Safety of Direct Oral Anticoagulants in Patients 75 Years and Older: Comments on the Consensus Opinion of Russian Experts

Bel'diev S. N.
MD, PhD, Associate Professor, Chair of therapy and cardiology¹

Medvedeva I. V.
MD, PhD, Associate Professor, Chair of therapy and cardiology¹

Egorova I. V.
MD, PhD, Associate Professor, Chair of therapy and cardiology¹

Berezina E. I.
MD, PhD, Associate Professor, Chair of therapy and cardiology¹

Trufanova G. Yu.
MD, PhD, Associate Professor, Chair of therapy and cardiology¹

Platonov D. Yu.
MD, PhD, MPH, Head, Chair of therapy and cardiology¹

1 - Tver State Medical University, Tver, Russia

Bel'diev Sergej; e-mail: sbeldiev@yandex.ru

Authors have no conflict of interest.

The study had no sponsorship.

The consensus opinion of Russian experts «Antithrombotic therapy in the elderly and senile age» (2021) contains selective and insufficiently correct data, obtained in randomized controlled trials RE-LY, ROCKET AF, ARISTOTLE and ENGAGE AF-TIMI 48. As a result, it makes the impression that dabigatran 150 mg twice daily showed the least safety compared to warfarin in patients 75 years or older. This paper presents the corrected and supplemented data of the ROCKET AF trial, indicating that in patients 75 years or older rivaroxaban compared with warfarin showed no better safety profile than dabigatran 150 mg twice daily in the RE-LY trial.

dabigatran, rivaroxaban, apixaban, edoxaban, elderly

10.29234/2308-9113-2021-9-4-1-20

1. Orlova I.A., Tkacheva O.N., Arutyunov G.P., Kotovskaya Y.V., Vasjuk Y.A., Lopatin Y.M., et al. Osobennosti diagnostiki i lechenija hronicheskoj serdechnoj nedostatochnosti u pacientov pozhilogo i starcheskogo vozrasta. Mnenie ekspertov Obshhestva specialistov po serdechnoj nedostatochnosti, Rossijskoj associacii gerontologov i geriatrov i Evrazijskoj associacii terapevtov [Features of diagnostics and treatment of chronic heart failure in elderly and senile patients. Expert opinion of the Society of Experts in Heart Failure, Russian Association of Gerontologists, and Eurasian Association of Therapists]. Kardiologiia [Cardiology] 2018; 58(12S): 42-72. doi: 10.18087/cardio.2560 (In Russ.)

2. Bel'diev S.N., Egorova I.V., Platonov D.Yu. Rekomendacii po primeneniju peroral'nyh antikoaguljantov u pacientov pozhilogo vozrasta: kriterii Birsa i dokazatel'naja medicina [Recommendations on the use of oral anticoagulants in elderly patients: Beers criteria and evidence-based medicine]. Medicina [Medicine] 2019; 7(4): 1-11. doi: 10.29234/2308-9113-2019-7-4-1-11 (In Russ.)

3. Ukhterova A.I., Ukhterov E.A., Kudryavtseva D.A., Nekrasov A.A., Ryumina P.Yu., Bel’diev S.N., Platonov D.Yu. Opisanie kriteriev Birsa v soglasitel'nom dokumente po diagnostike i lecheniju serdechnoj nedostatochnosti u pacientov pozhilogo i starcheskogo vozrasta [Beers criteria description in the consensus document for the diagnosis and treatment of heart failure in elderly and senile patients]. Verhnevolzhskij medicinskij zhurnal [Upper Volga Medical Journal] 2020; 19(3): 16-22. (In Russ.)

4. Tkacheva O.N., Vorobyeva N.M., Kotovskaya Yu.V., Runikhina N.K., Strazhesco I.D., Villevalde S.V., et al. Antitromboticheskaja terapija v pozhilom i starcheskom vozraste: soglasovannoe mnenie jekspertov Rossijskoj associacii gerontologov i geriatrov i Nacional'nogo obshhestva profilakticheskoj kardiologii [Antithrombotic therapy in the elderly and senile age: the consensus opinion of experts of the Russian Association of Gerontologists and Geriatricians and the National Society of Preventive Cardiology]. Kardiovaskuljarnaja terapija i profilaktika [Cardiovascular Therapy and Prevention] 2021; 20(3): 135-184. doi: 10.15829/1728-8800-2021-2847 (In Russ.).

5. Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldgren J., Parekh A., et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361(12): 1139-1151. doi: 10.1056/NEJMoa0905561

6. Patel M.R., Mahaffey K.W., Garg J., Pan G., Singer D.E., Hacke W., et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365(10): 883-891. doi: 10.1056/NEJMoa1009638

7. Granger C.B., Alexander J.H., McMurray J.J., Lopes R.D., Hylek E.M., Hanna M., et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365(11): 981-992. doi: 10.1056/NEJMoa1107039

8. Giugliano R.P., Ruff C.T., Braunwald E., Murphy S.A., Wiviott S.D., Halperin J.L., et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369(22): 2093-104. doi: 10.1056/NEJMoa1310907

9. Eikelboom J.W., Wallentin L., Connolly S.J., Ezekowitz M., Healey J.S., Oldgren J., 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(21): 2363-2372. doi: 10.1161/CIRCULATIONAHA.110.004747

10. Halperin J.L., Hankey G.J., Wojdyla D.M., Piccini J.P., Lokhnygina Y., Patel M.R., et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation 2014; 130(2): 138-146. doi: 10.1161/CIRCULATIONAHA.113.005008

11. Halvorsen S., Atar D., Yang H., De Caterina R., Erol C., Garcia D., et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J 2014; 35(28): 1864-1872. doi: 10.1093/eurheartj/ehu046

12. Kato E.T., Giugliano R.P., Ruff C.T., Koretsune Y., Yamashita T., Kiss R.G., et al. Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial. J Am Heart Assoc 2016; 5(5): e003432. doi: 10.1161/JAHA.116.003432

13. Oganov R.G., ed. Kachestvennaja klinicheskaja praktika s osnovami dokazatel'noj mediciny [Good clinical practice with the basics of evidence-based medicine]. Moscow: Silitseya-Polygraph; 2011. (In Russ.)

14. Martsevich S.Yu. Kak reshit' problemu vybora preparata vnutri odnogo klassa s pozicij dokazatel'noj mediciny? [How to solve the problem of drug choice within the same class from the standpoint of evidence-based medicine?] Racional'naja farmakoterapija v kardiologii [Rational Pharmacotherapy in Cardiology] 2019; 15(2): 271-276. (In Russ.)

15. Schäfer A., Flierl U., Berliner D., Bauersachs J. Anticoagulants for stroke prevention in atrial fibrillation in elderly patients. Cardiovasc Drugs Ther 2020; 34(4): 555-568. doi: 10.1007/s10557-020-06981-3

16. Bel'diev S.N., Medvedeva I.V., Platonov D.Yu. Lekarstvennye vzaimodejstvija novyh peroral'nyh antikoaguljantov: vnutri i vne jacheek tablicy [Drug interactions of new oral anticoagulants: inside and outside table cells]. Racional'naja farmakoterapija v kardiologii [Rational Pharmacotherapy in Cardiology] 2017; 13(5): 716-724. doi: 10.20996/1819-6446-2017-13-5-716-724 (In Russ.)

17. Bel'diev S.N., Medvedeva I.V., Platonov D.Yu., Trufanova G.Yu. Issledovanija antikoaguljantnoj terapii u «hrupkih» pozhilyh pacientov: problemy terminologii i metodologii [Studies of anticoagulant therapy in frail elderly patients: problems of terminology and methodology]. Racional'naja farmakoterapija v kardiologii [Rational Pharmacotherapy in Cardiology] 2019; 15(2): 251-257. doi: 10.20996/1819-6446-2019-15-2-251-257 (In Russ.)

18. Vorobyeva N.M., Tkacheva O.N. Antikoaguljantnaja terapija u pozhilyh pacientov: dilemma vybora mezhdu effektivnost'ju i bezopasnost'ju [Anticoagulant therapy in elderly patients: dilemma of choice between efficacy and safety]. Medicinskij alfavit [Medical alphabet] 2018; 2(16): 6-14. (In Russ.)

