Beyond 10-Year Risk: A Cost-Effectiveness Analysis of Statins for the Primary Prevention of Cardiovascular Disease.

BACKGROUND: Cholesterol guidelines typically prioritize primary prevention statin therapy on the basis of 10-year risk of cardiovascular disease. The advent of generic pricing may justify expansion of statin eligibility. Moreover, 10-year risk may not be the optimal approach for statin prioritization. We estimated the cost-effectiveness of expanding preventive statin eligibility and evaluated novel approaches to prioritization from a Scottish health sector perspective. METHODS: A computer simulation model predicted long-term health and cost outcomes in Scottish adults ≥40 years of age. Epidemiologic analysis was completed using the Scottish Heart Health Extended Cohort, Scottish Morbidity Records, and National Records of Scotland. A simulation cohort was constructed with data from the Scottish Health Survey 2011 and contemporary population estimates. Treatment and cost inputs were derived from published literature and health service cost data. The main outcome measure was the lifetime incremental cost-effectiveness ratio, evaluated as cost (2020 GBP) per quality-adjusted life-year (QALY) gained. Three approaches to statin prioritization were analyzed: 10-year risk scoring using the ASSIGN score, age-stratified risk thresholds to increase treatment rates in younger individuals, and absolute risk reduction (ARR)-guided therapy to increase treatment rates in individuals with elevated cholesterol levels. For each approach, 2 policies were considered: treating the same number of individuals as those with an ASSIGN score ≥20% (age-stratified risk threshold 20, ARR 20) and treating the same number of individuals as those with an ASSIGN score ≥10% (age-stratified risk threshold 10, ARR 10). RESULTS: Compared with an ASSIGN score ≥20%, reducing the risk threshold for statin initiation to 10% expanded eligibility from 804 000 (32% of adults ≥40 years of age without CVD) to 1 445 500 individuals (58%). This policy would be cost-effective (incremental cost-effectiveness ratio, £12 300/QALY [95% CI, £7690/QALY-£26 500/QALY]). Incremental to an ASSIGN score ≥20%, ARR 20 produced ≈8800 QALYs and was cost-effective (£7050/QALY [95% CI, £4560/QALY-£10 700/QALY]). Incremental to an ASSIGN score ≥10%, ARR 10 produced ≈7950 QALYs and was cost-effective (£11 700/QALY [95% CI, £9250/QALY-£16 900/QALY]). Both age-stratified risk threshold strategies were dominated (ie, more expensive and less effective than alternative treatment strategies). CONCLUSIONS: Generic pricing has rendered preventive statin therapy cost-effective for many adults. ARR-guided therapy is more effective than 10-year risk scoring and is cost-effective.

Changes over 15 years in the contribution of adiposity and smoking to deaths in England and Scotland.

BACKGROUND: For many years smoking has been the major threat to public health in developed countries. However, smoking prevalence has declined over a period when adiposity has increased. The aim of this study was to determine whether adiposity now accounts for more deaths than smoking in the general population as a whole or sub-groups of it. METHODS: This is a comparative risk assessment study using Health Surveys for England and Scottish Health Surveys from 2003 to 2017. Annual prevalence of overweight, obesity, current and former smoking were obtained and combined using population-based weights. Sex-specific risk ratios for all-cause mortality were obtained from the most recently published meta-analyses. Population attributable fractions across yeas were then estimated. FINDINGS: Overall, deaths attributable to current/former smoking declined from 23.1% (95% CI 20.6-25.8%) in 2003 to 19.4% (95% CI 17.3-21.6%) in 2017, whilst those attributable to adiposity (overweight or obesity) increased from 17.9% (95% CI 17.3-18.4%) in 2003 to 23.1% (95% CI 22.3-23.8%) in 2017 with cross-over occurring in 2013. Cross-over occurred earlier in men (2011) than women (2014). It occurred in 2006 for those aged over 65 years of age and in 2012 for those aged 45-64 years. Below 45 years, smoking remained the larger contributor to mortality. INTERPRETATION: Adiposity now accounts for more deaths in England and Scotland than smoking among people in middle- and old-age. National strategies to address adiposity should be a public health priority.

Comparison of Conventional Lipoprotein Tests and Apolipoproteins in the Prediction of Cardiovascular Disease.

