Following the European label of dabigatran benefits efficacy and safety

Patient outcomes using the European label for dabigatran. A post-hoc analysis from the RE-LY database.

Literature - Lip et al. Thromb Haemost. 2013 - Thromb Haemost. 2013 Dec 11

Lip GY, Clemens A, Noack H, et al.
Thromb Haemost. 2013 Dec 11;111(5). [Epub ahead of print]


In the RE-LY trial dabigatran etexilate 150 mg twice daily (D150) was found to be superior to warfarin for the primary endpoint of stroke and systemic embolism (SE) in atrial fibrillation, with a similar rate of major bleeding, while dabigatran 110 mg bid (D110) was non-inferior to warfarin with 20% fewer bleedings [1,2]. Subgroup analyses have revealed an age interaction for bleeding endpoints [3,4].
The European (EU) label recommends D110 when patients are >80 years old, or have an increased risk of bleeding (based on individual assessment of risk of bleeding in patients aged 75-80), or when they are on verapamil at baseline [5-8]. All other patients should receive the ‘preferred dose’ of D150.
In the United States, only D150 was approved by the FDA for the stroke prevention indication, with the availability of dabigatran 75 mg twice daily for patients with creatinine clearance 15-30 ml/min, although this dosage has not been tested in any phase III clinical trial [9]. It was considered by the FDA that no specific subgroups would benefit from D110.
This post-hoc simulation uses the RE-LY dataset to investigate how dabigatran, when used according to the recommended dose regimen in the EU label, would compare to well-controlled warfarin treatment (INR 2-3, median time in therapeutic range 67.3%).
For this simulation, a high risk of bleeding was defined by HAS-BLED score >3.  D110 and D150 recommended populations within the RE-LY population were defined. In both groups, the randomised doses (150 or 110 mg bid) or warfarin were compared with respect to efficacy and safety outcomes. Over- and undertreated groups were also considered within both groups.

Main results

  • EU label-simulated dabigatran treatment was associated with significant reductions in the primary endpoint of stroke and SE (relative risk reduction (RRR): 26%), and in the secondary endpoints of haemorrhagic stroke (RRR: 78%), death (RRR: 14%) and vascular death (RRR: 20%), but not ischaemic stroke and MI, compared to warfarin.
    Net clinical benefit was also significantly improved after dabigatran, as compared to warfarin.
  • Major bleeding was significantly reduced with EU label simulated dabigatran treatment (RRR: 15%), as well as life-threatening bleeding (RRR: 28%), ICH (RRR: 72%) and ‘any bleeding’ (RR: 14%), but not gastrointestinal bleeding, when compared to warfarin.
  • The number needed to treat vs. warfarin (NNTw) for net clinical benefit (NCB) was 107 (95%CI: 61-373) with EU label simulated treatment. NNTw for reduction of stroke/SE was 226 (95%CI: 133-748), for reducing death it was 173 (95%CI: 93-1118) and for vascular death it was 190 (95%CI: 108-747).
  • In the D150 recommended subpopulation, D110 only gave a significant reduction in haemorrhagic stroke and a positive NCB, as compared to warfarin, while D150 significantly reduced stroke and SE, haemorrhagic stroke, death and vascular death and gave a positive NCB in these patients.
  • Recommended treatment in the D110 recommended subpopulation was associated with a significant reduction in haemorrhagic stroke and ICH as compared to warfarin, just like treatment with D150. D150 treatment in this group gave fewer ischaemic strokes, but more major bleeding and GI major bleeding.


This posthoc analysis of the RE-LY trial shows that ‘EU label simulated dabigatran treatment’ has superior efficacy and safety compared to warfarin for stroke prevention in AF. Thus, these results are in support of the EU label and the ESC AF guideline recommendations [8]. Adherence to the European label and guideline yields  a meaningful and clinically relevant benefit for dabigatran over warfarin, both with regard to efficacy and safety. D150 should be the preferred dose for stroke prevention in atrial fibrillation, with D110 providing an alternative in the case of increased risk of bleeding, patients older than 80 years, and use of verapamil.

Find this article on Pubmed


1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 1875-1876.
2. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
3. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123: 2363-2372.
4. Canada: Boehringer Ingelheim, Available at Pradax (R) Monograph. 2012. Available at: ca_EN/documents/humanhealth/product_monograph/Pradax-pm.pdf. October 18, 2013.
5. Pradaxa Summary of Product Characteristics. European Medicine Agency. 2013. Available at: October 18, 2013.
6. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369-2429.
7. Lip GY, Frison L, Halperin JL, et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol 2011; 57: 173-180.
8. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33:  2719-2747.
9. FDA Pradaxa Label. 2013. Available at: October 18, 2013.

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free