The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis.

BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION: There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING: None.

Association of cognitive function with increased risk of cancer death and all-cause mortality: Longitudinal analysis, systematic review, and meta-analysis of prospective observational studies.

BACKGROUND: Disturbed cognitive function is associated with several causes of mortality; however, the association between cognitive function and the risk of cancer death has not been extensively investigated yet. We aimed to evaluate the association of cognitive function with the risk of cancer death and all-cause mortality in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) and Leiden 85-plus Study. Additionally, a systematic review and meta-analysis of longitudinal studies were conducted to evaluate the association of cognitive function and risk of cancer death. METHODS: Risk of cancer death and all-cause mortality were reported using hazard ratios (HRs) with 95% confidence interval (CI) in tertiles of cognitive function of PROSPER and Leiden85-Plus Study. Additionally, PubMed, Embase, Web of Science, Cochrane, PsycINFO, Academic Search Premier, CINHAL, and Emcare were searched up to November 1st, 2020 to perform a systematic review and meta-analysis. The relative risks (RRs) with 95%CI of cancer death per each standard deviation lower performance in cognitive measurements were calculated. RESULTS: Participants of PROSPER had 1.65-fold (95%CI 1.11-2.47) greater risk of cancer death (P for trend = 0.016) and 1.85-fold (95%CI 1.46-2.34) higher risk of all-cause mortality (P for trend<0.001), in multivariable models. Results of the Leiden-85 Plus Study showed that subjects with MMSE score below 24 had a lower chance of cancer death (HR 0.79, 95%CI 0.36-1.70, P for trend = 0.820) but had 2.18-fold (95%CI 1.57-3.02) higher risk of all-cause mortality compared to the reference group (P for trend<0.001). Besides, the results of systematic review and meta-analysis showed that per each standard deviation lower performance in cognitive function, individuals were at a 10% higher chance of cancer death (RR 1.10, 95%CI 1.00-1.20, P-value = 0.044). CONCLUSIONS: Lower cognitive function performance is associated with a marginally increased risk of cancer death, in line with a significantly greater risk of all-cause mortality.

General practitioners' deprescribing decisions in older adults with polypharmacy: a case vignette study in 31 countries.

BACKGROUND: General practitioners (GPs) should regularly review patients' medications and, if necessary, deprescribe, as inappropriate polypharmacy may harm patients' health. However, deprescribing can be challenging for physicians. This study investigates GPs' deprescribing decisions in 31 countries. METHODS: In this case vignette study, GPs were invited to participate in an online survey containing three clinical cases of oldest-old multimorbid patients with potentially inappropriate polypharmacy. Patients differed in terms of dependency in activities of daily living (ADL) and were presented with and without history of cardiovascular disease (CVD). For each case, we asked GPs if they would deprescribe in their usual practice. We calculated proportions of GPs who reported they would deprescribe and performed a multilevel logistic regression to examine the association between history of CVD and level of dependency on GPs' deprescribing decisions. RESULTS: Of 3,175 invited GPs, 54% responded (N = 1,706). The mean age was 50 years and 60% of respondents were female. Despite differences across GP characteristics, such as age (with older GPs being more likely to take deprescribing decisions), and across countries, overall more than 80% of GPs reported they would deprescribe the dosage of at least one medication in oldest-old patients (> 80 years) with polypharmacy irrespective of history of CVD. The odds of deprescribing was higher in patients with a higher level of dependency in ADL (OR =1.5, 95%CI 1.25 to 1.80) and absence of CVD (OR =3.04, 95%CI 2.58 to 3.57). INTERPRETATION: The majority of GPs in this study were willing to deprescribe one or more medications in oldest-old multimorbid patients with polypharmacy. Willingness was higher in patients with increased dependency in ADL and lower in patients with CVD.

Cost-utility and cost-effectiveness analysis of a clinical medication review focused on personal goals in older persons with polypharmacy compared to usual care: Economic evaluation of the DREAMeR study.

