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Sunday, July 27, 2025

Dabigatran


Dabigatran is a direct oral anticoagulant (DOAC) classified as a direct thrombin (factor IIa) inhibitor. It is primarily used for the prevention and treatment of thromboembolic events, offering an alternative to traditional vitamin K antagonists like warfarin. Approved under the brand name Pradaxa, dabigatran has gained wide acceptance due to its predictable pharmacokinetics, lack of routine monitoring, and fewer dietary and drug interactions compared to warfarin


Pharmacological Classification

  • Therapeutic Class: Anticoagulant

  • Pharmacologic Class: Direct thrombin inhibitor (DOAC)

  • ATC Code: B01AE07

  • Brand Name: Pradaxa

  • Legal Status: Prescription only (Rx)

  • Form: Oral capsule; also available as oral pellets in pediatric use

Mechanism of Action

Dabigatran etexilate is a prodrug that is converted in vivo by esterases to dabigatran, the active molecule. Dabigatran reversibly inhibits both free and clot-bound thrombin (factor IIa), the key enzyme that converts fibrinogen to fibrin, a crucial step in the final stage of the coagulation cascade.

By directly inhibiting thrombin, dabigatran:

  • Prevents the formation of fibrin clots

  • Inhibits thrombin-induced platelet aggregation

  • Reduces propagation of existing thrombi

This targeted mechanism enables effective anticoagulation with a relatively rapid onset of action and a predictable anticoagulant effect.

Approved Indications

Dabigatran is indicated for multiple thromboembolic conditions in both prevention and treatment settings.

Primary Indications

  • Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors

  • Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults

  • Prevention of recurrent DVT and PE following initial treatment

  • Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery

Pediatric Use

  • Approved in some jurisdictions for the treatment and secondary prevention of VTE in children ≥3 months old (age and weight-based dosing; oral pellets or capsules)

Dosage and Administration

Dabigatran is available in capsule strengths of 75 mg, 110 mg, and 150 mg. Dosage depends on indication, renal function, age, and concomitant medications.

Non-valvular Atrial Fibrillation

  • Standard dose: 150 mg twice daily

  • Dose reduction to 110 mg twice daily for:

    • Age ≥80 years

    • Age ≥75 with bleeding risk

    • Moderate renal impairment (eGFR 30–50 mL/min/1.73 m²)

    • Concomitant verapamil use

DVT/PE Treatment

  • Start after 5–10 days of parenteral anticoagulation (e.g., heparin)

  • Dose: 150 mg twice daily

VTE Prophylaxis (Post-Surgery)

  • 110 mg once daily first dose 1–4 hours post-op, then 220 mg once daily for 10–35 days (hip/knee replacement)

Renal Impairment

  • Contraindicated if eGFR <30 mL/min/1.73 m² (except under specialist guidance or in dialysis settings)

  • Dose adjustment required for moderate impairment

Contraindications

Dabigatran is contraindicated in:

  • Active clinically significant bleeding

  • Severe renal impairment (eGFR <30 mL/min/1.73 m²)

  • Hepatic impairment with coagulopathy

  • Mechanical heart valves (increased risk of thromboembolic and bleeding events)

  • Recent hemorrhagic stroke

  • Concomitant use with other anticoagulants (unless switching or bridging)

  • Hypersensitivity to dabigatran or excipients

Warnings and Precautions

  • Bleeding Risk: Major bleeding can occur at any site; risk increases with age, renal dysfunction, and concurrent NSAID or antiplatelet use

  • Spinal/Epidural Hematoma: Risk of paralysis in patients undergoing neuraxial anesthesia or spinal puncture

  • Renal Monitoring: Check creatinine clearance at baseline and periodically, especially in elderly

  • Surgical Considerations: Withhold 24–48 hours prior to surgery depending on bleeding risk and renal function

  • Capsule Swallowing: Capsules should not be opened or chewed — this increases bioavailability and bleeding risk

  • Adherence: Short half-life (12–17 hours) means missed doses reduce anticoagulant effect significantly

Adverse Effects

Common

  • Dyspepsia, gastritis-like symptoms

  • Bleeding (e.g., epistaxis, gastrointestinal, hematuria, bruising)

