In the March WMSHP Newsletter, Sara D. Schepcoff, a PGY-1 Pharmacy Resident at Spectrum Health, reviews the new oral anticoagulant dabigatran.

Dabigatran overview

For approximately half a century, warfarin has been the gold standard anticoagulant for patients living with atrial fibrillation (AF).  The new oral anticoagulant, dabigatran (Pradaxa – Boehringer Ingelheim), may be a simpler option for these patients.  On October 19^th, dabigatran became the first FDA-approved oral direct thrombin inhibitor in the United States.  Its sole indication is to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF.  Contrary to warfarin, dabigatran requires no monitoring of international normalized ratios (INRs), has minimal drug interactions, and comes with no known dietary restrictions. 

Dabigatran etexilate is a prodrug which is rapidly absorbed and then converted in vivo to the active form, dabigatran, through esterase-catalyzed hydrolysis in the plasma and liver. It inhibits thrombin, thereby preventing the conversion of fibrinogen to fibrin in the coagulation cascade.  Free thrombin, clot-bound thrombin and thrombin-induced platelet aggregation are inhibited by dabigatran.

Key studies

The efficacy and safety of dabigatran have been evaluated in numerous clinical studies.  The pivotal trial for US approval was RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), in which dabigatran 110 mg or 150 mg twice daily was compared to dose-adjusted warfarin in more than 18,000 patients with AF. After a median duration of 2 years, dabigatran 150 mg twice daily was associated with lower rates of stroke and systemic embolism versus warfarin.  The two drugs had similar rates of major bleeding (3.11% per year with dabigatran 150mg and 3.36% per year with warfarin).

In a more recent analysis of RE-LY, it was noted that for all vascular events, non-hemorrhagic events, and mortality, the advantages seen with dabigatran therapy were greater at sites with poor INR control than at those with good INR control. Therefore, many experts believe that dabigatran may be a good option for patients who have difficulty maintaining their INR within range, who are troubled by dietary or drug interactions, or who experience adherence issues. However, for patients who are currently stable on warfarin therapy, there may be no benefit to switching.

 

Dosing and therapeutic considerations

Dabigatran (Pradaxa)

Drug class:  Direct thrombin inhibitor Indication:  Reduce the risk of stroke and systemic embolism in patients with nonvalvular      atrial fibrillation (AF)

Dosage:  150 mg twice daily, by mouth, with or without food, for patients with a creatinine clearance (CrCl) above 30 mL/min. For patients with renal impairment (CrCl between 15 and 30 mL/min), the recommended dose should be reduced to 75 mg twice daily as dabigatran is primarily renally excreted (80%).  No dose recommendations are available for patients with CrCl less than 15 mL/min or for patients on dialysis.  Patients can be converted from warfarin to dabigatran by starting dabigatran once their INR is less than 2.0. Dabigatran should be discontinued 1 to 2 days (CrCl ≥ 50 mL/min) or 3 to 5 days (CrCl < 50 mL/min) before an invasive or surgical procedure.   Other considerations: Dabigatran is contraindicated for patients with active bleeding or those with a history of serious hypersensitivity to the drug.  As with all anticoagulants, dabigatran increases the risk of bleeding, especially when used in combination with other medications that increase this risk, such as antiplatelet agents, heparin, and NSAIDs.  While dabigatran is not a substrate, inhibitor, or inducer of cytochrome P450 enzymes, it is a P-glycoprotein (P-gp) substrate and should not be used with P-gp inducers such as rifampin, as exposure to the drug will be reduced.  No dosage adjustments are required if administered with P-gp inhibitors, such as ketoconazole, verapamil, amiodarone, quinidine, or clarithromycin.

 

Advantages and limitations

For patients treated with dabigatran, ecarin clotting time (ECT) is considered the best assessment of bleeding risk, but is not readily available.  The aPTT test provides an approximation of dabigatran’s anticoagulant activity, but is nonlinear at higher doses.  There is no readily available reversal agent for patients who develop bleeding complications with dabigatran.  Bleeding may be managed with diuresis and dialysis to remove the drug as well as replacement with fresh frozen plasma.                

The high rate of dyspepsia (11.5% of patients treated with dabigatran in the RE-LY trial versus 5.8% treated with warfarin) may also be a concern for clinicians and patients.  At the beginning of the study, nearly 14 % of the patients in each treatment group were taking a PPI and roughly 4% were taking an H2-receptor antagonist.  Researchers reported a 20% dropout rate by the year-2 follow-up visit. 

Dabigatran became available in US pharmacies at a wholesale acquisition cost of $6.75 per day.  An early-release article in the Annals of Internal Medicine found that dabigatran is cost effective compared with warfarin therapy because of the associated costs of warfarin monitoring and complications. However, for patients taking dabigatran as outpatient therapy, it may come at a high co-pay cost. For these patients, and for those requiring infrequent INR monitoring, cost savings may not occur.

Summary

Dabigatran (Pradaxa) is a promising new oral anticoagulant indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.  It may be a good alternative for patients who have difficulty maintaining a therapeutic INR on warfarin therapy as it requires no lab monitoring, has minimal drug interactions, and no dietary limitations. 

References

1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, et al, and the RE-LY Steering Committee and Investigators.  Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
2. Tanzi MG. Dabigatran: Anticoag simplifies therapy. Pharmacy Today 2010:34-35.
3. Thompson CA. First oral thrombin inhibitor enters market. Am J Health-Syst Pharm 2010;67:1974-76.
4. Pradaxa (dabigatran etaxilate mesylate) capsules for oral use (package insert).Ridgefield, CT; Boehringer Ingelheim Pharmaceuticals, Inc.;October 2010.
5. Freeman JV, Zhu RP, Owens DK, Garber AM, et al.  Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med 2011;154(1):1-11. Epub 2010 Nov 1.
6. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, et al; RE-LY Investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010;376:975-83.