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Dosage

Dabigatran elimination occurs predominantly (80%) via renal excretion.  Therefore, dabigatran administration is contraindicated in patients with significant renal insufficiency. ¹⁰   Recommended dosage is based on creatinine clearance. ¹¹

Table 2

Adverse Reaction

Dabigatran is well tolerated.  In the RE-LY study, the most common adverse reactions leading to discontinuation were bleeding and gastrointestinal (dyspepsia, nausea, and diarrhea). ¹² 

Drug Interactions

Dabigatran is not significantly metabolized by the cytochrome P450 enzyme system, thereby limiting the risk of significant drug interactions.  Bioavailability is not influenced by administration with food.  Rifampin, a P-glycoprotein transport inducer, may significantly decrease dabigatran levels and should be avoided. ^{10, 13}    Dronedarone increases dabigatran exposure 1.7-2 times. ¹¹

Treatment of Bleeding Complications or Overdose

No antidote exists should a major bleeding complication or overdose occur.  Additionally, no laboratory test for monitoring dabigatran’s anticoagulation effects has been adequately validated.  ¹⁴    Potential treatment options include dialysis (which can remove approximately 60% of dabigatran from plasma in 2-3 hours) and administration of activated prothrombin complex, recombinant factor VIIa and coagulation factors II, IX and X. ¹⁵ 

Table 3

Future Indications

Alternative uses for dabigatran beyond stroke prevention in AF are anticipated but have yet to be fully validated as safe and effective.  Preliminary studies of alternative uses of dabigatran, including the prevention of venous thromboembolism (VTE) following total knee or hip arthroplasty, treatment of acute VTE and pulmonary embolism (PE), and for thromboprophylaxis of mechanical heart valves, have either recently been published or are currently underway.

Four trials assessing dabigatran’s effectiveness for VTE prevention following total knee or hip arthroplasty have been published.  While three trials, RE-MODEL, ¹⁷  RE-NOVATE I, ¹⁸  and RE-NOVATE II, ¹⁹  found dabigtran equally effective in VTE prevention and with a comparable incidence of major bleeding, RE-MOBILZE ²⁰ found dabigatran to be inferior to enoxaparin for VTE prevention following total knee arthroplasty.  A meta-analysis of all four trials suggested dabigatran 220 mg daily had similar efficacy for VTE prevention and similar bleeding risk when compared to enoxaparin (40 mg daily or 30 mg BID). ²¹ While dabigatran is approved for VTE prevention following hip or knee arthroplasty in many other countries, it has yet to be approved in the United States.  ^{21, 22}

The RE-COVER trial compared Dabigatran (150 mg BID) to warfarin (INR 2.0-3.0) for the 6 month treatment of acute VTE.  The rates of recurrent VTE, VTE-related death and major bleeding were comparable.  ²³ 

Conclusion

Ischemic stroke is a devastating complication of AF.  Warfarin, previously the most effective pharmacologic treatment for stroke prevention in patients with AF, has several limitations which have led to its underutilization.  Dabigatran, having several potential advantages over warfarin, should be considered for those patients with labile international normalized ratio (INR’s) while taking warfarin, for those wishing to avoid routine coagulation monitoring, and for those with an ischemic stroke despite a therapeutic INR.   While recently approved in the United States for stroke prevention in patients with AF, alternative uses, including the prevention of VTE following total knee or hip arthroplasty, the treatment of acute VTE and PE, and thromboprophylaxis of mechanical heart valves, have yet to be approved in the United States.

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