AIMS: The ageing society may lead to increasing healthcare expenditure. A clinical medication review (CMR) could potentially reduce costs. The aim of this study is to perform a cost-utility and cost-effectiveness analysis from a societal perspective of a patient-centred CMR. METHODS: A trial-based cost-utility and cost-effectiveness analysis was performed as part of the DREAMeR study, a pragmatic controlled trial that randomised patients aged ≥70 years using at least seven drugs to either CMR or usual care. Over six months, healthcare consumption and drug use were collected to estimate costs, and effects were collected in terms of quality-adjusted life years (QALYs) measured with EQ-5D-5 L and EQ-VAS and as reduced health-related complaints with impact on patients' daily lives. RESULTS: The total mean costs per patient (n = 588) over six months were €4,189 ± 6,596 for the control group (n = 294) and €4,008 ± 6,678 for the intervention group (n = 294), including estimated intervention costs of €199 ± 67, which resulted in a mean incremental total cost savings of €181 for the intervention group compared to the control group. Compared to the control group, for the intervention group, the mean incremental QALYs over six months were: -0.00217 measured with EQ-5D and 0.003 measured with EQ-VAS. The incremental effect of reduced health-related complaints with impact was -0.34. There was a likelihood of >90% that the intervention was cost-saving. CONCLUSIONS: The benefits of a patient-centred CMR were inconsistent with no benefits on HR-QoL measured with EQ-5D-5 L and small benefits on HR-QoL measured with EQ-VAS and health-related complaints with impact on patients' daily lives. Additionally, a CMR could potentially be cost saving from a societal perspective.

What do older adults with multimorbidity and polypharmacy think about deprescribing? The LESS study - a primary care-based survey.

BACKGROUND: Multimorbidity and polypharmacy are very common in older adults in primary care. Ideally, general practitioners (GPs), should regularly review medication lists to identify inappropriate medication(s) and, where appropriate, deprescribe. However, it remains challenging to deprescribe given time constraints and few recommendations from guidelines. Further, patient related barriers and enablers to deprescribing have to be accounted for. The aim of this study was to identify barriers and enablers to deprescribing as reported by older adults with polypharmacy and multimorbidity. METHODS: We conducted a survey among participants aged ≥70 years, with multimorbidity (≥3 chronic conditions) and polypharmacy (≥5 chronic medications). We invited Swiss GPs, to recruit eligible patients who then completed a paper-based survey on demographics, medications and chronic conditions. We used the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire and added twelve additional Likert scale questions and two open-ended questions to assess barriers and enablers towards deprescribing, which we coded and categorized into meaningful themes. RESULT: Sixty four Swiss GPs consented to recruit 5-6 patients each and returned 300 participant responses. Participants were 79.1 years (SD 5.7), 47% female, 34% lived alone, and 86% managed their medications themselves. Sixty-seven percent of participants took 5-9 regular medicines and 24% took ≥10 medicines. The majority of participants (77%) were willing to deprescribe one or more of their medicines if their doctor said it was possible. There was no association with sex, age or the number of medicines and willingness to deprescribe. After adjustment for baseline characteristics, there was a strong positive association between willingness to deprescribe and saying that because they have a good relationship with their GP, they would feel that deprescribing was safe OR 11.3 (95% CI: 4.64-27.3) and agreeing that they would be willing to deprescribe if new studies showed an avoidable risk OR 8.0 (95% CI 3.79-16.9). From the open questions, the most mentioned barriers towards deprescribing were patients feeling well on their current medicines and being convinced that they need all their medicines. CONCLUSIONS: Most older adults with polypharmacy are willing to deprescribe. GPs may be able to increase deprescribing by building trust with their patients and communicating evidence about the risks of medication use.

Potentially inappropriate medication and attitudes of older adults towards deprescribing.

INTRODUCTION: Multimorbidity and polypharmacy are current challenges when caring for the older population. Both have led to an increase of potentially inappropriate medication (PIM), illustrating the need to assess patients' attitudes towards deprescribing. We aimed to assess the prevalence of PIM use and whether this was associated with patient factors and willingness to deprescribe. METHOD: We analysed data from the LESS Study, a cross-sectional study on self-reported medication and on barriers and enablers towards the willingness to deprescribe (rPATD questionnaire). The survey was conducted among multimorbid (≥3 chronic conditions) participants ≥70 years with polypharmacy (≥5 long-term medications). A subset of the Beers 2019 criteria was applied for the assessment of medication appropriateness. RESULTS: Data from 300 patients were analysed. The mean age was 79.1 years (SD 5.7). 53% had at least one PIM (men: 47.8%%, women: 60.4%%; p = 0.007). A higher number of medications was associated with PIM use (p = 0.002). We found high willingness to deprescribe in both participants with and without PIM. Willingness to deprescribe was not associated with PIM use (p = 0.25), nor number of PIMs (p = 0.81). CONCLUSION: The willingness of older adults with polypharmacy towards deprescribing was not associated with PIM use in this study. These results suggest that patients may not be aware if they are taking PIMs. This implies the need for raising patients' awareness about PIMs through education, especially in females, in order to implement deprescribing in daily practice.

