Dabigatran: A Direct Thrombin Inhibitor for Stroke Prevention in Atrial Fibrillation
Dabigatran is an oral direct thrombin inhibitor primarily indicated for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. 1
What is Dabigatran?
- Dabigatran etexilate is a prodrug that rapidly converts to the active direct thrombin (factor IIa) inhibitor dabigatran 2
- It works by directly inhibiting thrombin in the coagulation cascade 2
- Conversion is independent of cytochrome P-450, making drug-drug interactions less likely 2
- It has a half-life of 12-17 hours 2
- Dabigatran is predominantly excreted via the renal pathway (80% unchanged in urine) 2
FDA-Approved Indications
- To reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation 1
- For the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in adult patients who have been treated with a parenteral anticoagulant for 5-10 days 1
- To reduce the risk of recurrence of DVT and PE in adult patients who have been previously treated 1
Dosing in Atrial Fibrillation
- For patients with CrCl >30 mL/min: 150 mg orally, twice daily 1
- For patients with CrCl 15-30 mL/min: 75 mg twice daily 1
- No dosing recommendations exist for patients with CrCl <15 mL/min or on dialysis 1
Clinical Evidence for Stroke Prevention
- The RE-LY trial compared dabigatran (110 mg and 150 mg twice daily) with warfarin in 18,113 patients with non-valvular AF and at least one additional risk factor for stroke 2
- Dabigatran 150 mg twice daily was superior to warfarin for preventing stroke and systemic embolism (1.11% vs 1.71% per year; RR: 0.65; 95% CI: 0.52-0.81) 2
- Dabigatran 110 mg twice daily was non-inferior to warfarin (1.54% vs 1.71% per year) 2
- Risk of hemorrhagic stroke was 74% lower with both doses of dabigatran compared to warfarin 2
- Major bleeding was significantly decreased with the 110 mg dose but similar with the 150 mg dose compared to warfarin 2
Advantages Over Warfarin
- Does not require routine INR monitoring 2
- Has predictable pharmacokinetics and pharmacodynamics 2
- Fewer food interactions 2
- Lower rates of intracranial hemorrhage compared to warfarin 2
- Fixed dosing regimen 2
Important Precautions and Limitations
Contraindicated in patients with: 1
- Active pathological bleeding
- History of serious hypersensitivity reaction to dabigatran
- Mechanical prosthetic heart valves
- Patients with bioprosthetic heart valves
- Patients with triple-positive antiphospholipid syndrome
- Severe renal impairment (CrCl <15 mL/min)
- Advanced liver disease with impaired baseline clotting function
No specific antidote was initially available (idarucizumab is now approved as an antidote) 3
Increased risk of gastrointestinal bleeding with the 150 mg dose (1.6% vs 1.0% per year with warfarin) 2
Possible increased risk of myocardial infarction (0.73% vs 0.53% with warfarin) 4
Dyspepsia is more common with dabigatran than warfarin (6% vs 1.4%) 4
Drug Interactions
- P-glycoprotein inhibitors (verapamil, amiodarone, quinidine) may increase dabigatran levels 2
- Avoid coadministration with P-gp inducers 1
- For patients with CrCl 30-50 mL/min taking P-gp inhibitors: reduce dose or avoid 1
- For patients with CrCl <30 mL/min taking P-gp inhibitors: not recommended 1
Special Considerations
- Renal function must be monitored as impairment increases bleeding risk 4
- Temporarily discontinue before invasive or surgical procedures when possible, then restart promptly 1
- Risk of bleeding increases with age 1
- Excessive dose reduction to 75 mg twice daily (below recommended dosing) may lead to inadequate anticoagulation and increased risk of thromboembolism 5
- Premature discontinuation increases the risk of thrombotic events 1
Clinical Pearls
- Patients with excellent INR control on warfarin may have little to gain by switching to dabigatran 2
- Selection of patients who could benefit from dabigatran should consider compliance with twice-daily dosing, availability of anticoagulation monitoring programs, patient preferences, and cost 2
- Dabigatran was the first new oral anticoagulant to become available for clinical use in 50 years 2