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Background Older age is associated with a higher prevalence of multimorbidity. This often leads to the prescription of multiple medications and complex medication regimens. While multiple medication use is strongly correlated with regimen complexity, other factors contributing to the complexity of a medication regimen are dose forms, dose frequencies and additional directions for medication use. Medication-related problems and adverse drug events are leading causes of preventable hospitalisations. Polypharmacy, defined as either a continuous or categorical variable, has been associated with a range of adverse drug events including hospitalisation and mortality. However, there is mixed evidence for an association between polypharmacy and mortality. To date most studies on the clinical outcomes of complex medication regimens have focused on medication adherence. There has been limited research on the possible association between complex medication regimens and hospitalisation and poor quality of life. It is not known to what extent the ability to manage a complex medication regimen is associated with hospitalised older people being able to return to living independently in their own home. This is important because the majority of nursing home admissions are preceded by a hospital stay. It is not known to what extent the complexity of a medication regimen contributes to clinical outcomes over and above the clinical outcomes associated with the number of medications. There is also a lack of population-based research investigating clinical outcomes associated with medication regimen complexity. Aims and objectives The overall aim of the thesis was to investigate medication regimen complexity and clinical outcomes in older people. Therefore, the thesis was divided into four parts: Part A comprises the background, Part B contains investigations conducted in a prospective cohort of older people discharged from an Australian hospital, and Part C includes investigations in a population-based sample of older people in Sweden, and Part D comprises an updated systematic review of the literature, the discussion and conclusion. The aim of Part B was to investigate the potential association between medication regimen complexity and clinical outcomes in older people discharged form an Australian hospital. This included investigating the association between medication regimen complexity and both discharge destination and hospital readmission. The aim of Part C was to investigate factors associated with medication regimen complexity in a population-based study sample of older people in Stockholm, Sweden, and to compare the factors associated with medication regimen complexity to factors associated with number of medications. Part C focused on factors associated with medication regimen complexity, unplanned hospital admission and all-cause mortality. The aim of Part D was to systematically review the clinical outcomes associated with medication regimen complexity. Setting and methods The setting of Part B was the Geriatrics Evaluation and Management (GEM) unit of a public hospital in Adelaide, South Australia. Data were prospectively collected and included patients aged ≥70 years who were consecutively admitted to the GEM unit between October 22, 2010, and December 23, 2011. Medication regimen complexity was calculated using the 65-item validated Medication Regimen Complexity Index (MRCI). Logistic regression analyses were used to compute unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for medication-related factors associated with discharge destination. Cox proportional hazards regression was used to compute unadjusted and adjusted hazard ratios (HRs) with 95% CIs for factors associated with unplanned rehospitalisation. To account for deaths during the follow-up period, the analyses were censored at the time of a participant’s death or at the end of the follow-up period, whichever occurred first. The setting of Part C was the district of Kungsholmen in central Stockholm, Sweden. The study population comprised participants in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) with 11 age cohorts of people aged ≥60 years. Participants lived at home or in non-home settings and were randomly selected according to their date of birth. All participants underwent extensive baseline interviews and clinical examinations between 2001 and 2004. In both Part B and C, the MRCI was used to calculate medication regimen complexity. Cox proportional hazards regression was utilised to compute unadjusted and adjusted HRs with 95% CIs for factors associated with unplanned hospitalisation and all-cause mortality. Analyses were censored at the time of a participant’s death or at the end of the follow-up period, whichever occurred first. Multinomial logistic regression was used to compute unadjusted and adjusted ORs with 95% CIs to investigate factors associated with regimen complexity. Multivariable quantile regression was used to compare factors associated with regimen complexity and factors associated with number of medications. Part D included a systematic review of peer-reviewed English language literature. The literature search was performed in MEDLINE, EMBASE, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library using a series of Medical Subject Headings (MeSH), Emtree terms and key-words. Data extraction and assessment of the risk of bias were performed independently by two investigators using a standardised data extraction tool and an adapted version of the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review instrument critical appraisal tool for Descriptive / Case Series Studies. Results The main results of Part B were that high medication regimen complexity was a better predictor for discharge destination than polypharmacy. In contrast, neither medication regimen complexity nor the number of discharge medications or polypharmacy were associated with rehospitalisation in older people discharged from a GEM unit. Overall, 87 (53.4%) of the 163 eligible participants were discharged directly to home, while 76 were discharged to non-community settings. In adjusted analyses, high medication regimen complexity (MRCI>35) was inversely associated with discharge directly to home (RR 0.39; 95% CI 0.20–0.73), whereas polypharmacy (≥9 medications on a regular or as-needed basis) was not (RR 0.97; 95% CI 0.53–1.58). Of 163 eligible participants, 99 (60.7%) had one or more unplanned hospital readmissions throughout the follow-up period. In adjusted analyses, MRCI (HR 1.01; 95% CI 0.81–1.26), the number of discharge medications (HR 1.01; 95% CI 0.94–1.08), and polypharmacy (≥9 medications on a regular or as-needed basis; HR 1.12; 95% CI 0.69–1.80) were not associated with rehospitalisation. The main findings of Part C were that medication regimen complexity was overall not a better predictor for clinical outcomes than the number of medications. However, medication regimen complexity was a better predictor for mortality than the number of medications in SNAC-K participants. The SNAC-K cohort included 3348 people aged ≥60 years. In adjusted analyses, participants in the highest MRCI quintile (MRCI>20) were older, less likely to live at home, had greater comorbidities, higher cognitive status, a higher prevalence of self-reported pain, impaired dexterity and were more likely to receive help to sort their medications compared to those with low regimen complexity (MRCI >0–5.5). Similar factors were associated with both regimen complexity and number of medications. In total, 1125 participants (33.6%) had one or more unplanned hospitalisations. Regimen complexity (HR 1.22; 95% CI 1.14–1.34) and number of medications (HR 1.07; 95% CI 1.04–1.09) were both associated with unplanned hospitalisations. During a three-year follow-up, 14.0% (n=470) of the SNAC-K participants died. After adjusting for age, sex, comorbidity, educational level, activities of daily living, cognitive status and living place, higher MRCI was associated with mortality (HR 1.12; 95% CI 1.01–1.25). The number of medications was not associated with mortality (adjusted HR 1.03; 95% CI 0.99–1.06). When participants were stratified by sex, both MRCI and number of medications were associated with mortality in men but not in women. MRCI was associated with mortality in participants ≤80 years and in participants with MMSE ≥26, but not in participants aged >80 years or with MMSE