BACKGROUND: Total cholesterol and high-density lipoprotein cholesterol (HDL-C) measurements are central to cardiovascular disease (CVD) risk assessment, but there is continuing debate around the utility of other lipids for risk prediction. METHODS: Participants from UK Biobank without baseline CVD and not taking statins, with relevant lipid measurements (n=346 686), were included in the primary analysis. An incident fatal or nonfatal CVD event occurred in 6216 participants (1656 fatal) over a median of 8.9 years. Associations of nonfasting lipid measurements (total cholesterol, HDL-C, non-HDL-C, direct and calculated low-density lipoprotein cholesterol [LDL-C], and apolipoproteins [Apo] A1 and B) with CVD were compared using Cox models adjusting for classical risk factors, and predictive utility was determined by the C-index and net reclassification index. Prediction was also tested in 68 649 participants taking a statin with or without baseline CVD (3515 CVD events). RESULTS: ApoB, LDL-C, and non-HDL-C were highly correlated (r>0.90), while HDL-C was strongly correlated with ApoA1 (r=0.92). After adjustment for classical risk factors, 1 SD increase in ApoB, direct LDL-C, and non-HDL-C had similar associations with composite fatal/nonfatal CVD events (hazard ratio, 1.23, 1.20, 1.21, respectively). Associations for 1 SD increase in HDL-C and ApoA1 were also similar (hazard ratios, 0.81 [both]). Adding either total cholesterol and HDL-C, or ApoB and ApoA, to a CVD risk prediction model (C-index, 0.7378) yielded similar improvement in discrimination (C-index change, 0.0084; 95% CI, 0.0065, 0.0104, and 0.0089; 95% CI, 0.0069, 0.0109, respectively). Once total and HDL-C were in the model, no further substantive improvement was achieved with the addition of ApoB (C-index change, 0.0004; 95% CI, 0.0000, 0.0008) or any measure of LDL-C. Results for predictive utility were similar for a fatal CVD outcome, and in a discordance analysis. In participants taking a statin, classical risk factors (C-index, 0.7118) were improved by non-HDL-C (C-index change, 0.0030; 95% CI, 0.0012, 0.0048) or ApoB (C-index change, 0.0030; 95% CI, 0.0011, 0.0048). However, adding ApoB or LDL-C to a model already containing non-HDL-C did not further improve discrimination. CONCLUSIONS: Measurement of total cholesterol and HDL-C in the nonfasted state is sufficient to capture the lipid-associated risk in CVD prediction, with no meaningful improvement from addition of apolipoproteins, direct or calculated LDL-C.

Association of Total and Differential Leukocyte Counts With Cardiovascular Disease and Mortality in the UK Biobank.

OBJECTIVE: Elevated white blood cell count is associated with a higher risk of cardiovascular disease (CVD). We aimed to investigate whether specific leukocyte subpopulations, which may more closely indicate a specific inflammatory pathway, are specifically associated with CVD. APPROACH AND RESULTS: Participants (478 259) from UK Biobank with data for white blood cell count were included. Death because of CVD (n=1377) and non-CVD causes (n=8987) occurred during median follow-up time of 7.0 years (interquartile range, 6.3-7.6). In Cox models, deciles of leukocyte counts (lymphocytes, monocytes, neutrophils, eosinophils, and basophils) were examined using the fifth decile as the referent group. Models were stratified by sex and adjusted for a range of classical risk factors. A sensitivity analysis excluded participants with baseline comorbidites and the first 2 years of follow-up. Men (hazard ratio [HR], 1.59; 95% confidence interval, 1.22-2.08) and women (HR, 2.15; 95% confidence interval, 1.38-3.35) in the highest decile of neutrophil count were at higher risk of CVD mortality and nonfatal CVD (men HR, 1.28; 95% confidence interval, 1.16-1.42 and women HR, 1.21; 95% confidence interval, 1.06-1.38). In the sensitivity analysis, the power to investigate CVD mortality was limited, but for both sexes combined, the linear HRs for a 1×109/L cell count increase in white blood cell count and neutrophils, respectively, was 1.05 (1.03-1.07) and 1.07 (1.04-1.11). CONCLUSIONS: Among circulating leukocyte subpopulations, neutrophil count in men was most consistently associated with fatal and nonfatal CVD. Further studies of interventions that lower circulating neutrophils, such as canakinumab, are required to investigate causality.

Drug-related deaths in Scotland 1979-2013: evidence of a vulnerable cohort of young men living in deprived areas.

