Surgical or percutaneous coronary revascularization for heart failure: an in silico model using routinely collected health data to emulate a clinical trial.

AIMS: The choice of revascularization with coronary artery bypass grafting (CABG) vs. percutaneous coronary intervention (PCI) in people with ischaemic left ventricular dysfunction is not guided by high-quality evidence. METHODS AND RESULTS: A trial of CABG vs. PCI in people with heart failure (HF) was modelled in silico using routinely collected healthcare data. The in silico trial cohort was selected by matching the target trial cohort, identified from Hospital Episode Statistics in England, with individual patient data from the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Allocation to CABG vs. complex PCI demonstrated random variation across administrative regions in England and was a valid statistical instrument. The primary outcome was 5-year all-cause mortality or cardiovascular hospitalization. Instrumental variable analysis (IVA) was used for the primary analysis. Results were expressed as average treatment effects (ATEs) with 95 confidence intervals (CIs). The target population included 13 519 HF patients undergoing CABG or complex PCI between April 2009 and March 2015. After matching, the emulated trial cohort included 2046 patients. The unadjusted primary outcome rate was 51.1 in the CABG group and 70.0 in the PCI group. IVA of the emulated cohort showed that CABG was associated with a lower risk of the primary outcome (ATE 16.2, 95 CI 20.6 to 11.8), with comparable estimates in the unmatched target population (ATE 15.5, 95 CI 17.5 to 13.5). CONCLUSION: In people with HF, in silico modelling suggests that CABG is associated with fewer deaths or cardiovascular hospitalizations at 5 years vs. complex PCI. A pragmatic clinical trial is needed to test this hypothesis and this trial would be feasible.

Differences in the risk of cardiovascular disease across ethnic groups: UK Biobank observational study.

BACKGROUND AND AIMS: To describe sociodemographic, lifestyle, environmental and traditional clinical risk factor differences between ethnic groups and to investigate the extent to which such differences confound the association between ethnic groups and the risk of cardiovascular disease (CVD) METHODS AND RESULTS: A total of 440,693 white European (55.9% women), 7305 South Asian (48.6%) and 7628 black African or Caribbean (57.7%) people were included from UK Biobank. Associations between ethnicity and cardiovascular outcomes (composite of non-fatal stroke, non-fatal myocardial infarction and CVD death) were explored using Cox-proportional hazard models. Models were adjusted for sociodemographic, lifestyle, environmental and clinical risk factors. Over a median (IQR) of 12.6 (11.8, 13.3) follow-up years, there were 22,711 (5.15%) cardiovascular events in white European, 463 (6.34%) in South Asian and 302 (3.96%) in black African or Caribbean individuals. For South Asian people, the cardiovascular hazard ratio (HR) compared to white European people was 1.28 (99% CI [1.16, 1.43]). For black African or Caribbean people, the HR was 0.80 (0.66, 0.97). The elevated risk of CVD in South Asians remained after adjusting for differences in sociodemographic, lifestyle, environmental and clinical factors, whereas the lower risk in black African or Caribbean was largely attenuated. CONCLUSIONS: South Asian, but not black African or Caribbean individuals, have a higher risk of CVD compared to white European individuals. This higher risk in South Asians was independent of sociodemographic, lifestyle, environmental and clinical factors.

Risk of cancer incidence and mortality associated with diabetes: A systematic review with trend analysis of 203 cohorts.

AIM: Whether the relative risk of cancer incidence and mortality associated with diabetes has changed over time is unknown. DATA SYNTHESIS: On August 12th, 2020, we electronically searched for observational studies reporting on the association between diabetes and cancer. We estimated temporal trends in the relative risk of cancer incidence or mortality associated with diabetes and calculated the ratio of relative risk (RRR) comparing different periods. As many as 193 eligible articles, reporting data on 203 cohorts (56,852,381 participants; 3,735,564 incident cancer cases; 185,404 cancer deaths) and covering the period 1951-2013, were included. The relative risk of all-site cancer incidence increased between 1980 and 2000 [RRR 1990 vs.1980: (1.24; 95% CI: 1.16, 1.34); 2000 vs.1990: (1.23; 1.15, 1.31)] and stabilised thereafter at a relative risk of 1.2; the relative risk of all-site cancer mortality was constant at about 1.2 from 1980 to 2010. Both magnitudes and trends in relative risk varied across cancer sites: the relative risk of colorectal, female breast, and endometrial cancer incidence and pancreatic cancer mortality was constant during the observed years; it increased for bladder, stomach, kidney, and pancreatic cancer incidence until 2000; and decreased for liver while increased for prostate, colon and gallbladder cancer incidence after 2000. CONCLUSIONS: Alongside the increasing prevalence of diabetes, the temporal patterns of the relative risk of cancer associated with diabetes may have contributed to the current burden of cancer in people with diabetes.

