At a meeting held 17-20 October 2011, the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA), strengthened the instructions for doctors' use of dabigatran etexilate with particular focus on patients with impaired renal function.
This was done in response to reports of severe cases of bleeding occurring from the use of dabigatran etexilate (primarily in Japan and the USA).
The recommendation will be to assess renal function in patients before starting dabigatran etexilate treatment. Also, the renal function should be assessed in special clinical situations whenever a decline in renal function is suspected.
In patients older than 75 or patients with impaired renal function, the renal function should be assessed at least once a year. Renal function should be assessed by calculating creatinine clearance.
Dabigatran etexilate is still contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min.)
The revised summary of product characteristics and package leaflet now await the European Commission's final approval.
Bleeding is a well-known risk
Treatment with anticoagulant medicine is associated with an increased risk of bleeding, including potentially fatal bleeding in the brain and stomach/intestines. Patients with atrial fibrillation have for years been treated with warfarin (Marevan®) while closely monitoring INR. Despite this, bleeding cannot be avoided completely.
In the RE-LY study (i, ii), which compared the traditional warfarin treatment with dabigatran etexilate treatment in patients with atrial fibrillation, no overall difference in the occurrence of bleeding was found between the two treatments.
Whereas bleeding was observed in about 16 % of all patients regardless of treatment, severe bleeding was seen in 2.87 % of patients treated with dabigatran etexilate 110 mg twice daily and in 3.32 % of patients treated with dabigatran etexilate 150 mg twice daily. By comparison, severe bleeding was seen in 3.57 % of patients treated with warfarin.
Based on controlled clinical trials, there is therefore no immediate expectation that bleeding should occur more frequently for dabigatran etexilate treatment than for warfarin treatment. The Danish Medicines Agency and EMA will nonetheless follow the number of adverse reactions, including bleeding, closely.
Adverse reaction reports in Denmark
In Denmark, the Danish Medicines Agency has since the marketing of dabigatran etexilate (2008) and until 1 November 2011 received 33 adverse reaction reports for dabigatran and 66 for warfarin. For both of these drugs, the most frequently reported adverse reactions are bleeding episodes (nosebleed, bleeding in the stomach/intestines as well as brain haemorrhages).
In addition, the Danish Medicines Agency has received three reports of fatal outcomes during treatment with dabigatran, two of which occurred in patients enrolled in clinical testing of dabigatran etexilate.
Recommendation of the Danish Medicines Agency
The Danish Medicines Agency advises patients treated with warfarin, dabigatran etexilate or other anticoagulant treatment not to stop or change treatment without first discussing this with the treating doctor.
Patients who experience increased bleeding tendency or actual bleeding should consult their doctor to discuss their anticoagulant treatment.
Prescribers of dabigatran etexilate are advised to follow the above-mentioned recommendations regarding assessment of renal function before and during treatment.
(i) Ezekowitz MD, Conolly S, Parek A et al: Rationale and design of RE-LY: Randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 2009; 157: 805-810.
(ii) Conolly SJ, Ezekowitz MD, Pihl D et al: Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361: 1139-51.