Skeletal Effects of Levothyroxine for Subclinical Hypothyroidism in Older Adults: A TRUST Randomized Trial Nested Study.

CONTEXT: Both thyroid dysfunction and levothyroxine (LT4) therapy have been associated with bone loss, but studies on the effect of LT4 for subclinical hypothyroidism (SHypo) on bone yielded conflicting results. OBJECTIVE: To assess the effect of LT4 treatment on bone mineral density (BMD), Trabecular Bone Score (TBS), and bone turnover markers (BTMs) in older adults with SHypo. DESIGN AND INTERVENTION: Planned nested substudy of the double-blind placebo-controlled TRUST trial. Participants with SHypo were randomized to LT4 with dose titration versus placebo with computerized mock titration. SETTING AND PARTICIPANTS: 196 community-dwelling adults over 65 years enrolled at the Swiss TRUST sites had baseline and 1-year follow-up bone examinations; 4 participants withdrew due to adverse events not related to treatment. MAIN OUTCOME MEASURES: One-year percentage changes of BMD, TBS, and 2 serum BTMs (serum CTX-1 [sCTX] and procollagen type 1 N-terminal polypeptide [P1NP]). Student's t-test for unadjusted analyses and linear regression adjusted for clinical center and sex were performed. RESULTS: Mean age was 74.3 years ± 5.7, 45.4% were women, and 19.6% were osteoporotic. The unadjusted 1-year change in lumbar spine BMD was similar between LT4 (+0.8%) and placebo-treated groups (-0.6%; between-groups difference +1.4%: 95% confidence interval [CI] -0.1 to 2.9, P = .059). Likewise, there were no between-group differences in 1-year change in TBS (-1.3%: 95% CI -3.1 to 0.6, P = .19), total hip BMD (-0.2%: 95% CI -1.1 to 0.1, P = .61), or BTMs levels (sCTX +24.1%: 95% CI -7.9 to 56.2, P = .14), or after adjustment for clinical centers and sex. CONCLUSIONS: Over 1-year levothyroxine had no effect on bone health in older adults with SHypo. REGISTRATION: ClinicalTrial.gov NCT01660126 and NCT02491008.

Effects of a clinical medication review focused on personal goals, quality of life, and health problems in older persons with polypharmacy: A randomised controlled trial (DREAMeR-study).

BACKGROUND: Clinical medication reviews (CMRs) are increasingly performed in older persons with multimorbidity and polypharmacy to reduce drug-related problems (DRPs). However, there is limited evidence that a CMR can improve clinical outcomes. Little attention has been paid to patients' preferences and needs. The aim of this study was to investigate the effect of a patient-centred CMR, focused on personal goals, on health-related quality of life (HR-QoL), and on number of health problems. METHODS AND FINDINGS: This study was a randomised controlled trial (RCT) performed in 35 community pharmacies and cooperating general practices in the Netherlands. Community-dwelling older persons (≥70 years) with polypharmacy (≥7 long-term medications) were randomly assigned to usual care or to receive a CMR. Randomisation was performed at the patient level per pharmacy using block randomisation. The primary outcomes were HR-QoL (assessed with EuroQol [EQ]-5D-5L and EQ-Visual Analogue Scale [VAS]) and number of health problems (such as pain or dizziness), after 3 and 6 months. Health problems were measured with a self-developed written questionnaire as the total number of health problems and number of health problems with a moderate to severe impact on daily life. Between April 2016 and February 2017, we recruited 629 participants (54% females, median age 79 years) and randomly assigned them to receive the intervention (n = 315) or usual care (n = 314). Over 6 months, in the intervention group, HR-QoL measured with EQ-VAS increased by 3.4 points (95% confidence interval [CI] 0.94 to 5.8; p = 0.006), and the number of health problems with impact on daily life decreased by 12% (difference at 6 months -0.34; 95% CI -0.62 to -0.044; p = 0.024) as compared with the control group. There was no significant difference between the intervention group and control group for HR-QoL measured with EQ-5D-5L (difference at 6 months = -0.0022; 95% CI -0.024 to 0.020; p = 0.85) or total number of health problems (difference at 6 months = -0.30; 95% CI -0.64 to 0.054; p = 0.099). The main study limitations include the risk of bias due to the lack of blinding and difficulties in demonstrating which part of this complex intervention (for example, goal setting, extra attention to patients, reducing health problems, drug changes) contributed to the effects that we observed. CONCLUSIONS: In this study, we observed that a CMR focused on personal goals improved older patients' lives and wellbeing by increasing quality of life measured with EQ-VAS and decreasing the number of health problems with impact on daily life, although it did not significantly affect quality of life measured with the EQ-5D. Including the patient's personal goals and preferences in a medication review may help to establish these effects on outcomes that are relevant to older patients' lives. TRIAL REGISTRATION: Netherlands Trial Register; NTR5713.

