Associations between multiple long-term conditions and mortality in diverse ethnic groups

Background Multiple conditions are more prevalent in some minoritised ethnic groups and are associated with higher mortality rate but studies examining differential mortality once conditions are established is US-based. Our study tested whether the association between multiple conditions and mortality varies across ethnic groups in England. Methods and Findings A random sample of primary care patients from Clinical Practice Research Datalink (CPRD) was followed from 1st January 2015 until 31st December 2019. Ethnicity, usually self-ascribed, was obtained from primary care records if present or from hospital records. Cox regression models were used to estimate mortality by number of long-term conditions, ethnicity and their interaction, with adjustment for age and sex for 532,059 patients with complete data. During five years of follow-up, 5.9% of patients died. Each additional long-term condition at baseline was associated with increased mortality. This association differed across ethnic groups. Compared with 50-year-olds of white ethnicity with no conditions, the mortality rate was higher for white 50-year-olds with two conditions (HR 1.77) or four conditions (HR 3.13). Corresponding figures were higher for 50-year-olds of Black Caribbean ethnicity with two conditions (HR=2.22) or four conditions (HR 4.54). The direction of the interaction of number of conditions with ethnicity showed higher mortality associated with long-term conditions in nine out of ten minoritised ethnic groups, attaining statistical significance in four (Pakistani, Black African, Black Caribbean and Black other ethnic groups). Conclusions The raised mortality rate associated with having multiple conditions is greater in minoritised ethnic groups compared with white people. Research is now needed to identify factors that contribute to these inequalities. Within the health care setting, there may be opportunities to target clinical and self-management support for people with multiple conditions from minoritised ethnic groups.

Ethnic disparities in mortality among overweight or obese adults with newly diagnosed type 2 diabetes: a population-based cohort study

Purpose Ethnic variation in risk of type 2 diabetes is well established, but its impact on mortality is less well understood. This study investigated the risk of all-cause and cardiovascular mortality associated with newly diagnosed type 2 diabetes in White, Asian and Black adults who were overweight or obese. Methods This population-based cohort study used primary care records from the UK Clinical Practice Research Datalink, linked with secondary care and death registry records. A total of 193,528 obese or overweight adults (BMI of 25 or greater), with ethnicity records and no pre-existing type 2 diabetes were identified between 01 January 1995 and 20 April 2018. Multivariable Cox proportional hazards regression estimated hazards ratios (HR) for incident type 2 diabetes in different ethnic groups. Adjusted hazards ratios for all-cause and cardiovascular mortality were determined in individuals with newly diagnosed type 2 diabetes. Results During follow-up (median 9.8 years), the overall incidence rate of type 2 diabetes (per 1,000 person-years) was 20.10 (95% CI 19.90–20.30). Compared to Whites, type 2 diabetes risk was 2.2-fold higher in Asians (HR 2.19 (2.07–2.32)) and 30% higher in Blacks (HR 1.34 (1.23–1.46)). In individuals with newly diagnosed type 2 diabetes, the rates (per 1,000 person-years) of all-cause mortality and cardiovascular mortality were 24.34 (23.73–24.92) and 4.78 (4.51–5.06), respectively. Adjusted hazards ratios for mortality were significantly lower in Asians (HR 0.70 (0.55–0.90)) and Blacks (HR 0.71 (0.51–0.98)) compared to Whites, and these differences in mortality risk were not explained by differences in severity of hyperglycaemia. Conclusions/Interpretation Type 2 diabetes risk in overweight and obese adults is greater in Asian and Black compared to White ethnic populations, but mortality is significantly higher in the latter. Greater attention to optimising screening, disease and risk management appropriate to all communities with type 2 diabetes is needed.

Pharmacoepidemiology in pregnancy: analysis protocol for an observational cohort study in the UK Clinical Practice Research Datalink

Large numbers of women take prescription and over-the-counter medications during pregnancy. However, there is very little definitive evidence about the potential effects of these drugs on the mothers and offspring. We will investigate the risks and benefits of continuing prescriptive drug use for chronic pre-existing maternal conditions such as diabetes, hypertension and thyroid related conditions throughout pregnancy. If left untreated, these conditions are established risk factors for adverse neonatal and maternal outcomes. However, some treatments for these conditions are associated with adverse neonatal outcomes. Our primary aims are twofold. Firstly, we aim to estimate the beneficial effect on the mother of continuing treatment during pregnancy. Second, we aim to determine whether there is an associated detrimental impact on the neonate of continuation of maternal treatment during pregnancy. To establish this evidence, we will investigate the relationship between maternal drug prescriptions and adverse and beneficial offspring outcomes to provide evidence to guide clinical decisions. We will conduct a hypothesis testing observational intergenerational cohort study using data from the UK Clinical Practice Research Datalink (CPRD). We will apply four statistical methods: multivariable adjusted regression, propensity score regression, instrumental variables analysis and negative control analysis. These methods should account for potential confounding when estimating the association between the drug exposure and maternal or neonatal outcome. In this protocol we describe the aims, motivation, study design, cohort and statistical analyses of our study to aid reproducibility and transparency within research.

