Dabigatran etexilate (Pradaxa®) was recently approved for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF). As the first new oral anticoagulant in over 50 years, dabigatran provides an alternative to warfarin with predictable pharmacokinetics and pharmacodynamics. However, there is still limited real-world clinical experience. This article examines the evidence and practical considerations for using dabigatran in general practice.

Highlight

• Indications and dosing recommendations for dabigatran
• Adverse effects and interactions
• Selecting suitable patients for dabigatran
• Switching between warfarin and dabigatran
• Critique of pivotal RE-LY trial
• Managing bleeding complications

Dabigatran is indicated for stroke prevention in non-valvular AF

Dabigatran is approved for prevention of stroke and systemic embolism in patients with non-valvular AF. It is contraindicated in valvular AF and mechanical valves due to lack of evidence. Dabigatran is also indicated for short-term venous thromboembolism (VTE) prophylaxis after orthopedic surgery.

The recommended dose is 150 mg twice daily in patients with creatinine clearance 30 mL/min. A lower 110 mg twice daily dose is recommended for patients ≥80 years old. Dabigatran is contraindicated if creatinine clearance is30 mL/min due to dependence on renal elimination.

Unlike warfarin, dabigatran has predictable pharmacokinetics and does not require routine monitoring. However, twice daily dosing is essential to maintain efficacy. Dabigatran capsules must be swallowed whole and stored in original packaging to prevent decreased potency from moisture exposure.

Bleeding is the main adverse effect, limited antidote options

Bleeding is the most concerning adverse effect with dabigatran. Rates of major bleeding are comparable to warfarin. However, there is lower risk of intracranial hemorrhage and higher risk of gastrointestinal bleeding compared to warfarin.

Importantly, there is no specific reversal agent for dabigatran. For serious bleeding, dabigatran must be stopped and supportive treatment given. Activated partial thromboplastin time (aPTT) can help guide management. Hemodialysis can remove dabigatran if needed.

Interactions may occur with P-glycoprotein inhibitors like amiodarone, verapamil, and ketoconazole. Concomitant use with antiplatelets or NSAIDs also increases bleeding risk. Dyspepsia is more common with dabigatran due to the tartaric acid excipient.

Careful patient selection is crucial

Patients who may benefit include those with poor INR control on warfarin or who decline warfarin monitoring. Dabigatran may also be useful in patients starting anticoagulation.

Patients unsuitable for dabigatran include those with high bleeding risk, frequent falls, gastrointestinal ulcers, renal impairment (creatinine clearance30 mL/min), and interacting medications. Caution is advised in elderly patients and those with creatinine clearance 30-50 mL/min.

For patients well-controlled on warfarin, there is no compelling reason to switch to dabigatran given similar efficacy. Some patients may still prefer warfarin due to familiarity and ability to reverse bleeding.

Allow washout when switching between anticoagulants

When starting dabigatran, no loading dose is required. For patients switching from warfarin, dabigatran should only be started once INR is2.0. When switching from dabigatran to warfarin, a 2-3 day washout period is advised based on creatinine clearance before stopping dabigatran.

The INR should not be used to monitor dabigatran as effects are variable and unpredictable. The aPTT and thrombin time can help assess presence of anticoagulant activity but are not useful for routine monitoring.

RE-LY trial supports dabigatran but limitations exist

Approval of dabigatran for stroke prevention in AF was based primarily on the RE-LY trial. This was a large randomized trial in over 18,000 patients comparing two doses of dabigatran to well-controlled warfarin.

RE-LY found that 150 mg twice daily dabigatran was superior to warfarin for reducing stroke and systemic embolism. However, there are concerns about the open-label warfarin design, high withdrawal rates, and inclusion of patients on antiplatelets.

Long-term real-world safety (2 years in RE-LY trial) and utility in broader patient populations remains unknown. Additional post-marketing data is needed to better define benefits and risks compared to warfarin.

Act promptly for serious bleeding, refer to emergency care

For mild bleeding, supportive care and holding dabigatran may be sufficient. However, severe or life-threatening bleeding requires emergent medical attention given lack of reversal agent.

Dabigatran should be stopped and bleeding source identified. IV fluid resuscitation, activated charcoal, hemodialysis, anti-fibrinolytics, and blood products can be used as clinically indicated. A hematology consult is recommended.

In conclusion, dabigatran represents an exciting new option for stroke prevention in AF. However, use requires careful patient selection and additional real-world data is needed. Dabigatran does not eliminate the need for ongoing patient monitoring and assessment.