# Medication appropriateness and regimen complexity in chronic kidney disease

Tesfaye, WH ORCID: 0000-0001-7208-2330 2019 , 'Medication appropriateness and regimen complexity in chronic kidney disease', PhD thesis, University of Tasmania.

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## Abstract

The continuous growth in the incidence and prevalence of chronic (non-communicable) diseases, mainly fuelled by an ageing population, has led to an increasing use of multiple medications. In line with this, studies examining medication appropriateness and regimen complexity have been at the forefront of research in recent years, especially in high-risk patients, such as the elderly and those with chronic kidney disease (CKD). CKD is a growing public health problem that affects around 8-16% of the adult population worldwide. It is characterised by a substantial burden of multimorbidity and disease complications leading to the use of multiple medications. This, in turn, poses potential concerns regarding medication appropriateness, regimen feasibility, and adherence. However, despite the high medication burden in patients with CKD, previous studies have mainly focussed on evaluating the dosage appropriateness of renally-cleared and/or nephrotoxic medications. Further, little is published on clinical outcomes associated with medication-related factors in these patients. Therefore, investigating medication-related problems and understanding their determinants in patients with CKD is important in building an evidence base to inform future interventions and practice.
The overarching aim of this thesis was, therefore, to examine medication-related issues and associated outcomes in patients with CKD considering prescriber, regimen, healthcare environment, and patient factors. The specific objectives of the thesis were to: (i) summarise the evidence on the prevalence of inappropriate prescribing, associated clinical outcomes and the potential impact of interventions in CKD; (ii) measure the magnitude of, and evaluate the impact of hospitalisation on, medication inappropriateness in older patients with CKD; (iii) investigate the associations between medication-related factors, including regimen complexity, and risk of hospital readmission in older patients with CKD; (iv) investigate the associations between medication adherence and burden, and health-related quality of life (HRQOL) in adults with advanced pre-dialysis CKD; and (v) evaluate the influence of pharmacist-led medication review on medication appropriateness in older adults with CKD.
To address these objectives, two cohorts including adults with CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m$$^2$$) not receiving renal replacement therapy were examined using retrospective and prospective study designs. The first was a retrospective cohort of older adults (≥ 65 years) with CKD (eGFR 15-60 mL/min/1.73m$$^2$$ hospitalised in a tertiary care hospital in Tasmania, Australia over a six-month period (n = 204). The second cohort included a prospective cohort of adults with advanced pre-dialysis CKD (eGFR < 30 mL/min/1.73m$$^2$$ living in the community (n = 101).
A systematic review of the literature was conducted to summarise the magnitude of inappropriate prescribing, associated outcomes and the impact of interventions in patients with CKD. Based on this review of 49 studies, widespread prevalence of potentially inappropriate medications (PIMs) use was observed across a spectrum of the care continuum. The prevalence of PIMs use was 9.4%-81.1% for hospital settings, 13%-80.5% in ambulatory care settings and 16%-38% for long-term care facilities. A small number of studies reported an association between PIMs use and poor clinical outcomes, including prolonged hospitalisation and mortality. Although the heterogeneity between studies precluded a meta-analysis, the number of medications, comorbidities, and age were consistently identified as predictors of PIMs use. This review showed that, despite the regimen complexity in this patient group, previous studies were largely focused on assessing the appropriateness of renally-cleared and/or nephrotoxic medications, rather than more patient-centred outcomes, such as adherence.
Capitalising on the gaps identified in this review, a study was conducted to comprehensively assess medication appropriateness in older patients with CKD recruited via Tasmania’s principal tertiary care hospital. The Medication Appropriateness Index (MAI), an implicit set of criteria, was used to assess medication appropriateness, with higher scores on this index corresponding with higher medication inappropriateness. The 2015 Beers criteria, a list of medications recommended to be avoided in older adults or under certain conditions, was also applied to identify PIMs use. Overall, 204 older patients with CKD with a median age of 83 years (IQR 76-87 years) were included. This study revealed that most patients had some level of medication inappropriateness based on MAI (89%), while more than half of them (55%) were taking at least one medication from Beers criteria at hospital admission. A higher number of medications (β 0.72; 95% CI 0.56 to 0.88) and lower eGFR (β 0.11; 95% CI -0.18 to -0.04) were significantly associated with a higher level of medication inappropriateness. Hospitalisation was associated with a small but significant improvement in medication appropriateness in these patients, as shown by a decrease of MAI from admission to discharge (median [IQR]: 6 [3–12] to 5 [2–9]; p<0.01]). The number of patients with at least one PIM from Beers criteria also declined from 55% to 48% during hospitalisation. These findings indicate that, despite an improvement in medication appropriateness during hospitalisation, there was considerable scope for further improvement in medication use for these patients.
In the fourth study, the relationships between medication adherence and burden, and HRQOL was assessed using 101 adults with advanced pre-dialysis CKD (eGFR <30mL/min/1.73m$$^2$$. The findings of this study showed that medication non-adherence was reported by 43% and 60% of participants using two different self-report adherence measures (Morisky-Green-Levine Scale and the Tool for Adherence Behaviour Screening). Perceived medication burden, but not actual burden, was the main driver of medication non-adherence (adjusted OR 4.89; 95% CI 1.02-23.5). Further, poorer kidney disease-related and generic HRQOL measures were associated with higher regimen complexity (MRCI) and medication non-adherence was associated with a decline in physical HRQOL over time.