The <scp>DOAC‐FRAIL</scp> study, evaluation of direct oral anticoagulant‐levels in acutely admitted frail older patients: An exploratory study

Abstract

Anticoagulant therapy in frail older patients remains a challenge due to their increased susceptibility to thromboembolism and bleeding.1, 2 The direct oral anticoagulants (DOAC) have largely replaced vitamin K antagonists (VKA) for major indications such as atrial fibrillation (AF).3 With the aging population increasing, DOAC use in frail older patients is expected to rise. Caution is necessary as extrapolating risk–benefit ratios from younger adults to geriatric populations, often underrepresented in major trials, may not be valid.4 Recent findings showed higher rates of bleeding in frail older patients with AF switching from VKA to DOAC.5 A likely reason for this could be unexpected variations in how these patients respond to different doses. Currently, there is a scarcity of comprehensive data on DOAC levels in this population. As a result, guidelines for managing DOAC in frail older patients, especially in situations with alterations in renal function such as during hospital stays for acute illnesses, are not well-established.6 This exploratory study aims to fill these knowledge gaps by evaluating DOAC levels in frail older patients with acute illnesses, shedding light on an essential aspect of their anticoagulant management. This prospective exploratory cohort study was conducted at the Maastricht University Medical Center (MUMC+) in the Netherlands. Patients aged 65 years or older using a DOAC and admitted to the Department of Internal Medicine with acute illnesses between February 2022 and December 2022 were eligible for inclusion. Quantitative DOAC levels based on anti-IIa (dabigatran) or anti-Xa (factor Xa inhibitors) activity7 were measured as soon as possible after admission. The time interval between DOAC intake and blood collection was documented and expected DOAC levels (on-therapy range) were used as a reference (7). Statistical analyses included univariable and multivariable regression analyses to investigate factors associated with DOAC levels. A total of 77 patients were eligible. Ultimately, 42 patients (54.5%) with a mean age of 81.5 years were included (Table 1). The primary indication of DOAC use was AF (90.5%). Apixaban was the most prescribed DOAC (52.4%); additionally, 69% of patients had an impaired renal function. Analysis of DOAC levels revealed that 54.8% were outside the on-therapy range. Specifically, 40.5% of DOAC levels exceeded the on-therapy range, whereas 14.3% were below this range (Figure 1). Patients admitted due to an infection were less likely to have a DOAC level above the on-therapy range (OR 0.11, 95% 0.02–0.49, p = 0.003). Impaired renal function (eGFR <30 mL/min/1.73 m2), as well as rivaroxaban use, was associated with DOAC levels above the on-therapy range (OR 1.75, 95% 0.39–8.3, p = 0.14) and (OR 2.39, 95% 0.53–10.73, p = 0.07), respectively. Patients using a proton pump inhibitor (PPI) had a lower odds of DOAC levels below the on-therapy range (OR 0.09, 95% 0.10–0.88, p = 0.03) (Supplementary Material; Table S1). This is the first study to show that more than half of admitted frail older patients with acute illnesses on a DOAC display DOAC levels outside the recommended on-therapy range. Our findings show a strong negative association between having an infection and elevated DOAC levels. Possible explanations include changes in bioavailability and metabolization of DOAC due to aging and infection, altered body composition, and/or potential drug–drug interactions. The specific mechanisms linking these factors to DOAC levels remain inadequately understood and necessitate further investigation. This study observed a trend for rivaroxaban use and DOAC levels above the on-therapy range, a pattern that might be attributed to the enhanced absorption properties of rivaroxaban8 along with considerable interindividual variability in peak concentration.9 Furthermore, there appeared to be a link between impaired renal function and elevated DOAC levels. Although increased drug exposure is anticipated as renal function decreases, our findings imply that impaired renal function on its own may not be sufficient to explain the deviations in DOAC levels, the involvement of additional factors or comorbidities likely plays a role too. Patients on PPI were less likely to have a DOAC level below the on-therapy range. However, given the limited sample size and the specific study population, these results need confirmation. Currently, a large population-based cohort study is being conducted on the association between DOAC and PPI co-therapy and adverse outcomes.10 This study has some limitations. Mainly, the short duration of follow-up did not allow assessing the impact of deviant DOAC levels. Moreover, the small sample size may have hidden additional associations. Finally, our results cannot be extrapolated to stable outpatients, thereby limiting translation to the general frail population. Although the conception of DOAC included elimination of routine laboratory monitoring, our study underscores the potential impact of acute medical conditions on DOAC levels, especially in the frail older population. Our results highlight the multifaceted factors influencing DOAC levels in frail older patients, emphasizing the need for comprehensive and individualized anticoagulant management. We advocate further research to validate our results, as this may have significant implications for drug dosing strategies during hospital admission in the frail older population. M.J. de Jong and F.J.H. Magdelijns contributed to the design of the manuscript, performed statistical analyses, and were the main authors. H.Saadan collected clinical data. D.L.S. Hellenbrand performed laboratory analysis. H. ten Cate, D.L.S. Hellenbrand, B. Spaetgens, R.A.G. Brüggemann, S.M.J. van Kuijk, K. Winckers, and Y.M.C. Henskens contributed to the concept and design of the manuscript. The manuscript has been read and approved for submission to JAGS by all authors. There are no relevant financial, personal, or potential conflicts to declare. There was no funding or sponsor's role in the design, methods, subject recruitment, data collection, analysis, or preparation of the article. Table S1. Uni- and multivariable regression analyses to explore the association between clinical characteristics and DOAC levels. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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