Screening male prisoners for depression and anxiety with the PHQ-9 and GAD-7 at NHS Healthcheck: patterns of symptoms and caseness threshold.

BACKGROUND: Screening for depression and anxiety disorders has been proposed in prison populations but little is known about caseness thresholds on commonly used self-report measures in relation to core symptoms, risk factors and symptom patterns. METHOD: A cross-sectional prevalence survey measured depression and anxiety caseness (threshold scores > 10 and > 15 on PHQ-9 and GAD-7 and diagnostic algorithm on PHQ-9) in 1205 male prisoners aged 35-74 years eligible for an NHS Healthcheck from six English prisons. Caseness scores were compared with the presence or absence of daily core symptoms of depression and generalised anxiety disorder (GAD), demographic, prison and cardiovascular risk factors. Cluster analysis was applied to PHQ-9 and GAD-7 items in prisoners scoring > 10 on PHQ-9. RESULTS: 453(37.6%) and 249(20.7%) prisoners scored > 10 and > 15 respectively on PHQ-9; 216 (17.9%) had a depressive episode on the PHQ-9 algorithm; 378(31.4%) and 217(18.0%) scored > 10 and > 15 on GAD-7 respectively. Daily core items for depression were scored in 232(56.2%) and 139(74.3%) prisoners reaching > 10 and > 15 respectively on PHQ-9; daily core anxiety items in 282(74.9%) and 179(96.3%) reaching > 10 and > 15 on GAD-7. Young age, prison and previous high alcohol intake were associated with > 15 on the PHQ-9. Cluster analysis showed a cluster with core symptoms of depression, slowness, restlessness, suicidality, poor concentration, irritability or fear. Altered appetite, poor sleep, lack of energy, guilt or worthlessness belonged to other clusters and may not be indicative of depression. CONCLUSIONS: In male prisoners > 35 years, a score of > 10 on the PHQ-9 over diagnoses depressive episodes but a score of > 10 on the GAD-7 may detect cases of GAD more efficiently. Further research utilising standardised psychiatric interviews is required to determine whether the diagnostic algorithm, a higher cut-off on the PHQ-9 or the profile of symptoms on the PHQ-9 and GAD-7 used singly or in combination may be used to screen depressive episodes efficiently in prisoners.

Evaluation and refinement of the PRESTARt tool for identifying 12-14 year olds at high lifetime risk of developing type 2 diabetes compared to a clinicians assessment of risk: a cross-sectional study.

BACKGROUND: Traditionally Type 2 Diabetes Mellitus (T2DM) was associated with older age, but is now being increasingly diagnosed in younger populations due to the increasing prevalence of obesity and inactivity. We aimed to evaluate whether a tool developed for community use to identify adolescents at high lifetime risk of developing T2DM agreed with a risk assessment conducted by a clinician using data collected from five European countries. We also assessed whether the tool could be simplified. METHODS: To evaluate the tool we collected data from 636 adolescents aged 12-14 years from five European countries. Each participant's data were then assessed by two clinicians independently, who judged each participant to be at either low or high risk of developing T2DM in their lifetime. This was used as the gold standard to which the tool was evaluated and refined. RESULTS: The refined tool categorised adolescents at high risk if they were overweight/obese and had at least one other risk factor (High waist circumference, family history of diabetes, parental obesity, not breast fed, high sugar intake, high screen time, low physical activity and low fruit and vegetable intake). Of those found to be at high risk by the clinicians, 93% were also deemed high risk by the tool. The specificity shows that 67% of those deemed at low risk by the clinicians were also found to be a low risk by the tool. CONCLUSIONS: We have evaluated a tool for identifying adolescents with risk factors associated with the development of T2DM in the future. Future work to externally validate the tool using prospective data including T2DM incidence is required.

Statins and risk of thromboembolism: A meta-regression to disentangle the efficacy-to-effectiveness gap using observational and trial evidence.