Prevalence of Carriers of Intermediate and Pathological Polyglutamine Disease-Associated Alleles Among Large Population-Based Cohorts.

Importance: Nine hereditary neurodegenerative diseases are known as polyglutamine diseases, including Huntington disease, 6 spinocerebellar ataxias (SCAs) (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17), dentatorubral-pallidoluysion atrophy, and spinal bulbar muscular atrophy. Objective: To determine the prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among the general population. Design, Setting, and Participants: This observational cross-sectional study included data from 5 large European population-based cohorts that were compiled between 1997 and 2012, and the analyses were conducted in 2018. In total, 16 547 DNA samples were obtained from participants of the 5 cohorts. Individuals with a lifetime diagnosis of major depression were excluded (n = 2351). In the remaining 14 196 participants without an established polyglutamine disease diagnosis, the CAG repeat size in both alleles of all 9 polyglutamine disease-associated genes (PDAGs) (ie, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR) was determined. Exposure: The number of CAG repeats in the alleles of the 9 PDAGs. Main Outcomes and Measures: The number of individuals with alleles within the intermediate or pathological range per PDAG, as well as differences in sex, age, and body mass index between individuals carrying alleles within the normal or intermediate range and individuals carrying alleles within the pathological range of PDAGs. Results: In the 14 196 analyzed participants (age range, 18-99 years; 56.3% female), 10.7% had a CAG repeat number within the intermediate range of at least 1 PDAG. Moreover, up to 1.3% of the participants had a CAG repeat number within the disease-causing range, predominantly in the lower pathological range associated with elderly onset. No differences in sex, age, or body mass index were found between individuals with CAG repeat numbers within the pathological range and individuals with CAG repeat numbers within the normal or intermediate range. Conclusions and Relevance: These results indicate a high prevalence of individuals carrying intermediate and pathological ranges of polyglutamine disease-associated alleles among the general population. Therefore, a substantially larger proportion of individuals than previously estimated may be at risk of developing a polyglutamine disease later in life or bearing children with a de novo mutation.

Patient Characteristics and General Practitioners' Advice to Stop Statins in Oldest-Old Patients: a Survey Study Across 30 Countries.

BACKGROUND: Statins are widely used to prevent cardiovascular disease (CVD). With advancing age, the risks of statins might outweigh the potential benefits. It is unclear which factors influence general practitioners' (GPs) advice to stop statins in oldest-old patients. OBJECTIVE: To investigate the influence of a history of CVD, statin-related side effects, frailty and short life expectancy, on GPs' advice to stop statins in oldest-old patients. DESIGN: We invited GPs to participate in this case-based survey. GPs were presented with 8 case vignettes describing patients > 80 years using a statin, and asked whether they would advise stopping statin treatment. MAIN MEASURES: Cases varied in history of CVD, statin-related side effects and frailty, with and without shortened life expectancy (< 1 year) in the context of metastatic, non-curable cancer. Odds ratios adjusted for GP characteristics (ORadj) were calculated for GPs' advice to stop. KEY RESULTS: Two thousand two hundred fifty GPs from 30 countries participated (median response rate 36%). Overall, GPs advised stopping statin treatment in 46% (95%CI 45-47) of the case vignettes; with shortened life expectancy, this proportion increased to 90% (95CI% 89-90). Advice to stop was more frequent in case vignettes without CVD compared to those with CVD (ORadj 13.8, 95%CI 12.6-15.1), with side effects compared to without ORadj 1.62 (95%CI 1.5-1.7) and with frailty (ORadj 4.1, 95%CI 3.8-4.4) compared to without. Shortened life expectancy increased advice to stop (ORadj 50.7, 95%CI 45.5-56.4) and was the strongest predictor for GP advice to stop, ranging across countries from 30% (95%CI 19-42) to 98% (95% CI 96-99). CONCLUSIONS: The absence of CVD, the presence of statin-related side effects, and frailty were all independently associated with GPs' advice to stop statins in patients aged > 80 years. Overall, and within all countries, cancer-related short life expectancy was the strongest independent predictor of GPs' advice to stop statins.

