In Korea, the proportion of older adults, defined as those aged 65 or older, has doubled in only 17 years from 7% (an aging society) in 2000 to 14% (an aged society) in 2017 and is expected to grow to 21% (a super-aged society society) by 2026 [1]. Consequently, the prevalence of chronic diseases, non-specific symptoms caused by ageing, and functional impairment is expected to increase. Accordingly, the number of older people who require the services of a long-term care hospital (LTCH) in Korea has increased drastically due to the growth of the population in need of medical services for chronic multi-morbidity and personal care [2,3]. Frail older patients are hospitalized at LTCHs in Korea for extended durations because of the decrease in family support for older parents and easy access to inpatient care financed by the National Health Insurance Program [4].

Given the comorbidities in older adults, polypharmacy is common, thus raising the risk of using potentially inappropriate medications (PIMs), defined as medications with more risks than benefits. Polypharmacy and PIMs are growing concerns for older patients because of increased healthcare costs, adverse drug events, drug interactions, medication non-adherence, functional decline, and multiple geriatric syndromes [5,6]. Most drugs with anticholinergic properties (DAPs) are classified as PIMs, and their use in older patients is discouraged. DAPs are associated with dry mouth, dry eye, constipation, dizziness, falls, cognitive decline, and physical impairment [7–9]. Older patients with multi-morbidities, who are independent or frail, tend to complain of symptoms related to diseases or geriatric syndromes and are more likely to experience polypharmacy or take PIMs due to the prescribing cascade, resulting in adverse drug events [10–12]. Since the clinical and demographic characteristics of hospitalized patients at LTCHs are expected to differ from those of community-dwelling older patients, DAPs are likely to be prescribed more frequently for the older patients living in LTCHs. However, no study has identified the clinical characteristics of patients with a high DAP burden or the prescription pattern of DAPs in LTCHs in Korea.

The anticholinergic drug burden of an individual is defined by the cumulative effect of taking one or more DAPs. Several anticholinergic drug burden indices have been validated, and a higher anticholinergic drug index strongly correlates with poor cognitive and functional outcomes [13]. Due to differences in prescribing patterns and medication availability across countries, country-specific anticholinergic burden scales have been developed. In Korea, the Korean Anticholinergic Burden Scale (KABS) was developed and validated based on literature evaluation and a modified Delphi process [14,15]. KABS was validated in a claim-based case-control study on the dose-response relationship between KABS burden and incident dementia [15].

We aimed to investigate the clinical and demographic factors associated with the prescribing of more DAPs according to the KABS data in older patients. In addition, we explored the prevalence of DAPs and DAP burden, current status of polypharmacy, and patterns of DAP prescription in LTCH residents in Korea.

From September 5, 2019 to January 31, 2020, 508 patients were enrolled from LTCHs. After excluding 42 patients who did not complete an initial assessment because of unexpected death (n = 4), transfer to another institution or hospital (n = 16), discharge before assessment (n = 5), refusal for assessment (n = 16), or withdrawal of consent (n =1), 466 patients were included in the final analysis. The mean age of the participants was 81.8 ± 7.1 years and women accounted for 73.4% (n = 342). Hypertension was the most common comorbid condition (75.3%) followed by dementia (68.7%), diabetes (49.8%), cerebrovascular disease (36.5%), Parkinson’s disease (12.9%), heart failure (8.2%), and atrial fibrillation (7.9%). The mean number of medications and PIMs were 11.0 ± 4.6 and 1.14 ± 1.14, respectively, and 88.8% (n = 414) of patients were prescribed DAPs according to the KABS. The study found that 93.1% and 62% of the participants had polypharmacy and excessive polypharmacy, respectively. The mean KABS was 4.55 ± 3.34, and the proportion of patients with high KABS was 70.4% (n = 328) (Table 1).

The top 10 frequently prescribed DAPs were quetiapine (47.0%), chlorpheniramine (29.6%), tramadol (22.3%), clonazepam (17.0%), furosemide (16.5%), escitalopram (14.4%), cimetidine (13.1%), alprazolam (12.4%), trazodone (10.5%), and guaifenesin (5.6%). Drugs with a KABS score of 1, 2, and 3 contributed to 27.0%, 37.9%, and 35.1% of the cumulative KABS score, respectively. Quetiapine (KABS 2, 20.7%), chlorpheniramine (KABS 3, 19.5%), tramadol (KABS 2, 9.8%), cimetidine (KABS 2, 5.8%), and furosemide (KABS 1, 3.6%) had the highest contribution to the total KABS score (Fig. 1). According to drug category, the most frequently prescribed DAPs were antipsychotics (49.4%), antihistamines (36.1%), anxiolytics (32.2%), antidepressants (31.3%), and analgesics (23.0%).

Patients with a greater BMI had high KABS scores. Additionally, lower ADLH scale, communication scale, and EQ-5D scores and a higher MMSE score were associated with high KABS, as were polypharmacy, excessive polypharmacy, and the number of PIMs (Table 2). Logistic regression analysis adjusted for age, sex, BMI, medical aid beneficiary status, and length of hospital stay revealed a significant association between high KABS and a higher MMSE score (aOR, 1.028; 95% CI, 1.001 to 1.056), lower EQ-5D score (aOR, 0.385; 95% CI, 0.182 to 0.815), polypharmacy (aOR, 3.71; 95% CI, 1.691 to 8.144), excessive polypharmacy (aOR, 12.403; 95% CI, 5.541 to 27.760), moderate ADL dependence (ADLH ≥ 5, aOR, 0.489; 95% CI, 0.322 to 0.744), and moderate impairment of communication (COMM ≥ 4, aOR, 0.611; 95% CI, 0.400 to 0.933) (Table 3).

