Elderly AF and VTE patients benefit from DOACs compared to VKAs

Sadlon AH, Tsakiris DA
Swiss Med Wkly. 2016 Sep 28;146:w14356

Background

Atrial fibrillation (AF) and venous thromboembolism (VTE) are common indications for anticoagulation therapy. A large part of the target group of anticoagulants is represented by elderly (>75yrs). As of 2009, 4 DOACs have been approved by the FDA and EMA: rivaroxaban, apixaban, dabigatran and edoxaban. Their efficacy and safety have been assessed in large phase III trials and have been shown to harbour a favourable risk-benefit profile in patients with AF or VTE, compared with vitamin K antagonists (VKAs) [1-4].

VKAs are associated with a high risk for VKA-related bleedings. As VKAs are among the greatest medication-related risk factors for adverse drug reactions in the elderly [5], only 50-60% of patients with AF eligible for anticoagulation are under oral anticoagulant therapy. A second concern is nonadherence to VKAs. To circumvent these concerns, direct anticoagulants (DOACs) are increasingly prescribed for elderly patients. However, concerns on the external validity of the results of DOAC clinical trials with this age group, and particularly among frail elderly, have been raised [6,7]. Furthermore, direct head-to-head comparisons of DOACs have not been published before.

Therefore, by performing meta-analysis (n=30,655 patients ≥75 yrs, 8 studies, 4 AF, 4 VTE, including AMPLIFY, ARISTOTLE, EINSTEIN DVT, EINSTEIN PE, ENGAGE-AF TIMI 48, HOKUSAI VTE, RE-LY, ROCKET-AF), this study aimed to:

• Determine the efficacy and safety of rivaroxaban, apixaban, edoxaban and dabigatran compared with VKAs in nonvalvular AF or acute VTE patients ≥75yrs.
• Conduct indirect comparisons between the different DOACs, to set the frame for discussion about the use of DOACs in elderly, and in particular frail elderly.

Meta-analysis was performed with apixaban, rivaroxaban plus high-dose dabigatran (150 mg) or edoxaban (60 mg) or low-dose of these agents (110 mg and 30 mg respectively).

Main results

Efficacy & safety in AF patients:

• Apixaban/rivaroxaban/high-dose dabigatran or edoxaban were associated with a significant 29% odds reduction in stroke or systemic embolism compared to VKAs (95% CI: 62-82%, I² was 0%, P-heterogeneity = 0.63).
• For apixaban/rivaroxaban/low-dose dabigatran or edoxaban this was similar (OR: 0.84, 95% CI: 0.73-0.96, I² was 0%, P-heterogeneity = 0.51) but this was mainly driven by the ARISTOTLE and ROCKET trials. After separate analyses, this was not significant anymore.
• There was no statistical difference in bleeding risk but high heterogeneity between apixaban/rivaroxaban/high-dose dabigatran or edoxaban and VKAs (OR 0.98, 95% CI: 0.90-1.06, I² was 89%, P-heterogeneity <0.0001).
• For apixaban/rivaroxaban/low-dose dabigatran or edoxaban bleeding risk was significantly reduced (OR: 0.88, 95% CI: 0.80-0.96, P=0.004) however this was also associated with high heterogeneity (I² was 95%, P-heterogeneity < 0.0001).

Efficacy & safety in VTE patients:

• Regarding VTE or VTE-related deaths, DOACs significantly reduced the number of events (OR: 0.54, 95% CI: 0.35-0.82) with low heterogeneity (I² was 0%, P-heterogeneity = 0.79).
• Also non-major bleeding events were significantly reduced with DOACs compared to VKAs (OR: 0.63, 95% CI: 0.46-0.85, P=0.003) but with moderate heterogeneity (I² was 73%, P-heterogeneity = 0.01) and results were mainly driven by the HOKUSAI-VTE study.

Efficacy & safety of different DOACs:

• Between apixaban, rivaroxaban, high-dose and low-dose dabigatran or edoxaban, there was no statistical difference in stroke or systemic embolism prevention in AF patients.
• However, regarding major or clinically relevant non-major bleeding, apixaban did show a statistically significant odds reduction compared with dabigatran high-dose (OR: 0.54, 95% CI: 0.41-0.73), low-dose (OR: 0.63, 95% CI: 0.47-0.86) and rivaroxaban (OR: 0.57, 95% CI: 0.45-0.73) in AF patients.
• Rivaroxaban showed more odds reduction than edoxaban at both doses (low-dose, OR: 0.41, 95% CI: 0.32-0.53, high-dose, OR: 0.71, 95% CI: 0.57-0.89) in AF patients.
• Dabigatran (both doses) was associated with increased odds ratios for bleeding compared with apixaban (high-dose OR: 1.84, 95% CI: 1.37-2.47, low-dose OR: 1.58, 95% CI: 1.17-2.13), compared with low-dose edoxaban (OR: 2.19, 95% CI: 1.62-2.96) and with high-dose edoxaban (OR: 1.49, 95% CI: 1.13-1.96) in AF patients.
• Regarding VTE or VTE-related death, there were no differences between agents. However, edoxaban showed a significant higher odds ratio for bleeding compared to apixaban (OR: 3.58, 95% CI: 1.13-11.40) and rivaroxaban (OR: 2.94, 95% CI: 1.22-7.08).

Conclusion

In elderly AF or VTE patients, DOACs were superior to VKAs in prevention of stroke or systemic embolism as well as VTE or VTE-related death. Bleeding risk was not statistically significant different between DOACs and VKAs, but these results were associated with a moderate to high heterogeneity and should therefore be interpreted with caution.

Find this article online at Swiss Medical Weekly

References

1. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–510
2. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808. doi:http://dx.doi.org/10.1056/NEJMoa1302507.
3.Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, et al. Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15. doi:http://dx.doi.org/10.1056/NEJMoa1306638.
4.Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51. Erratum in: N Engl J Med. 2010;363(19):1877.
5. Hajjar ER, Hanlon JT, Artz MB, Lindblad CI, Pieper CF, Sloane RJ, et al. Adverse drug reaction risk factors in older outpatients. Am J Geriatr Pharmacother. 2003;1(2):82–9.
6. Stöllberger C, Finsterer J. Concerns about the use of new oral anticoagulants for stroke prevention in elderly patients with atrial fibrillation. Drugs Aging. 2013;30(12):949–58.
7. Ho P, Brooy BL, Hayes L, Lim WK. Direct oral anticoagulants in frail older adults: a geriatric perspective. Semin Thromb Hemost. 2015;41(4):389–94.