The use of goal attainment scaling during clinical medication review in older persons with polypharmacy.

BACKGROUND: Studies have shown that a clinical medication review (CMR) reduces drug-related problems (DRPs), but the effects on clinical outcomes are less clear. Perhaps, CMRs in older persons could me more effective when they focus on patients' personal goals and health-related complaints. OBJECTIVE: The aim of this study was to investigate whether goal attainment scaling (GAS) is a useful tool for determining goals and monitoring their attainment during CMR. METHODS: This study was an analysis based on data of the intervention group of the DREAMeR-study; a randomised controlled trial investigating the effects of CMR in primary care. 315 persons aged ≥70 years using ≥7 drugs were randomised to the intervention: a CMR focused on personal goals using GAS. Outcome measures were: percentage of persons with health-related goals, attainment of goals measured with GAS-scores after three and six months, type of health-related goals and implementation rates of recommendations for GAS-related DRPs and other DRPs. RESULTS: A total of 406 health-related goals were set for 283 of 315 included persons (90%). Of the 350 evaluated goals (86%), 37% was attained after three months and 43% after six months. The goals 'reduce pain' (n = 66, 16%), 'improve mobility' (n = 57, 14%) and 'reduce number of pills' (n = 37, 9.1%) were most prevalent. The implementation rate of recommendations for GAS-related DRPs was 81% compared to 62% for not GAS-related DRPs (p < 0.05). CONCLUSION: Goal setting is important for prioritizing the most important problems during clinical medication review and Goal Attainment Scaling seems to be a useful tool for monitoring the attainment of these goals.

How general practitioners would deprescribe in frail oldest-old with polypharmacy - the LESS study.

BACKGROUND: Many oldest-old (> 80-years) with multimorbidity and polypharmacy are at high risk of inappropriate use of medication, but we know little about whether and how GPs would deprescribe, especially in the frail oldest-old. We aimed to determine whether, how, and why Swiss GPs deprescribe for this population. METHODS: GPs took an online survey that presented case-vignettes of a frail oldest-old patient with and without history of cardiovascular disease (CVD) and asked if they would deprescribe any of seven medications. We calculated percentages of GPs willing to deprescribe at least one medication in the case with CVD and compared these with the case without CVD using paired t-tests. We also included open-ended questions to capture reasons for deprescribing and asked which factors could influence their decision to deprescribe by asking for their agreement on a 5-point-Likert-scale. RESULTS: Of the 282 GPs we invited, 157 (56%) responded: 73% were men; mean age was 56. In the case-vignette without CVD, 98% of GPs deprescribed at least one medication (usually cardiovascular preventive medications) stating it had no indication nor benefit. They would lower the dose or prescribe pain medication as needed to reduce side effects. Their response was much the same when the patient had a history of CVD. GPs reported they were influenced by 'risk' and 'benefit' of medications, 'quality of life', and 'life expectancy', and prioritized the patient's wishes and priorities when deprescribing. CONCLUSION: Swiss GPs were willing to deprescribe cardiovascular preventive medication when it lacked indication but tended to retain pain medication. Developing tools for GPs to assist them in balancing the risks and benefits of medication in the context of patient values may improve deprescribing activities in practice.

DREAMeR: Drug use Reconsidered in the Elderly using goal Attainment scales during Medication Review; study protocol of a randomised controlled trial.