Consultation rates in people with type 2 diabetes with and without vascular complications: a retrospective analysis of 141,328 adults in England

Objective To assess trends in primary and specialist care consultation rates and average length of consultation by cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), or cardiometabolic multimorbidity exposure status. Methods Observational, retrospective cohort study used linked Clinical Practice Research Datalink primary care data from 01/01/2000 to 31/12/2018 to assess consultation rates in 141,328 adults with newly diagnosed T2DM, with or without CVD. Patients who entered the study with either a diagnosis of T2DM or CVD and later developed the second condition during the study are classified as the cardiometabolic multimorbidity group. Face to face primary and specialist care consultations, with either a nurse or general practitioner, were assessed over time in subjects with T2DM, CVD, or cardiometabolic multimorbidity. Changes in the average length of consultation in each group were investigated. Results 696,255 (mean 4.9 years [95% CI, 2.02–7.66]) person years of follow up time, there were 10,221,798 primary and specialist care consultations. The crude rate of primary and specialist care consultations in patients with cardiometabolic multimorbidity (N = 11,881) was 18.5 (95% CI, 18.47–18.55) per person years, 13.5 (13.50, 13.52) in patients with T2DM only (N = 83,094) and 13.2 (13.18, 13.21) in those with CVD (N = 57,974). Patients with cardiometabolic multimorbidity had 28% (IRR 1.28; 95% CI: 1.27, 1.31) more consultations than those with only T2DM. Patients with cardiometabolic multimorbidity had primary care consultation rates decrease by 50.1% compared to a 45.0% decrease in consultations for those with T2DM from 2000 to 2018. Specialist care consultation rates in both groups increased from 2003 to 2018 by 33.3% and 54.4% in patients with cardiometabolic multimorbidity and T2DM, respectively. For patients with T2DM the average consultation duration increased by 36.0%, in patients with CVD it increased by 74.3%, and in those with cardiometabolic multimorbidity it increased by 37.3%. Conclusions Annual primary care consultation rates for individuals with T2DM, CVD, or cardiometabolic multimorbidity have fallen since 2000, while specialist care consultations and average consultation length have both increased. Individuals with cardiometabolic multimorbidity have significantly more consultations than individuals with T2DM or CVD alone. Service redesign of health care delivery needs to be considered for people with cardiometabolic multimorbidity to reduce the burden and health care costs.

Respiratory-related death in individuals with incident asthma and COPD: a competing risk analysis

Background Distinguishing between mortality attributed to respiratory causes and other causes among people with asthma, COPD, and asthma-COPD overlap (ACO) is important. This study used electronic health records in England to estimate excess risk of death from respiratory-related causes after accounting for other causes of death. Methods We used linked Clinical Practice Research Datalink (CPRD) primary care and Office for National Statistics mortality data to identify adults with asthma and COPD from 2005 to 2015. Causes of death were ascertained using death certificates. Hazard ratios (HR) and excess risk of death were estimated using Fine-Gray competing risk models and adjusting for age, sex, smoking status, body mass index and socioeconomic status. Results 65,021 people with asthma and 45,649 with COPD in the CPRD dataset were frequency matched 5:1 with people without the disease on age, sex and general practice. Only 14 in 100,000 people with asthma are predicted to experience a respiratory-related death up to 10 years post-diagnosis, whereas in COPD this is 98 in 100,000. Asthma is associated with an 0.01% excess incidence of respiratory related mortality whereas COPD is associated with an 0.07% excess. Among people with asthma-COPD overlap (N = 22,145) we observed an increased risk of respiratory-related death compared to those with asthma alone (HR = 1.30; 95% CI 1.21–1.40) but not COPD alone (HR = 0.89; 95% CI 0.83–0.94). Conclusions Asthma and COPD are associated with an increased risk of respiratory-related death after accounting for other causes; however, diagnosis of COPD carries a much higher probability. ACO is associated with a lower risk compared to COPD alone but higher risk compared to asthma alone.

