Cost-effectiveness of a structured medication review approach for multimorbid older adults: Within-trial analysis of the OPERAM study.

BACKGROUND: Inappropriate polypharmacy has been linked with adverse outcomes in older, multimorbid adults. OPERAM is a European cluster-randomized trial aimed at testing the effect of a structured pharmacotherapy optimization intervention on preventable drug-related hospital admissions in multimorbid adults with polypharmacy aged 70 years or older. Clinical results of the trial showed a pattern of reduced drug-related hospital admissions, but without statistical significance. In this study we assessed the cost-effectiveness of the pharmacotherapy optimisation intervention. METHODS: We performed a pre-planned within-trial cost-effectiveness analysis (CEA) of the OPERAM intervention, from a healthcare system perspective. All data were collected within the trial apart from unit costs. QALYs were computed by applying the crosswalk German valuation algorithm to EQ-5D-5L-based quality of life data. Considering the clustered structure of the data and between-country heterogeneity, we applied Generalized Structural Equation Models (GSEMs) on a multiple imputed sample to estimate costs and QALYs. We also performed analyses by country and subgroup analyses by patient and morbidity characteristics. RESULTS: Trial-wide, the intervention was numerically dominant, with a potential cost-saving of CHF 3'588 (95% confidence interval (CI): -7'716; 540) and gain of 0.025 QALYs (CI: -0.002; 0.052) per patient. Robustness analyses confirmed the validity of the GSEM model. Subgroup analyses suggested stronger effects in people at higher risk. CONCLUSION: We observed a pattern towards dominance, potentially resulting from an accumulation of multiple small positive intervention effects. Our methodological approaches may inform other CEAs of multi-country, cluster-randomized trials facing presence of missing values and heterogeneity between centres/countries.

Optimizing Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older Adults (OPERAM): cluster randomised controlled trial.

OBJECTIVE: To examine the effect of optimising drug treatment on drug related hospital admissions in older adults with multimorbidity and polypharmacy admitted to hospital. DESIGN: Cluster randomised controlled trial. SETTING: 110 clusters of inpatient wards within university based hospitals in four European countries (Switzerland, Netherlands, Belgium, and Republic of Ireland) defined by attending hospital doctors. PARTICIPANTS: 2008 older adults (≥70 years) with multimorbidity (≥3 chronic conditions) and polypharmacy (≥5 drugs used long term). INTERVENTION: Clinical staff clusters were randomised to usual care or a structured pharmacotherapy optimisation intervention performed at the individual level jointly by a doctor and a pharmacist, with the support of a clinical decision software system deploying the screening tool of older person's prescriptions and screening tool to alert to the right treatment (STOPP/START) criteria to identify potentially inappropriate prescribing. MAIN OUTCOME MEASURE: Primary outcome was first drug related hospital admission within 12 months. RESULTS: 2008 older adults (median nine drugs) were randomised and enrolled in 54 intervention clusters (963 participants) and 56 control clusters (1045 participants) receiving usual care. In the intervention arm, 86.1% of participants (n=789) had inappropriate prescribing, with a mean of 2.75 (SD 2.24) STOPP/START recommendations for each participant. 62.2% (n=491) had ≥1 recommendation successfully implemented at two months, predominantly discontinuation of potentially inappropriate drugs. In the intervention group, 211 participants (21.9%) experienced a first drug related hospital admission compared with 234 (22.4%) in the control group. In the intention-to-treat analysis censored for death as competing event (n=375, 18.7%), the hazard ratio for first drug related hospital admission was 0.95 (95% confidence interval 0.77 to 1.17). In the per protocol analysis, the hazard ratio for a drug related hospital admission was 0.91 (0.69 to 1.19). The hazard ratio for first fall was 0.96 (0.79 to 1.15; 237 v 263 first falls) and for death was 0.90 (0.71 to 1.13; 172 v 203 deaths). CONCLUSIONS: Inappropriate prescribing was common in older adults with multimorbidity and polypharmacy admitted to hospital and was reduced through an intervention to optimise pharmacotherapy, but without effect on drug related hospital admissions. Additional efforts are needed to identify pharmacotherapy optimisation interventions that reduce inappropriate prescribing and improve patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02986425.