BACKGROUND: Clinical medication reviews (CMR) are increasingly performed in older patients with polypharmacy. Studies have shown positive effects of CMR on process- and intermediate outcomes, like drug-related problems (DRPs). Little effect has been shown on clinical outcomes, like hospital admissions or health-related quality of life (HR-QoL). In particular, HR-QoL is related to the individual health-related goals and complaints of patients. The aim of this study is to investigate the effects of a CMR focused on personal goals on HR-QoL and health-related complaints in older patients with polypharmacy. METHODS: A randomised controlled trial will be performed in 35 Dutch community pharmacies aiming to include 630 patients aged 70 years and older using seven or more chronic drugs. Patients will be randomly assigned to control or intervention group by block-randomisation per pharmacy. Patients in the intervention group receive a CMR focused on patients' preferences, personal goals and health-related complaints. With every goal a goal attainment scale (GAS) will be proposed. Primary outcome measures are HR-QoL, measured with the EQ-5D-5L and EQ-VAS and the number of health-related complaints per patient measured with a written questionnaire, during a follow-up period of six months. Secondary outcomes are healthcare utilisation, number and type of drug changes, number and type of health-related goals, scores on GAS and number and type of DRPs and interventions. DISCUSSION: This study is expected to add evidence on the effects of a CMR on HR-QoL and health-related complaints in older patients with polypharmacy. New in this study is the use of personal goals measured with GAS and health-related complaints as patient-related outcome measures. TRIAL REGISTRATION: Netherlands Trial Register; NTR5713 .

Prediction of functional decline in community-dwelling older persons in general practice: a cohort study.

BACKGROUND: A first step to offer community-dwelling older persons proactive care is to identify those at risk of functional decline within a year. This study investigates the predictive value of registered information, questionnaire and GP-opinion on functional decline. METHODS: In this cohort study, embedded within the ISCOPE-trial, participants (≥75 years) completed the ISCOPE-screening questionnaire on four health domains. GPs gave their opinion on vulnerability of participants. Functional status was measured at baseline and 12 months (Groningen Activities Restriction Scale [GARS]). The outcome was functional decline (death, nursing home admission, 10% with greatest functional decline). The predictive value of pre-selected variables (age, sex, polypharmacy, multimorbidity, living situation; GPs' opinion on vulnerability, number of domains with problems [ISCOPE-score]) was compared with the area under the curves (AUC) for logistic regression models. RESULTS: 2018 of the 2211 participants (median age 82.1 years [IQR 78.8-86.5], 68.0% female, median GARS 31 [IQR 24-41]) were visited at 12 months (median GARS 34 [IQR 26-44]). 394 participants (17.8%) had functional decline (148 died, 45 nursing home admissions, 201 with greatest functional decline). The AUC for age and sex was 0.602, increasing to 0.620 (p = 0.029) with polypharmacy, multimorbidity and living situation. The GPs' opinion added more (AUC 0.672, p < 0.001) than the ISCOPE-score (AUC 0.649, p = 0.007). AUC with all variables was 0.686 (p = 0.016), and 0.643 for GPs' opinion alone. CONCLUSIONS: The GPs' opinion and ISCOPE-score improve this prediction model for functional decline based on readily available variables. GPs could identify older patients for further assessment with their clinical judgement. TRIAL REGISTRATION: Netherlands trial register, NTR1946 . Registered 10 August 2009.

Prevalence of potentially inappropriate prescribing in a subpopulation of older European clinical trial participants: a cross-sectional study.

OBJECTIVES: To estimate and compare the prevalence and type of potentially inappropriate prescribing (PIP) and potential prescribing omissions (PPOs) among community-dwelling older adults (≥65 years) enrolled to a clinical trial in three European countries. DESIGN: A secondary analysis of the Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial dataset. PARTICIPANTS: A subset of 48/80 PIP and 22/34 PPOs indicators from the Screening Tool of Older Persons Prescriptions/Screening Tool to Alert doctors to Right Treatment (STOPP/START) V2 criteria were applied to prescribed medication data for 532/737 trial participants in Ireland, Switzerland and the Netherlands. RESULTS: The overall prevalence of PIP was lower in the Irish participants (8.7%) compared with the Swiss (16.7%) and Dutch (12.5%) participants (P=0.15) and was not statistically significant. The overall prevalence of PPOs was approximately one-quarter in the Swiss (25.3%) and Dutch (24%) participants and lower in the Irish (14%) participants (P=0.04) and the difference was statistically significant. The hypnotic Z-drugs were the most frequent PIP in Irish participants, (3.5%, n=4), while it was non-steroidal anti-inflammatory drug and oral anticoagulant combination, sulfonylureas with a long duration of action, and benzodiazepines (all 4.3%, n=7) in Swiss, and benzodiazepines (7.1%, n=18) in Dutch participants. The most frequent PPOs in Irish participants were vitamin D and calcium in osteoporosis (3.5%, n=4). In the Swiss and Dutch participants, they were bone antiresorptive/anabolic therapy in osteoporosis (9.9%, n=16, 8.6%, n=22) respectively. The odds of any PIP after adjusting for age, sex, multimorbidity and polypharmacy were (adjusted OR (aOR)) 3.04 (95% CI 1.33 to 6.95, P<0.01) for Swiss participants and aOR 1.74 (95% CI 0.79 to 3.85, P=0.17) for Dutch participants compared with Irish participants. The odds of any PPOs were aOR 2.48 (95% CI 1.27 to 4.85, P<0.01) for Swiss participants and aOR 2.10 (95% CI 1.11 to 3.96, P=0.02) for Dutch participants compared with Irish participants. CONCLUSIONS: This study has estimated and compared the prevalence and type of PIP and PPOs among this cohort of community-dwelling older people. It demonstrated a significant difference in the prevalence of PPOs between the three populations. Further research is urgently needed into the impact of system level factors as this has important implications for patient safety, healthcare provision and economic costs.

