Dabigatran etexilate

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An oral, direct thrombin inhibitor with ever widening licensed indications (in Phase III trials for acute VTE, wider secondary prevention VTE, ACS). Gained UK licence in April 2008 for thromboprophylaxis following knee and hip arthroplasty. Gained the potential blockbuster FDA indication of prevention of stroke and blood clots in patients with atrial fibrillation in October 2010 and introduced into Europe for this indication from August 2011. Analysis of safety issues since launch is strongly suggestive that most issues arise from use in patients with contraindications. The elderly and those with renal impairment may be at most risk from some quite marked variation in drug levels which it has been postulated could provide a guide to even safer use[1][2]. The place in therapy is still evolving and there is differential international regulatory interpretation of the evidence base so prescribers should see the latest medicines regulation advice for your jurisdiction[3].

Contents

Clinical Use

Large clinical trials are taking place in thromboembolic disease with promising results to date in multiple clinical indications against standard treatment. In those who can not establish stable warfarin anticoagulation it may be superior:

Indications

Administration

Oral

  • For thromboprophylaxis
    • Normal adults:110mg between 1 and 4 hours after surgery, continuing with 220mg daily for 10 days in total knee replacement and 28 to 35 days in hip replacement.
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See SPC for AF and cautions

  • Up to 80 years 150 mg twice daily
  • Patients aged 80 years or above 110 mg capsule twice daily
  • Do not use with <CrCl 30 mL/min
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See manufacturers information for AF and cautions

  • For patients with CrCl >30 mL/min: 150 mg orally, twice daily
  • For patients with CrCl 15-30 mL/min: 75 mg orally, twice daily
  • For AF
    • Usual dose of 150mg bd needs reduction in several common patient groups and the amount of reduction is not consistent between licensing authorities due to different ways the evidence base for the needed reduction can be interpreted. Essentially its a risk benefit balance, and different societies might value different outcomes differently (ie gastrointestinal bleeding compared to stroke). The cuts off for dose reduction are generally biological age of greater than 75 or moderate renal dysfunction.
    • The dose in the treatment studies was up to 150 mg twice daily, and these are in younger patients with good renal function which are unlikely to be representative of usual patient populations Post licensing there are isolated clinical reports of adverse outcomes where prescribers have not adhered to the licensing advice.
  • For treatment and prevention of recurrent VTE. As for AF after minimum 5 days of parental anticoagulant.

Clinical Issues

Reversal

Idarucizumab is a rapid reversal agent[9] and others may be in development[10] so care must be supportive and by stopping the drug.

Contra-indications

See latest medicines regulation advice for your jurisdiction

  • Active bleeding
  • Concomitant treatment with any other anticoagulant (except switching therapy or when UFH is given at doses necessary to maintain a central venous or arterial catheter)
  • Severe renal impairment (creatinine clearance (CrCL) < 30 ml/min)
  • Lesion or condition at significant risk of major bleeding:
    • Current or recent gastrointestinal ulceration, oesophageal varices
    • Neoplasms at high risk of bleeding
    • Recent brain or spinal injury or surgery
    • Recent ophthalmic surgery
    • Recent intracranial haemorrhage
    • Arteriovenous malformations
    • Vascular aneurysms
  • Hepatic impairment or liver disease expected to have any impact on survival
  • Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole, tacrolimus and dronedarone
  • Prosthetic heart valves requiring anticoagulant treatment (the phase II trial RE-ALIGNTM showed this did not work)

Cautions and Interactions

Side effects

  • Bleeding - appears to be less minor bleeding than warfarin for same clinical efficacy
  • Dyspepsia - can be a reason for patients discontinuing drug
  • Diarrhoea (possible)

Special advice

Pharmacology

  • Contains micropellets with dabigatran etexilate around a tartaric acid core as low pH needed for good drug absorption.
  • The drug must be stored in original packaging as it rapidly loses potency on exposure to moisture

External link

References

  1. Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ (Clinical research ed.). 2014; 349:g4670.(Epub)
  2. Charlton B, Redberg R. The trouble with dabigatran. BMJ (Clinical research ed.). 2014; 349:g4681.(Epub)
  3. Moore TJ, Cohen MR, Mattison DR. Dabigatran, bleeding, and the regulators. BMJ (Clinical research ed.). 2014; 349:g4517.(Epub)
  4. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Kälebo P, Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Büller HR. Dabigatran etexilate versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. 2007 Aug 24.(Epub ahead of print) (Link to article – subscription may be required.)
  5. Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial Lancet 2007 ;370:949-956
  6. Holmes M, Carroll C, Papaioannou D. Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip and knee surgery: a single technology appraisal. Health technology assessment (Winchester, England). 2009 Sep; 13 Suppl 2:55-62.(Link to article – subscription may be required.)
  7. Dabigatran versus Warfarin in Patients with Atrial Fibrillation NEJM accessed 30 Aug 09 DOI 10.1056/NEJMoa0905561
  8. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. NEJM accessed 06 Dec 09 DOI 10.1056/NEJMoa0906598
  9. Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI. Idarucizumab for Dabigatran Reversal. The New England journal of medicine. 2015 Aug 6; 373(6):511-20.(Link to article – subscription may be required.)
  10. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4; 124(14):1573-9.(Link to article – subscription may be required.)