Article date: March 2013

Dabigatran (Pradaxa) is a reversible inhibitor of free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation. It is licensed for primary prevention of venous thromboembolic events in adults who have had elective total hip or knee replacement surgery (at 220 mg/day), and for prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation and one or more cardiovascular risk factors (at 300 mg/day).

Increased risk of thrombosis and bleeding events

Previously, the product information for dabigatran recommended not to use dabigatran in patients with prosthetic heart valves. This warning has now been upgraded to a contraindication as a result of new data from the RE-ALIGN trial.

RE-ALIGN was an investigational phase II trial involving 252 patients, which compared dabigatran with warfarin in patients with recent mechanical heart valve replacement (during the current hospital stay), and in patients who underwent heart valve replacement more than three months beforehand.

There was a higher frequency of either thromboembolic events or bleeding events in patients treated with dabigatran compared with warfarin, regardless of the length of time elapsed since valve implantation. In the early post-operative patients, major bleeding manifested mainly as haemorrhagic pericardial effusion (unpublished data).

The reasons for these anomalous findings are not yet known; possible explanations include the higher-than-approved doses that the majority of patients in the dabigatran-treated group received (up to 300 mg twice daily) which may have been associated with the bleeding events, and that the trough plasma concentrations of dabigatran were lower than expected which may have led to thrombotic events in some patients.

Updated advice on the timing of using dabigatran after cardiac surgery may be issued when this has been further assessed.

No change to licensed indications

The results of the RE-ALIGN trial do not impact on the positive balance of benefits and risks of dabigatran in its currently licensed indications for:

primary prevention of venous thromboembolic events after elective total hip or knee replacement

prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and one or more cardiovascular risk factors

Advice for healthcare professionals

Dabigatran is contraindicated in patients with prosthetic heart valve(s) requiring anticoagulant treatment related to their valve surgery, regardless of the length of time that has elapsed since valve replacement took place.

A full list of contraindications and warnings, together with updated product information for dabigatran, can be found in the summaries of product characteristics

Further information

Letter sent to healthcare professionals in January 2013

Information from European Medicines Agency on Pradaxa

BNF section 2.8.2: Oral anticoagulants

Article citation: Drug Safety Update March 2013, vol 6, issue 8: A1