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Dabigatran etexilate (Pradaxa®) associated with significantly lower rates of fatal and traumatic intracranial haemorrhage compared with Warfarin

Posted: 18 April 2012 | | No comments yet

A new analysis of the 18,113 patient…

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A new analysis of the 18,113 patient, RE-LY® trial highlights significantly lower rates of both fatal and traumatic intracranial haemorrhage (ICH) in patients treated with dabigatran etexilate (Pradaxa®) 110mg and 150mg bid compared to those treated with well-controlled warfarin. 1 As part of the primary safety endpoint, the analysis evaluated 154 intracranial haemorrhages that occurred in153 patients during the trial, including bleeding sites, rates, risk factors, associated trauma, and outcomes. Results of this safety analysis were recently published online in Stroke: The Journal of the American Heart Association.

Intracranial haemorrhage is mostly seen in older patients with atrial fibrillation (AF), and is one of the most devastating complications of anticoagulation therapy. Intracranial haemorrhage, which comprises intracerebral haemorrhage, subdural haematoma and subarachnoid haemorrhage, 1 is responsible for the majority of disability and death from bleeding related to treatment with the long time standard of care warfarin. 2

In the RE-LY® trial, Pradaxa® 110mg bid and Pradaxa® 150mg significantly reduced the rate of ICH by 70% and 59% respectively, compared to well-controlled warfarin. 3,4 This new detailed analysis of 154 intracranial haemorrhages across treatment groups in the RE-LY® trial showed:

  • Pradaxa® 110mg bid and 150mg bid were both associated with significantly fewer fatal (110mg: 11 vs. 32, P<0.001 / 150mg: 13 vs. 32, P<0.001) ICH events compared to well-controlled warfarin 1
  • In a combined analysis, Pradaxa® 110mg & 150mg bid were associated with significantly fewer traumatic (11 vs. 24, P<0.05) ICH events compared to well-controlled warfarin 1
  • When ICH did occur, the prognosis was similar across all treatment groups 1
  • In an historic comparison, the rates of ICH seen with both doses of Pradaxa® in RE-LY were similarly low as the rate seen in patients with AF receiving antiplatelet therapy. 1,5

“The risk of intracranial haemorrhage is a key factor when healthcare professionals are reviewing the benefit-risk profile of anticoagulation therapy, and this analysis highlights that both dosing regimens of Pradaxa® are safer than warfarin in this respect,” said Hans-Christoph Diener, M.D., Ph.D., Professor and Chairman, Department of Neurology, University Duisburg-Essen, Germany.

Dr. Stuart Connolly, Director, Division of Cardiology at McMaster University and member of The Population Health Research Institute, Hamilton, Ontario commented, “Intracranial haemorrhage is one of the most feared complications of anticoagulation therapy. In our hospital, we see patients frequently presenting with intracranial haemorrhage as a result of warfarin and unfortunately, this complication is associated with a high mortality rate. These data show us that not only is Pradaxa® associated with lower rates of intracranial haemorrhage overall, but that fatal and traumatic intracranial bleeding is also reduced, highlighting the favourable safety profile of Pradaxa®.”

The analysis showed that in RE-LY®, patients who experienced an ICH were, on average, older (mean age 75 [with ICH] vs. 71.5 [without ICH] P<0.001), associated with a higher frequency of previous history of stroke or TIA (P=0.001), used aspirin concomitantly more often (P=0.001), and had lower estimated creatinine clearance levels (P<0.001) compared with other study participants. 1 Differences were consistent across treatment arms. 1 A history of falling was not an independent risk factor for ICH amongst patients in the RE-LY® trial. 1

In the landmark RE-LY® trial, Pradaxa® 150mg bid significantly reduced the risk of stroke and systemic embolism by 35% compared to well-controlled warfarin (median time in therapeutic range (TTR) 67% 6), providing significantly superior stroke prevention in non-valvular atrial fibrillation (AF). 3,4 Pradaxa 110mg bid was shown to be non-inferior to well-controlled warfarin for the prevention of stroke and systemic embolism in patients with non-valvular AF. Pradaxa® 150mg bid is the only novel oral anticoagulant shown to significantly reduce both ischaemic and haemorrhagic stroke in patients with non-valvular AF compared to well-controlled warfarin. 3,4

RE-LY® was a PROBE trial (prospective, randomized, open-label with blinded endpoint evaluation), comparing two fixed doses of the oral direct thrombin inhibitor dabigatran etexilate (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin. 3

References

  1. Hart RG, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with Warfarin or Dabigatran: The RE-LY Trial. Stroke 2012; 112: 1-18.
  2. Fang MC, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007; 120:700 –705.
  3. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-51.
  4. Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363(19):1875-76.
  5. Hart RG, et al. Avoiding Central Nervous System Bleeding During Antithrombotic Therapy: Recent Data and Ideas. Stroke 2005; 36:1588-1593.
  6. FDA Advisory Committee Briefing Document, September 2010,http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisory Committee/UCM226009.pdf
  7. Stewart S, Murphy N, Walker A, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004; 90:286-92.
  8. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042-6.
  9. Fuster V, Rydn LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation – executive summary. Circulation 2006; 114:700-52.
  10. Kannel WB, et al. Final Draft Status of the Epidemiology of Atrial Fibrillation. Med Clin North Am. 2008; 92(1): 17–40.
  11. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed Dec 2010 at www.who.int/cardiovascular_diseases/en/ cvd_atlas_15_burden_stroke.pdf .
  12. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991: 22(8);983-8.
  13. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischaemic stroke: results from a population-based study. Stroke 2005; 36:1115-9.
  14. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27:1760-4.
  15. Hart RG, et al. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007; 146:857-67.
  16. Bruggenjurgen B et al. The Impact of Atrial Fibrillation on the Cost of Stroke: The Berlin Acute Stroke Study. Value Health 2007; 10: 137–43.
  17. Di Nisio M, et al. Direct Thrombin Inhibitors. N Engl J Med 2005; 353:1028-40.

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