  • Nausea, abdominal discomfort

Serious

  • Major hemorrhage, including gastrointestinal bleeding and intracranial hemorrhage

  • Hemorrhagic stroke

  • Hypersensitivity reactions

  • Hepatic enzyme elevations

  • Spinal/epidural hematomas

Less Common

  • Thrombocytopenia

  • Allergic dermatitis

  • Anemia due to occult blood loss

  • Hepatotoxicity (rare, monitor if symptomatic)

Drug Interactions

P-glycoprotein (P-gp) Substrate

Dabigatran is a substrate of the P-glycoprotein transporter. Drugs affecting P-gp significantly alter dabigatran absorption and plasma levels.

P-gp Inhibitors

  • Increase dabigatran levels → bleeding risk

  • Examples: Verapamil, Amiodarone, Dronedarone, Ketoconazole, Quinidine, Ciclosporin

  • Dose adjustment or avoidance may be necessary

P-gp Inducers

  • Decrease dabigatran efficacy

  • Examples: Rifampicin, Carbamazepine, Phenytoin, St. John’s Wort

  • Concomitant use is generally discouraged

Other Interactions

  • Antiplatelets (aspirin, clopidogrel): Additive bleeding risk

  • NSAIDs: Increase risk of gastrointestinal bleeding

  • Other anticoagulants: Avoid unless in transition (e.g., warfarin, heparin)

  • Proton Pump Inhibitors (PPIs): May reduce absorption slightly but often used to manage GI side effects

Reversal Agent

  • Idarucizumab (Praxbind) is a humanized monoclonal antibody fragment that binds dabigatran with high affinity, neutralizing its anticoagulant effect within minutes

  • Used in life-threatening bleeding or emergency surgery

  • Dose: 5 g IV, administered as two 2.5 g doses

Pregnancy and Lactation

Pregnancy

  • Dabigatran is not recommended due to insufficient human data and potential teratogenicity observed in animal studies

  • Use safer alternatives (e.g., LMWH) during pregnancy

Lactation

  • Unknown if dabigatran is excreted in breast milk

  • Use is not advised in breastfeeding women

Use in Pediatrics

  • Approved in some regions (e.g., EU, USA) for pediatric VTE from 3 months of age

  • Formulated as oral pellets for children unable to swallow capsules

  • Dosing based on age and weight; specialist input essential

Clinical Trials and Efficacy

RE-LY Trial

  • Compared dabigatran (110 mg and 150 mg twice daily) to warfarin in NVAF

  • 150 mg dose showed superior stroke prevention

  • Lower rate of intracranial hemorrhage compared to warfarin

  • 110 mg had similar efficacy with lower bleeding risk

RE-COVER Trials

  • Evaluated dabigatran for DVT/PE treatment

  • Non-inferior to warfarin with similar bleeding rates

  • Preferred for long-term anticoagulation due to fixed dosing and no INR monitoring

RE-MEDY / RE-SONATE

  • Studied extended VTE prophylaxis

  • Dabigatran reduced recurrence of VTE compared to placebo

  • Less bleeding compared to warfarin during long-term use

Comparison with Other Anticoagulants

Dabigatran vs. Warfarin

  • No INR monitoring required

  • Fewer food and drug interactions

  • Faster onset/offset of action

  • Lower rates of intracranial bleeding

  • Higher rates of GI bleeding

Dabigatran vs. Rivaroxaban / Apixaban

  • Dabigatran is the only DOAC with a specific reversal agent

  • Dabigatran requires twice daily dosing, others may be once daily

  • Dyspepsia is more common with dabigatran

  • All offer comparable efficacy for stroke and VTE prevention

Counseling Points

  • Take with food or a full glass of water to reduce gastric discomfort

  • Do not chew, crush, or open capsules – this alters drug absorption and increases bleeding risk

  • Missed dose: If within 6 hours, take it; otherwise skip

  • Be alert for signs of bleeding: easy bruising, blood in stool or urine, prolonged bleeding from cuts

  • Inform all healthcare providers (especially dentists and surgeons) of dabigatran use

  • Store in original packaging to protect from moisture

  • Do not stop abruptly – abrupt discontinuation increases thromboembolic risk




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