Abstract
Introduction. Thanks to the achievements of modern medicine, it was possible to significantly increase the life expectancy of the population. Molecular mechanisms of aging include telomere shortening, DNA damage accumulation, mitochondrial dysfunction, leading to decreased functional reserves of organs and systems. The cohort of geriatric patients is at risk of polypragmasy and has features of drug pharmacokinetics.
Objective: To evaluate factors that increase the risk of taking direct oral anticoagulants in elderly patients with polypragmasy and chronic kidney disease taking into account molecular mechanisms of drug action and individual pharmacogenetic features.
Material and methods. For this study, a database of 503 patients seen in «GVH No.2 DZM» from April to September 2023 was collected. The method of questionnaire was used, as well as the collection of clinical and laboratory data allowing to evaluate DOAC-dependent complications – cases of bleeding, duration of DOAC administration. Additionally, renal function biomarkers (cystatin C, NGAL), coagulation parameters and CYP3A4/CYP2C19 activity by indirect markers were analyzed.
Results. DOAC administration increases bleeding risks when creatinine clearance is significantly decreased, especially when dabigatran is administered. Administration of apixaban and rivaroxaban have no statistically significant increase in the incidence of hemorrhagic complications as renal impairment progresses. Concomitant DOAC and heparins significantly increase the risk of bleeding during 1 year of therapy. Co-administration of dabigatran and verapamil increases the risk of bleeding, which is not seen with other DOACs.
Conclusion. Investigation of drug interactions and the association of DOAC intake with various endpoints in larger samples will help to identify predictors of adverse outcomes and adjust therapy. Personalized approach considering pharmacogenetic features and molecular biomarkers can significantly improve the safety of anticoagulant therapy in elderly patients.
Keywords
Authors and affiliations
A.P. Kondrahin(1, 2), E.G. Silina(3), M.S. Chernyaeva(2, 4), M.L. Maksimov(1, 5, 6),
A.S. Belokopytov(1(, A.N. Babichev(1), Yu.E. Smirnova(1), S.A. Martynova(1), K.O. Schnаider(1, 6)
1-Federal State Autonomous Educational Institution of Higher Education “Russian National Research Medical University
named after N.I. Pirogov” of the Ministry of Health of the Russian Federation, Ostrovityanova str., 1, Moscow, 117997,
Russian Federation; 2Moscow State Budgetary Healthcare Institution “Hospital for War Veterans No.2 of the Moscow City Healthcare Department”, Volgogradskiy Prospekt, 168, Moscow, 109472, Russian Federation; 3-Federal State Budgetary Educational Institution of Higher Education “Russian University of Medicine” of The Ministry of Health of the Russian Federation, Dolgorukovskaya st., 4, Moscow, 127006, Russian Federation; 4Federal State Budgetary Institution of Continuing Professional Education “Central State
Medical Academy” of the Administrative Department of the President of the Russian Federation, Marshal Timoshenko St.,
19, build. 1A, Moscow, 121359, Russian Federation; 5-Kazan State Medical Academy – branch of the Russian Medical Academy
of Continuous Professional Education of the Ministry of Health of Russia, Butlerova st., 49, Kazan, Republic of Tatarstan, 420012, Russian Federation; 6Federal State Budgetary Educational Institution of Additional Professional Education “Russian Medical Academy
of Continuous Professional Education”, Ministry of Health of Russia, Barrikadnaya st., 2/1, Moscow, 123995, Russian Federation
References
Lоpez-Otero D., Trillo-Nouche R., Gonzаlez-Ferreiro R., et al. Molecular mechanisms of aging and anticoagulation: implications for personalized medicine. Nature Aging. 2019; 1: 234–45. DOI: https://doi.org/10,1038/s41586-019-1365-2
Heijman J., Voigt N., Nattel S., Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res. 2014; 114 (9): 1483–99. DOI: https://doi.org/10,1161/CIRCRESAHA.114.302226
Maher R.L., Hanlon J., Hajjar E.R. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014; 13 (1): 57–65. DOI: https://doi.org/10,1517/14740338.2013.827660.
