Publications by authors named "Mar Pujades-Rodriguez"

73 Publications

Non-communicable disease, sociodemographic factors, and risk of death from infection: a UK Biobank observational cohort study.

Lancet Infect Dis 2021 Mar 1. Epub 2021 Mar 1.

Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, UK. Electronic address:

Background: Non-communicable diseases (NCDs) have been highlighted as important risk factors for COVID-19 mortality. However, insufficient data exist on the wider context of infectious diseases in people with NCDs. We aimed to investigate the association between NCDs and the risk of death from any infection before the COVID-19 pandemic (up to Dec 31, 2019).

Methods: For this observational study, we used data from the UK Biobank observational cohort study to explore factors associated with infection death. We excluded participants if data were missing for comorbidities, body-mass index, smoking status, ethnicity, and socioeconomic deprivation, and if they were lost to follow-up or withdrew consent. Deaths were censored up to Dec 31, 2019. We used Poisson regression models including NCDs present at recruitment to the UK Biobank (obesity [defined by use of body-mass index] and self-reported hypertension, chronic heart disease, chronic respiratory disease, diabetes, cancer, chronic liver disease, chronic kidney disease, previous stroke or transient ischaemic attack, other neurological disease, psychiatric disorder, and chronic inflammatory and autoimmune rheumatological disease), age, sex, ethnicity, smoking status, and socioeconomic deprivation. Separate models were constructed with individual NCDs replaced by the total number of prevalent NCDs to define associations with multimorbidity. All analyses were repeated with non-infection-related death as an alternate outcome measure to establish differential associations of infection death and non-infection death. Associations are reported as incidence rate ratios (IRR) accompanied by 95% CIs.

Findings: After exclusion of 9210 (1·8%) of the 502 505 participants in the UK Biobank cohort, our study sample comprised 493 295 individuals. During 5 273 731 person-years of follow-up (median 10·9 years [IQR 10·1-11·6] per participant), 27 729 deaths occurred, of which 1385 (5%) were related to infection. Advancing age, male sex, smoking, socioeconomic deprivation, and all studied NCDs were independently associated with the rate of both infection death and non-infection death. Compared with White ethnicity, a pooled Black, Asian, and minority ethnicity group was associated with a reduced risk of infection death (IRR 0·64, 95% CI 0·46-0·87) and non-infection death (0·80, 0·75-0·86). Stronger associations with infection death than with non-infection death were observed for advancing age (age 65 years vs 45 years: 7·59, 95% CI 5·92-9·73, for infection death vs 5·21, 4·97-5·48, for non-infection death), current smoking (vs never smoking: 3·69, 3·19-4·26, vs 2·52, 2·44-2·61), socioeconomic deprivation (most vs least deprived quintile: 2·13, 1·78-2·56, vs 1·38, 1·33-1·43), class 3 obesity (vs non-obese: 2·21, 1·74-2·82, vs 1·55, 1·44-1·66), hypertension (1·36, 1·22-1·53, vs 1·15, 1·12-1·18), respiratory disease (2·21, 1·96-2·50, vs 1·28, 1·24-1·32), chronic kidney disease (5·04, 4·28-7·31, vs 2·50, 2·20-2·84), psychiatric disease (1·56, 1·30-1·86, vs 1·23, 1·18-1·29), and chronic inflammatory and autoimmune rheumatological disease (2·45, 1·99-3·02, vs 1·41, 1·32-1·51). Accrual of multimorbidity was also more strongly associated with risk of infection death (five or more comorbidities vs none: 9·53, 6·97-13·03) than of non-infection death (5·26, 4·84-5·72).

Interpretation: Several NCDs are associated with an increased risk of infection death, suggesting that some of the reported associations with COVID-19 mortality might be non-specific. Only a subset of NCDs, together with the accrual of multimorbidity, advancing age, smoking, and socioeconomic deprivation, were associated with a greater IRR for infection death than for other causes of death. Further research is needed to define why these risk factors are more strongly associated with infection death, so that more effective preventive strategies can be targeted to high-risk groups.

Funding: British Heart Foundation.
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http://dx.doi.org/10.1016/S1473-3099(20)30978-6DOI Listing
March 2021

Both incidence and prevalence of ischaemic heart disease are declining in parallel: a national data-linkage study in New Zealand (ANZACS-QI 52).

Eur J Prev Cardiol 2020 Dec 17. Epub 2020 Dec 17.

Department of Medicine and Section of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand.

Aims: To examine trends in ischaemic heart disease (IHD) incidence and prevalence in New Zealand from 2005 to 2016, using comprehensive linked national hospitalization and mortality data as proxy measures of all significant events.

Methods And Results: Incident and prevalent cases of IHD in people aged ≥25 years were identified using individual patient-linkage of routinely collected ICD-10-coded hospitalization and mortality data. Incidence rates and prevalence proportions were calculated by sex and age group and then age-standardized to the 2016 New Zealand population. Ischaemic heart disease incidence and prevalence declined in men and women in all age groups. The average annual rate of decline in age-standardized IHD incidence was 3.3% for women and 2.7% for men, and the rate of decline in age-standardized IHD prevalence was 3.2% for women and 2.2% for men. Despite a 17% increase in the New Zealand population aged 25 years and over during the study period, the total number of people living with IHD also decreased, particularly in those aged 65 years and older.

Conclusion: In contrast to observations from other countries, where IHD incidence but not IHD prevalence has been falling, declining IHD incidence in New Zealand in recent decades is now mirrored by declining IHD prevalence.
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http://dx.doi.org/10.1093/eurjpc/zwaa120DOI Listing
December 2020

Changes in the pharmacological management of rheumatoid arthritis over two decades.

Rheumatology (Oxford) 2021 Jan 6. Epub 2021 Jan 6.

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

Objectives: To assess whether modern management of rheumatoid arthritis (RA) has reduced the prescription of oral corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) and to evaluate use of pharmacological prophylaxis strategies.

Methods: Using the Clinical Practice Research Datalink, we explored long-term (≥3/12 months; ≥6/12 in sub-analyses) disease modifying antirheumatic drug (DMARD), corticosteroid and NSAID prescribing (annually, in the year post-diagnosis and across the patient's life-course to 15 years post-diagnosis), annual proportion with co-prescribing for prophylaxis of associated bone (corticosteroids, women only) and gastrointestinal (NSAIDs) comorbidity.

Results: Reported incidence of RA was 5.98 (±0.37) per 10 000 person-years and prevalence was 0.91% (±0.014) in 2017. In 71 411 RA patients, long-term DMARD prescribing initially rose post-diagnosis from 41.6% in 1998-67.9% in 2009. Corticosteroid prescribing changed little, overall (22.2% in 1998, 19.1% in 2016; incident risk ratio (IRR) 0.92, 95% CI 0.82-1.03) and across the life-course from the first to fifteenth year (22.2% to 16.9%). NSAID prescribing declined from 57.7% in 1998, and significantly so from 2008, to 27.1% in 2016 (IRR 0.50, 95% CI 0.44-0.56). This continued across the life-course (41.2% to 28.4%). Bone prophylaxis increased to 68.1% in 2008 before declining to 56.4% in 2017; gastrointestinal prophylaxis increased from 11.5% in 1998-62.6% in 2017. Sub-analyses showed consistent patterns.

Conclusion: Despite modern treatment strategies, corticosteroid prescribing in RA patients remains substantial and persists beyond 6 months once initiated. Rheumatologists need to determine causes and develop strategies to reduce corticosteroid use to minimise adverse event occurrence.
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http://dx.doi.org/10.1093/rheumatology/keaa892DOI Listing
January 2021

Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study.

