ADD-ONS / MEDICATION / ANTICOAGULANTS
Direct Oral Anticoagulants (DOACs)
Created 06/10/2022, last revision 06/11/2023
- 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)
- are associated with the same or lower incidence of ischemic stroke and bleeding (especially ICH)
- 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)
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) |
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| nonvalvular atrial fibrillation |
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| intracardiac thrombus |
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mechanical heart valve |
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| moderate to severe mitral valve stenosis |
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| other valve defects, mild-moderate |
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| severe aortic valve stenosis |
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| bioprosthetic valve (>3 months since implantation) |
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| hypertrophic cardiomyopathy (HCM) |
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| transcatheter aortic valve implantation (TAVI) |
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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
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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 | |||||
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mechanism of action
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direct thrombin inhibitor |
factor Xa inhibitor |
factor Xa inhibitor |
factor Xa inhibitor
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| time to peak |
1.5h |
2-4h |
2-4h |
1-2h |
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| 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)
- azole antifungals (fluconazole, ketoconazole) and antiretrovirals (ritonavir, nelfinavir) are strong CYP3A4 and P-qp inhibitors
- 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]
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Dosing
- rivaroxaban should be taken with food; other DOACs have no such limitation
| 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 | ||
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2x 110mg |
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| apixaban (ELIQUIS) |
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 |
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| rivaroxaban (XARELTO) |
1x 20 mg (with food) | 1x 15mg (with food) | ||
| edoxaban (LIXIANA) |
1x 60 mg | 1x 30mg | ||
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1x 30mg |
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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
- 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
- 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)
- 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
- 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)
- start DOACs immediately while stopping acetylsalicylic acid (ASA) or clopidogrel unless combination therapy is indicated
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
- 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 | |||
| PT (Prothrombin Time) |
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–
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| INR (International Normalized Ratio) |
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–
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| APTT (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 !!! |
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| 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 |
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| dTT (Hemoclot) |
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)
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| specific anti-Xa |
–
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quantification of the effect
no verified thresholds for increased risk of thromboembolism or bleeding |
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| ECT (Ecarin Clotting Time) |
dose-response linearity
an increase of ≥3 represents an increased risk of bleeding |
–
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APTT
- 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
Hemoclot
- 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
| dabigatran |
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 |
- 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
Elective surgery
- 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:
- idarucizumab in patients using dabigatran
- andexanet alfa in patients using xabans (problem with availability and price)
- 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
Regional anesthesia
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