BACKGROUND AND AIMS: Meta-analyses of randomised controlled trials (RCTs) and observational studies indicate a lower risk of venous thromboembolism (VTE) associated with statin treatment. We aimed to compare the effect of statin therapy in these two settings and to identify and quantify potential factors to explain statin efficacy and effectiveness. METHODS AND RESULTS: We electronically searched on December 11th, 2018, articles reporting on first VTE events in RCTs (statin vs placebo) and in observational studies (participants exposed vs non-exposed to statin). We performed Knapp-Hartung random-effect meta-analyses to calculate pooled relative risks (RRs) of VTE events associated with statin treatment, separately for RCTs and observational studies; and estimated the ratio of the relative risk (RRR) comparing RCTs and observational studies using meta-regressions, progressively adjusted for study-level characteristics. Twenty-one RCTs (115,107 participants; 959 events) and 8 observational studies (2,898,096 participants; 19,671 events) were included. Pooled RRs for RCTs and observational studies were 0.82 (95% confidence interval (CI): 0.67-1.00; I2 19.2%) and 0.60 (95% CI: 0.42-0.86; I2 86.3%), respectively. In meta-regressions, the unadjusted RRR indicated a nonsignificant 23% smaller benefit in RCTs (RRR 0.77; 95% CI: 0.52-1.13); accounting for age, sex, geographical region, and duration of follow-up, there was a sensible change of the RRR which resulted 0.30 (95% CI: 0.13-0.68). CONCLUSION: Differences in the characteristics between patients included in RCTs and those in observational studies may account for the differential effect of statins in preventing VTE in the two settings.

Association of ethnicity and socioeconomic status with health outcomes in women with gestational diabetes: Clinical practice research datalink cohort study.

AIMS: To investigate in women with prior gestational diabetes mellitus (GDM), differences by ethnicity and socioeconomic status in the incidence of recurrent GDM, type 2 diabetes (T2D), hypertension, and depression. METHODS: This was a retrospective cohort study including 10,868 women diagnosed with GDM in the Clinical Practice Research Datalink (CPRD GOLD) between January 01, 2000 and November 05, 2018. Linked data were obtained for Hospital Episode Statistics and the Index of Multiple Deprivation. We estimated incidence rates and hazard ratios, by ethnicity and socioeconomic status. RESULTS: During a follow-up of 58,479 person years (mean (SD): 5.38 (3.67) years), the crude incidence was 9.67 (95 % confidence interval: 9.30-10.00) per 100 person years for recurrent GDM, 3.86 (3.70-4.02) for depression, 2.15 (2.03-2.27) for T2D and 0.89 (0.81-0.97) for hypertension. South Asian ethnicity was associated with an increased risk of T2D compared to White (adjusted hazard ratio: 1.65; 1.34-2.05) and Black ethnicity was associated with a greater risk of hypertension (2.93; 1.93-4.46). Black and South Asian ethnicity were associated with a reduced risk of depression compared to White: 0.23 (0.13-0.39) and 0.37 (0.29-0.46), respectively. Incidence rates were higher for all conditions with increasing deprivation level. CONCLUSIONS: The risk of health complications in women with a prior history of GDM differs by ethnicity and socio-economic status, suggesting the opportunity for targeted assessment in the years following pregnancy. These findings may inform future guidelines on screening for health outcomes in women with GDM.

Screening for type 2 diabetes after a diagnosis of gestational diabetes by ethnicity: A retrospective cohort study.

AIMS: To estimate rates and identify determinants of post-partum glucose screening attendance in women with a history of gestational diabetes mellitus (GDM). METHODS: Retrospective cohort study using the Clinical Practice Research Datalink linked to Hospital Episode Statistics, to identify women diagnosed with GDM between 01/01/2000 and 05/11/2018. Age adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression models. RESULTS: In 10,868 women with GDM, with an average follow-up of 5.38 years (95% CI 5.31,5.45), there was an average of 3.79 (95% CI 3.70,3.89) screening episodes per individual, with a mean time to first screening test of 1.22 (95% CI 1.18, 1.25) years. South Asian women had a significantly greater likelihood of being screened compared to White women within the first 5 years post-partum, aOR: 1.89 95% CI (1.20,2.98). A low proportion of women received at least one test per year of follow-up (23.87%). Older age at GDM diagnosis, polycystic ovary syndrome, prescribed medication for GDM, and living in England, were all associated with a greater likelihood of being screened. CONCLUSION: While the majority of women with previous GDM receive at least one glucose screening test within the first 5 years post-partum, fewer than a quarter of them receive on average one test per year of follow-up. Developing strategies to motivate more women to attend screening in primary care is essential.