PLoS Med 2020 12 3;17(12):e1003432. Epub 2020 Dec 3.

School of Dentistry, University of Leeds, Leeds, United Kingdom.

Background: Glucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases.

Methods And Findings: We conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998-2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n = 25,581), inflammatory bowel disease (n = 27,739), rheumatoid arthritis (n = 25,324), systemic lupus erythematosus (n = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person-years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0-14.9 mg, 1.6% for 15.0-24.9 mg, and 1.2% for ≥25.0 mg. Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events. One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64-1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54-1.85) for atrial fibrillation, 1.75 (95% CI 1.56-1.97) for heart failure, 1.76 (95% CI 1.51-2.05) for acute myocardial infarction, 1.78 (95% CI 1.53-2.07) for peripheral arterial disease, 1.32 (95% CI 1.15-1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47-2.53) for abdominal aortic aneurysm. The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose-response estimates.

Conclusions: In this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.
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http://dx.doi.org/10.1371/journal.pmed.1003432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714202PMC
December 2020

Glucocorticoid dose-dependent risk of type 2 diabetes in six immune-mediated inflammatory diseases: a population-based cohort analysis.

BMJ Open Diabetes Res Care 2020 07;8(1)

School of Medicine, University of Leeds, Leeds, UK

Introduction: In immune-mediated inflammatory diseases, there is a lack of -estimates of glucocorticoid dose-response diabetes risk that consider changes in prescribed dose over time and disease activity.

Research Design And Methods: Population-based longitudinal analysis of electronic health records from the UK Clinical Practice Research Datalink, linked to hospital admissions and the mortality registry (1998-2017). We included 100 722 adult patients without diabetes history, diagnosed with giant cell arteritis or polymyalgia rheumatica (n=32 593), inflammatory bowel disease (n=29 272), rheumatoid arthritis (n=28 365), vasculitis (n=6082), or systemic lupus erythematosus (n=4410). We estimated risks and HRs of type 2 diabetes associated with time-variant daily and total cumulative prednisolone-equivalent glucocorticoid dose using Cox regression methods.

Results: Average patient age was 58.6 years, 65 469 (65.0%) were women and 8858 (22.6%) had a body mass index (BMI) ≥30 kg/m. Overall, 8137 (8.1%) people developed type 2 diabetes after a median follow-up of 4.9 years. At 1 year, the cumulative risk of diabetes increased from 0.9% during periods of non-use to 5.0% when the daily prednisolone-equivalent dose was ≥25.0 mg. We found strong dose-dependent associations for all immune-mediated diseases, BMI levels and underlying disease duration, even after controlling for periods of active systemic inflammation. Adjusted HR for a <5.0 mg daily dose versus non-use was 1.90, 95% CI 1.44 to 2.50; range 1.70 for rheumatoid arthritis to 2.93 for inflammatory bowel disease.

Conclusions: We report dose-dependent risks of type 2 diabetes associated with glucocorticoid use for six common immune-mediated inflammatory diseases. These results underline the need for regular diabetic risk assessment and testing during glucocorticoid therapy in these patients.
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http://dx.doi.org/10.1136/bmjdrc-2020-001220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389515PMC
July 2020

Oral glucocorticoids and incidence of hypertension in people with chronic inflammatory diseases: a population-based cohort study.

CMAJ 2020 03;192(12):E295-E301

Leeds Institute of Biomedical and Clinical Sciences (Mebrahtu); Leeds Institute of Cardiovascular and Metabolic Medicine (Morgan), School of Medicine, University of Leeds; NIHR Biomedical Research Centre (Morgan, Stewart), Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital; Leeds Institute of Health Sciences, (West, Pujades-Rodriguez), School of Medicine; Dean's office, Faculty of Medicine & Health (Stewart), University of Leeds, Leeds, UK

Background: Only a few population-based studies have examined the association between glucocorticoids and hypertension, with inconsistent results. We aimed to investigate the effect of oral glucocorticoids on incidence of hypertension in adults with chronic inflammatory diseases.

Methods: We analyzed electronic health records from 389 practices in England during 1998-2017 of adults diagnosed with any of 6 chronic inflammatory diseases but with no previous diagnosis of hypertension. We used glucocorticoid prescription data to construct time-variant daily and cumulative variables of prednisolone-equivalent dose (cumulated from 1 year before the start of follow-up) and estimated incidence rates and adjusted hazard ratios (HRs) for hypertension using Cox regression analysis.

Results: Among 71 642 patients in the cohort, 24 896 (34.8%) developed hypertension during a median follow-up of 6.6 years. The incidence rate of hypertension was 46.7 (95% confidence interval [CI] 46.0-47.3) per 1000 person-years. Incidence rates increased with higher cumulative glucocorticoid prednisolone-equivalent dose, from 44.4 per 1000 person-years in periods of nonuse to 45.3 per 1000 person-years for periods with between > 0.0 and 959.9 mg (HR 1.14, 95% CI 1.09-1.19), to 49.3 per 1000 person-years for periods with 960-3054.9 mg (HR 1.20, 95% CI 1.14-1.27), and to 55.6 per 1000 person-years for periods with ≥ 3055 mg (HR 1.30, 95% CI 1.25-1.35). Cumulative effects were seen for the 6 diseases studied, but dose-response effects were not found for daily dose.

Interpretation: Cumulative dose of oral glucocorticoids was associated with increased incidence of hypertension, suggesting that blood pressure should be monitored closely in patients routinely treated with these drugs. Given that glucocorticoids are widely prescribed, the associated health burden could be high. ClinicalTrials. gov, no. NCT03760562.
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http://dx.doi.org/10.1503/cmaj.191012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101178PMC
March 2020

Feasibility and Face Validity of Outcome Measures for Use in Future Studies of Polymyalgia Rheumatica: An OMERACT Study.

J Rheumatol 2020 09 1;47(9):1379-1384. Epub 2020 Feb 1.

From the Epidemiology Centre Versus Arthritis, Norwich Medical School, University of East Anglia, Norwich, UK; Department of Rheumatology, East Suffolk and North Essex Foundation Trust, Ipswich, UK; Department of Rheumatology, Austin Health; Department of Medicine, University of Melbourne, Melbourne, Australia; Primary Care Centre Versus Arthritis, Research Institute for Primary Care and Health Sciences, Keele University, Keele; PMRGCA Scotland, Scotland, UK; Department of Epidemiology and Biostatistics, and Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, the Netherlands; Leeds Institute of Health Sciences, University of Leeds, Leeds, UK; Department of Rheumatology, and Department of Medicine, Hospital for Special Surgery, New York, New York, USA; Department of Rheumatology and Immunology, Medical University Graz, Graz, Austria; Department of Rheumatology, Hospital of Bruneck, Bruneck, Italy; Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, UK; Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark; Department of Rheumatology, Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK; SDG LLC, Cambridge, Massachusetts, USA; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds; National Institute for Health Research (NIHR) Leeds Biomedical Research Centre, Leeds Teaching Hospitals National Health Service (NHS) Trust, Leeds, UK; Discipline of Medicine, The University of Adelaide; the Rheumatology Unit, The Queen Elizabeth and Royal Adelaide Hospitals, Adelaide, Australia.

Objective: To survey participants with polymyalgia rheumatica (PMR) to evaluate the face validity, acceptability, and domain match of proposed candidate outcome measures.