BACKGROUND: Even after accounting for deprivation, mortality rates are higher in Scotland relative to the rest of Western Europe. Higher mortality from alcohol- and drug-related deaths (DRDs), violence and suicide (particularly in young adults) contribute to this 'excess' mortality. Age-period and cohort effects help explain the trends in alcohol-related deaths and suicide, respectively. This study investigated whether age, period or cohort effects might explain recent trends in DRDs in Scotland and relate to exposure to the changing political context from the 1980s. METHODS: We analysed data on DRDs from 1979 to 2013 by sex and deprivation using shaded contour plots and intrinsic estimator regression modelling to identify and quantify relative age, period and cohort effects. RESULTS: The peak age for DRDs fell around 1990, especially for males as rates increased for those aged 18 to 45 years. There was evidence of a cohort effect, especially among males living in the most deprived areas; those born between 1960 and 1980 had an increased risk of DRD, highest for those born 1970 to 1975. The cohort effect started around a decade earlier in the most deprived areas compared to the rest of the population. CONCLUSION: Age-standardised rates for DRDs among young adults rose during the 1990s in Scotland due to an increased risk of DRD for the cohort born between 1960 and 1980, especially for males living in the most deprived areas. This cohort effect is consistent with the hypothesis that exposure to the changing social, economic and political contexts of the 1980s created a delayed negative health impact.

Temporal trends and risk factors for readmission for infections, gastrointestinal and immobility complications after an incident hospitalisation for stroke in Scotland between 1997 and 2005.

BACKGROUND: Improvements in stroke management have led to increases in the numbers of stroke survivors over the last decade and there has been a corresponding increase of hospital readmissions after an initial stroke hospitalisation. The aim of this study was to examine the one year risk of having a readmission due to infective, gastrointestinal or immobility (IGI) complications and to identify temporal trends and any risk factors. METHODS: Using a cohort of first hospitalised for stroke patients who were discharged alive, time to first event (readmission for IGI complications or death) within 1 year was analysed in a competing risks framework using cumulative incidence methods. Regression on the cumulative incidence function was used to model the risks of having an outcome using the covariates age, sex, socioeconomic status, comorbidity, discharge destination and length of hospital stay. RESULTS: There were a total of 51,182 patients discharged alive after an incident stroke hospitalisation in Scotland between 1997-2005, and 7,747 (15.1%) were readmitted for IGI complications within a year of the discharge. Comparing incident stroke hospitalisations in 2005 with 1997, the adjusted risk of IGI readmission did not increase (HR = 1.00 95% CI (0.90, 1.11). However, there was a higher risk of IGI readmission with increasing levels of deprivation (most deprived fifth vs. least deprived fifth HR = 1.16 (1.08, 1.26). CONCLUSIONS: Approximately 15 in 100 patients discharged alive after an incident hospitalisation for stroke in Scotland between 1997 and 2005 went on to have an IGI readmission within one year. The proportion of readmissions did not change over the study period but those living in deprived areas had an increased risk.

Spoilt for choice: implications of using alternative methods of costing hospital episode statistics.

In the absence of a 'gold standard' to estimate the economic burden of disease, a decision about the most appropriate costing method is required. Researchers have employed various methods to cost hospital stays, including per diem or diagnosis-related group (DRG)-based costs. Alternative methods differ in data collection and costing methodology. Using data from Scotland as an illustrative example, costing methods are compared, highlighting the wider implications for other countries with a publicly financed healthcare system. Five methods are compared using longitudinal data including baseline survey data (Midspan) linked to acute hospital admissions. Cost variables are derived using two forms of DRG-type costs, costs per diem, costs per episode-using a novel approach that distinguishes between variable and fixed costs and incorporates individual length of stay (LOS), and costs per episode using national average LOS. Cost estimates are generated using generalised linear model regression. Descriptive analysis shows substantial variation between costing methods. Differences found in regression analyses highlight the magnitude of variation in cost estimates for subgroups of the sample population. This paper emphasises that any inference made from econometric modelling of costs, where the marginal effect of explanatory variables is assessed, is substantially influenced by the costing method.

A comparison of routine and case-managed pathways for recovery from musculoskeletal disorders in people in employment.

