
rivaroxaban
(XARELTO)
1x 20 mg (with food) 1x 15mg (with food)
edoxaban
(LIXIANA)
1x 60 mg 1x 30mg

1x 30mg
either risk factor is present:
P-gp inhibitors (cyclosporine, dronedarone, erythromycin, ketoconazole)
weight ≤ 60 kg

Incorrect use of DOACs

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Dose reduction according to renal function

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Other specific situations in DOAC therapy

  • advanced hepatopathy is associated with ↑ risk of bleeding but also with prothrombotic states
  • in addition, liver disease can affect hepatic clearance and drug metabolism
  • warfarin is problematic due to spontaneously elevated INR values, making it difficult to choose the appropriate dose
  • all DOACs are contraindicated in patients with liver disease associated with coagulopathy and clinically apparent risk of bleeding
  • dabigatran, apixaban, and edoxaban may be used with caution in patients with Child-Pugh A and B cirrhosis – multidisciplinary management (including hepatologist and hematologist) is advisable
    • rivaroxaban is contraindicated in Child-Pugh B and C
Child-pugh and DOACs dosing
  • overweight and obesity (BMI > 25 and 30 kg/m2)
    • no difference in efficacy and safety was found for apixaban or rivaroxaban in patients < 60 kg vs. > 60 kg or with BMI ≥ 35 kg/m2
    • because data on extreme obesity are limited, administration of VKAs may be considered in patients with BMI ≥ 40 kg/m2 or weight > 120 (150) kg
    • if DOAC treatment is necessary, specific laboratory monitoring is appropriate
  • low body weight ( ≤ 50-60kg) – dose reduction is recommended
    • DOAC concentration and risk of bleeding may be increased; these patients often have associated diseases that may increase the risk of stroke and bleeding. Renal function may be overestimated in patients with low weight
    • dabigatran: dose reduction may be considered in b.w. ≤ 50 kg but is unnecessary
    • apixaban: dose reduction at weight ≤ 60 kg together with at least one other factor (age ≥ 80 years, blood clearance ≥ 133 μmol/l)
    • rivaroxaban: no dose adjustment required – equal efficacy and safety in patients < 70 kg vs. > 70 kg. Extremes in body weight (<50 kg or >120 kg) had little effect on rivaroxaban plasma concentrations (< 25%)
    • edoxaban: dose reduction to 30mg at weight ≤ 60kg
  • patients with Afib lasting ≥ 48 h (or of unknown duration) scheduled for electrical or pharmacological cardioversion should be maintained on effective anticoagulation therapy for ≥ 3 weeks prior to the procedure or should undergo TEE to rule out intracardiac thrombosis
  • anticoagulation therapy is required for at least 4 weeks after successful cardioversion; in high-risk patients keep permanent anticoagulation
  • fragility, advanced age, nor dementia do not exclude anticoagulant therapy
    • DOAC trials included a number of people ≥ 75 years of age and the use of DOACs led to a decrease in absolute risk compared to VKA
  • older patients are at risk of worsening renal function and also falls, which are often mistakenly considered as a contraindication to anticoagulant therapy
  • a Markov decision analytic model demonstrated that a patient on vitamin K antagonists (VKA) has to fall 295 times for the risk of subdural hematoma to outweigh the benefit of anticoagulation
  • adherence to treatment is essential
  • rule out pregnancy and recommend contraception before starting therapy
  • DOACs may be associated with prolonged menstrual bleeding compared to VKA and LMWH
  • DOACs are contraindicated during pregnancy and breastfeeding
  • atrial fibrillation is a common arrhythmia in athletes
  • for athletes taking oral anticoagulation for venous thromboembolism, it is recommended to avoid contact sports
  • increased risk of bleeding due to injury during a seizure (with or without a fall)
    • especially patients with generalized atonic seizures are at high risk of head injury
    • generalized tonic seizures increase the risk of bleeding when the tongue is injured
  • anticoagulants have numerous interactions with antiepileptics
  • with some severe interactions, DOACs should not be the preferred choice of anticoagulant drug
  • tumors and atrial fibrillation are common in elderly patients; older age and malignancy are independent risk factors for thrombosis and bleeding
    • VTE – several meta-analyzes of small cohorts of patients with cancer in VTE studies have described equal or better efficacy of DOACs compared to VKA/LMWH
    • atrial fibrillation – analysis of data in patients with active malignancy or history of malignancy in the ARISTOTLE trial showed superior efficacy and safety of apixaban compared to warfarin
  • an interdisciplinary approach is advisable
  • in view of the short duration of action (12-24h), noncompliance with DOACs is associated with a higher thromboembolic risk than with warfarin
  • consider switching to VKA in these patients – skipping one dose of VKA will not cause significant decrease in anticoagulant activity

Anticoagulant therapy switching

VKA → DOAC
  • all DOACs can be started immediately if the INR is < 2
  • official recommendation:
    • rivaroxaban – INR < 3
    • edoxaban – INR ≤ 2.5
    • apixaban/dabigatran – INR < 2
  • if INR is > 2.5, check INR the next day, or you can start using rivaroxaban if INR < 3
  • once starting with rivaroxaban, apixaban, or dabigatran, INR measurement is unreliable and may be falsely elevated
Warfarin - DOAC switch
DOAC → VKA
  • DOAC and VKA (vitamin K antagonist) can be administered simultaneously until INR >2
  • DOACs may affect INR (falsely elevated values) – always measure INR before taking another DOAC during concomitant administration and measure again 24-48h after discontinuing DOACs
  • it is recommended to reduce the dose when starting VKAs while using edoxaban
    • for patients taking the 60 mg dose, administer edoxaban at 30 mg once daily along with an appropriate dose of a VKA
    • for patients taking the 30 mg dose, administer edoxaban at 15 mg once daily with a proper dose of a VKA
  • close monitoring of INR is recommended during the first month until stable INR values are achieved
  • if intermediate concomitant DOAC + VKA is not appropriate, consider converting DOAC to LMWH and then switch from LMWH to VKA (especially in patients at high risk of thromboembolism)
Warfarin - DOAC switch
LMWH/heparin → DOAC
  • from heparin: DOACs can be started 0-2h after discontinuation of IV heparin
  • from LMWH: DOACs should be given at the time when the next LMWH dose was scheduled (some authors recommend to start 0-2 hr before the next scheduled LMWH administration)
    • in patients with renal insufficiency, beware of prolonged LMWH elimination
DOAC → LMWH/heparin
  • heparin/LMWH can be started at the time of the next scheduled DOAC dose
  • do not start with a heparin bolus   → heparin protocol
DOAC → DOAC
  • start the new DOAC at the time when the next dose of the original DOAC should have been given, except in situations where a higher than therapeutic plasma concentration is expected (e.g., in patients with renal insufficiency)
Antiplatelet therapy → DOAC
  • start DOACs immediately while stopping acetylsalicylic acid (ASA) or clopidogrel unless combination therapy is indicated

Monitoring

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Discontinuation of DOACs before surgery

  • DOACs, compared to warfarin, have predictable Cmax and T1/2
  • consider:
    • age + weight
    • renal function
    • history of bleeding
    • concomitant medication and comorbidities
    • specific bleeding risk of the procedure

Acute procedures

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DOAC and recanalization therapy

  • strokes can happen even to anticoagulated patients
  • there is no contraindication to mechanical recanalization
  • follow specific protocols when considering intravenous thrombolysis

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