Medication appropriateness and regimen complexity in chronic kidney disease

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 (‚Äöv¢‚Ä¢ 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 (˜í‚⧠0.72; 95% CI 0.56 to 0.88) and lower eGFR (˜í‚⧠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‚Äö-12] to 5 [2‚Äö-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 subsequent two studies, the association between medication-related factors (including medication appropriateness, regimen complexity and the use of selected medications) at hospital discharge and hospital readmission was explored. Overall, people who were readmitted within 30 and 90 days of discharge had a higher level of medication inappropriateness (MAI) compared with their non-readmitted counterparts. Those with higher MAI scores were also likely to be readmitted to hospital relatively sooner within 90 days of discharge. However, after statistical modelling, medication inappropriateness was not independently associated with the occurrence of 30-day (adjusted OR 1.03; 95% CI 0.97-1.09) or 90-day readmissions (adjusted OR 1.06; 95% CI 1.00-1.12). Similarly, regimen complexity (MRCI) was not independently associated with 30-day (adjusted OR 1.27; 95% CI 0.94-1.73) or 90-day readmissions (adjusted OR 1.31; 95% CI 0.99-1.72). However, higher medication regimen complexity (MRCI) was associated with a shorter time to readmission within one year of discharge (HR 1.18 95% CI 1.01-1.36). In contrast, use of renin-angiotensin system blocking drugs was associated with a lower occurrence of 30-day (OR 0.39; 95% CI 0.19-0.79) and 90- day readmissions (OR 0.45; 95% CI 0.24-0.84), and longer time to 90-day readmission (HR 0.52; 95% CI 0.33-0.83). 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. In the final study, the effect of hospital pharmacist-led medication review on medication appropriateness was retrospectively assessed in older adults with CKD. Medication appropriateness was evaluated before and after medication review and after acceptance/nonacceptance by physicians of pharmacist recommendations. Of 204 eligible patients, medication review was conducted in 95 (46%). Medication review by pharmacists improved medication appropriateness significantly, as shown by a median MAI reduction from 7 [3-12] to 5 [2-10]; p<0.001. More importantly, medication appropriateness showed greater improvement upon implementation of all pharmacists' recommendations by physicians (median MAI decreased from 7 to 3; p<0.05). Of note, medication appropriateness also improved in patients with no medication review by pharmacists, indicating hospitalisation alone improved medication appropriateness in these patients. However, the overall trend was indicative of greater improvement in medication appropriateness with pharmacist-led medication review, particularly when the recommendations were acted upon by physicians. In conclusion, this thesis presents a series of interconnected studies that thoroughly examined medication-related factors and their consequences in adults living with CKD. Generally, the studies revealed that these patients are prone to high levels of medication regimen complexity and inappropriateness. People who were readmitted within 30 and 90 days had higher levels of medication inappropriateness and regimen complexity, albeit these variables did not independently predict readmissions within these periods. Further, patients with more complex regimens were more likely to be readmitted relatively sooner within 12 months of discharge. The findings, overall, suggest that these medication-related variables may be important proxy measures of overall health status in this patient group. Also, these findings imply that medication inappropriateness and regimen complexity can be used to prioritise patients who can benefit from optimisation of medication regimens. This is potentially important in contexts like community pharmacies, where there is limited clinical information available for decision-making. The association ...