19. Vorobyeva N.M., Tkacheva O.N. Peroral'nye antikoaguljanty prjamogo dejstvija u pozhilyh pacientov s fibrilljaciej predserdij: fokus na rivaroksaban [Direct effect oral anticoagulants in elderly patients with atrial fibrillation: focus on rivaroxaban]. Jeffektivnaja farmakoterapija [Effective pharmacotherapy] 2019; 15(9): 14-21. doi: 10.33978/2307-3586-2019-15-9-14-21 (In Russ.)

20. Fox K.A., Piccini J.P., Wojdyla D., Becker R.C., Halperin J.L., Nessel C.C., et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011; 32(19): 2387-2394. doi: 10.1093/eurheartj/ehr342

21. Hankey G.J., Patel M.R., Stevens S.R., Becker R.C., Breithardt G., Carolei A., et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol 2012; 11(4): 315-322. doi: 10.1016/S1474-4422(12)70042-X

22. van Diepen S., Hellkamp A.S., Patel M.R., Becker R.C., Breithardt G., Hacke W., et al. Efficacy and safety of rivaroxaban in patients with heart failure and nonvalvular atrial fibrillation: insights from ROCKET AF. Circ Heart Fail 2013; 6(4):740-747. doi: 10.1161/CIRCHEARTFAILURE.113.000212

23. Jones W.S., Hellkamp A.S., Halperin J., Piccini J.P., Breithardt G., Singer D.E., et al. Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF. Eur Heart J 2014; 35(4): 242-249. doi: 10.1093/eurheartj/eht492

24. Bansilal S., Bloomgarden Z., Halperin J.L., Hellkamp A.S., Lokhnygina Y., Patel M.R., et al. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial). Am Heart J 2015; 170(4): 675-682.e8. doi: 10.1016/j.ahj.2015.07.006

25. Wong K.S., Hu D.Y., Oomman A., Tan R.S., Patel M.R., Singer D.E., et al. Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial. Stroke 2014; 45(6): 1739-1747. doi: 10.1161/STROKEAHA.113.002968

26. Cohen D. Data on trial of anticoagulant is to be reanalyzed after discovery that investigators used faulty device. BMJ 2015; 351: h6431. doi: 10.1136/bmj.h6431

27. Cohen D. Rivaroxaban: can we trust the evidence? BMJ 2016; 352: i575. doi: 10.1136/bmj.i575

28. Christopoulos C. Questions about the reliability of ROCKET-AF anticoagulation data. BMJ 2016; 352: i1039. doi: 10.1136/bmj.i1039

29. Patel M.R., Hellkamp A.S., Fox K.A. Point-of-care warfarin monitoring in the ROCKET AF trial. N Engl J Med 2016; 374(8): 785-788. doi: 10.1056/NEJMc1515842

30. Matos J.D., Zimetbaum P.J. Controversy surrounding ROCKET-AF: a call for transparency, but should we be changing practice? Arrhythm Electrophysiol Rev 2016; 5(1): 12-13. doi: 10.15420/aer.2016.24.2

31. Powell J.R. Point-of-care warfarin monitoring in the ROCKET AF trial. N Engl J Med 2016; 375(4): 390. doi: 10.1056/NEJMc1604020

32. Patel M.R., Hellkamp A.S., Fox K.A. Point-of-care warfarin monitoring in the ROCKET AF trial. N Engl J Med 2016; 375(4): 390-391. doi: 10.1056/NEJMc1604020

33. Cohen D. Manufacturer failed to disclose faulty device in rivaroxaban trial. BMJ 2016; 354: i5131. doi: 10.1136/bmj.i5131

34. European Medicines Agency. Assessment report. Xarelto. International non-proprietary name: rivaroxaban. February 5, 2016. https://www.ema.europa.eu/en/documents/variation-report/xarelto-h-c-944-leg-0037-epar-assessment-report-variation­_en.pdf

35. FDA Center For Drug Evaluation and Research. ROCKET AF reanalysis reviews. September 26, 2016. https://www.accessdata.fda.gov/drugsatfda­_docs/nda/2011/202439Orig1s000RocketAFReanalysis.pdf