Wednesday, January 26, 2011

Dabigatran, and what about its use in Nephrology and Transplantation?

Dabigatran etexilate is an oral direct thrombin inhibitor that has been now approved by FDA as of Oct 2010 for clinical use. Its been FDA approved for stroke prevention in non valvular Atrial Fibrillation.  A recent paper in Circulation also listed below, approved it for cardioversion as well. The dosages to be used are: 75mg to 150mg BID and no levels to check and blood thinning effects are similar to warfarin. The RE-LY study presented in NEJM showed it to be superior to warfarin when used at a dose of 150mg and non inferior when a dose of 110mg was used. At a dose of 110mg the rates of stroke and embolism were similar to warfarin and bleeding rates were lower with this agent compared to warfarin.  With a dose of 150mg , the rates of stroke and embolism were lower.; the bleeding risks were similar to  warfarin. Compared with warfarin, patients on dabigatran 150mg had a 35% reduction in the incidence of stroke, and the rate of major bleeding each year was 3.3% with the new agent and 3.6% per year with warfarin It works as its a direct inhibitor of thrombin. It has an absolute bioavailability of 6.5%, 80% of the given dose is excreted by the kidneys, its serum half-life is 12 to 17 hours. Its precursor drug had hepatic toxicity, this drug so far didn't have that problem.

What is the question at our front? Can we use this agent in our transplant patients who are on immunosuppresion and if there is any interactions?
The other question is in ESRD or CKD patients since this is excreted via the kidney?
One study listed below was to investigate the effect of renal impairment on the pharmacokinetics and pharmacodynamics of dabigatran following administration of a single oral dose of dabigatran etexilate in subjects with renal impairment (150 mg) or end-stage renal disease (ESRD) on maintenance haemodialysis (50 mg). In subjects with severe renal impairment, half life was doubled from 14 hours to 28 hours. As a result AUC was high and activated PTT was also higher in those patients. Hemodialysis removed 62-68% of the dose. Dabigatran etexilate was well tolerated in all groups. The study concluded that "Exposure to dabigatran is increased by renal impairment and correlates with the severity of renal dysfunction. A decrease in the dose and/or an increase in the administration interval in these patients may be appropriate. In patients with ESRD, dabigatran can be partly removed from the plasma by haemodialysis." This is the only study we could find in the literature regarding this drug.
The other question is about transplantation patients. So far no mention about such cases or reports of being used in transplantation patients. Cyclosporine is a p gp inhibitor and based on the interactions data, dabigatran dose reductions might be required if used with calcineurin inhibitors. No interactions were found with MMF, Steroids, Azathioprine or sirolimus.



  1. I found this information re use in renal impairment.( from based on RE-LY trial and others)
    US labelling:
    If Crcl >30: no dose adjustments needed
    Clcr 15-30 mL/minute: 75 mg twice daily; Note: Patients with Clcr <30 mL/minute were excluded from the RE-LY trial
    Clcr <15 mL/minute or hemodialysis dependent: No recommendation provided due to insufficient evidence; Note: Hemodialysis removes ~60% over 2-3 hours

  2. I have had a bad experience with this drug in an elderly renal transplant patient. She was admitted to hospital with acute renal failure and had been on the drug for atrial fib. It took 7 days of daily dialysis before we could biopsy the graft.

    1. What did you find in the biopsy?


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