Background: Adverse drug events are a leading cause of hospitalization among older people. Up to half of all medication-related hospitalizations are potentially preventable. The objective of this study was to investigate and compare the association between medication regimen complexity and number of medications with unplanned hospitalizations over a 3-year period. Methods: Data were analyzed for 3,348 participants aged 60 years or older in Sweden. Regimen complexity was assessed using the 65-item Medication Regimen Complexity Index (MRCI) and number of medications was assessed as a continuous variable. Cox proportional hazard models were used to compute unadjusted and adjusted hazard ratios with 95% confidence intervals (CIs) for associations between regimen complexity and number of medications with unplanned hospitalizations over a 3-year period. Receiver operating characteristics curves with corresponding areas under the curve were calculated for regimen complexity and number of medications in relation to unplanned hospitalizations. The population attributable fraction of unplanned hospitalizations was calculated for MRCI and number of medications. Results: In total, 1,125 participants (33.6%) had one or more unplanned hospitalizations. Regimen complexity (hazard ratio 1.22; 95% CI 1.14-1.34) and number of medications (hazard ratio 1.07; 95% CI 1.04-1.09) were both associated with unplanned hospitalizations and had similar sensitivity and specificity (area under the curve 0.641 for regimen complexity and area under the curve 0.644 for number of medications). The population attributable fraction was 14.08% (95% CI 9.62-18.33) for MRCI and 17.61% (95% CI 12.59-22.35) for number of medications. Conclusions: There was no evidence that using a complex tool to assess regimen complexity was better at predicting unplanned hospitalization than number of medications. Refereed/Peer-reviewed

Purpose: There is a lack of population-based research about factors associated with medication regimen complexity. This study investigated factors associated with medication regimen complexity in older people, and whether factors associated with regimen complexity were similar to factors associated with number of medications. Methods: This cross-sectional population-based study included 3348 people aged ≥60 years. Medication regimen complexity was computed using the validated 65-item Medication Regimen Complexity Index (MRCI). Multinomial logistic regression was used to compute unadjusted and adjusted odds ratios (ORs) with 95 % confidence intervals (CIs) for factors associated with regimen complexity. Multivariable quantile regression was used to compare factors associated with regimen complexity and number of medications. Results: In adjusted analyses, participants in the highest MRCI quintile (MRCI > 20) were older (OR = 1.04, 95 % CI 1.02;1.05), less likely to live at home (OR = 0.35, 95 % CI 0.15;0.86), had greater comorbidities (OR = 2.17, 95 % CI 1.89;2.49), had higher cognitive status (OR = 1.06, 95 % CI 1.01;1.11), a higher prevalence of self-reported pain (OR = 2.85, 95 % CI 2.16;3.76), had impaired dexterity (OR = 2.39, 95 % CI 1.77;3.24) and were more likely to receive help to sort their medications (OR = 4.43 95 % CI 2.39;8.56) than those with low regimen complexity (MRCI >0–5.5). Similar factors were associated with both regimen complexity and number of medications. Conclusion: Older people with probable difficulties managing complex regimens, including those with impaired dexterity and living in institutional settings, had the most complex medication regimens even after adjusting for receipt of help to sort medications. The strong correlation between regimen complexity and number of medications suggests that clinicians could use a person’s number of medications to target interventions to reduce complexity. Refereed/Peer-reviewed

Background: Older people often take multiple medications. It is a policy priority to facilitate older people to stay at home longer. Three-quarters of nursing home placements in the US are preceded by a hospitalization. Objective: To investigate the association between polypharmacy and medication regimen complexity with hospital discharge destination among older people Methods: This prospective cohort study comprised patients aged C70 years consecutively admitted to the Geriatric Evaluation and Management unit at a tertiary hospital in Adelaide, Australia, between October 2010 and December 2011. Medication regimen complexity at discharge was calculated using the 65-item validated Medication Regimen Complexity Index (MRCI). Unadjusted and adjusted relative risks (RRs) with 95 % confidence intervals (CIs) were calculated for medication-related factors associated with discharge directly to home versus non-community settings(rehabilitation, transition care, and residential aged care). Results From 163 eligible patients, 87 were discharged directly to home (mean age 84.6 years, standard deviation[SD] 6.9; mean MRCI 26.1, SD 9.7), while 76 were discharged to non-community settings (mean age 85.8 years,SD 5.8; mean MRCI 29.9, SD 13.2). After adjusting forage, sex, comorbidity, and activities of daily living, having a high medication regimen complexity (MRCI>35) was inversely associated with discharge directly to home (RR0.39; 95 % CI 0.20–0.73), whereas polypharmacy (≥9medications) was not significantly associated with discharge directly to home (RR 0.97; 95 % CI 0.53–1.58). Conclusion Having high medication regimen complexity was inversely associated with discharge directly to home, while polypharmacy was not associated with discharge destination. Refereed/Peer-reviewed