Interventions for preventing falls and fall-related fractures in community-dwelling older adults: A systematic review and network meta-analysis.

OBJECTIVE: To compare the effectiveness of single, multiple, and multifactorial interventions to prevent falls and fall-related fractures in community-dwelling older persons. METHODS: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) evaluating the effectiveness of fall prevention interventions in community-dwelling adults aged ≥65 years, from inception until February 27, 2019. Two large RCTs (published in 2020 after the search closed) were included in post hoc analyses. Pairwise meta-analysis and network meta-analysis (NMA) were conducted. RESULTS: NMA including 192 studies revealed that the following single interventions, compared with usual care, were associated with reductions in number of fallers: exercise (risk ratio [RR] 0.83; 95% confidence interval [CI] 0.77-0.89) and quality improvement strategies (e.g., patient education) (RR 0.90; 95% CI 0.83-0.98). Exercise as a single intervention was associated with a reduction in falls rate (RR 0.79; 95% CI 0.73-0.86). Common components of multiple interventions significantly associated with a reduction in number of fallers and falls rate were exercise, assistive technology, environmental assessment and modifications, quality improvement strategies, and basic falls risk assessment (e.g., medication review). Multifactorial interventions were associated with a reduction in falls rate (RR 0.87; 95% CI 0.80-0.95), but not with a reduction in number of fallers (RR 0.95; 95% CI 0.89-1.01). The following single interventions, compared with usual care, were associated with reductions in number of fall-related fractures: basic falls risk assessment (RR 0.60; 95% CI 0.39-0.94) and exercise (RR 0.62; 95% CI 0.42-0.90). CONCLUSIONS: In keeping with Tricco et al. (2017), several single and multiple fall prevention interventions are associated with fewer falls. In addition to Tricco, we observe a benefit at the NMA-level of some single interventions on preventing fall-related fractures.

An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms.

In subclinical hypothyroidism, the presence of depressive symptoms is often a reason for starting levothyroxine treatment. However, data are conflicting on the association between subclinical thyroid dysfunction and depressive symptoms. We aimed to examine the association between subclinical thyroid dysfunction and depressive symptoms in all prospective cohorts with relevant data available. We performed a systematic review of the literature from Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to 10th May 2019. We included prospective cohorts with data on thyroid status at baseline and depressive symptoms during follow-up. The primary outcome was depressive symptoms measured at first available follow-up, expressed on the Beck's Depression Inventory (BDI) scale (range 0-63, higher values indicate more depressive symptoms, minimal clinically important difference: 5 points). We performed a two-stage individual participant data (IPD) analysis comparing participants with subclinical hypo- or hyperthyroidism versus euthyroidism, adjusting for depressive symptoms at baseline, age, sex, education, and income (PROSPERO CRD42018091627). Six cohorts met the inclusion criteria, with IPD on 23,038 participants. Their mean age was 60 years, 65% were female, 21,025 were euthyroid, 1342 had subclinical hypothyroidism and 671 subclinical hyperthyroidism. At first available follow-up [mean 8.2 (± 4.3) years], BDI scores did not differ between participants with subclinical hypothyroidism (mean difference = 0.29, 95% confidence interval = - 0.17 to 0.76, I2 = 15.6) or subclinical hyperthyroidism (- 0.10, 95% confidence interval = - 0.67 to 0.48, I2 = 3.2) compared to euthyroidism. This systematic review and IPD analysis of six prospective cohort studies found no clinically relevant association between subclinical thyroid dysfunction at baseline and depressive symptoms during follow-up. The results were robust in all sensitivity and subgroup analyses. Our results are in contrast with the traditional notion that subclinical thyroid dysfunction, and subclinical hypothyroidism in particular, is associated with depressive symptoms. Consequently, our results do not support the practice of prescribing levothyroxine in patients with subclinical hypothyroidism to reduce the risk of developing depressive symptoms.

L-Thyroxine Therapy for Older Adults With Subclinical Hypothyroidism and Hypothyroid Symptoms: Secondary Analysis of a Randomized Trial.