Methods: A structured, online, anonymous survey was disseminated by patient support groups through their networks and online forums. The candidate outcome measures comprised (1) visual analog scale (VAS) and numerical rating score (NRS) to assess pain; (2) VAS, NRS, and duration to assess stiffness; (3) the modified Health Assessment Questionnaire and Health Assessment Questionnaire Disability Index to assess physical function; and (4) C-reactive protein and erythrocyte sedimentation rate to assess inflammation. Free-text answers were analyzed using descriptive thematic analysis to determine respondents' views of the candidate instruments.

Results: Seventy-eight people with PMR from 6 countries (UK, France, USA, Canada, Australia, and New Zealand) participated in the survey. Most respondents agreed candidate instruments were acceptable or "good to go." Free-text analysis identified 5 themes that participants considered inadequately covered by the proposed instruments. These related to (1) the variability, context, and location of pain; (2) the variability of stiffness; (3) fatigue; (4) disability; and (5) the correlation of inflammatory marker levels and severity of symptoms, sometimes reflecting disease activity and other times not.

Conclusion: Participants reported additional aspects of their experience that are not covered by the proposed instruments, particularly for the experience of stiffness and effect of fatigue. New patient-reported outcome measures are required to increase the relevance of results from clinical trials to patients with PMR.
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http://dx.doi.org/10.3899/jrheum.190575DOI Listing
September 2020

Metformin use and cardiovascular outcomes after acute myocardial infarction in patients with type 2 diabetes: a cohort study.

Cardiovasc Diabetol 2019 12 9;18(1):168. Epub 2019 Dec 9.

The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.

Background: The use of metformin after acute myocardial infarction (AMI) has been associated with reduced mortality in people with type 2 diabetes mellitus (T2DM). However, it is not known if it is acutely cardioprotective in patients taking metformin at the time of AMI. We compared patient outcomes according to metformin status at the time of admission for fatal and non-fatal AMI in a large cohort of patients in England.

Methods: This study used linked data from primary care, hospital admissions and death registry from 4.7 million inhabitants in England, as part of the CALIBER resource. The primary endpoint was a composite of acute myocardial infarction requiring hospitalisation, stroke and cardiovascular death. The secondary endpoints were heart failure (HF) hospitalisation and all-cause mortality.

Results: 4,030 patients with T2DM and incident AMI recorded between January 1998 and October 2010 were included. At AMI admission, 63.9% of patients were receiving metformin and 36.1% another oral hypoglycaemic drug. Median follow-up was 343 (IQR: 1-1436) days. Adjusted analyses showed an increased hazard of the composite endpoint in metformin users compared to non-users (HR 1.09 [1.01-1.19]), but not of the secondary endpoints. The higher risk of the composite endpoint in metformin users was only observed in people taking metformin at AMI admission, whereas metformin use post-AMI was associated with a reduction in risk of all-cause mortality (0.76 [0.62-0.93], P = 0.009).

Conclusions: Our study suggests that metformin use at the time of first AMI is associated with increased risk of cardiovascular disease and death in patients with T2DM, while its use post-AMI might be beneficial. Further investigation in well-designed randomised controlled trials is indicated, especially in view of emerging evidence of cardioprotection from sodium-glucose co-transporter-2 (SGLT2) inhibitors.
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http://dx.doi.org/10.1186/s12933-019-0972-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900858PMC
December 2019

Bleeding in cardiac patients prescribed antithrombotic drugs: electronic health record phenotyping algorithms, incidence, trends and prognosis.

BMC Med 2019 11 20;17(1):206. Epub 2019 Nov 20.

Health Data Research UK, University College London, 222 Euston Road, London, NW1 2DA, UK.

Background: Clinical guidelines and public health authorities lack recommendations on scalable approaches to defining and monitoring the occurrence and severity of bleeding in populations prescribed antithrombotic therapy.

Methods: We examined linked primary care, hospital admission and death registry electronic health records (CALIBER 1998-2010, England) of patients with newly diagnosed atrial fibrillation, acute myocardial infarction, unstable angina or stable angina with the aim to develop algorithms for bleeding events. Using the developed bleeding phenotypes, Kaplan-Meier plots were used to estimate the incidence of bleeding events and we used Cox regression models to assess the prognosis for all-cause mortality, atherothrombotic events and further bleeding.

Results: We present electronic health record phenotyping algorithms for bleeding based on bleeding diagnosis in primary or hospital care, symptoms, transfusion, surgical procedures and haemoglobin values. In validation of the phenotype, we estimated a positive predictive value of 0.88 (95% CI 0.64, 0.99) for hospitalised bleeding. Amongst 128,815 patients, 27,259 (21.2%) had at least 1 bleeding event, with 5-year risks of bleeding of 29.1%, 21.9%, 25.3% and 23.4% following diagnoses of atrial fibrillation, acute myocardial infarction, unstable angina and stable angina, respectively. Rates of hospitalised bleeding per 1000 patients more than doubled from 1.02 (95% CI 0.83, 1.22) in January 1998 to 2.68 (95% CI 2.49, 2.88) in December 2009 coinciding with the increased rates of antiplatelet and vitamin K antagonist prescribing. Patients with hospitalised bleeding and primary care bleeding, with or without markers of severity, were at increased risk of all-cause mortality and atherothrombotic events compared to those with no bleeding. For example, the hazard ratio for all-cause mortality was 1.98 (95% CI 1.86, 2.11) for primary care bleeding with markers of severity and 1.99 (95% CI 1.92, 2.05) for hospitalised bleeding without markers of severity, compared to patients with no bleeding.

Conclusions: Electronic health record bleeding phenotyping algorithms offer a scalable approach to monitoring bleeding in the population. Incidence of bleeding has doubled in incidence since 1998, affects one in four cardiovascular disease patients, and is associated with poor prognosis. Efforts are required to tackle this iatrogenic epidemic.
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http://dx.doi.org/10.1186/s12916-019-1438-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864929PMC
November 2019

Lower Urinary Tract Infections: Management, Outcomes and Risk Factors for Antibiotic Re-prescription in Primary Care.

EClinicalMedicine 2019 Sep 12;14:23-31. Epub 2019 Aug 12.

Leeds Institute for Data Analytics, School of Medicine, University of Leeds, UK.

Background: Urinary tract infections (UTIs) are major drivers of antibiotic prescribing in primary care. Inappropriate antibiotic prescribing for UTIs likely drives antibiotic resistance. We aimed to describe current investigation and antibiotic treatment to examine opportunities for improved antimicrobial stewardship.

Methods: We identified a cohort of all patients with lower UTI diagnosis between 2011 and 2015 in the 390 primary care practices contributing data to ResearchOne in England. We examined investigation, antibiotic treatment and antibiotic re-prescription within 28 days according to guideline-defined patient groups. We assessed risk factors for re-prescription using mixed-effect logistic regression.

Findings: In total, 494,675 UTIs were diagnosed in 300,354 patients. Median age was 54 years, and 83.3% were women. Same-day antibiotic was prescribed for 85.7% of UTIs; 56.8% were treated with trimethoprim, and urine sampling was undertaken in 25.0%. The antibiotic re-prescription rate was low (17,430, 4.1%) and increased slightly over time in men (from 5.2% in 2011 to 6.2% in 2015). Overall, 21.1% of pre-prescription were for the same antibiotic. The percentage of adults with recurrent UTIs ranged from 1.0% in 18-64 year-old men to 2.6% in women ≥ 65 years. The risk of antibiotic re-prescription increased with age, calendar year, recent antibiotic prescribing and treatment with antibiotic other than trimethoprim or nitrofurantoin.

