Geersing, Geert-Jan

Trinks-Roerdink, Emmy M

Utrecht University Repository

Received: 13 April 2023 - Revised: 18 May 2023 - Accepted: 20 May 2023https://doi.org/10.1016/j.rpth.2023.100199COMMENTARYAnticoagulants in frail elderly patients with atrial fibrillation:a delicate balanceEmmy M. Trinks-Roerdink MD, PhD | Geert-Jan Geersing MD, PhDDepartment of General Practice & Nursing Science, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University,Utrecht, the NetherlandsCorrespondenceEmmy M. Trinks-Roerdink, Department of General Practice & Nursing Science, Julius Center for Health Sciences and Primary Care, University Medical CenterUtrecht, Utrecht University Universiteitsweg 100, 3584 CX Utrecht, the Netherlands.Email: e.m.roerdink-2@umcutrecht.nlHandling Editor: Dr Kristen SanfilippoThe relationship between frailty, aging, and anticoagulant prescriptionfor stroke prevention in atrial fibrillation (AF) is a topic of ongoingclinical interest as well as research. We know, for instance, that elderlypatients with AF and multimorbidity have a high thromboembolic risknecessitating anticoagulants. Yet, when anticoagulated, they alsopossess a very high risk of bleeding due to an accumulation ofbleeding risk factors, notably including aging. For example, in a studyby Kooistra et al. [1], already nearly 10 years ago, the incidence rate(IR) of major or clinically relevant nonmajor bleeding while on avitamin K antagonist (VKA) increased from 14.8 events per 100person-years in patients with AF aged 70 to 79 years to 18.1 eventsper 100 person-years in patients with AF aged >90 years (hazardratio, 1.26; 95% CI, 1.05-1.50). Interestingly, in that study, thethromboembolic IR was lower, yet this also increased with increasingage: from 0.8 events per 100 person-years in the age group 70 to 79years to 1.8 events per 100 person-years in those aged >90 years [1].In a more recent study by Patti et al. [2], including also patients ondirect oral anticoagulant (DOAC) therapy, similar results were found:the IR of major bleeding increased from 1.9 events per 100 person-years in those aged <75 years to 4.0 per 100 person-years in thoseaged >85 years (P = .003), with a nearly similar increase in thethromboembolic risk, ie, from 1.8 events per 100 person-years inthose aged <75 years to 4.8 per 100 person-years in those aged above85 years (P < .001) [2].Moreover, apart from aging, frailty by itself also complicatesclinical decision making regarding optimal anticoagulant management.Dynamic changes over time in both bleeding and thromboembolicrisk—caused by altering pharmacokinetics, drug-drug interactions,increased susceptibility to falls (leading to traumatic bleeds), cognitiveimpairment (potentially impacting treatment adherence), and finally a© 2023 The Author(s). Published by Elsevier Inc. on behalf of International Society onNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Res Pract Thromb Haemost. 2023;7:e100199https://doi.org/10.1016/j.rpth.2023.100199decreased renal function—may impact anticoagulation safety [3]. Thus,this requires continuous monitoring and balancing of these risks infrail patients with AF, yet at the context of a paucity of evidence.Specific recommendations for these populations are lacking as frailindividuals are often excluded from trial participation, and even ifevidence is available, the complexity and heterogeneity of the frailtysyndrome often hampers direct transferability of inferences to theindividual patient seen during our consultations. Further research onthis topic is thus highly welcomed.In this edition of Research and Practice in Thrombosis and Haemo-stasis, Nishimura et al. [4] describe the results of their study on theassociation between frailty and bleeding and ischemic stroke/tran-sient ischemic attack (TIA) in patients with AF at the time of antico-agulant initiation. Patients aged ≥65 years with nonvalvular AF whoinitiated anticoagulants were selected from an administrative claimsdatabase in Japan between 2012 and 2018. Frailty was assessed usingthe electronic frailty index, which is a validated tool for identifyingfrail individuals from routine healthcare databases [5]. In total, 12,585patients were included in the analysis. During a median follow-up of31 months, the overall IR of the composite of major and nonmajorbleeding (all bleeding events registered in an inpatient or outpatientsetting) was 15.5 per 100 person-years, the overall IR of majorbleeding was 1.2 per 100 patient-years, and the overall IR of ischemicstroke/TIA was 1.5 per 100 patient-years. With increasing levels offrailty, the incidence of the composite bleeding outcome increasedrapidly: for patients classified as “not frail,” the IR of bleeding was 11.2per 100 person-years, while this nearly doubled to 21.0 per 100person-years for patients with severe frailty, mainly driven by an in-crease in nonmajor bleeding events. Interestingly, the incidence ofischemic stroke/TIA in these anticoagulated patients remainedThrombosis and Haemostasis. This is an open access article under the CC BY-www.rpthjournal.org - 1 of 22 of 2 - COMMENTARYremarkably stable with increasing levels of frailty: for patients clas-sified as “not frail,” the IR of ischemic stroke/TIA was 1.5 per 100person-years, and this increased only slightly to 1.7 per 100 person-years for patients with severe frailty.An important observation of this study is that it confirms that inanticoagulated patients with AF, frailty greatly impacts bleeding risk.Yet, at the same time, the impact of frailty on thromboembolic risk isalmost negligible as the residual risk of ischemic stroke/TIA remainedlow even in those with severe frailty. This study serves as a furtherexemplification of the importance of monitoring (notably) bleedingrisk in frail patients with AF using anticoagulants. Importantly, itshould not serve as an argument not to prescribe anticoagulants infrail