PURPOSE: To compare outcomes in employed people from an enhanced routine management pathway for musculoskeletal disorders within National Health Service Scotland with an existing active case-management system, Working Health Services Scotland. MATERIALS AND METHODS: The study comprised a service evaluation using anonymised routinely collected data from all currently employed callers presenting with musculoskeletal disorder to the two services. Baseline demographic and clinical data were collected. EuroQol EQ-5DTM scores at the start and end of treatment were compared for both groups, overall and by age, sex, socio-economic status, and anatomical site, and the impact of mental health status at baseline was evaluated. RESULTS: Active case-management resulted in greater improvement than enhanced routine care. Case-managed service users entered the programme earlier in the recovery pathway; there was evidence of spontaneous improvement during the longer waiting time of routine service clients but only if they had good baseline mental health. Those most disadvantaged through mental health co-morbidity showed the greatest benefit. CONCLUSIONS: People with musculoskeletal disorders who have poor baseline mental health status derive greatest benefit from active case-management. Case-management therefore contributes to reducing health inequalities and can help to minimise long-term sickness absence. Shorter waiting times contributed to better outcomes in the case-managed service. Implications for RehabilitationMusculoskeletal disorders are a major cause of inability to work.Case-management is effective in helping people with musculoskeletal disorders to return to work.People who have the poorest mental health are likely to gain the greatest benefit from case-management of their musculoskeletal disorders.

Frailty in COPD: an analysis of prevalence and clinical impact using UK Biobank.

BACKGROUND: Frailty, a state of reduced physiological reserve, is common in people with chronic obstructive pulmonary disease (COPD). Frailty can occur at any age; however, the implications in younger people (eg, aged <65 years) with COPD are unclear. We assessed the prevalence of frailty in UK Biobank participants with COPD; explored relationships between frailty and forced expiratory volume in 1 second (FEV1) and quantified the association between frailty and adverse outcomes. METHODS: UK Biobank participants (n=3132, recruited 2006-2010) with COPD aged 40-70 years were analysed comparing two frailty measures (frailty phenotype and frailty index) at baseline. Relationship with FEV1 was assessed for each measure. Outcomes were mortality, major adverse cardiovascular event (MACE), all-cause hospitalisation, hospitalisation with COPD exacerbation and community COPD exacerbation over 8 years of follow-up. RESULTS: Frailty was common by both definitions (17% frail using frailty phenotype, 28% moderate and 4% severely frail using frailty index). The frailty phenotype, but not the frailty index, was associated with lower FEV1. Frailty phenotype (frail vs robust) was associated with mortality (HR 2.33; 95% CI 1.84 to 2.96), MACE (2.73; 1.66 to 4.49), hospitalisation (incidence rate ratio 3.39; 2.77 to 4.14) hospitalised exacerbation (5.19; 3.80 to 7.09) and community exacerbation (2.15; 1.81 to 2.54), as was frailty index (severe vs robust) (mortality (2.65; 95% CI 1.75 to 4.02), MACE (6.76; 2.68 to 17.04), hospitalisation (3.69; 2.52 to 5.42), hospitalised exacerbation (4.26; 2.37 to 7.68) and community exacerbation (2.39; 1.74 to 3.28)). These relationships were similar before and after adjustment for FEV1. CONCLUSION: Frailty, regardless of age or measure, identifies people with COPD at risk of adverse clinical outcomes. Frailty assessment may aid risk stratification and guide-targeted intervention in COPD and should not be limited to people aged >65 years.

Lipoprotein(a) and cardiovascular disease: prediction, attributable risk fraction, and estimating benefits from novel interventions.