Factors associated with excess all-cause mortality in the first wave of the COVID-19 pandemic in the UK: A time series analysis using the Clinical Practice Research Datalink

Background Excess mortality captures the total effect of the Coronavirus Disease 2019 (COVID-19) pandemic on mortality and is not affected by misspecification of cause of death. We aimed to describe how health and demographic factors were associated with excess mortality during, compared to before, the pandemic. Methods and findings We analysed a time series dataset including 9,635,613 adults (≥40 years old) registered at United Kingdom general practices contributing to the Clinical Practice Research Datalink. We extracted weekly numbers of deaths and numbers at risk between March 2015 and July 2020, stratified by individual-level factors. Excess mortality during Wave 1 of the UK pandemic (5 March to 27 May 2020) compared to the prepandemic period was estimated using seasonally adjusted negative binomial regression models. Relative rates (RRs) of death for a range of factors were estimated before and during Wave 1 by including interaction terms. We found that all-cause mortality increased by 43% (95% CI 40% to 47%) during Wave 1 compared with prepandemic. Changes to the RR of death associated with most sociodemographic and clinical characteristics were small during Wave 1 compared with prepandemic. However, the mortality RR associated with dementia markedly increased (RR for dementia versus no dementia prepandemic: 3.5, 95% CI 3.4 to 3.5; RR during Wave 1: 5.1, 4.9 to 5.3); a similar pattern was seen for learning disabilities (RR prepandemic: 3.6, 3.4 to 3.5; during Wave 1: 4.8, 4.4 to 5.3), for black or South Asian ethnicity compared to white, and for London compared to other regions. Relative risks for morbidities were stable in multiple sensitivity analyses. However, a limitation of the study is that we cannot assume that the risks observed during Wave 1 would apply to other waves due to changes in population behaviour, virus transmission, and risk perception. Conclusions The first wave of the UK COVID-19 pandemic appeared to amplify baseline mortality risk to approximately the same relative degree for most population subgroups. However, disproportionate increases in mortality were seen for those with dementia, learning disabilities, non-white ethnicity, or living in London.

Associations of Cardiovascular and Non-Cardiovascular Comorbidities with Dementia Risk in Patients with Diabetes: Results from a Large UK Cohort Study

Background: Type 2 diabetes (T2D) is an established risk factor for dementia. However, it remains unclear whether the presence of comorbidities could further increase dementia risk in diabetes patients. Objectives: To examine the associations between cardiovascular and non-cardiovascular comorbidities and dementia risk in T2D patients. Design: Population-based cohort study. Setting: The UK Clinical Practice Research Datalink (CPRD). Participants: 489,205 T2D patients aged over 50 years in the UK CPRD. Measurements: Major cardiovascular and non-cardiovascular comorbidities were extracted as time-varying exposure variables. The outcome event was dementia incidence based on dementia diagnosis or dementia-specific drug prescription. Results: During a median of six years follow-up, 33,773 (6.9%) incident dementia cases were observed. Time-varying Cox regressions showed T2D patients with stroke, peripheral vascular disease, atrial fibrillation, heart failure or hypertension were at higher risk of dementia compared to those without such comorbidities (HR [95% CI] = 1.64 [1.59-1.68], 1.37 [1.34-1.41], 1.26 [1.22-1.30], 1.15 [1.11-1.20] or 1.10 [1.03-1.18], respectively). Presence of chronic obstructive pulmonary disease or chronic kidney disease was also associated with increased dementia risk (HR [95% CI] = 1.05 [1.01-1.10] or 1.11 [1.07-1.14]). Conclusions: A range of cardiovascular and non-cardiovascular comorbidities were associated with further increases of dementia risk in T2D patients. Prevention and effective management of these comorbidities may play a significant role in maintaining cognitive health in T2D patients.

Risk factors associated with poor pain outcomes following primary knee replacement surgery: Analysis of data from the clinical practice research datalink, hospital episode statistics and patient reported outcomes as part of the STAR research programme

