Dabigatran (Pradaxa) is the first oral, fixed-dose, direct thrombin inhibitor licensed in the UK.

Both a full review of dabigatran and a briefing sheet for primary care can be accessed from this webpage.

 It is licensed for the prevention of venous thromboembolic events in adult patients following elective total hip or total knee replacement surgery.  No monitoring of its coagulation effects is necessary.

By specifically and selectively inhibiting thrombin, dabigatran prevents the conversion of fibrinogen to fibrin and the development of clots.

The first oral direct thrombin inhibitor, ximelagatran was withdrawn from the EU market due to the potential to cause severe hepatic injury when used for more than 11 days.  Abnormal liver function tests had also been reported with shorter durations of use. 

 Three main phase III studies were conducted:  RE-MODEL (total knee replacement), RE-NOVATE (total hip replacement) and RE-MOBILIZE (total knee replacement). 

  RE-MODEL and RE-NOVATE were the two pivotal studies and were conducted in Europe.  Dabigatran (150mg and 220mg, both started 1-4 hours after surgery) was compared with enoxaparin 40mg, started the evening before surgery.

RE-MOBLIZE was a supportive study conducted in North America and differed from the pivotal studies with respect to:

- patient randomisation (after surgery),

-   the dose of enoxaparin used (30mg twice daily instead of 40mg, started 12-24 hours after surgery)

-   and when dabigatran was given (after a delay of 12-25 hours; reflective of the US perception of the bleeding risk and inconsistent with the recommendations in the UK Summary of Product Characteristics).

  A limited number of patients in the RE-MODEL and RE-NOVATE trials had concomitant diseases, such as coronary artery disease, heart failure or history of prior VTE.  A large proportion of patients (63%-70%) had never smoked, and over 90% were abstinent at trial entry.  Only 3.3% to 4.1% of patients were also taking aspirin, which may reflect clinical practice when patient discontinue prior to surgery. 

 As with other trials in this disease area, a quarter of patients randomised into the RE-NOVATE and RE-MODEL trials were not eligible for the primary efficacy analysis, mainly due to missing or inadequate venography data.

The primary efficacy analysis for both trials was the total number of venous thromboembolic events (VTE) both asymptomatic (as shown on venograms) and symptomatic (deep vein thrombosis (DVT) or pulmonary embolism (PE)) and all-cause mortality during treatment.

The secondary endpoints included major VTEs (composite of proximal DVT and PE) and VTE-related mortality.

In both pivotal studies a clear dose-response for dabigatran was seen with no significant difference in the rates of major VTE and thrombosis related death with either dose of dabigatran versus enoxaparin. (a trend towards higher efficacy with the 220mg dose, but with an associated small increase in bleeding risk).  The absolute difference in the rate of major VTE and VTE related mortality with either dose of dabigatran versus enoxaparin during the treatment period was not significant.  For all bleeding outcomes, there was no significant difference between either dose of dabigatran and enoxaparin in either trial.

 RE-MODEL and RE-NOVATE were non-inferiority trials.  This means that the aim of the trials was to demonstrate that dabigatran was not worse than enoxaparin by more than a pre-specified, small amount (the non-inferiority margin).   

  Non-inferiority of dabigatran to enoxaparin for both doses of dabigatran was shown (for both the primary and secondary endpoints).    

 Dabigatran should not be used in patients with raised liver transaminases (more than 2x upper limit of normal).

The NHS list prices of dabigatran etexilate are:  10x75mg capsules £21.00; 60 x 110mg capsules £126.00.  These prices do not take into account any local purchasing agreements.

 The Scottish Medicines Consortium has recently accepted dabigatran for use within NHS Scotland for the primary prevention of VTE events in adult patients who have undergone elective total hip or total knee replacement surgery.