• 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

Stroke prevention in patients with atrial fibrillation

  • in this indication, DOACs have long been preferred over VKAs in expert recommendations (EHRA 2018 I/A)
Indications and contraindications for anticoagulants in patients with atrial fibrillation and associated cardiac comorbidities (ESC guidelines 2018)
nonvalvular atrial fibrillation
  • DOAC
  • warfarin
intracardiac thrombus

mechanical heart valve

  • warfarin
  • DOAC contraindicated
    • dabigatran was inferior to warfarin in the RE-ALIGN trial
moderate to severe mitral valve stenosis
  • warfarin
  • DOAC contraindicated
other valve defects, mild-moderate
  • DOAC
  • warfarin
severe aortic valve stenosis
  • warfarin
  • DOAC –  limited data (exclusion criterion in the RE-LY trial)
bioprosthetic valve (>3 months since implantation)
  • warfarin
  • DOAC
    • rivaroxaban is non-inferior to warfarin in bioprosthetic MI valves (RIVER trial)
    • no robust data for the other DOACs
    • do not use in rheumatic etiology
hypertrophic cardiomyopathy (HCM)
  • warfarin
  • DOAC – insufficient data, but may be considered (ESC 2018)
transcatheter aortic valve implantation (TAVI)
  • warfarin
  • no data for DOAC

VTE treatment and prevention

  • therapy and prevention of deep vein thrombosis (DVT) and/or pulmonary embolism (PE)
  • for 3 months if the risk factor for thrombosis has passed – so-called secondary thrombosis (e.g., after surgery, after an accident, after childbirth)
  • for 6 months if no risk factor has been identified (idiopathic thrombosis)
  • for 12 months in patients with significant thrombophilia, especially congenital thrombophilia, or recurrence of proximal phlebothrombosis or symptomatic PE and an increased risk of recurrence due to an acquired ongoing thrombophilic condition
    • DOACs are not recommended in patients with a history of thrombosis diagnosed with antiphospholipid syndrome. In particular, in patients with triple positivity (for lupus anticoagulants, anticardiolipin antibodies, and antibodies to beta 2-glycoprotein I), DOAC treatment may be associated with ↑ incidence of recurrent thrombotic events compared with warfarin

VTE prevention in knee and hip surgery

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 CYP isoenzymes (mainly CYP3A4) substrates, which influence their transformation to inactive metabolites. Inhibition of P-gp 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
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 (reduce dose by 50%)
idarucizumab (specific) andexanet
4F-PCC (nonspecific)
4F-PCC (nonspecific)
4F-PCC (nonspecific)
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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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  • rivaroxaban should be taken with food; other DOACs have no such limitation
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 4 hours 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 4 hours after surgery)
then 150 mg (2x75mg)  once daily
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 (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 (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)
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/minute, 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)
2x 150 mg 2x 110mg

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

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
1x 20 mg (with food) 1x 15mg (with food)
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 ↑ bleeding risk but also with prothrombotic states
  • in addition, liver disease may 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 evident bleeding risk
  • 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 required, specific laboratory monitoring is appropriate
  • low body weight ( ≤ 50-60kg) – dose reduction is recommended
    • DOAC concentration and bleeding risk may be increased; these patients often have comorbidities that may increase the risk of stroke and bleeding. Renal function may be overestimated in patients with low body weight
    • dabigatran: dose reduction may be considered in patients with body weight ≤ 50 kg, but is not necessary
    • apixaban: dose reduction in patients with body weight ≤ 60 kg in combination 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 in patients weighing ≤ 60 kg
  • patients with Afib lasting ≥ 48 h (or of unknown duration) scheduled for electrical or pharmacologic 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; permanent anticoagulation should be maintained in high-risk patients
  • fragility, advanced age, or dementia do not exclude anticoagulant therapy
    • DOAC trials included a number of people ≥ 75 years of age, and the use of DOACs resulted in a reduction 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) would have 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
  • athletes taking oral anticoagulation for venous thromboembolism are advised to avoid contact sports
  • increased risk of bleeding from injury during a seizure (with or without a fall)
    • patients with generalized atonic seizures are at particularly at risk of head injury
    • generalized tonic seizures increase the risk of bleeding from the tongue injury
  • 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
  • given 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 result in a significant decrease in anticoagulant activity

Anticoagulant therapy switching

  • 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 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 an appropriate 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 applicable, consider switching from DOAC to LMWH and then 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
  • 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


Clinical monitoring

At each appointment with a patient on anticoagulation therapy, determine the following:

