Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated with Dabigatran or Warfarin for Non-Valvular Atrial Fibrillation

Graham DJ, Reichman ME, Wernecke M, et al.,
Circulation. 2014 Oct 30. pii: CIRCULATIONAHA.114.012061. [Epub ahead of print]

Background

The Randomised evaluation of long-term anticoagulation therapy (RE-LY) trial showed that patients with atrial fibrillation (AF) randomised to the direct thrombin inhibitor dabigatran (150 mg twice daily) had a lower risk of stroke and intracranial haemorrhage than patients randomised to the vitamin K antagonist warfarin. Dabigatran treatment was associated with an increased risk of major gastrointestinal (GI) haemorrhage than warfarin [1].
Dabigatran has a favourable net clinical benefit when compared with warfarin, but no validated assay exists with which anticoagulation intensity can be monitored, and to date no proven method of rapid reversal of its anticoagulant effect is available [1-3].
AF primarily affects the elderly. The safety profile of dabigatran as seen in controlled trial settings may be different in general practice. This study therefore compared the risk of stroke, major GI and intracranial bleeding, acute myocardial infarction (AMI) and mortality in elderly Medicare beneficiaries with non-valvular AF who initiated warfarin or dabigatran (propensity score match obtained for 67.207 new dabigatran users, dabigatran: 18.205 person-years of on-therapy follow-up time, warfarin: 19.382 person years). This study was performed as part of the SafeRx Project, a joint initiative of the Centers for Medicare & Medicaid Services (CMS) and the US Food and Drug Administration (FDA).

Main results

• 2.715 primary outcome events were observed in the follow-up period (Oct 2010-Dec 2012), including 475 ischaemic strokes, 1628 major bleeding events and 612 AMIs.
• Dabigatran use was associated with reduced risk of stroke (adjHR: 0.80, 95%CI: 0.67-0.96), intracranial haemorrhage (adjHR: 0.34, 95%CI: 0.26-0.46), and mortality (adjHR: 0.86, 95%CI: 0.77-0.96), as compared with warfarin use.
• AMIs or all hospitalised bleeds were seen at similar frequencies in both treatment groups.
• A higher risk of major GI bleedings was seen with dabigatran as compared with warfarin (adjHR: 1.28, 95%CI: 1.14-1.44).
• The absolute incidence of ischaemic stroke, major GI bleeding, intracranial haemorrhage and death were highest during the first 90 days of therapy for both warfarin and dabigatran. HRs did not differ substantially across different time intervals.
• Subgroup analyses showed that risk of major GI bleeds was increased in women of 75 years and older and in men of at least 85 years old, who are treated with dabigatran as compared with warfarin. In younger individuals, no significant difference was seen in GI bleeding risk between warfarin and dabigatran.
• An interaction between age and a mortality benefit of dabigatran compared with warfarin was seen such that women of 85 years or older showed a trend to an increased risk of death.
• Stronger effects were seen with dabigatran 150 mg, as compared with patients treated with 75 mg (~16% of patients), since a dose of 75 mg was only associated with a significantly lower risk of intracranial haemorrhage, as compared with warfarin.

Conclusion

This analysis in a large real-life cohort of elderly people with non-valvular AF confirms a reduced risk of ischaemic stroke, intracranial haemorrhage and mortality with dabigatran 150 mg as compared with warfarin, as previously seen in the RE-LY trial. The increased risk of major GI bleedings associated with dabigatran was also confirmed in this cohort, although this risk seemed restricted to women of 75 years or older, and to men of at least 85 years old. The data suggest that the benefit-risk profile of dabigatran is less favourable for women of 85 years or older.
 Approximately simultaneously, Hernandez et al. published a study into bleeding risk associated with dabigatran use in real-world clinical practice in JAMA Intern Med, using data of a 5% random sample of Medicare beneficiaries, newly diagnosed with AF between Oct 2010 and Oct 2011 and who initiated dabigatran (n=1302) or warfarin (n=8102). Follow-up was until Dec 2011.
This study found that dabigatran was associated with a higher risk of any bleeding (HR: 1.30, 95%CI: 1.20-1.41), for major bleeding (HR: 1.58, 95%CI: 1.36-1.83) and GI bleeding (HR: 1.85, 95%CI: 1.64-2.07). Risk of intracranial bleeding was lower with dabigatran as compared with warfarin (HR: 0.32, 95%CI: 0.20-0.50). All subgroups analysed (>75 years old, African Americans, those with chronic kidney disease and those with more than 7 concomitant comorbidities) showed an increased risk of major bleeding and GI bleeding.
These data on GI and intracranial bleeding are consistent with RE-LY trial, but conflict with the Mini-Sentinel analysis from the FDA in 2012, about which the authors note that the FDA failed to adjust for differences in patient characteristics. They write that not adjusting would bias the results. The authors conclude that dabigatran should be prescribed with caution, especially in high-risk patients.  

In a press release Boehringer Ingelheim reacts to the publication of both studies, and the difference between their respective results. They point out that the FDA analysis (Graham et al., Circulation) studied a much larger population (over 67.000 dabigatran users vs 1.302), and with longer follow-up than the analysis by Hernandez, published in JAMA Intern Med. Based on the Medicare analyses of the FDA they are therefore confident that the positive safety- and efficacy profile of dabigatran as seen in the RE-LY trial is also achieved in real-world clinical practice.

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References

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al., and the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;161:1139-1151.
2. Product label for Pradaxa (dabigatran etexilate mesylate). Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022512s011lbl.pdf. Accessed July 3, 2012.
3. Bauer KA. Reversal of antithrombotic agents. Am J Hematol. 2012;87:S119-S126.
4. Hernandez I., Baik SH, Pinera A et al., Risk of bleeding with dabigatran in Atrial Fibrillation. JAMA Intern Med. 2014. doi: 10.1001/jamainternmed.2014.5398.