AIMS: To investigate the population attributable fraction due to elevated lipoprotein (a) (Lp(a)) and the utility of measuring Lp(a) in cardiovascular disease (CVD) risk prediction. METHODS AND RESULTS: In 413 734 participants from UK Biobank, associations of serum Lp(a) with composite fatal/non-fatal CVD (n = 10 066 events), fatal CVD (n = 3247), coronary heart disease (CHD; n = 18 292), peripheral vascular disease (PVD; n = 2716), and aortic stenosis (n = 901) were compared using Cox models. Median Lp(a) was 19.7 nmol/L (interquartile interval 7.6-75.3 nmol/L). About 20.8% had Lp(a) values >100 nmol/L; 9.2% had values >175 nmol/L. After adjustment for classical risk factors, 1 SD increment in log Lp(a) was associated with a hazard ratio for fatal/non-fatal CVD of 1.12 [95% confidence interval (CI) 1.10-1.15]. Similar associations were observed with fatal CVD, CHD, PVD, and aortic stenosis. Adding Lp(a) to a prediction model containing traditional CVD risk factors in a primary prevention group improved the C-index by +0.0017 (95% CI 0.0008-0.0026). In the whole cohort, Lp(a) above 100 nmol/L was associated with a population attributable fraction (PAF) of 5.8% (95% CI 4.9-6.7%), and for Lp(a) above 175 nmol/L the PAF was 3.0% (2.4-3.6%). Assuming causality and an achieved Lp(a) reduction of 80%, an ongoing trial to lower Lp(a) in patients with CVD and Lp(a) above 175 nmol/L may reduce CVD risk by 20.0% and CHD by 24.4%. Similar benefits were also modelled in the whole cohort, regardless of baseline CVD. CONCLUSION: Population screening for elevated Lp(a) may help to predict CVD and target Lp(a) lowering drugs, if such drugs prove efficacious, to those with markedly elevated levels.

Trends in incidence and in short term survival following a subarachnoid haemorrhage in Scotland, 1986-2005: a retrospective cohort study.

BACKGROUND: To examine age and sex specific incidence and 30 day case fatality for subarachnoid haemorrhage (SAH) in Scotland over a 20 year period. METHODS: A retrospective cohort study using routine hospital discharge data linked to death records. RESULTS: Between 1986 and 2005, 12,056 individuals experienced an incident SAH. Of these 10,113 (84%) survived to reach hospital. Overall age-standardised incidence rates were greater in women than men and remained relatively stable over the study period. In 2005, incidence in women was 12.8 (95% CI 11.5 to 14.2) and in men 7.9 (95% CI 6.9 to 9.1). 30 day case fatality in individuals hospitalised with SAH declined substantially, falling from 30.0% in men and 33.9% in women in 1986-1990 to 24.5% in men and 29.1% in women in 2001-2005. For both men and women, the largest reductions were observed in those aged between 40 to 59 years. After adjustment for age, socio-economic status and co-morbidity, the odds of death at 30 days in 2005 compared to odds of death in 1986 was 0.64 (0.54 to 0.76), p < 0.001 for those below 70 years, and 1.14 (0.83 to 1.56), p = 0.4 in those 70 years and above. CONCLUSIONS: Incidence rates for SAH remained stable between 1986 and 2005 suggesting that a better understanding of SAH risk factors and their reduction is needed. 30 day case fatality rates have declined substantially, particularly in middle-age. However, they remain high and it is important to ensure that this is not due to under-diagnosis or under-treatment.

Real-World Estimates of Adrenal Insufficiency-Related Adverse Events in Children With Congenital Adrenal Hyperplasia.

BACKGROUND: Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear. METHODS: Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC. RESULTS: A total of 518 children-with a median of 11 children (range 1, 53) per center-had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P < 0.001), respectively, and the median AC per patient-year was 0 (0, 2.2) vs 0 (0, 3.0) (P = 0.43), respectively. CONCLUSIONS: The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency-related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.

Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003: a population study of 5.1 million people.

BACKGROUND: We examined whether population-level hospitalization rates for heart failure (HF) and subsequent survival have continued to improve since the turn of the century. We also examined trends in the prescribing of evidence-based pharmacological treatment for HF. METHODS AND RESULTS: All patients in Scotland hospitalized with a first episode of HF between 1986 and 2003 were followed up until death or the end of 2004. Prescriptions of evidence-based treatments issued from 1997 to 2003 by a sample of primary care practices were also examined. A total of 116 556 individuals (52.6% women) had a first hospital discharge for HF. Age-adjusted first hospitalization rates for HF (per 100 000; 95% CI in parentheses) rose from 124 (119 to 129) in 1986 to 162 (157 to 168) in 1994 and then fell to 105 (101 to 109) in 2003 in men; in women, they rose from 128 (123 to 132) in 1986 to 160 (155 to 165) in 1993, falling to 101 (97 to 105) in 2003. Case-fatality rates fell steadily over the period. Adjusted 30-day case-fatality rates fell after discharge (adjusted odds [2003 versus 1986] 0.59 [95% CI 0.45 to 0.63] in men and 0.77 [95% CI 0.67 to 0.88] in women). Adjusted 1- and 5-year survival improved similarly. Median survival increased from 1.33 to 2.34 years in men and from 1.32 to 1.79 years in women. Age-adjusted prescribing rates for angiotensin-converting enzyme inhibitors, beta-blockers, and spironolactone increased from 1997 to 2003 (all P<0.0001 for trend). CONCLUSIONS: After rising between 1986 and 1994, rates of first hospitalization for HF declined. Case-fatality rates also fell. Prescribing rates for HF therapies increased from 1997 to 2003. These findings suggest that improvements in the prevention and treatment of HF may have had progressive, sustained effects on outcomes at the population level; however, prognosis remains poor in HF.