Interpretation: Most patients diagnosed with lower UTI in primary care receive same-day empirical antibiotics with little diversity in choice of agent. The antibiotic re-prescription rate is low. Microbiological investigation and re-prescription of the same antibiotic given for the initial episode happened in one quarter of UTIs.

Funding: UK National Health Service Improvement.
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http://dx.doi.org/10.1016/j.eclinm.2019.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833446PMC
September 2019

Quality of life trajectories in survivors of acute myocardial infarction: a national longitudinal study.

Heart 2020 01 7;106(1):33-39. Epub 2019 Nov 7.

Leeds Institute of Cardiovascular and Metabolic Medicine/Leeds Institute of Data Analytics, University of Leeds, Leeds, UK.

Aim: To define trajectories of perceived health-related quality of life (HRQoL) among survivors of acute myocardial infarction (AMI) and identify factors associated with trajectories.

Methods: Data on HRQoL among 9566 survivors of AMI were collected from 77 National Health Service hospitals in England between 1 November 2011 and 24 June 2015. Longitudinal HRQoL was collected using the EuroQol five-dimension questionnaire measured at hospitalisation, 1, 6 and 12 months post-AMI. Trajectories of perceived HRQoL post-MI were determined using multilevel regression analysis and latent class growth analysis (LCGA).

Results: One or more percieved health problems in mobility, self-care, usual activities, pain/discomfort and anxiety/depression was reported by 69.1% (6607/9566) at hospitalisation and 59.7% (3011/5047) at 12 months. Reduced HRQoL was associated with women (-4.07, 95% CI -4.88 to -3.25), diabetes (-2.87, 95% CI -3.87 to -1.88), previous AMI (-1.60, 95% CI -2.72 to -0.48), previous angina (-1.72, 95% CI -2.77 to -0.67), chronic renal failure (-2.96, 95% CI -5.08 to -0.84; -3.10, 95% CI -5.72 to -0.49), chronic obstructive pulmonary disease (-3.89, 95% CI -5.07 to -2.72) and cerebrovascular disease (-2.60, 95% CI -4.24 to -0.96). LCGA identified three subgroups of HRQoL which we labelled: improvers (68.1%), non-improvers (22.1%) and dis-improvers (9.8%). Non-improvers and dis-improvers were more likely to be women, non-ST-elevation myocardial infarction (NSTEMI) and have long-term health conditions, compared with improvers.

Conclusions: Quality of life improves for the majority of survivors of AMI but is significantly worse and more likely to decline for women, NSTEMI and those with long-term health conditions. Assessing HRQoL both in hospital and postdischarge may be important in determining which patients could benefit from tailored interventions.

Trial Registration: NCT01808027 and NCT01819103.
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http://dx.doi.org/10.1136/heartjnl-2019-315510DOI Listing
January 2020

Variation in methods, results and reporting in electronic health record-based studies evaluating routine care in gout: A systematic review.

PLoS One 2019 24;14(10):e0224272. Epub 2019 Oct 24.

Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom.

Objective: To perform a systematic review examining the variation in methods, results, reporting and risk of bias in electronic health record (EHR)-based studies evaluating management of a common musculoskeletal disease, gout.

Methods: Two reviewers systematically searched MEDLINE, Scopus, Web of Science, CINAHL, PubMed, EMBASE and Google Scholar for all EHR-based studies published by February 2019 investigating gout pharmacological treatment. Information was extracted on study design, eligibility criteria, definitions, medication usage, effectiveness and safety data, comprehensiveness of reporting (RECORD), and Cochrane risk of bias (registered PROSPERO CRD42017065195).

Results: We screened 5,603 titles/abstracts, 613 full-texts and selected 75 studies including 1.9M gout patients. Gout diagnosis was defined in 26 ways across the studies, most commonly using a single diagnostic code (n = 31, 41.3%). 48.4% did not specify a disease-free period before 'incident' diagnosis. Medication use was suboptimal and varied with disease definition while results regarding effectiveness and safety were broadly similar across studies despite variability in inclusion criteria. Comprehensiveness of reporting was variable, ranging from 73% (55/75) appropriately discussing the limitations of EHR data use, to 5% (4/75) reporting on key data cleaning steps. Risk of bias was generally low.

Conclusion: The wide variation in case definitions and medication-related analysis among EHR-based studies has implications for reported medication use. This is amplified by variable reporting comprehensiveness and the limited consideration of EHR-relevant biases (e.g. data adequacy) in study assessment tools. We recommend accounting for these biases and performing a sensitivity analysis on case definitions, and suggest changes to assessment tools to foster this.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224272PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812805PMC
March 2020

Statistics on mortality following acute myocardial infarction in 842 897 Europeans.

Cardiovasc Res 2020 01;116(1):149-157

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Aims: To compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments.

Methods And Results: National data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 patients, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART)] and the UK [n = 247, 662 529 patients, Myocardial Ischaemia National Audit Project (MINAP)] between 2003 and 2013. There were lower rates of revascularization [STEMI (43.8% vs. 74.9%); NSTEMI (27.5% vs. 43.6%)] and pharmacotherapies at time of hospital discharge including [aspirin (82.9% vs. 90.2%) and (79.9% vs. 88.0%), β-blockers (73.4% vs. 86.4%) and (65.3% vs. 85.1%)] in the UK compared with Sweden, respectively. Standardized net probability of death (NPD) between admission and 1 month was higher in the UK for STEMI [8.0 (95% confidence interval 7.4-8.5) vs. 6.7 (6.5-6.9)] and NSTEMI [6.8 (6.4-7.2) vs. 4.9 (4.7-5.0)]. Between 6 months and 1 year and more than 1 year, NPD remained higher in the UK for NSTEMI [2.9 (2.5-3.3) vs. 2.3 (2.2-2.5)] and [21.4 (20.0-22.8) vs. 18.3 (17.6-19.0)], but was similar for STEMI [0.7 (0.4-1.0) vs. 0.9 (0.7-1.0)] and [8.4 (6.7-10.1) vs. 8.3 (7.5-9.1)].

Conclusion: Short-term mortality following STEMI and NSTEMI was higher in the UK compared with Sweden. Mid- and longer-term mortality remained higher in the UK for NSTEMI but was similar for STEMI. Differences in mortality may be due to differential use of guideline-indicated treatments.
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http://dx.doi.org/10.1093/cvr/cvz197DOI Listing
January 2020

Incidence of infections associated with oral glucocorticoid dose in people diagnosed with polymyalgia rheumatica or giant cell arteritis: a cohort study in England.

CMAJ 2019 06;191(25):E680-E688

School of Dentistry (Wu), University of Leeds; Leeds Institute for Data Analytics (Keeley, Morgan, Pujades-Rodriguez), University of Leeds, Leeds, UK; Arthritis Research UK Primary Care Centre (Mallen), University of Keele, Staffordshire, UK; Leeds Institute of Cardiovascular and Metabolic Medicine (Morgan), School of Medicine, University of Leeds; NIHR Leeds Biomedical Research Centre (Morgan), Leeds Teaching Hospitals NHS Trust; Leeds Institute of Health Sciences (Pujades-Rodriguez), School of Medicine, University of Leeds, Leeds, UK

Background: Most patients with polymyalgia rheumatica or giant cell arteritis are treated with glucocorticoid therapy in primary care. We estimated dose-response risks of infection for this population in England.

Methods: We conducted a retrospective record-linkage study involving a cohort of people with polymyalgia rheumatica or giant cell arteritis registered in family practices across England (1998-2017). Estimates of first occurring infection per level of time-variant current and cumulative dose were obtained using Kaplan-Meier methods and multilevel proportional-hazards Cox models.