  • Adherence – compliance + repeated education each visit
    • switching from warfarin to DOACs in the presence of fluctuating INR is conditional on good adherence (missing one dose of DOACs has a more significant impact than missing one warfarin dose)
    • repeatedly instruct on the correct use of the medication, the need to carry the medication schedule and the personal pocket card regarding the anticoagulant therapy
  • Bleeding risk assessment  (each visit)
    • evaluate HAS-BLED score repeatedly
    • look for bleeding complications
    • consider PPI
    • assess the need for dose reduction or drug substitution
  • Creatinine clearance  (use Cockcroft-Gault formula)
    • monitor renal function, adjust DOACs dose if required
    • every 12 months in otherwise healthy patients < 75 years of age
    • every  6 months (age ≥ 75 let or fragile)
    • interval CrCl/10 months if CrCl < 60 mL/min
  • Drug interaction – verify drug interactions
    • drugs that increase the risk of bleeding (e.g., antirheumatic drugs, verapamil for dabigatran, etc.)
  • Examination and others
    • monitor BP, weight
    • watch for bleeding risk factors
    • any signs of thromboembolism?
    • any side effects?
    • blood test
      • CBC
      • renal and liver function tests (at least annually)
      • specific tests to verify the anticoagulant effect of the DOAC
Laboratory monitoring of DOACs
  • generally, no specific monitoring of the coagulation effect is needed
    • it may be helpful to check levels in patients with decreased CrCl (e.g., near thresholds for reduced dose), in patients with hepatopathy or with any of the CYP3A4/P-gp inhibitors,  with extremely low or high weight
  • testing is useful in the following situations:
    • severe bleeding/thromboembolic event
    • acute surgery/therapy (e.g., thrombolysis)
    • renal/hepatic insufficiency
    • potential drug interactions
    • suspected overdose
  • according to some authors, intermittent monitoring is appropriate in most patients;  no study has investigated whether measuring drug concentrations and adjusting dose based on laboratory parameters reduces the risk of both bleeding/thromboembolic complications
dabigatran rivaroxaban – apixaban – edoxaban
(Prothrombin Time)
(International Normalized Ratio)
(Activated Partial Thromboplastin Time)
a 2-fold increase represents an increased risk of bleeding
the dose-response relationship is non-linear
there is a relatively steep rise at low concentrations with an almost linear increase in concentrations > 200 ng/mL (at a dabigatran level of 200 ng/mL, the APTT is prolonged approximately 2.5 times)
normal APTT does not entirely exclude an anticoagulant effect
unreliable test for xabans
normal level does not exclude anticoagulant activity !!!
TT (Thrombin Time)
normal TT = normal hemostatic function
increased TT may (or may not) indicate residual activity; with normal APTT and Hemoclot, the elevated TT may persist without significant risk of bleeding
dose-response linearity (quantitative test)
dTT > 200ng/mL before the next dose poses a higher risk of bleeding
dTT < 30-50 ng/mL poses a minimal risk of bleeding (even in surgery or thrombolysis)
specific anti-Xa
quantification of the effect
no verified thresholds for increased risk of thromboembolism or bleeding
(Ecarin Clotting Time)
dose-response linearity
an increase of ≥3 represents an increased risk of bleeding
Specific tests - dabigatran


  • normal aPTT 
    • no clinically significant anticoagulant effect of dabigatran
    • dabigatran level < 50 ng/mL
  • slight prolongation of aPTT (typically 1.5 times) – effective dabigatran level
  • aPTT > 70-90 s – high concentration of dabigatran
  • aPTT > 90 s – suspected dabigatran overdose
Dabigatran levels during 24 hours
Correlation of coalgulations tests and dabigatran concentration


  • calibrated for dabigatran levels of 50-500 ng/mL
  • the kit is approved for testing hirudin, argatroban, and dabigatran in the citrate plasma sample
  • plasma dabigatran concentration > 200 ng/mL (> 65 sec.) 10-16 h after the previous dose (at a dose of 2×150 mg) ⇒ ↑ risk of bleeding
average peak concentration
(approx 2-3h after the last dose; ng/mL)
(25-75 percentile)
average minimal concentration
(10-12 h after the last dose; ng/mL)
(25-75 percentile)
2x 150 mg 175 (117-275) ng/mL 91 (61-143) ng/mL
2x 110 mg 126 (85-200) ng/mL 65 (43-102) ng/mL
Correlation of hemoclot and dabigatran concetration


Specific test - xabans
  • the anticoagulant effect can be assessed using a modified anti-Xa test
  • results are reported in μg/mL or μg/L (standard anti-Xa used with LMWH therapy is reported in IU/mL)
  • to verify the optimal dose, it is advisable to determine the maximum and minimum levels
    • peak level: examine anti-Xa 3-4 hours after the last dose is taken (<0.215 µg/mL)
    • minimum level:  examine anti-Xa 12 hours (apixaban ) or 24 hours (rivaroxaban) after the last dose is taken (>0.032 µg/mL)
peak concentration (μg/L)
minimal concentration (μg/L)
rivaroxaban 1x 20 mg 215 (22-535) 32 (6-239)
apixaban 2x 5 mg 171 (91-321) 103 (41-230)
apixaban 2x 2.5 mg 123 (69-221) 79 (34-162)


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
  • check:
    • serum chemistry panel, including renal function
    • CBC
    • coagulation tests, incl. specific tests corresponding to the particular drug
      • detection of the anticoagulant effect or other hemostatic disorders (thrombocytopenia, etc.)
  • if needed, preferably use specific antidotes:
  • if the specific antidote is not applicable, consider substitution therapy (prothrombin complex concentrate, FFP)
  • consider delaying surgery until APTT/anti-Xa is normalized; consult a hematologist if urgent surgery is required

DOAC and recanalization therapy

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

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Direct Oral Anticoagulants (DOACs)
link: https://www.stroke-manual.com/direct-oral-anticoagulants-doacs/