Temporal trends in hospitalisation for stroke recurrence following incident hospitalisation for stroke in Scotland.

BACKGROUND: There are few studies that have investigated temporal trends in risk of recurrent stroke. The aim of this study was to examine temporal trends in hospitalisation for stroke recurrence following incident hospitalisation for stroke in Scotland during 1986 to 2001. METHODS: Unadjusted survival analysis of time to first event, hospitalisation for recurrent stroke or death, was undertaken using the cumulative incidence method which takes into account competing risks. Regression on cumulative incidence functions was used to model the temporal trends of first recurrent stroke with adjustment for age, sex, socioeconomic status and comorbidity. Complete five year follow-up was obtained for all patients. Restricted cubic splines were used to determine the best fitting relationship between the survival events and study year. RESULTS: There were 128,511 incident hospitalisations for stroke in Scotland between 1986 and 2001, 57,351 (45%) in men. A total of 13,835 (10.8%) patients had a recurrent hospitalisation for stroke within five years of their incident hospitalisation. Another 74,220 (57.8%) patients died within five years of their incident hospitalisation without first having a recurrent hospitalisation for stroke. Comparing incident stroke hospitalisations in 2001 with 1986, the adjusted risk of recurrent stroke hospitalisation decreased by 27%, HR = 0.73 95% CI (0.67 to 0.78), and the adjusted risk of death being the first event decreased by 28%, HR = 0.72 (0.70 to 0.75). CONCLUSIONS: Over the 15-year period approximately 1 in 10 patients with an incident hospitalisation for stroke in Scotland went on to have a hospitalisation for recurrent stroke within five years. Approximately 6 in 10 patients died within five years without first having a recurrent stroke hospitalisation. Using hospitalisation and death data from an entire country over a 20-year period we have been able to demonstrate not only an improvement in survival following an incident stroke, but also a reduction in the risk of a recurrent event.

Estimating the impact of stroke unit care in a whole population: an epidemiological study using routine data.

BACKGROUND AND PURPOSE: Randomised trials indicate that organised inpatient (stroke unit) care has an important impact on patient outcomes with an absolute risk difference (ARD) of 3% for survival and 5% for returning home. However, it is unclear what impact this complex intervention actually has in routine practice. A comprehensive national dataset was used to study the impact of stroke unit implementation. METHODS: The Scottish linked discharge database was used to identify all patients admitted to hospital with an incident stroke. Analyses compared case fatality and discharge home (adjusted for age, sex, deprivation and comorbidity) for hospitals with or without a stroke unit during four consecutive study periods: 1986-1990, 1991-1995, 1996-2000 and 2001-2005. RESULTS: During the study period, the percentage of admissions to hospitals that had a stroke unit increased from 0% to 87%, the 6 month case fatality decreased from 45% to 29% and discharges home increased from 46% to 59%. Adjusted ORs (95% CI) for case fatality (stroke unit versus no unit) in each study period were as follows: not calculable (no units before 1991), 0.83 (0.78-0.89), 0.90 (0.86-0.94) and 0.87 (0.82-0.91). These equate to an ARD of 3.0% over the whole study period. Equivalent data for discharge home indicated an increased odds of discharge home: not calculable, 1.23 (1.15-1.31), 1.15 (1.10-1.21) and 1.17 (1.11-1.23) with an overall ARD of 5%. CONCLUSIONS: These results indicate a positive impact of a policy of stroke unit care on case fatality and discharge home. The estimated impact, after adjusting for case mix, appears very similar to that calculated using clinical trial data.

Do age, period or cohort effects explain circulatory disease mortality trends, Scotland 1974-2015?