BACKGROUND: L-thyroxine does not improve hypothyroid symptoms among adults with subclinical hypothyroidism (SCH). However, those with greater symptom burden before treatment may still benefit. OBJECTIVE: To determine whether L-thyroxine improves hypothyroid symptoms and tiredness among older adults with SCH and greater symptom burden. DESIGN: Secondary analysis of the randomized, placebo-controlled trial TRUST (Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial). (ClinicalTrials.gov: NCT01660126). SETTING: Switzerland, Ireland, the Netherlands, and Scotland. PARTICIPANTS: 638 persons aged 65 years or older with persistent SCH (thyroid-stimulating hormone level of 4.60 to 19.9 mIU/L for >3 months and normal free thyroxine level) and complete outcome data. INTERVENTION: L-thyroxine or matching placebo with mock dose titration. MEASUREMENTS: 1-year change in Hypothyroid Symptoms and Tiredness scores (range, 0 to 100; higher scores indicate more symptoms) on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire among participants with high symptom burden (baseline Hypothyroid Symptoms score >30 or Tiredness score >40) versus lower symptom burden. RESULTS: 132 participants had Hypothyroid Symptoms scores greater than 30, and 133 had Tiredness scores greater than 40. Among the group with high symptom burden, the Hypothyroid Symptoms score improved similarly between those receiving L-thyroxine (mean within-group change, -12.3 [95% CI, -16.6 to -8.0]) and those receiving placebo (mean within-group change, -10.4 [CI, -15.3 to -5.4]) at 1 year; the adjusted between-group difference was -2.0 (CI, -5.5 to 1.5; P = 0.27). Improvements in Tiredness scores were also similar between those receiving L-thyroxine (mean within-group change, -8.9 [CI, -14.5 to -3.3]) and those receiving placebo (mean within-group change, -10.9 [CI, -16.0 to -5.8]); the adjusted between-group difference was 0.0 (CI, -4.1 to 4.0; P = 0.99). There was no evidence that baseline Hypothyroid Symptoms score or Tiredness score modified the effects of L-thyroxine versus placebo (P for interaction = 0.20 and 0.82, respectively). LIMITATION: Post hoc analysis, small sample size, and examination of only patients with 1-year outcome data. CONCLUSION: In older adults with SCH and high symptom burden at baseline, L-thyroxine did not improve hypothyroid symptoms or tiredness compared with placebo. PRIMARY FUNDING SOURCE: European Union FP7.

Statin therapy and recurrent venous thromboembolism in the elderly: a prospective cohort study.

Previous studies reported lower rates of recurrent venous thromboembolism (rVTE) among statin users, but this association could be influenced by concurrent anticoagulation and confounding by statin indication. This study aimed to confirm the beneficial association between statins and rVTE, stratified according to periods with and without anticoagulation, and additionally employ propensity score weighted approach to reduce risk of confounding by indication. The setting was a prospective multicentre cohort study and the outcome was time to first rVTE in statin vs. non-statin users. 980 participants with acute VTE were enrolled (mean age 75.0 years, 47% women), with median follow-up of 2.5 years. Of 241 (24.3%) statin users, 21 (8.7%) suffered rVTE vs. 99 (13.4%) among 739 non-users. The overall adjusted sub-hazard ratio (aSHR) for rVTE comparing statin users to non-users was 0.72 (95%CI 0.44 to 1.19, p = 0.20). This association was only apparent during periods without anticoagulation (aSHR 0.50, 95%CI 0.27 to 0.92, p = 0.03; vs. with anticoagulation: aSHR 1.34, 95%CI 0.54 to 3.35, p = 0.53). Using propensity scores, the rVTE risk during periods without anticoagulation fell further (aSHR 0.20, 95%CI 0.08 to 0.49, p < 0.001). In conclusion, statin use is associated with a more pronounced risk reduction for rVTE than previously estimated, but only during periods without anticoagulation.

Subclinical thyroid dysfunction and depressive symptoms: protocol for a systematic review and individual participant data meta-analysis of prospective cohort studies.

