Medication-related harm due to non-adherence may explain the relationship between polypharmacy and mortality

Introduction Strong evidence exists for a relationship between polypharmacy and mortality[1], independent of comorbidity. The mechanisms underlying this relationship are unclear. Medication-related harm (MRH) may occur due to non-adherence or adverse drug reactions. We sought to determine if MRH due to non-adherence or adverse drug reactions may explain the association between polypharmacy and mortality. Methods The PRIME study recruited 1280 older adults at hospital discharge from 5 hospitals in England between 2013 to 2015[2]. Patients were followed up in the community for 8-weeks by senior pharmacists to identify MRH using data from hospital readmissions, GP records and patient interviews. Mortality data at 12 months post-discharge were obtained from hospital records. Non-adherence was determined using a modified version of a validated questionnaire[3]. Adverse drug reactions were assessed using the Naranjo algorithm[4]. Adjusted logistic regression models were used to investigate the relationship between (1) number of medicines and MRH, (2) MRH and mortality. Results 1116 out of 1280 patients completed follow-up (median age 82 years, range 65-103 years, 58% female). Patients were discharged with a median of 9 medicines (range 0-27). A higher number of medicines was strongly associated with MRH due to non-adherence (p<0.01) and adverse drug reactions (p<0.001). In multivariable analysis, MRH due to non-adherence was associated with one-year all-cause mortality (OR 1.80, 95% CI 1.08-2.99, p=0.02), however MRH due to ADR was not (OR 1.20, 95% CI 0.86-1.68, p=0.28). Key Conclusions Harm from non-adherence to medications may explain the relationship between polypharmacy and mortality

Age-related changes to the expression of nuclear factor erythroid 2-like 2 (Nrf2), a regulatory antioxidant and xenobiotic defence gene

Introduction Multimorbidity, polypharmacy and susceptibility to adverse drug reactions (ADR) are common problems in old age. Understanding the age-related biological changes that occur at a cellular level, may assist in identifying novel therapeutic targets. The nuclear factor erythroid 2-like 2 (Nrf2) transcription factor regulates antioxidant and drug metabolising pathways in the cell. Data from rodent models showed that Nrf2 protein expression declines with age. If similar findings are observed in humans, it may help to explain why older people are vulnerable to multimorbidity and ADRs. This study investigates whether Nrf2 expression (both mRNA and protein) decreases with increasing age in humans. Methods Fifty-five adults were recruited to our study (age range: 18-75 years). Participants donated 6 mL of venous blood, from which peripheral blood mononuclear cells (PBMCs) were separated and analysed for Nrf2 mRNA and protein expression (real time quantitative polymerase chain reaction and enzyme-linked immunosorbant assay respectively). Results Our data showed that Nrf2 protein expression was approximately 50% lower in individuals aged >30 years (0.065 ±0.014 EU 30 years, p70 year age categories respectively; p<0.0001). Conclusions The expression of Nrf2 transcription factor is reduced in old age, potentially contributing to the increased risk of multimorbidity and adverse drug reactions

Association of a regulatory anti-oxidant and drug-metabolising gene with multi-morbidity and adverse drug reactions in older adults

Introduction Multimorbidity and adverse drug reactions (ADR) are problems associated with ageing populations. Exploring underlying genetic predispositions might help to risk-stratify patients for early intervention. The nuclear factor erythroid 2-like 2 (Nrf2) protein regulates antioxidant and de-toxifying effectors in the cell. Nrf2 expression declines with age, potentially increasing vulnerability to multimorbidity and ADR. We hypothesise that single nucleotide polymorphisms (SNPs) at 3 loci in the Nrf2 gene are associated with multimorbidity and ADR in older adults. Methods One-hundred and twenty-seven patients were recruited from a sub-population of the PRIME study (a multicentre prospective cohort study that followed older adults over 8-weeks post-discharge to determine ADR status). Donated genetic material was sequenced to determine genotype at 3 loci: rs6721961, rs35652124 and rs6706649 and then analysed for association with ADR (Naranjo Algorithm), multimorbidity (3 conditions defined by the Charlson Index (CI)). Results One-hundred and twelve patients (mean age 76.6±7.3 years, 55.4% female) were successfully genotyped. In patients aged 65-79, those with the rs35652124 A allele showed increased odds of having 3 co-morbidities (OR 9.03 95%CI 1.16-70.2, p=0.0127). Individuals with the CGG haplotype in this age-group showed reduced odds of multimorbidity (OR 0.11, 95% CI 0.01-0.86, p=0.001). No association between Nrf2 geno/haplotype and ADR was identified. Conclusions Polymorphisms in the Nrf2 gene are associated with multimorbidity, but not ADR, in older adults

Can supporting health literacy reduce medication-related harm in older adults?

