Sarcopenia and vascular risk in a healthy elderly UK population (BRAVES study)

Introduction Sarcopenia, the loss of skeletal muscle mass and strength that occurs with advancing age [1] is correlated with functional decline and disability but little is known about its relationship with cardiovascular risk. Bioimpedence analysis (BIA) is a validated technique for measuring muscle mass, convenient for use in large cohort studies. Arterial stiffness (compliance) is an independent predictor of cardiovascular events. Methods The BRAVES study was designed to compare cardiovascular risk between two healthy elderly cohorts in the UK and in Italy. We used data from the UK cohort to investigate the relationship between sarcopenia and vascular compliance. Participants were eligible if aged 65-85 years, lived within the Brighton area and had weight loss of no more than 5% in the last month. All underwent physical exam, BIA assessment of skeletal mass index (SMI) and two measures of arterial compliance. Pulse wave velocity (PWV) was measured between carotid-femoral and carotid-radial arteries and the augmentation index (AIx) derived from carotid and radial arteries. A bivariate correlation was performed. Results Ninety patients (64 female; 26 male) had mean age 73, mean FFM 46.84kg (range 34.7-74.7) and mean SMI 6.77 (range 4.84-10.09). There was a negative relationship between SMI and Radial AIx (R=0.-542, p=0.000) as well as Carotid AIx (R=-0.391, p=0.002) but not PWV. Using multiple regression to control for the effects of age and gender, SMI was independently related to radial AIx (p=.013). Conclusions Skeletal muscle mass index is strongly negatively correlated with augmentation index, a measure of vascular stiffness. This finding suggests that elderly patients with higher muscle mass have a more compliant aorta and hence lower cardiovascular risk. Whether sarcopenia acts as a marker for CV risk or plays an active role in cardiovascular disease progression is not yet established and deserves further investigation

Cardio-ankle vascular index and carotid-femoral pulse wave velocity are closely associated with chronological age

Background: Vascular stiffening is part of the ageing process. However, it is not clear which vascular stiffness parameters are closely associated with chronological age. Methods: Fifty-eight participants (38 men), age 69.57 ± 10.46 (mean ± SD, range = 47-90 years) who have had transient ischaemic attack or lacunar stroke within the last 2 weeks, had vascular stiffness parameters, brachial and central blood pressures measured. Cardio-ankle vascular index (CAVI) was measured with VaSera VS-1500N® (Fukuda Denshi, Japan); carotid-femoral pulse wave velocity (cfPWV) and carotid-radial pulse wave velocity (crPWV) were measured with Complior® (ALAM Medical, France); radial augmentation index (rAIx) and central blood pressure were measured with SphygmoCor® (AtCor, Australia). Results: The mean and standard error of the mean for each parameter (mean ± SEM) was as follows: CAVI=9.77 ± 0.21, cfPWV = 10.61 ± 0.46 m/s, crPWV = 11.05 ± 0.30 m/s, rAIx = 31.34 ± 1.60 %, and central pulse pressure (cPP) = 50.22 ± 1.81 mmHg. In a bivariate analysis, CAVI (r = 0.59, p<0.01) and cfPWV (r = 0.39, p<0.01) were significantly associated with age, but rAIx (r = 0.12, p = 0.371) and crPWV (r = 0.06, p=0.682) were not. A multivariate regression analysis, performed with age as the dependent factor and CAVI, cfPWV, crPWV, cPP, and rAIx as independent parameters, showed that CAVI was the only significant parameter (β = 0.49, p = 0.002) associated with age. Conclusion: CAVI and cfPWV are closely associated with chronological age, whereas crPWV and rAIx are less so. We suggest that the vascular parameter which best predicts biological age is CAVI, followed closely by cfPWV

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

The role of novel biomarkers of inflammation in arterial stiffness, and in predicting further vascular events after TIA and lacunar stroke

Objective: To explore the role of biomarkers (hsCRP, sRANKL, PRDX1 and EPO) in arterial stiffness and in predicting further vascular events. Methods: Patients from the ongoing ASIST study each attended a laboratory visit within fourteen days of their diagnosed TIA or lacunar stroke. Arterial stiffness was calculated using cfPWV (carotid-femoral pulse wave velocity) measured with Complior ®Artech, France, and with the CAVI ®Fukuda, Japan (cardio-ankle vascular index) method. Blood samples were taken for ELISA assays. Analysis was completed with SPSS software. Results: Forty patients were evaluated in this preliminary project (29 male/11 female, mean age 70.7 ± 11.99), with four experiencing a further event during the six month follow up (10%). All biomarkers and both measurements for arterial stiffness had a higher mean value in patients with a further event (hsCRP 3.89 vs 1.42 ug/ml, P=0.08; EPO 9.06 vs 9.01 mU/ml, P=0.85; sRANKL 0.05 vs 0.03 pmol/L, P=0.31; PRDX1 6.27 vs 6.21 ng/ml, P=0.95; CAVI 11.13 vs 9.69, P=0.15; cfPWV 10.82 vs 10.2 m/s, P=0.55), however none were statistically significant. Levels of PRDX1 were elevated acutely post-event before falling significantly (R=-0.475, P=0.002), while hsCRP and EPO continued to be elevated at >10 days post-event. In addition, CAVI correlated closely with hsCRP (R=0.28, P=0.09) and EPO (R=0.29, P=0.08), but cfPWV was not closely related to any of the biomarkers. Conclusions: This preliminary data suggests that biomarkers, particularly EPO and hsCRP, are more closely related to CAVI than cfPWV. hsCRP was the most relevant as an independent predictive factor for further vascular events