Results: Of 39 938 patients attending 389 family practices, 22 234 (55.7%) had at least 1 infection over a median follow-up period of 4.8 years, with 5937 (26.7%) requiring hospital admission and 1616 (7.3%) dying within 7 days of diagnosis. Cumulative risks of all-cause infection were 18.3% (95% confidence interval [CI] 17.9%-18.7%) at 1 year, 54.7% (95% CI 54.1%-55.2%) at 5 years and 76.9% (95% CI 76.2%-77.5%) at 10 years. Lower respiratory tract infections, conjunctivitis and herpes zoster were the most commonly diagnosed infections. The increases in adjusted hazard ratios (HRs) for all-cause infection per 5 mg prednisolone-equivalent daily dose increase and per 1000 mg cumulative dose increase in the last year from the patient's end date of follow-up were 1.13 (95% CI 1.12-1.14) and 1.50 (95% CI 1.49-1.52), respectively. Adjusted HRs associated with periods of current glucocorticoid versus no glucocorticoid use ranged from 1.48 (95% CI 1.39-1.57) for fungal to 1.70 (95% CI 1.60-1.80) for bacterial infection. Stepwise dose-related associations were found for bacterial, viral, parasitic and fungal infections, irrespective of patient age, duration of underlying chronic disease and baseline vaccination status.

Interpretation: We quantified the excess risk of all-cause, bacterial, viral, parasitic and fungal infection conferred by oral glucocorticoids in people with polymyalgia rheumatica or giant cell arteritis and found strong dose responses for all types, even at daily doses of less than 5 mg prednisolone.
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http://dx.doi.org/10.1503/cmaj.190178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592810PMC
June 2019

Dose dependency of iatrogenic glucocorticoid excess and adrenal insufficiency and mortality: a cohort study in England.

J Clin Endocrinol Metab 2019 Apr 22. Epub 2019 Apr 22.

Leeds Institute of Health Sciences, School of Medicine, University of Leeds, UK.

Context: Adrenal insufficiency and Cushing's syndrome are known adverse events of glucocorticoids. However, no population estimates of dose-related risks are available.

Objective: To investigate dose-related risks of adrenal dysfunction and death in adults with six chronic inflammatory diseases treated with oral glucocorticoids.

Design And Setting: Retrospective record-linkage open-cohort study spanning primary and hospital care in England.

Patients: 70,638 people oral glucocorticoid-users and 41,166 non-users aged ≥18 years registered in 389 practices in 1998-2017.

Main Outcome Measures: Incidence rates and hazard ratios (HRs) of diagnosed adrenal dysfunction and death.

Results: During a median follow-up of 5.5 years, 183 patients had glucocorticoid-induced adrenal insufficiency and 248 glucocorticoid-induced Cushing's syndrome. A total of 22,317 (31.6%) and 7,544 (18.3%) deaths occurred amongst glucocorticoid users and non-users, respectively. Incidence of all outcomes increased with higher current daily and cumulative doses. For adrenal insufficiency, the increases in HRs were of 1.07 (95% CI 1.04-1.09) for every increase of 5mg per day and of 2.25 (95% CI 2.15-2.35) per 1000mg of cumulative prednisolone-equivalent dose over the past year. The respective increases in HRs for Cushing's syndrome were of 1.09 (95% CI 1.08-1.11) and 2.31 (95% CI 2.23-2.40) and for mortality of 1.26 (95% CI 2.24-1.28) and 2.05 (95% CI 2.04-2.06).

Conclusion: We report a high glucocorticoid dose-dependent increased risk of adrenal adverse events and death. The low observed absolute risk of adrenal insufficiency highlights a potential lack of awareness, and a need for increased physician and patient education about the risks of adrenal dysfunction induced by glucocorticoids.
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http://dx.doi.org/10.1210/jc.2019-00153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656418PMC
April 2019

Socio-economic inequalities in life expectancy of older adults with and without multimorbidity: a record linkage study of 1.1 million people in England.

Int J Epidemiol 2019 08;48(4):1340-1351

Department of Applied Health Research, University College London, London, UK.

Background: Age of onset of multimorbidity and its prevalence are well documented. However, its contribution to inequalities in life expectancy has yet to be quantified.

Methods: A cohort of 1.1 million English people aged 45 and older were followed up from 2001 to 2010. Multimorbidity was defined as having 2 or more of 30 major chronic diseases. Multi-state models were used to estimate years spent healthy and with multimorbidity, stratified by sex, smoking status and quintiles of small-area deprivation.

Results: Unequal rates of multimorbidity onset and subsequent survival contributed to higher life expectancy at age 65 for the least (Q1) compared with most (Q5) deprived: there was a 2-year gap in healthy life expectancy for men [Q1: 7.7 years (95% confidence interval: 6.4-8.5) vs Q5: 5.4 (4.4-6.0)] and a 3-year gap for women [Q1: 8.6 (7.5-9.4) vs Q5: 5.9 (4.8-6.4)]; a 1-year gap in life expectancy with multimorbidity for men [Q1: 10.4 (9.9-11.2) vs Q5: 9.1 (8.7-9.6)] but none for women [Q1: 11.6 (11.1-12.4) vs Q5: 11.5 (11.1-12.2)]. Inequalities were attenuated but not fully attributable to socio-economic differences in smoking prevalence: multimorbidity onset was latest for never smokers and subsequent survival was longer for never and ex smokers.

Conclusions: The association between social disadvantage and multimorbidity is complex. By quantifying socio-demographic and smoking-related contributions to multimorbidity onset and subsequent survival, we provide evidence for more equitable allocation of prevention and health-care resources to meet local needs.
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http://dx.doi.org/10.1093/ije/dyz052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693817PMC
August 2019

Time spent at blood pressure target and the risk of death and cardiovascular diseases.

PLoS One 2018 5;13(9):e0202359. Epub 2018 Sep 5.

Health Data Research UK London, University College London, London, United Kingdom.

Background: The time a patient spends with blood pressure at target level is an intuitive measure of successful BP management, but population studies on its effectiveness are as yet unavailable.

Method: We identified a population-based cohort of 169,082 individuals with newly identified high blood pressure who were free of cardiovascular disease from January 1997 to March 2010. We used 1.64 million clinical blood pressure readings to calculate the TIme at TaRgEt (TITRE) based on current target blood pressure levels.

Result: The median (Inter-quartile range) TITRE among all patients was 2.8 (0.3, 5.6) months per year, only 1077 (0.6%) patients had a TITRE ≥11 months. Compared to people with a 0% TITRE, patients with a TITRE of 3-5.9 months, and 6-8.9 months had 75% and 78% lower odds of the composite of cardiovascular death, myocardial infarction and stroke (adjusted odds ratios, 0.25 (95% confidence interval: 0.21, 0.31) and 0.22 (0.17, 0.27), respectively). These associations were consistent for heart failure and any cardiovascular disease and death (comparing a 3-5.9 month to 0% TITRE, 63% and 60% lower in odds, respectively), among people who did or did not have blood pressure 'controlled' on a single occasion during the first year of follow-up, and across groups defined by number of follow-up BP measure categories.