Tornio A., Backman J.T. Cytochrome P450 in pharmacogenetics: an update. Adv Pharmacol. 2018; 83: 3–32. DOI: https://doi.org/10,1016/bs.apha.2018.04.007
Steffel J., Verhamme P., Potpara T.S. et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur. Heart J. 2018; 39 (16): 1330–93. DOI: https://doi.org/10,1093/eurheartj/ehy136
Ruff C.T., Giugliano R.P., Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014; 383 (9921): 955–62. DOI: https://doi.org/10,1016/S0140-6736(13)62343-0
Gallagher P., Ryan C., Byrne S. et al. STOPP (Screening Tool of Older Person’s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation. Int. J. Clin. Pharmacol. Ther. 2008; 46 (2): 72–83. DOI: 10,5414/CPP46072.
Asiimwe I.G., Zhang E.J., Osanlou R. et al. Warfarin dosing algorithms: a systematic review. Br. J. Clin. Pharmacol. 2020; 87 (4): 1717–29. DOI: https://doi.org/10,1111/bcp.14608
Machado-Duque M.E., Castaño-Montoya J.P., Medina-Morales D.A., Castro-Rodriguez A., González-Montoya A., Machado-Alba J.E. Drugs With Anticholinergic Potential and Risk of Falls With Hip Fracture in the Elderly Patients: A Case-Control Study. J. Geriatr Psychiatry Neurol. 2018; 31 (2): 63–9. DOI: 10,1177/0891988718757370, Epub 2018 Mar 11. PMID: 29528764.
Ostermann M., Bellomo R., Burdmann E.A., et al. Controversies in acute kidney injury: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int. 2020; 98 (2): 294–309. DOI: https://doi.org/10,1016/j.kint.2020,04.020
Weitz J.I., Fredenburgh J.C., Eikelboom J.W. A Test in Context: D-Dimer. J Am Coll Cardiol. 2017; 70 (19): 2411–20. DOI: https://doi.org/10,1016/j.jacc.2017.09.024
Härtter S., Sennewald R., Nehmiz G., Reilly P. Oral bioavailability of dabigatran etexilate (Pradaxa®) after co-medication with verapamil in healthy subjects. Br. J. Clin. Pharmacol. 2013; 75 (4): 1053–62. DOI: https://doi.org/10,1111/j.1365-2125.2012.04453.x
Heidbuchel H., Verhamme P., Alings M. et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015; 17 (10): 1467–507. DOI: https://doi.org/10,1093/europace/euv309
. Hanlon J.T., Handler S.M., Maher R.L., Schmader K.E. Geriatric Pharmacotherapy and Polypharmacy. In: Fillit H.M., Rockwood K., Young J.B. Brocklehurst’s Textbook of Geriatric Medicine and Gerontology. 8th ed. Elsevier. 2017; 849–54.
. Leelakanok N., Holcombe A.L, Lund B.C., et al. Association between polypharmacy and death: A systematic review and metaanalysis. J. Am. Pharm Assoc. 2017; 57 (6): 729–38. DOI: https://doi.org/10,1016/j.japh.2017.06.002
. Johnson J.A., Caudle K.E., Gong L. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther. 2017; 102 (3): 397–404. DOI: https://doi.org/10,1002/cpt.668
. Baruth J.M., Gentry M.T, Rummans T.A. et al. Multidisciplinary Guideline for Polypharmacy in older people. Hosp Pract (1995). 2020; 48 (1): 56–62. DOI: https://doi.org/10,1080/21548331.2019.1706995
. Tripodi A. Thrombin Generation Assay and Its Application in the Clinical Laboratory. Clin Chem. 2016; 62 (5): 699–707. DOI: https://doi.org/10,1373/clinchem.2015.248625
. Steffel J., Collins R., Antz M. et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace. 2021; 23 (10): 1612–76. DOI: https://doi.org/10,1093/europace/euab065
. Shameer K., Johnson K.W., Glicksberg B.S. et al. Machine learning in cardiovascular medicine: are we there yet? Heart. 2018; 104 (14): 1156–64. DOI: https://doi.org/10,1136/heartjnl-2017-311198