Dabigatran etexilate: prodrug of the direct thrombin inhibitor
Dabigatran etexilate (brand name Pradaxa) is the orally active ester prodrug of dabigatran, a direct thrombin inhibitor (DTI) from the class of non-vitamin K antagonist oral anticoagulants (NOACs or DOACs). Boehringer Ingelheim launched the substance in the EU in 2008. Pradaxa was the first NOAC to displace warfarin and other vitamin K antagonists as standard of care in many indications.
The prodrug is hydrolysed by esterases in the gut and plasma into the active drug dabigatran. Only 6 to 7 % of the orally absorbed prodrug eventually reaches the circulation as the active form, which is why relatively high doses (110 mg or 150 mg twice daily) are needed.
Mechanism of action
Dabigatran competitively and reversibly binds the catalytic site of thrombin (factor IIa), the key enzyme of the clotting cascade. Thrombin converts fibrinogen to fibrin, activates factors V, VIII, XI and XIII and platelets. By directly inhibiting thrombin, all these steps are interrupted, regardless of whether thrombin is free in plasma or already bound within a thrombus.
Compared with heparin, which only inhibits free thrombin via antithrombin III, dabigatran also blocks fibrin-bound thrombin. This property contributes to effective anticoagulation and prevention of thrombus growth.
Maximum anticoagulant effect occurs about 2 hours after dosing. The half-life is 12 to 17 hours and is markedly longer with renal impairment. About 80 % of the elimination is renal, which puts dabigatran at a disadvantage compared with the factor Xa inhibitors rivaroxaban or apixaban in renal impairment.
Indications
- Stroke prophylaxis in non-valvular atrial fibrillation (AF): main indication; non-inferiority or superiority versus warfarin (RE-LY)
- Treatment and secondary prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE): after 5 to 10 days of parenteral anticoagulation
- Primary prevention of venous thromboembolism after elective hip or knee replacement: in reduced dose
- Paediatric use: treatment and secondary prophylaxis of VTE in children from 8 years (oral suspension)
Dabigatran is not approved in mechanical heart valves or antiphospholipid syndrome, where vitamin K antagonists remain superior.
Dosing and administration
Atrial fibrillation (stroke prophylaxis): 150 mg twice daily. In patients aged 80 or above, on concomitant verapamil, or with elevated bleeding risk: 110 mg twice daily. In moderate renal impairment (CrCl 30 to 50 ml/min) individual decision; below 30 ml/min contraindicated.
VTE treatment and secondary prophylaxis: 150 mg twice daily after 5 to 10 days of parenteral anticoagulation.
VTE prophylaxis after hip or knee surgery: 220 mg once daily, starting 1 to 4 hours postoperatively with 110 mg, then 220 mg once daily.
Capsules are taken whole with a glass of water. Important: never open or crush them, since the inner pellet is tartaric acid based and opening can raise bioavailability by up to 75 % with a markedly increased bleeding risk.
For missed doses: catch up if the next dose is more than 6 hours away. Otherwise skip the missed dose and never double up.
Side effects
Common (1 to 10 %): anaemia, gastrointestinal complaints (dyspepsia, abdominal pain, nausea, diarrhoea, reflux), minor bleeds (epistaxis, haematuria, skin haematomas, gum bleeding).
Uncommon: thrombocytopenia, allergic reactions, pruritus, rash, raised liver enzymes.
Rare and very rare: major bleeding (gastrointestinal, intracranial, retroperitoneal), anaphylaxis, bronchospasm, hepatitis, hair loss.
Specifics for dabigatran:
- Higher rate of gastrointestinal side effects than factor Xa inhibitors (because of the acidic pellet)
- Slightly higher rate of GI bleeding than warfarin (RE-LY trial)
- Lower rate of intracranial bleeding than warfarin
- For acute bleeding or emergency surgery a specific antidote is available: idarucizumab (Praxbind), which neutralises dabigatran within minutes
Interactions
Dabigatran is a substrate of P-glycoprotein (P-gp) and is not subject to relevant CYP metabolism.
- Strong P-gp inhibitors (systemic ketoconazole, itraconazole, ciclosporin, dronedarone, tacrolimus): markedly raised dabigatran levels, combination contraindicated or only with strict indication
- Verapamil, amiodarone, quinidine, clarithromycin: moderate P-gp inhibition; dose may need to drop to 110 mg twice daily
- Strong P-gp inducers (rifampicin, St John's wort, carbamazepine, phenytoin): reduced efficacy, avoid where possible
- Other anticoagulants: combination with other NOACs, heparins or warfarin markedly increases bleeding risk and is usually contraindicated
- Aspirin and P2Y12 inhibitors such as clopidogrel: increased bleeding risk, triple therapy only on strict indication and as short as possible
- NSAIDs: increased GI bleeding risk, avoid where possible
- SSRIs and SNRIs: slightly increased bleeding risk
Special considerations
Pregnancy: contraindicated. Low molecular weight heparins are the anticoagulants of choice during pregnancy as they do not cross the placenta.
Breastfeeding: not recommended due to lack of data.
Surgery: pause therapy 24 to 96 hours before elective procedures depending on bleeding risk and renal function. For urgent emergency procedures idarucizumab can be used.
Renal impairment: contraindicated below CrCl 30 ml/min. Renal function should be checked at least annually, more often if impaired.
Liver disease: contraindicated in severe hepatic impairment (Child-Pugh C).
Storage: Pradaxa is moisture sensitive. Capsules must be kept in their original blister or original bottle and never repacked into a weekly pill organiser.
Identification in the emergency department: patients should carry an anticoagulation card. In an emergency, information on substance, dose and last intake is decisive for treatment.
Related substances
- Rivaroxaban, oral factor Xa inhibitor
- Apixaban, another factor Xa NOAC
- Edoxaban, once daily factor Xa inhibitor
- Idarucizumab, specific antidote for dabigatran
- Warfarin, classic vitamin K antagonist
Frequently asked questions
How does dabigatran differ from rivaroxaban or apixaban?
Dabigatran inhibits thrombin (factor IIa) directly, whereas rivaroxaban and apixaban inhibit factor Xa. Dabigatran is 80 % renally cleared and is contraindicated in severe renal impairment. The factor Xa inhibitors have more leeway with kidney function. On the other hand, idarucizumab is a specific antidote for dabigatran.
Why must I not open the capsule?
The capsule contains a tartaric acid based pellet that protects the drug and controls absorption. Opening the capsule causes a sharp rise in bioavailability and bleeding risk. Patients with swallowing difficulties should discuss alternatives with their doctor.
What about elective surgery?
Before elective procedures dabigatran is paused 24 to 96 hours depending on renal function and bleeding risk. In emergency surgery idarucizumab can reverse the effect within minutes.
Do I need regular blood tests?
Unlike with warfarin, no routine coagulation monitoring is needed. Renal function should however be checked at least annually, more often if impaired, since dosing depends on it.
Sources
- EMA Pradaxa (dabigatran etexilate) EPAR
- BfArM Federal Institute for Drugs and Medical Devices
- AWMF guideline atrial fibrillation and VTE
- Gelbe Liste dabigatran etexilate monograph
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The information on this page is provided for general information purposes only and does not constitute medical advice, diagnosis or treatment recommendation. It does not replace the advice of a licensed physician or pharmacist. Medicines should only be used after a doctor's prescription or pharmacy supply. All information is based on summaries of product characteristics and accepted scientific sources at the time of writing; the current SmPC of the manufacturer is always decisive. Sanoliste accepts no liability for completeness, timeliness or accuracy. In a medical emergency, dial the emergency number 112.