More people than ever before are living into old age. The increased longevity is partly due to the increased use of medicines. Despite the potential benefits of medicines, they can still cause significant harm. Medication-related harm (MRH) may be from adverse drug reactions or harm from inappropriate drug use, for example, nonadherence or medication error. The European Commission estimated in 2008 that MRH contribute to at least 100,800 deaths in member states annually and costs society €79 billion.1 Older adults are most at risk due to their high exposure to medicines and age-related pharmacokinetic and pharmacodynamic changes. A recent systematic review found that 1 in 10 hospitalized older adults are admitted due to MRH, and approximately the same proportion experience MRH as an inpatient.2 Avoidable health service use due to MRH is substantial. A study in the Netherlands estimated the average cost of an avoidable MRH hospitalization in an older adult at €5500.3 Top-down interventions to reduce MRH and unplanned admissions, such as pharmacist-led medicines review, have shown limited effectiveness. There is a need to consider a bottom-up approach, exploring patient-centred modifiable determinants. Health literacy is one such determinant that is being explored in relation to MRH. A survey of eight countries in the European Union (EU) found that 30–60% of people are not health literate, with the older population representing a particularly high-risk group.4 A ‘mandate’ to enhance health literacy has been sent out to policy- makers in the 2016 World Health Organization (WHO) 9th Global Conference on Health Promotion. In this editorial we consider how health literacy can be conceptualized as a fundamental principle in reducing MRH in the older adult

'They must help if the doctor gives them to you’: a qualitative study of the older person’s lived experience of medication-related problems

Objective: medication-related problems (MRP) are common for older adults and can lead to harm. The older person’s perspective on MRP has been seldom reported in published literature. This study explored the lived experience of MRP in older adults with varying functional levels, focussing on the hospital discharge period. Design, setting, participants: this qualitative study was conducted in Brighton and Hove, UK. A purposive sample of 20 older people with experience of MRP, involving carers, took part in focus groups and semi-structured interviews. Data were thematically analysed using a ‘framework’ approach. Results: four major themes associated with MRP were identified; (1) experience of the healthcare system, (2) practicalities of using medicines, (3) management of medication problems and (4) participant beliefs. Participants encountered problems in communication with healthcare professionals such as passive listening and paternalistic consultations. A conflict was acknowledged between participants’ implicit trust in the healthcare system and their negative experience of MRP. Participants felt vulnerable around hospital discharge, describing reduced capacity to comprehend information, pressured discharge circumstances and lack of integrated care in the community. Drug formulations, packaging and information leaflets were felt to be poorly tailored to the needs of older people. Conclusions: the lived experience of older people with MRP in this study was multifaceted and complex. Participants felt communication was poor around hospital discharge, and insufficient support with medicines was offered in the community when problems arose. Harm due to MRP might be reduced if the contributory factors described by patients inform clinical and policy-level intervention

Incidence of medication-related harm in older adults following hospital discharge: a systematic review

Objectives To determine the incidence, severity, preventability and risk factors for medication-related harm (MRH)in community-dwelling older adults following hospital discharge. Design: Systematic review Setting: A search of Medline, EMBASE, CINAHL, and the Cochrane Library was undertaken without time restrictions Participants Older adults (average age 65 years) participating in observational studies investigating adverse drug reactions (ADR) or adverse drug events (ADE)post-discharge within a defined follow-up period Measurements The abstracts of all articles were initially screened by one author to exclude obviously irrelevant articles. The remaining articles were independently screened by two authors for inclusion. Data extraction,including study characteristics, MRH incidence and risk factors, and, critical appraisal was performed by two authors independently, and verified by a third reviewer. Disagreements were resolved through discussion. Results Out of 584 potentially relevant articles, eight studies met our inclusion criteria; five North American and three European. Most of the included studies were of moderate quality. There was a wide range in MRH incidence, from 0.4% to 51.2% of patients, and 35% to 59% of MRH was preventable. The MRH incidence within 30 days post-discharge ranges from 167 to 500 events per 1000 patients discharged (17-51% of patients. Substantial methodological heterogeneity exists across multiple domains of the studies, including ADR and ADE definitions, characteristics of recruited populations, the follow-up duration post-discharge, and data collection. Conclusions Medication-related harm is common following hospital discharge in older adults. However, a clear understanding of the epidemiology is hampered by methodological inconsistencies between studies and a paucity of data on risk factors. There is need for international consensus on conducting and reporting MRH studies.Data from large, multicentre studies examining a range of biopsychosocial risk factors could add insight to this important area of patient safety

Frailty predicts medication-related harm requiring healthcare: a UK multicentre prospective cohort study