The study results revealed a higher administration of DAPs to LTCH patients who are less dependent and have better communication and cognitive functions. This trend was maintained even after adjusting for age, sex, BMI, status of medical aid beneficiary, and length of hospital stay. Patients with a high burden of DAPs had a poorer quality of life and tended to use more drugs (7.93 vs. 12.32, respectively; p < 0.001). This pattern was similar to that observed in previous studies conducted in LTCF in Helsinki [30]. The drugs with the highest contribution to the total KABS score were quetiapine (KABS 2, 20.7%), chlorpheniramine (KABS 3, 19.5%), tramadol (KABS 2, 9.8%), cimetidine (KABS 2, 5.8%), and furosemide (KABS 1, 3.6%).

The prevalence of DAP prescription in LTCHs was 88.8% (n = 414), and this was higher than in previous research conducted in LTCF, which ranged from 30% to 77% [31,32]. This difference in DAP prevalence is likely due to the varied drug list used to define DAPs and the different population characteristics. Possibly, the patients in Korean LTCHs had excellent access to prescriptions, and the proportion of severe dementia was relatively small compared to those in nursing homes (mean cognitive performance score: 2.7 vs. 3.2); thus, more complaints of pain or non-specific symptoms for various geriatric diseases, such as urinary incontinence, dermatitis, insomnia, or allergy, could be expected [32]. Contrary to other countries where most long-term care institutions are nursing homes, in Korea, various medical services, including subacute, palliative, and rehabilitation care, are provided in LTCHs. Patients pay only 10% to 20% of the total medical fees because most of the citizens are eligible for coverage under the National Health Insurance Program. The prescription pattern observed in this study is characterized by frequent use of central nervous system active drugs (antipsychotics, 49.4%; anxiolytics, 32.2%; and antidepressants, 31.3%), antihistamines (36.1%), and analgesics (23.0%), which is consistent with that observed in a previous study conducted in LTCF [33].

In previous observational and retrospective cohort studies, a high burden of DAPs was associated with adverse cognitive impact or incident dementia [15,34]. However, in another study, similar to the current study, the use of DAPs was associated with better cognition and functioning [9,30]. This finding may be related to several medical and non-medical factors. First, since the priority of medical treatment in LTCHs is improving quality of life rather than improving survival or guideline-based chronic disease management, patients with poor cognitive or communication function are likely to have been prescribed a lower number of DAPs because their symptom complaints are not frequent or clear. Second, previous studies have emphasized the avoidance of DAPs, which may impact cognition, delirium, or behavioural symptoms [35,36]. Therefore, patients with low cognitive function may have possibly tried adjusting medications or reducing the unnecessary DAPs to improve delirium. An increase in the number of DAPs according to the KABS, from 0 to more than 3 (p = 0.28 in Kruskal-Wallis test), was associated with a stepwise decrease in the quality of life (Fig. 2). Although further study is needed to investigate causality between DAP use and cognitive function, physical function, or quality of life, we showed a dose-response relationship between the DAP burden and quality of life of LTCH patients.

DAPs have central and peripheral antagonist effects on muscarinic receptors, leading to delirium, falls, cognitive impairments, constipation, and dry mouth [31,33]. In a previous study, DAPs were widely prescribed for various diseases in older adults, including Parkinson’s disease, depression, cardiovascular disease, urinary incontinence, asthma, and allergies [37]. Older patients in LTCHs were more likely to be exposed to polypharmacy, PIMs, and DAPs because of their disease patterns, frailty, pain, and non-specific symptoms. In this study, although there was no difference in the number of PIMs (1.20 vs. 1.12, p = 0.571) and anticholinergic burden (KABS, 4.65 vs. 4.53, p = 0.746) according to disease burden (number of comorbidities ≥ 4), more medications (11.98 vs. 10.77, p = 0.022) were prescribed to the group of patients with high disease burden. As the use of DAPs in LTCHs is inevitable, a periodic automatic monitoring system is needed for proper management of the patients. The medical staff in LTCHs also need an appropriate consultation system to facilitate the control of symptoms and to prevent disease aggravation without the need to transfer the patients to regional acute care hospitals. To solve these unmet needs for patients and medical staff in LTCHs, access to information on PIMs could be provided by linking the electronic medication record of the LTCH to the Health-RESPECT platform, along with periodic videoconferencing with the geriatrician of the regional acute care hospital, to ensure timely care of acute conditions [17]. In addition, linking the Health-RESPECT system to the health information exchange network system can ensure real-time monitoring and adjustment of PIMs and DAPs.

Our study had several methodological strengths. In contrast to previous research that used claim data, we used cross-sectional drug exposure data, which can be considered more reliable because the data were extracted directly from each electronic medication record of the LTCH. In addition, the Health-RESPECT program, a system to share and cooperate with regional acute care hospitals, was established to access PIMs or DAPs and facilitate intervention in further practice. However, our study was limited by the cross-sectional design, which cannot determine causality. Further observational studies are needed to identify the prevalence of adverse outcomes related to DAP administration.

In conclusion, the prevalence of DAP administration in this study was 88.8% (n = 414), and 70.4% (n = 328) of the patients had a high burden of DAPs. Patients with a prescription of many DAPs (high KABS) tended to have higher BMI, less dependence, better communication and cognitive functions, and poorer quality of life. The long-term relationship between DAP administration and adverse clinical outcomes in older LTCH patients should be investigated in further observational or cohort studies.