patients with AF: although bleeding events can be very burden-some for patients, the benefit of anticoagulants (ie, the prevention ofdebilitating ischemic stroke) still outweighs the harm caused bybleeding in most patients [3]. The results of this study do, however,emphasize that these frail patients with AF on anticoagulants shouldbe closely monitored, eg, to evaluate whether the dosing of antico-agulants is still appropriate to prevent overdosing and underdosing. Inaddition, we believe that more research is needed on the impact ofreducing so-called modifiable risk factors for bleeding, for instance,blood pressure management or stopping (or reconsider) of concurrentmedication that may increase bleeding risk (eg, nonsteroidal anti-inflammatory drugs). Managing modifiable risk factors for bleedingis part of the current guidelines, for instance, from the European So-ciety of Cardiology, yet these recommendations are mainly basedupon consensus and observational studies with little or no supportingtrial evidence [3].Finally, we believe that clinical trials, specifically targeting anti-coagulation to this vulnerable and frail population, are needed toprovide insight into both their bleeding and thromboembolic risk.Unfortunately, frail individuals were underrepresented in the land-mark DOAC trials. Subsequently, evidence on comparative efficacyand safety of DOAC therapy vs VKA therapy in frail patients with AFmainly comes from observational, postmarketing studies, yet thesestudies obviously are affected by confounding bias [6–8]. Clinical trialsin frail individuals can be performed, however, and one example ofsuch a trial specifically enrolling frail, elderly patients with AF that iscurrently ongoing is the FRAIL-AF trial exploring whether it is safe toswitch frail patients with AF from VKA to DOAC [9]. Additionally,research on factor XIa inhibition—an anticoagulant strategy that af-fects hemostasis less and, therefore, may lead to less bleeding—maybe particularly interesting for frail patients with AF. Ongoing phase 3clinical trials on factor XIa inhibition should thus strive to target andenroll a large proportion of frail patients with AF as well or at the veryleast not deny trial participation so that subgroup or interaction an-alyses can be performed.To conclude, the study by Nishimura et al. [4] once again dem-onstrates the association between frailty and bleeding in frail elderlypatients with AF. This emphasizes the need for monitoring bleedingrisk in clinical practice and exploring more optimal anticoagulantstrategies for these vulnerable patients in research.FUNDINGThis research received no specific grant from any funding agency inthe public, commercial, or not-for-profit sectors.AUTHOR CONTRIBUTIONSBoth authors were involved in the conception of the article, draftingand revising of the article, and approving the final version of the article.RELATIONSHIP DISCLOSUREThere are no competing interests to disclose.REFERENCES[1] Kooistra HAM, Calf AH, Piersma-Wichers M, Kluin-Nelemans HC,Izaks GJ, Veeger NJGM, et al. Risk of bleeding and thrombosis inpatients 70 years or older using vitamin K antagonists. JAMA InternMed. 2016;176:1176–83.[2] Patti G, Lucerna M, Pecen L, Siller-Matula JM, Cavallari I, Kirchhof P,et al. Thromboembolic risk, bleeding outcomes and effect of differentantithrombotic strategies in very elderly patients with atrial fibrilla-tion: a sub-analysis from the PREFER in AF (PREvention oF Throm-boembolic Events–European Registry in Atrial Fibrillation). J Am HeartAssoc. 2017;6:e005657. https://doi.org/10.1161/JAHA.117.005657[3] Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. 2020 ESC guidelines for the diagnosis and man-agement of atrial fibrillation developed in collaboration with the Eu-ropean Association for Cardio-Thoracic Surgery (EACTS): the TaskForce for the diagnosis and management of atrial fibrillation of theEuropean Society of Cardiology (ESC) developed with the specialcontribution of the European Heart Rhythm Association (EHRA) ofthe ESC. Eur Heart J. 2021;42:373–498.[4] Nishimura S, Kumamaru H, Shoji S, Nakatani E, Yamamoto H,Ichihara N, et al. Frailty and subsequent adverse outcomes in olderpatients with atrial fibrillation treated with oral anticoagulants: theShizuoka study. Res Pract Thromb Haemost. 2023;7:100129. https://doi.org/10.1016/j.rpth.2023.100129[5] Clegg A, Bates C, Young J, Ryan R, Nichols L, Ann Teale E, et al.Development and validation of an electronic frailty index usingroutine primary care electronic health record data. Age Ageing.2016;45:353–60.[6] Sardar P, Chatterjee S, Chaudhari S, Lip GYH. New oral anticoagulantsin elderly adults: evidence from a meta-analysis of randomized trials.J Am Geriatr Soc. 2014;62:857–64.[7] Kim IS, Kim HJ, Kim TH, Uhm JS, Joung B, Lee MH, et al. Non-vitaminK antagonist oral anticoagulants have better efficacy and equivalentsafety compared to warfarin in elderly patients with atrial fibrillation:a systematic review and meta-analysis. J Cardiol. 2018;72:105–12.[8] Deitelzweig S, Keshishian A, Li X, Kang A, Dhamane AD, Luo X, et al.Comparisons between oral anticoagulants among older nonvalvularatrial fibrillation patients. J Am Geriatr Soc. 2019;67:1662–71.[9] Joosten LPT, Van Doorn S, Hoes AW, Nierman MC, Wiersma NM,Koek HL, et al. Safety of switching from vitamin K antagonist to non-vitamin K antagonist oral anticoagulant in frail elderly with atrialfibrillation: rationale and design of the FRAIL-AF randomisedcontrolled trial. BMJ Open. 2019;9:e032488. https://doi.org/10.1136/bmjopen-2019-032488

Anticoagulants in frail elderly patients with atrial fibrillation: a delicate balance

https://dspace.library.uu.nl/bitstream/1874/449602/1/PIIS2475037923001747.pdf

Anticoagulants in frail elderly patients with atrial fibrillation: a delicate balance

Abstract

Similar works

Full text

Available Versions

Utrecht University Repository