Conclusion: Based on the current frequency of measurement of blood pressure this study suggests that few newly hypertensive patients sustained a complete, year-round on target blood pressure over time. The inverse associations between a higher TITRE and lower risk of incident cardiovascular diseases were independent of widely-used blood pressure 'control' indicators. Randomized trials are required to evaluate interventions to increase a person's time spent at blood pressure target.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202359PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124703PMC
February 2019

Clinically recorded heart rate and incidence of 12 coronary, cardiac, cerebrovascular and peripheral arterial diseases in 233,970 men and women: A linked electronic health record study.

Eur J Prev Cardiol 2018 09 2;25(14):1485-1495. Epub 2018 Jul 2.

1 Institute of Health Informatics, University College London.

Background In healthy population cohorts, resting heart rate above 90 bpm is associated with mortality from coronary heart disease, but it is not clear whether associations are present at lower heart rates or whether these associations differ between women. Methods The CALIBER resource of linked electronic health records from primary care, hospitalisations, myocardial infarction registry and cause-specific mortality in the UK was used to assess associations between resting heart rate and 12 fatal and non-fatal coronary, cardiac, cerebral and peripheral vascular cardiovascular diseases and death using Cox proportional hazard models. Results Among 233,970 patients, 29,690 fatal and non-fatal events occurred. Fully adjusted models showed that resting heart rate was not associated in men or women with cerebrovascular events. In men a resting heart rate of 70-79 bpm (29.1% of all men) versus less than 60 bpm was associated with an increased risk of heart failure (hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.26-2.16), unheralded coronary death (HR 1.65, 95% CI 1.13-2.41), total cardiovascular events (HR 1.22, 95% CI 1.15-1.28) and all-cause mortality (HR 1.39, 95% CI 1.22-1.58). Women with a higher resting heart rate level of 80-89 bpm versus 60 bpm had a higher risk of total cardiovascular disease events (HR 1.17, 95% CI 1.07-1.24) and all-cause mortality (HR 1.21, 95% CI 1.07-1.35) compared to a resting heart rate less than 60 bpm. The risk was also present at higher heart rates (>90 bpm) for heart failure and sudden cardiac death. Conclusions A resting heart rate that clinicians currently consider as 'normal' in the general population is specifically associated with the incidence of certain major cardiovascular diseases and death, with the risk starting at lower resting heart rate levels in men compared to women. Further research is required to evaluate whether interventions to lower resting heart rate are warranted to prevent disease. The study is registered at: clinicaltrials.gov (ID: NCT01947361).
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http://dx.doi.org/10.1177/2047487318785228DOI Listing
September 2018

The diagnosis, burden and prognosis of dementia: A record-linkage cohort study in England.

PLoS One 2018 26;13(6):e0199026. Epub 2018 Jun 26.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Objectives: Electronic health records (EHR) might be a useful resource to study the risk factors and clinical care of people with dementia. We sought to determine the diagnostic validity of dementia captured in linked EHR.

Methods And Findings: A cohort of adults in linked primary care, hospital, disease registry and mortality records in England, [CALIBER (CArdiovascular disease research using LInked Bespoke studies and Electronic health Records)]. The proportion of individuals with dementia, Alzheimer's disease, vascular and rare dementia in each data source was determined. A comparison was made of symptoms and care between people with dementia and age-, sex- and general practice-matched controls, using conditional logistic regression. The lifetime risk and prevalence of dementia and mortality rates in people with and without dementia were estimated with random-effects Poisson models. There were 47,386 people with dementia: 12,633 with Alzheimer's disease, 9540 with vascular and 1539 with rare dementia. Seventy-four percent of cases had corroborating evidence of dementia. People with dementia were more likely to live in a deprived area (conditional OR 1.26;95%CI:1.20-1.31 most vs least deprived), have documented memory impairment (cOR = 11.97;95%CI:11.24-12.75), falls (cOR = 2.36;95%CI:2.31-2.41), depression (cOR = 2.03; 95%CI:1.98-2.09) or anxiety (cOR = 1.27; 95%CI:1.23-1.32). The lifetime risk of dementia at age 65 was 9.2% (95%CI:9.0%-9.4%), in men and 14.9% (95%CI:14.7%-15.1%) in women. The population prevalence of recorded dementia increased from 0.3% in 2000 to 0.7% in 2010. A higher mortality rate was observed in people with than without dementia (IRR = 1.56;95%CI:1.54-1.58).

Conclusions: Most people with a record of dementia in linked UK EHR had some corroborating evidence for diagnosis. The estimated 10-year risk of dementia was higher than published population-based estimations. EHR are therefore a promising source of data for dementia research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199026PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019102PMC
January 2019

HIV treatment is associated with a two-fold higher probability of raised triglycerides: Pooled Analyses in 21 023 individuals in sub-Saharan Africa.

Glob Health Epidemiol Genom 2018 8;3. Epub 2018 May 8.

Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

Background: Anti-retroviral therapy (ART) regimes for HIV are associated with raised levels of circulating triglycerides (TG) in western populations. However, there are limited data on the impact of ART on cardiometabolic risk in sub-Saharan African (SSA) populations.

Methods: Pooled analyses of 14 studies comprising 21 023 individuals, on whom relevant cardiometabolic risk factors (including TG), HIV and ART status were assessed between 2003 and 2014, in SSA. The association between ART and raised TG (>2.3 mmol/L) was analysed using regression models.

Findings: Among 10 615 individuals, ART was associated with a two-fold higher probability of raised TG (RR 2.05, 95% CI 1.51-2.77, I=45.2%). The associations between ART and raised blood pressure, glucose, HbA1c, and other lipids were inconsistent across studies.

Interpretation: Evidence from this study confirms the association of ART with raised TG in SSA populations. Given the possible causal effect of raised TG on cardiovascular disease (CVD), the evidence highlights the need for prospective studies to clarify the impact of long term ART on CVD outcomes in SSA.
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http://dx.doi.org/10.1017/gheg.2018.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985947PMC
May 2018

An electronic health records cohort study on heart failure following myocardial infarction in England: incidence and predictors.

BMJ Open 2018 03 3;8(3):e018331. Epub 2018 Mar 3.

Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, London, UK.

Objectives: To investigate the incidence and determinants of heart failure (HF) following a myocardial infarction (MI) in a contemporary cohort of patients with MI using routinely collected primary and hospital care electronic health records (EHRs).

Methods: Data were used from the CALIBER programme, linking EHRs in England from primary care, hospital admissions, an MI registry and mortality data. Subjects were eligible if they were 18 years or older, did not have a history of HF and survived a first MI. Factors associated with time to HF were examined using Cox proportional hazard models.

Results: Of the 24 479 patients with MI, 5775 (23.6%) developed HF during a median follow-up of 3.7 years (incidence rate per 1000 person-years: 63.8, 95% CI 62.2 to 65.5). Baseline characteristics significantly associated with developing HF were: atrial fibrillation (HR 1.62, 95% CI 1.51 to 1.75), age (per 10 years increase: 1.45, 1.41 to 1.49), diabetes (1.45, 1.35 to 1.56), peripheral arterial disease (1.38, 1.26 to 1.51), chronic obstructive pulmonary disease (1.28, 1.17 to 1.40), greater socioeconomic deprivation (5th vs 1st quintile: 1.27, 1.13 to 1.41), ST-segment elevation MI at presentation (1.19, 1.11 to 1.27) and hypertension (1.16, 1.09 to 1.23). Results were robust to various sensitivity analyses such as competing risk analysis and multiple imputation.

Conclusion: In England, one in four survivors of a first MI develop HF within 4 years. This contemporary study demonstrates that patients with MI are at considerable risk of HF. Baseline patient characteristics associated with time until HF were identified, which may be used to target preventive strategies.
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http://dx.doi.org/10.1136/bmjopen-2017-018331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855447PMC
March 2018

Identifying unmet clinical need in hypertrophic cardiomyopathy using national electronic health records.