Associations between frailty trajectories and cardiovascular, renal, and mortality outcomes in chronic kidney disease.

BACKGROUND: Frailty is characterized by the loss of biological reserves and vulnerability to adverse outcomes. In individuals with chronic kidney disease (CKD), numerous pathophysiological factors may be responsible for frailty development including inflammation, physical inactivity, reduced energy intake, and metabolic acidosis. Given that both CKD and frailty incur a significant healthcare burden, it is important to understand the relationship of CKD and frailty in real-world routine clinical practice, and how simple frailty assessment methods (e.g. frailty indexes) may be useful. We investigated the risk of frailty development in CKD and the impact of frailty status on mortality and end-stage kidney disease (ESKD). METHODS: A retrospective cohort study using primary care records from the Clinical Practice Research Datalink linked to Hospital Episode Statistics and the UK Office for National Statistics was undertaken in 819 893 participants aged ≥40 years, of which 140 674 had CKD. Frailty was defined using an electronic frailty index, generated electronically from primary care records. Cox proportional hazard and flexible parametric survival models were used to investigate the risk of developing frailty and the effect of frailty on risk of all-cause and cardiovascular mortality, and ESKD. RESULTS: The mean age of those with CKD was 77.5 (SD 9.7) years [61.0 (SD 12.1) years in no-CKD group]; 62.0% of the CKD group were female (compared with 53.3% in no-CKD group). The mean estimated glomerular filtration rate of those with CKD was 46.1 (SD 9.9) mL/min/1.73 m2 . The majority of those with CKD (75.3%) were frail [vs. 45.4% in those without CKD (no-CKD)]. Over 3 years (median), 69.5% of those with CKD developed frailty. Compared with no-CKD, those with CKD had increased rates of developing mild (hazard ratio: 1.02; 95% confidence interval: 1.01-1.04), moderate (1.30; 1.26-1.34), and severe (1.50; 1.37-1.65) frailty. Mild (1.22; 1.19-1.24), moderate (1.60; 1.56-1.63), and severe (2.16; 2.11-2.22) frailty was associated with increased rates of all-cause and cardiovascular-related mortality (mild 1.35; 1.31-1.39; moderate 1.96; 1.90-2.02; and severe 2.91; 2.81-3.02). All stages of frailty significantly increased ESKD rates. CONCLUSIONS: Frailty is highly prevalent and associated with adverse outcomes in people with CKD, including mortality and risk of ESKD. Preventative interventions should be initiated to mitigate the development of frailty. The use of a simple frailty index, generated electronically from health records, can predict outcomes and may aid prioritization for management of people with frailty.

Association of sarcopenia with mortality and end-stage renal disease in those with chronic kidney disease: a UK Biobank study.

BACKGROUND: Sarcopenia, a degenerative and generalized skeletal muscle disorder involving the loss of muscle function and mass, is an under-recognized problem in clinical practice, particularly in chronic kidney disease (CKD). We aimed to investigate the prevalence of sarcopenia in individuals with CKD, its risk factors, and its association with all-cause mortality and progression to end-stage renal disease (ESRD). METHODS: UK Biobank participants were grouped according to the presence of CKD (defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 ) and as having probable (low handgrip strength), confirmed (plus low muscle mass), and severe sarcopenia (plus poor physical performance) based on the 2019 European Working Group of Sarcopenia in Older People and Foundation for the National Institutes of Health criteria. Risk factors were explored using logistic regression analysis. Survival models were applied to estimate risk of mortality and ESRD. RESULTS: A total of 428 320 participants, of which 8767 individuals with CKD (46% male, aged 62.8 (standard deviation 6.8) years, median estimated glomerular filtration rate 54.5 (interquartile range 49.0-57.7) mL/min/1.72 m2 ) were included. Probable sarcopenia was present in 9.7% of individuals with CKD compared with 5.0% in those without (P < 0.001). Sarcopenia was associated with being older; inflammation; poorer renal function; and lower serum albumin, total testosterone, and haemoglobin. The largest risk factors for sarcopenia were having three or more comorbidities (odds ratio: 2.30; 95% confidence interval: 1.62 to 3.29; P < 0.001) and physical inactivity: participants in the highest quartile of weekly activity were 43% less likely to have sarcopenia compared to the lowest quartile (odds ratio: 0.57; 0.42 to 0.76; P < 0.001). Participants with CKD and sarcopenia had a 33% (7% to 66%; P = 0.011) higher hazard of mortality compared with individuals without. Sarcopenic CKD individuals had a 10 year survival probability of 0.85 (0.82 to 0.88) compared with 0.89 (0.88 to 0.30) in those without sarcopenia, an absolute difference of 4%. Those with sarcopenia were twice as likely to develop ESRD (hazard ratio: 1.98; 1.45 to 2.70; P < 0.001). CONCLUSIONS: Participants with reduced kidney function are at an increased risk of premature mortality. The presence of sarcopenia increases the risk of mortality and ESRD. Appropriate measurement of sarcopenia should be used to identify at-risk individuals. Interventions such as physical activity should be encouraged to mitigate sarcopenia.