Introduction Frailty has been under investigated as a risk factor for medication-related harm (MRH) in older adults[1]. We sought to determine whether frailty is independently associated with MRH in a large multicentre prospective cohort, the PRIME study. Methods The PRIME study recruited 1280 older adults at hospital discharge from 5 hospitals in England between 2013 to 2015[2]. MRH and associated healthcare use within 8-weeks post-discharge were identified by senior pharmacists using (1) hospital readmission data, (2) primary care records, (3) patient telephone interviews. Based on the Rockwood approach[3], we developed a frailty index including 55 deficits from multiple domains (morbidity, cognition, mood, strength and mobility, nutrition, daily function). Frailty was defined using the established cut-off of 20% deficits[4], and internally validated using Kaplan-Meier plots comparing survival in frail and non-frail patients. We then used logistic regression analysis to investigate the relationship between frailty and MRH requiring healthcare. Results 1116 patients completed follow-up (median age 81.9 years, range 65-103 years, 58.4% female). 446 patients (40%) were frail in our cohort. 36% of frail patients experienced MRH compared with 25% in non-frail patients. There was a strong relationship between frailty and MRH (OR 1.67, 95% CI 1.29-2.17, p<0.001). A significant relationship between frailty and MRH remained on multivariable regression, adjusting for polypharmacy, age and gender (OR 1.37, 95% CI 1.04-1.81, p=0.027). Frail patients had significantly reduced 18-month survival (Log-Rank test p<0.001). Key Conclusions Frailty is a predictor of MRH requiring healthcare, independent of polypharmacy

TheSTUDGene Is Required for Male-Specific Cytokinesis after Telophase II of Meiosis inArabidopsis thaliana

AbstractDuring male meiosis in wild-typeArabidopsisthe pollen mother cell (PMC) undergoes two meiotic nuclear divisions in the absence of cell division. Only after telophase II is a wall formed which partitions the PMC into four microspores. Each microspore undergoes two subsequent mitotic divisions to produce one vegetative cell and two sperm cells in the mature pollen grain. In this paper we describe the isolation and the phenotypic characterization of mutations in theSTUD(STD) gene, which is specifically required for male-specific cytokinesis after telophase II of meiosis. Although the male meiotic nuclear divisions are normal instdmutant plants, no walls are formed resulting in a tetranucleate microspore. Despite the absence of cell division in the PMC, postmeiotic development in the coenocytic microspore proceeds relatively normally, resulting in the formation of large pollen grains which contain four vegetative nuclei and up to eight sperm cells. Interestingly, these enlarged pollen grains which contain multiple vegetative nuclei and extra sperm cells behave as single male gametophytes, producing only single pollen tubes and resulting in partial male fertility instdmutant plants. Characterization of the process of pollen development and pollen function instdmutants thus reveals two different types of developmental regulation. Each of the four nuclei found in astdmicrospore following meiosis is capable of independently undergoing the complete mitotic cell division (including cytokinesis) which the single nucleus of a wild-type microspore would normally undertake. The ability of the four meiotic products to independently continue through mitosis does not depend on their division into separate cells, but is controlled by some subcellular component found within the coenocytic micropsore. By contrast, the maturestdpollen grain functions as a unit and produces only a single pollen tube despite the presence of multiple nuclei within the vegetative cell, suggesting that this process is controlled at the cellular level independently of the extra subcellular components

The association of a single-nucleotide polymorphism in the nuclear factor (erythroid derived 2)-like 2 gene with adverse drug reactions, multimorbidity and frailty in older people

Susceptibility to adverse drug reactions (ADRs), multimorbidity, and frailty are associated with human ageing, yet there is wide variation in the severity and age at which individuals are afflicted. Identifying genetic markers of increased risk of this phenotype would help stratify individuals to specialist interventions. Nuclear factor erythroid derived-2 like 2 (Nrf2) regulates a cell’s response to stressors, including the expression of enzymes involved in drug-metabolism. Its expression has been shown to decline in animal ageing models. In this study we tested the hypothesis that Nrf2 gene transcription/translation decline in human ageing, and that single nucleotide polymorphisms (SNPs) in the Nrf2 gene are associated with increased ADR risk, multi-morbidity, and frailty in older people. Gene expression and protein levels were measured in peripheral blood mononuclear cells (PBMCs) donated from healthy patients aged 18-80 years old. Nrf2 genotypes were determined at three loci in a sub-population of patients recruited to the PRIME study (a multicentre prospective cohort study that followed older adults for 8-weeks post-discharge to determine ADR). Both Nrf2 gene and protein expression declined significantly with age in human PBMCs. In the PRIME sub-study population, the rs35652124 Nrf2 SNP was associated with increased ADR risk, and decreased frailty and multi-morbidity scores