PLoS One 2018 11;13(1):e0191214. Epub 2018 Jan 11.

Farr Institute of Health Informatics Research, Institute of Health Informatics, University College London, London, United Kingdom.

Introduction: To evaluate unmet clinical need in unselected hypertrophic cardiomyopathy (HCM) patients to determine the risk of a wide range of subsequent cardiovascular disease endpoints and safety endpoints relevant for trial design.

Methods: Population based cohort (CALIBER, linked primary care, hospital and mortality records in England, period 1997-2010), all people diagnosed with HCM were identified and matched by age, sex and general practice with ten randomly selected people without HCM. Random-effects Poisson models were used to assess the associations between HCM and cardiovascular diseases and bleeding.

Results: Among 3,290,455 eligible people a diagnosis of hypertrophic cardiomyopathy was found in 4 per 10,000. Forty-one percent of the 1,160 individuals with hypertrophic cardiomyopathy were women and the median age was 57 years. The median follow-up was 4.0 years. Compared to general population controls, people with HCM had higher risk of ventricular arrhythmia (incidence rate ratio = 23.53, [95% confidence interval 12.67-43.72]), cardiac arrest or sudden cardiac death (6.33 [3.69-10.85]), heart failure (4.31, [3.30-5.62]), and atrial fibrillation (3.80 [3.04-4.75]). HCM was also associated with a higher incidence of myocardial infarction ([MI] 1.90 [1.27-2.84]) and coronary revascularisation (2.32 [1.46-3.69]).The absolute Kaplan-Meier risks at 3 years were 8.8% for the composite endpoint of cardiovascular death or heart failure, 8.4% for the composite of cardiovascular death, stroke or myocardial infarction, and 1.5% for major bleeding.

Conclusions: Our study identified major unmet need in HCM and highlighted the importance of implementing improved cardiovascular prevention strategies to increase life-expectancy of the contemporary HCM population. They also show that national electronic health records provide an effective method for identifying outcomes and clinically relevant estimates of composite efficacy and safety endpoints essential for trial design in rare diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191214PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764451PMC
February 2018

Association analyses based on false discovery rate implicate new loci for coronary artery disease.

Nat Genet 2017 Sep 17;49(9):1385-1391. Epub 2017 Jul 17.

William Harvey Research Institute, Barts &the London Medical School, Queen Mary University of London, London, UK.

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n = 10,801) as well as a stricter definition without angina (HARD; n = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.
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http://dx.doi.org/10.1038/ng.3913DOI Listing
September 2017

Ethnicity and the first diagnosis of a wide range of cardiovascular diseases: Associations in a linked electronic health record cohort of 1 million patients.

PLoS One 2017 9;12(6):e0178945. Epub 2017 Jun 9.

The Farr Institute of Health Informatics Research and the National Institute for Health Research, Biomedical Research Centre, University College London, London, United Kingdom.

Background: While the association of ethnic group with individual cardiovascular diseases has been studied, little is known about ethnic differences in the initial lifetime presentation of clinical cardiovascular disease in contemporary populations.

Methods And Results: We studied 1,068,318 people, aged ≥30 years and free from diagnosed CVD at baseline (90.9% White, 3.6% South Asian and 2.9% Black), using English linked electronic health records covering primary care, hospital admissions, acute coronary syndrome registry and mortality registry (CALIBER platform). During 5.7 years median follow-up between 1997-2010, 95,224 people experienced an incident cardiovascular diagnosis. 69.9% (67.2%-72.4%) of initial presentation in South Asian <60 yrs were coronary heart disease presentations compared to 47.8% (47.3%-48.3%) in White and 40.1% (36.3%-43.9%) in Black patients. Compared to White patients, Black patients had significantly lower age-sex adjusted hazard ratios (HRs) for initial lifetime presentation of all the coronary disease diagnoses (stable angina HR 0.80 (95% CI 0.68-0.93); unstable angina- 0.75 (0.59-0.97); myocardial infarction 0.49 (0.40-0.62)) while South Asian patients had significantly higher HRs (stable angina- 1.67 (1.52-1.84); unstable angina 1.82 (1.56-2.13); myocardial infarction- 1.67 (1.49-1.87). We found no ethnic differences in initial presentation with heart failure (Black 0.97 (0.79-1.20); S Asian 1.04(0.87-1.26)). Compared to White patients, Black patients were more likely to present with ischaemic stroke (1.24 (0.97-1.58)) and intracerebral haemorrhage (1.44 (0.97-2.12)). Presentation with peripheral arterial disease was less likely for Black (0.63 (0.50-0.80)) and South Asian patients (0.70 (0.57-0.86)) compared with White patients.

Discussion: While we found the anticipated substantial predominance of coronary heart disease presentations in South Asian and predominance of stroke presentations in Black patients, we found no ethnic differences in presentation with heart failure. We consider the public health and research implications of our findings.

Trial Registration: NCT02176174, www.clinicaltrials.gov.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178945PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466321PMC
September 2017

Personalising the decision for prolonged dual antiplatelet therapy: development, validation and potential impact of prognostic models for cardiovascular events and bleeding in myocardial infarction survivors.

Eur Heart J 2017 04;38(14):1048-1055

The Farr Institute of Health Informatics Research, University College London, London, UK.

Aims: The aim of this study is to develop models to aid the decision to prolong dual antiplatelet therapy (DAPT) that requires balancing an individual patient's potential benefits and harms.

Methods And Results: Using population-based electronic health records (EHRs) (CALIBER, England, 2000-10), of patients evaluated 1 year after acute myocardial infarction (MI), we developed (n = 12 694 patients) and validated (n = 5613) prognostic models for cardiovascular (cardiovascular death, MI or stroke) events and three different bleeding endpoints. We applied trial effect estimates to determine potential benefits and harms of DAPT and the net clinical benefit of individuals. Prognostic models for cardiovascular events (c-index: 0.75 (95% CI: 0.74, 0.77)) and bleeding (c index 0.72 (95% CI: 0.67, 0.77)) were well calibrated: 3-year risk of cardiovascular events was 16.5% overall (5.2% in the lowest- and 46.7% in the highest-risk individuals), while for major bleeding, it was 1.7% (0.3% in the lowest- and 5.4% in the highest-risk patients). For every 10 000 patients treated per year, we estimated 249 (95% CI: 228, 269) cardiovascular events prevented and 134 (95% CI: 87, 181) major bleeding events caused in the highest-risk patients, and 28 (95% CI: 19, 37) cardiovascular events prevented and 9 (95% CI: 0, 20) major bleeding events caused in the lowest-risk patients. There was a net clinical benefit of prolonged DAPT in 63-99% patients depending on how benefits and harms were weighted.

Conclusion: Prognostic models for cardiovascular events and bleeding using population-based EHRs may help to personalise decisions for prolonged DAPT 1-year following acute MI.
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http://dx.doi.org/10.1093/eurheartj/ehw683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400049PMC
April 2017

Prognostic burden of heart failure recorded in primary care, acute hospital admissions, or both: a population-based linked electronic health record cohort study in 2.1 million people.

Eur J Heart Fail 2017 09 23;19(9):1119-1127. Epub 2016 Dec 23.

Farr Institute of Health Informatics Research, London, UK.