Objective Identify risk factors for poor pain outcomes six months after primary knee replacement surgery. Methods Observational cohort study on patients receiving primary knee replacement from the UK Clinical Practice Research Datalink, Hospital Episode Statistics and Patient Reported Outcomes. A wide range of variables routinely collected in primary and secondary care were identified as potential predictors of worsening or only minor improvement in pain, based on the Oxford Knee Score pain subscale. Results are presented as relative risk ratios and adjusted risk differences (ARD) by fitting a generalized linear model with a binomial error structure and log link function. Results Information was available for 4,750 patients from 2009 to 2016, with a mean age of 69, of whom 56.1% were female. 10.4% of patients had poor pain outcomes. The strongest effects were seen for pre-operative factors: mild knee pain symptoms at the time of surgery (ARD 18.2% (95% Confidence Interval 13.6, 22.8), smoking 12.0% (95% CI:7.3, 16.6), living in the most deprived areas 5.6% (95% CI:2.3, 9.0) and obesity class II 6.3% (95% CI:3.0, 9.7). Important risk factors with more moderate effects included a history of previous knee arthroscopy surgery 4.6% (95% CI:2.5, 6.6), and use of opioids 3.4% (95% CI:1.4, 5.3) within three months after surgery. Those patients with worsening pain state change had more complications by 3 months (11.8% among those in a worse pain state vs. 2.7% with the same pain state). Conclusions We quantified the relative importance of individual risk factors including mild pre-operative pain, smoking, deprivation, obesity and opioid use in terms of the absolute proportions of patients achieving poor pain outcomes. These findings will support development of interventions to reduce the numbers of patients who have poor pain outcomes.

Prevalence and incidence of neuromuscular conditions in the UK between 2000 and 2019: A retrospective study using primary care data

Background In the UK, large-scale electronic primary care datasets can provide up-to-date, accurate epidemiological information on rarer diseases, where specialist diagnoses from hospital discharges and clinic letters are generally well recorded and electronically searchable. Current estimates of the number of people living with neuromuscular disease (NMD) have largely been based on secondary care data sources and lacked direct denominators. Objective To estimate trends in the recording of neuromuscular disease in UK primary care between 2000–2019. Methods The Clinical Practice Research Datalink (CPRD) database was searched electronically to estimate incidence and prevalence rates (per 100,000) for a range of NMDs in each year. To compare trends over time, rates were age standardised to the most recent CPRD population (2019). Results Approximately 13 million patients were actively registered in each year. By 2019, 28,230 active patients had ever received a NMD diagnosis (223.6), which was higher among males (239.0) than females (208.3). The most common classifications were Guillain-Barre syndrome (40.1), myasthenia gravis (33.7), muscular dystrophy (29.5), Charcot-Marie-Tooth (29.5) and inflammatory myopathies (25.0). Since 2000, overall prevalence grew by 63%, with the largest increases seen at older ages (≥65-years). However, overall incidence remained constant, though myasthenia gravis incidence has risen steadily since 2008, while new cases of muscular dystrophy fell over the same period. Conclusions Lifetime recording of many NMDs on primary care records exceed current estimates of people living with these conditions; these are important data for health service and care planning. Temporal trends suggest this number is steadily increasing, and while this may partially be due to better recording, it cannot be simply explained by new cases, as incidence remained constant. The increase in prevalence among older ages suggests increases in life expectancy among those living with NMDs may have occurred.

Therapies for Long COVID in non-hospitalised individuals - from symptoms, patient-reported outcomes, and immunology to targeted therapies (The TLC Study): Study protocol

Introduction Individuals with COVID-19 frequently experience symptoms and impaired quality of life beyond 4-12 weeks, commonly referred to as Long COVID. Whether Long COVID is one or several distinct syndromes is unknown. Establishing the evidence base for appropriate therapies is needed. We aim to evaluate the symptom burden and underlying pathophysiology of Long COVID syndromes in non-hospitalised individuals and evaluate potential therapies. Methods and analysis A cohort of 4000 non-hospitalised individuals with a past COVID-19 diagnosis and 1000 matched controls will be selected from anonymised primary care records from the Clinical Practice Research Datalink (CPRD) and invited by their general practitioners to participate on a digital platform (Atom5TM). Individuals will report symptoms, quality of life, work capability, and patient reported outcome measures. Data will be collected monthly for one year. Statistical clustering methods will be used to identify distinct Long COVID symptom clusters. Individuals from the four most prevalent clusters and two control groups will be invited to participate in the BioWear sub-study which will further phenotype Long COVID symptom clusters by measurement of immunological parameters and actigraphy. We will review existing evidence on interventions for post-viral syndromes and Long COVID to map and prioritise interventions for each newly characterised Long COVID syndrome. Recommendations will be made using the cumulated evidence in an expert consensus workshop. A virtual supportive intervention will be coproduced with patients and health service providers for future evaluation. Individuals with lived experience of Long COVID will be involved throughout this programme through a patient and public involvement group. Ethics and dissemination Ethical approval was obtained from the Solihull Research Ethics Committee, West Midlands (21/WM/0203). The study is registered on the ISRCTN Registry (1567490). Research findings will be presented at international conferences, in peer-reviewed journals, to Long COVID patient support groups and to policymakers.