OBJECTIVE: We aimed to explore whether age, period or cohort effects explain the trends and inequalities in ischaemic heart disease (IHD) and cerebrovascular disease (CeVD) mortality in Scotland. METHODS: We analysed IHD and CeVD deaths for 1974-2015 by sex, age and area deprivation, visually explored the data using heatmaps and dotplots and built regression models. RESULTS: CeVD mortality improved steadily over time while IHD mortality improved more rapidly from the late 1980s. Age effects were evident; both outcomes showed an exponential relationship with age for all except males for IHD in the 1980s and 1990s. The mortality profiles by age became older, although improvement was slower for those aged <50 years for IHD, especially for males, and faster for CeVD in females aged <65 years. Rates were higher, and inequalities greater, among males, especially for IHD. For IHD, increased risk for males over females reduced with age (incidence rate ratio for 41-50 year old males=4.28 (95% CI 4.12 to 4.44) and 1.17 (95% CI 1.16 to 1.18) for 71-80 year olds). Inequalities in IHD mortality by area deprivation persisted over time, increasing from around 10% to around 25% higher risk in the most deprived areas between 1974 and 1986 before declining in absolute terms from around 2000. Inequalities for CeVD increased after the late 1980s. CONCLUSIONS: IHD and CeVD mortality in Scotland exhibit age but not recent distinct period or cohort effects. The improvements in mortality rates have been more sustained for CeVD and inequalities greater for IHD.

How did a lower drink-drive limit affect bar trade and drinking practices? A qualitative study of how alcohol retailers experienced a change in policy.

INTRODUCTION AND AIMS: Reducing the legal drink-drive limit from 0.08% to 0.05% blood alcohol concentration (BAC) can reduce road traffic accidents and deaths if properly enforced. Reduced limits may be opposed by alcohol retail and manufacturing industries on the basis of commercial impact. Our aim was to qualitatively explore how a reduction in the drink-drive limit from 0.08% to 0.05% BAC in Scotland, was experienced by bar owners or managers, including any resultant changes in customer drinking or business practice. This is the first study of this type. DESIGN AND METHODS: Semi-structured interviews were conducted with 16 owners and managers of on-trade premises in Scotland in 2018, approximately three years after the drink-drive limit was reduced. Data were analysed using thematic analysis. RESULTS: Most participants reported no long-term financial impact on their business, but a few, mainly from rural areas, reported some reduction in alcohol sales. Observed drinking changes included fewer people drinking after work or leaving premises earlier on weekdays. Adaptations to businesses included improving the range of no/low-alcohol drinks and food offered. Changes such as these were seen as key to minimising economic impact. DISCUSSION AND CONCLUSIONS: Opposition to legislative measures that impact on commercial interests is often strong and receives significant public attention. This study found that Scottish businesses that adapted to the drink-drive limit change reported little long-term economic impact. These findings are of international relevance as potential BAC limit reductions in several other jurisdictions remain the subject of debate, including regarding the impact on business.

Evidence synthesis for constructing directed acyclic graphs (ESC-DAGs): a novel and systematic method for building directed acyclic graphs.

BACKGROUND: Directed acyclic graphs (DAGs) are popular tools for identifying appropriate adjustment strategies for epidemiological analysis. However, a lack of direction on how to build them is problematic. As a solution, we propose using a combination of evidence synthesis strategies and causal inference principles to integrate the DAG-building exercise within the review stages of research projects. We demonstrate this idea by introducing a novel protocol: 'Evidence Synthesis for Constructing Directed Acyclic Graphs' (ESC-DAGs)'. METHODS: ESC-DAGs operates on empirical studies identified by a literature search, ideally a novel systematic review or review of systematic reviews. It involves three key stages: (i) the conclusions of each study are 'mapped' into a DAG; (ii) the causal structures in these DAGs are systematically assessed using several causal inference principles and are corrected accordingly; (iii) the resulting DAGs are then synthesised into one or more 'integrated DAGs'. This demonstration article didactically applies ESC-DAGs to the literature on parental influences on offspring alcohol use during adolescence. CONCLUSIONS: ESC-DAGs is a practical, systematic and transparent approach for developing DAGs from background knowledge. These DAGs can then direct primary data analysis and DAG-based sensitivity analysis. ESC-DAGs has a modular design to allow researchers who are experienced DAG users to both use and improve upon the approach. It is also accessible to researchers with limited experience of DAGs or evidence synthesis.

Risk assessments and structured care interventions for prevention of foot ulceration in diabetes: development and validation of a prognostic model.