Aims: The prognosis of patients hospitalized for worsening heart failure (HF) is well described, but not that of patients managed solely in non-acute settings such as primary care or secondary outpatient care. We assessed the distribution of HF across levels of healthcare, and assessed the prognostic differences for patients with HF either recorded in primary care (including secondary outpatient care) (PC), hospital admissions alone, or known in both contexts.

Methods And Results: This study was part of the CALIBER programme, which comprises linked data from primary care, hospital admissions, and death certificates for 2.1 million inhabitants of England. We identified 89 554 patients with newly recorded HF, of whom 23 547 (26%) were recorded in PC but never hospitalized, 30 629 (34%) in hospital admissions but not known in PC, 23 681 (27%) in both, and 11 697 (13%) in death certificates only. The highest prescription rates of ACE inhibitors, beta-blockers, and mineralocorticoid receptor antagonists was found in patients known in both contexts. The respective 5-year survival in the first three groups was 43.9% [95% confidence interval (CI) 43.2-44.6%], 21.7% (95% CI 21.1-22.2%), and 39.8% (95% CI 39.2-40.5%), compared with 88.1% (95% CI 87.9-88.3%) in the age- and sex-matched general population.

Conclusion: In the general population, one in four patients with HF will not be hospitalized for worsening HF within a median follow-up of 1.7 years, yet they still have a poor 5-year prognosis. Patients admitted to hospital with worsening HF but not known with HF in primary care have the worst prognosis and management. Mitigating the prognostic burden of HF requires greater consistency across primary and secondary care in the identification, profiling, and treatment of patients.

Trial Registration: NCT02551016.
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http://dx.doi.org/10.1002/ejhf.709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420446PMC
September 2017

Mortality and clinical outcomes in children treated with antiretroviral therapy in four African vertical programmes during the first decade of paediatric HIV care, 2001-2010.

Trop Med Int Health 2017 03 26;22(3):340-350. Epub 2017 Jan 26.

Epicentre, Paris, France.

Objective: To assess mortality and clinical outcomes in children treated with antiretroviral therapy (ART) in four African vertical programmes between 2001 and 2010.

Methods: Cohort analysis of data from HIV-infected children (<15 years old) initiating ART in four sub-Saharan HIV programmes in Kenya, Uganda and Malawi, between December 2001 and December 2010. Rates of mortality, programme attrition and first-line clinico-immunological failure were calculated by age group (<2, 2-4 and 5-14 years), 1 or 2 years after ART initiation, and risk factors were examined.

Results: A total of 3949 children, 22.7% aged <2 years, 32.2% 2-4 years and 45.1% 5-14 years, were included. At ART initiation, 60.8% had clinical stage 3 or 4, and 46.5% severe immunosuppression. Overall mortality, attrition and 1-year failure rates were 5.1, 10.8 and 9.0 per 100 person-years, respectively. Immunosuppression, stage 3 or 4, and underweight were associated with increased rates of mortality, attrition and treatment failure. Adjusted estimates showed lower mortality hazard ratios (HR) among children aged 2-4 years (HR = 0.57, 95% CI 0.42-0.77 than children aged 5-14 years). One-year treatment failure incidence rate ratios (IRR) were similar regardless of age (IRR = 0.91, 95% CI 0.67-1.25 for <2 years; 1.01, 95% CI 0.83-1.23 for 2-4 years, vs. 5-14 years).

Conclusions: Good treatment outcomes were achieved during the first decade of HIV paediatric care despite the late start of therapy. Encouraging early HIV infant diagnosis in and outside prevention of mother-to-child transmission programmes, and linkage to care services for early ART initiation, is needed to reduce mortality and delay treatment failure.
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http://dx.doi.org/10.1111/tmi.12830DOI Listing
March 2017

Using big data from health records from four countries to evaluate chronic disease outcomes: a study in 114 364 survivors of myocardial infarction.

Eur Heart J Qual Care Clin Outcomes 2016 Jul;2(3):172-183

Farr Institute of Health Informatics Research, University College London, London, UK.

Aims: To assess the international validity of using hospital record data to compare long-term outcomes in heart attack survivors.

Methods And Results: We used samples of national, ongoing, unselected record sources to assess three outcomes: cause death; a composite of myocardial infarction (MI), stroke, and all-cause death; and hospitalized bleeding. Patients aged 65 years and older entered the study 1 year following the most recent discharge for acute MI in 2002-11 [n = 54 841 (Sweden), 53 909 (USA), 4653 (England), and 961 (France)]. Across each of the four countries, we found consistent associations with 12 baseline prognostic factors and each of the three outcomes. In each country, we observed high 3-year crude cumulative risks of all-cause death (from 19.6% [England] to 30.2% [USA]); the composite of MI, stroke, or death [from 26.0% (France) to 36.2% (USA)]; and hospitalized bleeding [from 3.1% (France) to 5.3% (USA)]. After adjustments for baseline risk factors, risks were similar across all countries [relative risks (RRs) compared with Sweden not statistically significant], but higher in the USA for all-cause death [RR USA vs. Sweden, 1.14 (95% confidence interval 1.04-1.26)] and hospitalized bleeding [RR USA vs. Sweden, 1.54 (1.21-1.96)].

Conclusion: The validity of using hospital record data is supported by the consistency of estimates across four countries of a high adjusted risk of death, further MI, and stroke in the chronic phase after MI. The possibility that adjusted risks of mortality and bleeding are higher in the USA warrants further study.
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http://dx.doi.org/10.1093/ehjqcco/qcw004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815620PMC
July 2016

Pediatric Access and Continuity of HIV Care Before the Start of Antiretroviral Therapy in Sub-Saharan Africa.

Pediatr Infect Dis J 2016 09;35(9):981-6

From the *Epicentre, Clinical Research Department, Paris, France; †Médecins Sans Frontières, Medical Department, Paris, France; and ‡Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, United Kingdom.

Background: The number of HIV-infected children starting antiretroviral treatment (ART) has increased in resource-limited settings during the past decades. However, there are still few published data on the characteristics of pediatric patients at program enrolment and on the dynamics of dropping out before the start of ART.

Methods: We performed a retrospective cohort study among HIV-infected pediatric patients (age, 5-14 years) not yet started on ART enrolled in 4 HIV sub-Saharan African programs. Descriptive and risk factors for mortality and lost to follow-up (LFU) were investigated using adjusted parametric or Cox proportional hazard models.

Results: A total of 2244 patients (52.8% girls) were enrolled in HIV care, a median of 2 days [interquartile range (IQR), 0-8 days] after HIV diagnosis. Baseline median CD4 cell count was 409 cells/μL (IQR, 203-478 cells/μL); 43% were in clinical stage 3 or 4, 71% required ART and 76.2% of these patients initiated therapy. Of those eligible not started on ART, 14% died and 59% were LFU. Median pre-ART follow-up was 4.4 months (IQR, 1.3-20 months) and was shorter for eligible patients. Mortality rates were 6.2 of 100 person-years [95% confidence interval (CI), 4.6-8.3] in the 0- to 6-month period and 1.3 of 100 person-years (95% CI, 0.9-2.0) in the 6- to 60-month period. LFU rates were 37.4 of 100 (95% CI, 33.0-42.4) and 8.3 of 100 person-years (95% CI, 7.1-9.8), respectively. Advanced HIV disease at presentation (low body mass index, stage 3 or 4, low CD4 count or tuberculosis diagnosis) was associated with increased mortality and LFU.

Conclusions: Late presentation and delays in initiating ART among eligible children were responsible for the large incidence of patient losses during pre-ART follow-up in sub-Saharan Africa.
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http://dx.doi.org/10.1097/INF.0000000000001213DOI Listing
September 2016