Cardiovascular risk profiles and the uptake of the NHS Healthcheck programme in male prisoners in six UK prisons: an observational cross-sectional survey.

INTRODUCTION: Half of all deaths in custody are due to natural causes, the most common being cardiovascular disease (CVD). National Health Service Healthchecks should be available to all eligible prisoners; it is not clear who receives them. Mental health issues are common in prisoners and may affect how healthcare interventions should be delivered. Current policy is to offer Healthchecks to those serving over 2 years in prison. OBJECTIVES, METHODS, SETTING AND DESIGN: An observational cross-sectional survey in six male prisons in England between September 2017 and January 2019 in prisoners aged 35-74 to identify who was eligible for a Healthcheck and compare CVD risk data with those that were not, and factors associated with uptake. OUTCOME MEASURES: Characteristics of those accepting a Healthcheck were compared with those declining. Assessments of anxiety and depression were compared with CVD risk factors. RESULTS: 1207 prisoners completed a Healthcheck. 21.8% of prisoners were ineligible due to existing comorbidities. 76.4% of those invited took up a Healthcheck, and of those, 12.1% were found to have new significant CVD comorbidity. CVD risk was similar to community levels but this population was 10 years younger. Definite case-level depression or anxiety was present in 20.7% and 18.0%, respectively, of participants. An association was found between ethnicity and those invited (p=0.023, φ=0.1) and accepting (p=0.008, φ=0.1) a Healthcheck. 9.7% of prisoners serving less than 2 years had CVD risk scores of 10% or more, and had similar CVD risk profiles but much higher levels of anxiety (p<0.001, φ=0.2) or depression (p=0.009, φ=0.2) than those serving 2 years or more. CONCLUSION: Cardiovascular risk was comparable with community rates and in some prisons, much higher. Rates of anxiety and depression were high. The national policy for selecting prisoners for Healthchecks may leave many high-risk prisoners without appropriate cardiovascular preventative assessments.

Association of Type 2 Diabetes With Cancer: A Meta-analysis With Bias Analysis for Unmeasured Confounding in 151 Cohorts Comprising 32 Million People.

BACKGROUND AND PURPOSE: Whether the association between type 2 diabetes (T2D) and cancer is causal remains controversial. The goal of this work is to assess the robustness of the observational associations between T2D and cancer to unmeasured confounding. DATA SOURCES AND STUDY SELECTION: PubMed, Web of Science, and the Cochrane library were systematically searched on 10 January 2019 for observational studies investigating associations between T2D and cancer incidence or mortality. DATA EXTRACTION AND DATA SYNTHESIS: Cohort-level relative risk (RR) was extracted. RRs were combined in random-effects meta-analyses and pooled estimates used in bias analyses. A total of 151 cohorts (over 32 million people, 1.1 million cancer cases, and 150,000 cancer deaths) were included. In meta-analyses, T2D was associated with incidence of several cancers, from prostate (RR 0.83; 95% CI 0.79, 0.88) to liver (2.23; 1.99, 2.49), and with mortality from pancreatic cancer (1.67; 1.30, 2.14). In bias analyses, assuming an unmeasured confounding associated with both T2D and cancer with a RR of 1.5, the proportion of studies with a true effect size larger than a RR of 1.1 (i.e., 10% increased risk in individuals with T2D) was nearly 100% for liver, pancreatic, and endometrial, 86% for gallbladder, 67% for kidney, 64% for colon, 62% for colorectal, and <50% for other cancer incidences, and 92% for pancreatic cancer mortality. LIMITATIONS: Biases other than unmeasured confounding were not analytically assessed. CONCLUSIONS: Our findings strongly suggest a causal association between T2D and liver, pancreatic, and endometrial cancer incidence, and pancreatic cancer mortality. Conversely, associations with other cancers were less robust to unmeasured confounding.