INTRODUCTION: Prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms have yielded conflicting findings, possibly because of differences in age, sex, thyroid-stimulating hormone cut-off levels or degree of baseline depressive symptoms. Analysis of individual participant data (IPD) may help clarify this association. METHODS AND ANALYSIS: We will conduct a systematic review and IPD meta-analysis of prospective studies on the association between subclinical thyroid dysfunction and depressive symptoms. We will identify studies through a systematic search of the literature in the Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases from inception to April 2019 and from the Thyroid Studies Collaboration. We will ask corresponding authors of studies that meet our inclusion criteria to collaborate by providing IPD. Our primary outcome will be depressive symptoms at the first available individual follow-up, measured on a validated scale. We will convert all the scores to the Beck Depression Inventory scale. For each cohort, we will estimate the mean difference of depressive symptoms between participants with subclinical hypothyroidism or hyperthyroidism and control adjusted for depressive symptoms at baseline. Furthermore, we will adjust our multivariable linear regression analyses for age, sex, education and income. We will pool the effect estimates of all studies in a random-effects meta-analysis. Heterogeneity will be assessed by I2. Our secondary outcomes will be depressive symptoms at a specific follow-up time, at the last available individual follow-up and incidence of depression at the first, last and at a specific follow-up time. For the binary outcome of incident depression, we will use a logistic regression model. ETHICS AND DISSEMINATION: Formal ethical approval is not required as primary data will not be collected. Our findings will have considerable implications for patient care. We will seek to publish this systematic review and IPD meta-analysis in a high-impact clinical journal. PROSPERO REGISTRATION NUMBER: CRD42018091627.

Hypospadias surgery in England: Higher volume centres have lower complication rates.

INTRODUCTION: Hypospadias surgery has progressed steadily over recent years. There remains considerable variation in the operative management of boys with hypospadias in the UK, and it is therefore difficult to identify acceptable standards with regards to reoperation rates. OBJECTIVE: To determine the frequency of reoperations and complications from all centres performing hypospadias surgery in England and to identify variables that influence outcome. METHODS: All children undergoing NHS hypospadias surgery in England between 1999 and 2009 were identified using the Hospital Episode Statistics database. Patient demographics, centre type, and associated diagnostic (ICD-10) and treatment codes (OPCS4.6) were collected for both primary repairs and postoperative complications. Centres were classed as high volume if they performed an average of 20 or more operations a year. Operative complications were split into revisions (repeat repairs), repairs of urethral fistulae, repairs of meatal stenosis, or urethral stricture repairs. Statistical analysis included logistic regression, Spearman's correlation, and Mann-Whitney U for non-parametric data, with p < 0.05 taken as significant. Data are presented as median (interquartile range) unless otherwise stated. RESULTS: children underwent a total of 23,962 operations at 75 centres in England during the study period. The median age at primary repair was 21 (15-38) months. The overall complication rate was 18.1%. The median complication rate for individual centres was 20.0% (13.9-27.4%) overall; 10.8% (4.7-15.9%) for revision procedures, 8.1% (5.5-11.7%) for urethral fistulae, 2.3% (1.1-3.7%) for meatal stenosis repairs, and 1.8% (0-2.8%) for urethral strictures. High volume centres had significantly lower complication rates than low volume centres (17.5% vs. 25%, p = 0.01) (Figure), and this was proven to be an independent predictor of outcomes (p = 0.01). Staged repairs were associated with more complications (p < 0.001); however, patient age and centre type were not. Median time to repair of complication was 13 (8-22) months. DISCUSSION: This national population-based study used hospital episode statistics data. While accuracy is high and it has been validated for use in research, it has intrinsic limitations which affect our study. We are unable to fully account for the severity of hypospadias or the number of operating surgeons within institutions. CONCLUSIONS: This study has found a clear relationship between caseload volume and complications following hypospadias surgery. Furthermore, there is significant variability between centres in terms of their surgical outcomes. Taken together these results suggest that surgeons, particularly those in centres with small caseloads should assess their results against such benchmarks when evaluating the service they provide.