Predicting Risk of Cognitive Decline in Very Old Adults Using Three Models: The Framingham Stroke Risk Profile; the Cardiovascular Risk Factors, Aging, and Dementia Model; and Oxi-Inflammatory Biomarkers.

OBJECTIVES: To examine the Framingham Stroke Risk Profile (FSRP); the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score, and oxi-inflammatory load (cumulative risk score of three blood biomarkers-homocysteine, interleukin-6, C-reactive protein) for associations with cognitive decline using three cohort studies of very old adults and to examine whether incorporating these biomarkers with the risk scores can affect the association with cognitive decline. DESIGN: Three longitudinal, population-based cohort studies. SETTING: Newcastle-upon-Tyne, United Kingdom; Leiden, the Netherlands; and Lakes and Bay of Plenty District Health Board areas, New Zealand. PARTICIPANTS: Newcastle 85+ Study participants (n = 616), Leiden 85-plus Study participants (n = 444), and Life and Living in Advanced Age, a Cohort Study in New Zealand (LiLACS NZ Study) participants (n = 396). MEASUREMENTS: FSRP, CAIDE risk score, oxi-inflammatory load, FSRP incorporating oxi-inflammatory load, and CAIDE risk score incorporating oxi-inflammatory load. Oxi-inflammatory load could be calculated only in the Newcastle 85+ and the Leiden 85-plus studies. Measures of global cognitive function were available for all three data sets. Domain-specific measures were available for the Newcastle 85+ and the Leiden 85-plus studies. RESULTS: Meta-analysis of pooled results showed greater risk of incident global cognitive impairment with higher FSRP (hazard ratio (HR) = 1.46, 95% confidence interval (CI) = 1.08-1.98), CAIDE (HR = 1.53, 95% CI = 1.09-2.14), and oxi-inflammatory load (HR = 1.73, 95% CI = 1.04-2.88) scores. Adding oxi-inflammatory load to the risk scores increased the risk of cognitive impairment for the FSRP (HR = 1.65, 95% CI = 1.17-2.33) and the CAIDE model (HR = 1.93, 95% CI = 1.39-2.67). CONCLUSION: Adding oxi-inflammatory load to cardiovascular risk scores may be useful for determining risk of cognitive impairment in very old adults.

The association of thyroid function and the risk of kidney function decline: a population-based cohort study.

OBJECTIVES: Thyroid dysfunction has been associated with kidney function decline, but mainly in cross-sectional studies. Therefore, we aimed to determine the association between thyroid and kidney function in a prospective population-based cohort study longitudinally. DESIGN: Prospective cohort study. METHODS: Participants aged ≥45 years from the Rotterdam Study with thyroid and kidney function assessment were included. Kidney function and new onset chronic kidney disease (CKD) were defined using estimated glomerular filtration ate (eGFR), with CKD defined as eGFR <60 mL/min/1.73 m2 according to the CKD-EPI formula. RESULTS: We included 5103 participants (mean age of 63.6 years) with a mean follow-up of 8.1 years. Cross-sectionally, higher TSH levels were associated with lower eGFR (Beta (ß): -1.75 mL/min; 95% confidence interval (CI): -2.17, -1.33), in multivariable models adjusting for several cardiovascular risk factors including smoking, hypertension and history of coronary heart disease among others. In contrast, longitudinally, higher TSH levels were associated with less annual eGFR decline (ß: -0.06 mL/min; CI: -0.11, -0.01) and lower CKD incidence (odds ratio 0.85, CI; 0.75, 0.96). Compared with euthyroid participants, subclinical hyperthyroid individuals had an increased risk for CKD whereas hypothyroid individuals had a decreased risk (P for trend = 0.04). CONCLUSIONS: Hyperactive thyroid function is associated with increased risk of kidney function decline while hypothyroidism is associated with a decreased CKD risk. More insight is needed in the pathophysiological pathways connecting high thyroid function and kidney function decline.

Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis.

CONTEXT: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously. DESIGN AND SETTING: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L. RESULTS: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T4 analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes. CONCLUSION: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.

Drug prescription rates in secondary cardiovascular prevention in old age: Do vulnerability and severity of the history of cardiovascular disease matter?

OBJECTIVE: To assess the influence vulnerability and severity of cardiovascular disease (CVD), on prescription rates of secondary cardiovascular preventive drugs in old age. DESIGN: Population-based observational study within the ISCOPE study. SETTING: General practices in the Netherlands. SUBJECTS: A total of 1350 patients with a history of CVD (median age 81 years, 50% female). MAIN OUTCOME MEASURES: One-year prescription rates of lipid-lowering drugs and antithrombotics were obtained from the electronic medical records of 46 general practitioners (GPs). Prescription of both drugs for ≥ 270 days per year was considered optimal. GPs made a judgement of vulnerability. Severity of CVD was expressed as major (myocardial infarction, stroke, or arterial surgery) versus minor (angina, transient ischaemic attack, or claudication). RESULTS: GPs considered 411 (30%) participants to be vulnerable and 619 (55%) participants had major CVD. Optimal treatment was prescribed to 680 (50%) participants, whereas 370 (27%) received an antithrombotic drug only, 53 (4%) a lipid-lowering drug only, and 247 (18%) received neither. Optimal treatment was lower in participants aged ≥ 85 years (OR 0.37 [95% CI 0.29-0.48]), in females (OR 0.63 [0.50-0.78]), in vulnerable persons (OR 0.79 [0.62-0.99]) and in participants with minor CVD (OR 0.65 [0.53-0.81]). Multivariate ORs remained similar whereas vulnerability lost its significance (OR 0.88 [0.69-1.1]). CONCLUSION: In old age, GPs' judgement of vulnerability is not independently associated with lower treatment rates of both lipid-lowering drugs and antithrombotics, whereas a history of minor CVD is. Individual proactive re-evaluation of preventive treatment in older (female) patients, especially those with a history of minor CVD, is recommended. Key points Prescriptions of lipid-lowering drugs and antithrombotics in secondary cardiovascular prevention tend to decline with age. In this study with median age 81 years, 50% of participants received optimal treatment with both lipid-lowering drugs and antithrombotics. GPs' judgement of vulnerability was not independently associated with optimal treatment. A history of less severe cardiovascular disease was independently associated with lower prescription rates of lipid-lowering drugs and antithrombotics. Proactive individual re-evaluation of cardiovascular preventive treatment in older (female) patients, especially patients with less severe cardiovascular disease, is recommended.

Exploring the variation in implementation of a COPD disease management programme and its impact on health outcomes: a post hoc analysis of the RECODE cluster randomised trial.

This study aims to (1) examine the variation in implementation of a 2-year chronic obstructive pulmonary disease (COPD) management programme called RECODE, (2) analyse the facilitators and barriers to implementation and (3) investigate the influence of this variation on health outcomes. Implementation variation among the 20 primary-care teams was measured directly using a self-developed scale and indirectly through the level of care integration as measured with the Patient Assessment of Chronic Illness Care (PACIC) and the Assessment of Chronic Illness Care (ACIC). Interviews were held to obtain detailed information regarding the facilitators and barriers to implementation. Multilevel models were used to investigate the association between variation in implementation and change in outcomes. The teams implemented, on average, eight of the 19 interventions, and the specific package of interventions varied widely. Important barriers and facilitators of implementation were (in)sufficient motivation of healthcare provider and patient, the high starting level of COPD care, the small size of the COPD population per team, the mild COPD population, practicalities of the information and communication technology (ICT) system, and hurdles in reimbursement. Level of implementation as measured with our own scale and the ACIC was not associated with health outcomes. A higher level of implementation measured with the PACIC was positively associated with improved self-management capabilities, but this association was not found for other outcomes. There was a wide variety in the implementation of RECODE, associated with barriers at individual, social, organisational and societal level. There was little association between extent of implementation and health outcomes.