BACKGROUND: Diabetes-related foot ulcers give rise to considerable morbidity, generate a high monetary cost for health and social care services and precede the majority of diabetes-related lower extremity amputations. There are many clinical prediction rules in existence to assess risk of foot ulceration but few have been subject to validation. OBJECTIVES: Our objectives were to produce an evidence-based clinical pathway for risk assessment and management of the foot in people with diabetes mellitus to estimate cost-effective monitoring intervals and to perform cost-effectiveness analyses and a value-of-information analysis. DESIGN: We developed and validated a prognostic model using predictive modelling, calibration and discrimination techniques. An overview of systematic reviews already completed was followed by a review of randomised controlled trials of interventions to prevent foot ulceration in diabetes mellitus. A review of the health economic literature was followed by the construction of an economic model, an analysis of the transitional probability of moving from one foot risk state to another, an assessment of cost-effectiveness and a value-of-information analysis. INTERVENTIONS: The effects of simple and complex interventions and different monitoring intervals for the clinical prediction rules were evaluated. MAIN OUTCOME MEASURE: The main outcome was the incidence of foot ulceration. We compared the new clinical prediction rules in conjunction with the most effective preventative interventions at different monitoring intervals with a 'treat-all' strategy. DATA SOURCES: Data from an electronic health record for 26,154 people with diabetes mellitus in one Scottish health board were used to estimate the monitoring interval. The Prediction Of Diabetic foot UlcerationS (PODUS) data set was used to develop and validate the clinical prediction rule. REVIEW METHODS: We searched for eligible randomised controlled trials of interventions using search strategies created for Ovid® (Wolters Kluwer, Alphen aan den Rijn, the Netherlands), MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. Randomised controlled trials in progress were identified via the International Standard Randomised Controlled Trial Number Registry and systematic reviews were identified via PROSPERO. Databases were searched from inception to February 2019. RESULTS: The clinical prediction rule was found to accurately assess the risk of foot ulceration. Digital infrared thermometry, complex interventions and therapeutic footwear with offloading devices were found to be effective in preventing foot ulcers. The risk of developing a foot ulcer did not change over time for most people. We found that interventions to prevent foot ulceration may be cost-effective but there is uncertainty about this. Digital infrared thermometry and therapeutic footwear with offloading devices may be cost-effective when used to treat all people with diabetes mellitus regardless of their ulcer risk. LIMITATIONS: The threats to the validity of the results in some randomised controlled trials in the review and the large number of missing data in the electronic health record mean that there is uncertainty in our estimates. CONCLUSIONS: There is evidence that interventions to prevent foot ulceration are effective but it is not clear who would benefit most from receiving the interventions. The ulceration risk does not change over an 8-year period for most people with diabetes mellitus. A change in the monitoring interval from annually to every 2 years for those at low risk would be acceptable. FUTURE WORK RECOMMENDATIONS: Improving the completeness of electronic health records and sharing data would help improve our knowledge about the most clinically effective and cost-effective approaches to prevent foot ulceration in diabetes mellitus. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016052324. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 62. See the NIHR Journals Library website for further project information.

People with diabetes sometimes have problems with their feet that can become serious and make getting around harder and life less enjoyable. We have developed a test based on a simple score to find out a person's risk of getting a foot ulcer. We also wanted to know how often the test needs to be done. People who have been tested and learn that they might go on to have foot problems rightly expect to be given treatment that stops the problem happening in the first place. In this project, we read many written reports about the best treatments to prevent foot ulcers. We found that some things can prevent foot ulcers, such as wearing special shoes and insoles, taking the temperature of the skin of the foot and resting when the temperature rises, and receiving specialist care from diabetes foot care teams. However, we also looked at the costs of the test and treatments and found that some treatments are better value for money than others. By using people's health data from NHS computers, we discovered that very few people with diabetes develop a worse risk score for foot ulcers as time goes on, and it seems that being tested every year is not necessary for everyone. New clinical trials might help to improve foot health for people with diabetes, but if all of the researchers who have collected data from people in clinical trials shared their data it would be possible to find out more about who will gain most from these treatments without spending a lot on new research. It is clear that better input of patients' health data into NHS computers will benefit diabetes research in the future.

Author Correction: Glomerular filtration rate by differing measures, albuminuria and prediction of cardiovascular disease, mortality and end-stage kidney disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.