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

Does arterial ageing differ between Europeans and Japanese and Korean patient samples? Results from current UK studies

Objective: Vascular stiffness has long been linked with the ageing process. However, it is only since the development of accurate methods for measuring arterial compliance that unravelling this relationship has become possible. Arterial stiffening over time appears to differ between ethnic groups and/or geographic areas. We investigated how the cardio-ankle vascular index (CAVI) varied with chronological age to make initial comparisons of its change with age between this European study and published data from Japanese and Korean patient populations. Method: 312 participants (180 men, 132 women), age 63.7±12.9 (mean±SD), range 25-92 years. The following were measured: CAVI using VaSera VS-1500N® (Fukuda Denshi, Japan); brachial BP using OMRON705-IT; baseline characteristics and physical examination of cardiovascular health. These data are from current UK studies of healthy volunteers with approximately 20% having two or more cardiovascular risk factors. Results: CAVI was significantly correlated with age (r=0.63, p<0.001), more closely in men (r=0.71, p<0.001) than women (r=0.54, p<0.001). These data were used to create a preliminary set of ‘usual’ average CAVI values for each age category (Table) and compared against data from Japan[1] and Korea[2] (plot 1 & 2). Korean men had lower CAVI values at each age. Conclusions: This suggests CAVI is closely related to ageing and may be a useful indicator of vascular age. In initial comparisons, the slope of arterial ‘ageing’ may be steeper for Europeans, especially men over 60 years, than for Japanese and particularly Koreans, but detailed analysis has not yet been done due to lack of raw data

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

Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial

BACKGROUND: Venous thromboembolism is a common, potentially avoidable cause of death and morbidity in patients in hospital, including those with stroke. In surgical patients, intermittent pneumatic compression (IPC) reduces the risk of deep vein thrombosis (DVT), but no reliable evidence exists about its effectiveness in patients who have had a stroke. We assessed the effectiveness of IPC to reduce the risk of DVT in patients who have had a stroke. METHODS: The CLOTS 3 trial is a multicentre parallel group randomised trial assessing IPC in immobile patients (ie, who cannot walk to the toilet without the help of another person) with acute stroke. We enrolled patients from day 0 to day 3 of admission and allocated them via a central randomisation system (ratio 1:1) to receive either IPC or no IPC. A technician who was masked to treatment allocation did a compression duplex ultrasound (CDU) of both legs at 7-10 days and, wherever practical, at 25-30 days after enrolment. Caregivers and patients were not masked to treatment assignment. Patients were followed up for 6 months to determine survival and later symptomatic venous thromboembolism. The primary outcome was a DVT in the proximal veins detected on a screening CDU or any symptomatic DVT in the proximal veins, confirmed on imaging, within 30 days of randomisation. Patients were analysed according to their treatment allocation. TRIAL REGISTRATION: ISRCTN93529999. FINDINGS: Between Dec 8, 2008, and Sept 6, 2012, 2876 patients were enrolled in 94 centres in the UK. The included patients were broadly representative of immobile stroke patients admitted to hospital and had a median age of 76 years (IQR 67-84). The primary outcome occurred in 122 (8·5%) of 1438 patients allocated IPC and 174 (12·1%) of 1438 patients allocated no IPC; an absolute reduction in risk of 3·6% (95% CI 1·4-5·8). Excluding the 323 patients who died before any primary outcome and 41 without any screening CDU, the adjusted OR for the comparison of 122 of 1267 patients vs 174 of 1245 patients was 0·65 (95% CI 0·51-0·84; p=0·001). Deaths in the treatment period occurred in 156 (11%) patients allocated IPC and 189 (13%) patients allocated no IPC died within the 30 days of treatment period (p=0·057); skin breaks on the legs were reported in 44 (3%) patients allocated IPC and in 20 (1%) patients allocated no IPC (p=0·002); falls with injury were reported in 33 (2%) patients in the IPC group and in 24 (2%) patients in the no-IPC group (p=0·221). INTERPRETATION: IPC is an effective method of reducing the risk of DVT and possibly improving survival in a wide variety of patients who are immobile after stroke. FUNDING: National Institute of Health Research (NIHR) Health Technology Assessment (HTA) programme, UK; Chief Scientist Office of Scottish Government; Covidien (MA, USA)

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