Novel Multiplexed Plasma Biomarker Panel Has Diagnostic and Prognostic Potential in Children With Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death risk in adult patients with HCM. The aim of this study was to investigate the utility of adult biomarkers and perform new discoveries in proteomics in childhood-onset HCM. METHODS: Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel pediatric plasma proteomic biomarker panels. RESULTS: Four previously identified adult HCM markers (aldolase fructose-bisphosphate A, complement C3a, talin-1, and thrombospondin 1) and 3 new markers (glycogen phosphorylase B, lipoprotein a, and profilin 1) were elevated in pediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training data set (sensitivity 100% [95% CI, 95-100]; specificity 100% [95% CI, 96-100]) and 0.82 in the validation data set (sensitivity 75% [95% CI, 59-86]; specificity 88% [95% CI, 75-94]). Reduced circulating levels of 4 other peptides (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, and serum amyloid A4 peptides) found in children with high sudden cardiac death risk provided complete separation from the low and intermediate risk groups and predicted mortality and adverse arrhythmic outcomes (hazard ratio, 2.04 [95% CI, 1.0-4.2]; P=0.044). CONCLUSIONS: In children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and a second 4-biomarker panel identifies those at high risk of adverse arrhythmic outcomes, including sudden cardiac death.

Electronic health record-wide association study for atrial fibrillation in a British cohort.

Background: Atrial fibrillation (AF) confers a major healthcare burden from hospitalisations and AF-related complications, such as stroke and heart failure. We performed an electronic health records-wide association study to identify the most frequent reasons for healthcare utilization, pre and post new-onset AF. Methods: Prospective cohort study with the linked electronic health records of 5.6 million patients in the United Kingdom Clinical Practice Research Datalink (1998-2016). A cohort study with AF patients and their age-and sex matched controls was implemented to compare the top 100 reasons of frequent hospitalisation and primary consultation. Results: Of the 199,433 patients who developed AF, we found the most frequent healthcare interactions to be cardiac, cerebrovascular and peripheral-vascular conditions, both prior to AF diagnosis (41/100 conditions in secondary care, such as cerebral infarction and valve diseases; and 33/100 conditions in primary care), and subsequently (47/100 conditions hospital care and 48 conditions in primary care). There was a high representation of repeated visits for cancer and infection affecting multiple organ systems. We identified 10 novel conditions which have not yet been associated with AF: folic acid deficiency, pancytopenia, idiopathic thrombocytopenic purpura, seborrheic dermatitis, lymphoedema, angioedema, laryngopharyngeal reflux, rib fracture, haemorrhagic gastritis, inflammatory polyneuropathies. Conclusion: Our nationwide data provide knowledge and better understanding of the clinical needs of AF patients suggesting: (i) groups at higher risk of AF, where screening may be more cost-effective, and (ii) potential complications developing following new-onset AF that can be prevented through implementation of comprehensive integrated care management and more personalised, tailored treatment. Clinical trial registration: NCT04786366.

Incidence, morbidity, mortality and disparities in dementia: A population linked electronic health records study of 4.3 million individuals.

INTRODUCTION: We report dementia incidence, comorbidities, reasons for health-care visits, mortality, causes of death, and examined dementia patterns by relative deprivation in the UK. METHOD: A longitudinal cohort analysis of linked electronic health records from 4.3 million people in the UK was conducted to investigate dementia incidence and mortality. Reasons for hospitalization and causes of death were compared in individuals with and without dementia. RESULTS: From 1998 to 2016 we observed 145,319 (3.1%) individuals with incident dementia. Repeated hospitalizations among senior adults for infection, unknown morbidity, and multiple primary care visits for chronic pain were observed prior to dementia diagnosis. Multiple long-term conditions are present in half of the individuals at the time of diagnosis. Individuals living in high deprivation areas had higher dementia incidence and high fatality. DISCUSSION: There is a considerable disparity of dementia that informs priorities of prevention and provision of patient care.

Impact of anti-arrhythmic drugs and catheter ablation on the survival of patients with atrial fibrillation: a population study based on 199 433 new-onset atrial fibrillation patients in the UK.

AIMS: Utilizing real-world UK data, we aimed to understand: (i) whether anti-arrhythmic drugs and catheter ablation are effective in improving the survival of atrial fibrillation (AF) patients and (ii) which rhythm control option produces better results for the whole AF population and for specific groups of patients, stratified by age, sex, and history of heart failure. METHODS AND RESULTS: We identified 199 433 individuals (mean age at diagnosis 75.7 ± 12.7 years; 50.2% women) with new-onset AF diagnosis in nationwide electronic health records linking primary care consultation with hospital data and death registry data from 1998 to 2016. We investigated the survival and causes of death of new-onset AF patients receiving vs. not-receiving rhythm control therapies. During a median follow-up of 2.7 (0.7-6.0) years, we observed a significantly lower mortality in patients receiving rhythm control [multivariate-adjusted hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.84-0.88]. Pulmonary vein isolation was associated with a two-third significant mortality reduction compared with no rhythm control (HR = 0.36, 95% CI 0.28-0.48), flecainide with 50% reduction (HR = 0.52, 95% CI 0.48-0.57), and propafenone and sotalol with reduction by a third (HR = 0.63, 95% CI 0.50-0.81, 0.71, 95% CI 0.68-0.74, respectively). Amiodarone showed no survival benefit in individuals <70 years (HR = 0.99, 95% CI 0.97-1.02). Otherwise, the effect of rhythm control on survival did not differ by age, sex, nor history of heart failure. CONCLUSION: Among individuals with new-onset AF, favourable survival was observed for patients receiving rhythm control treatment. Among different rhythm control strategies, pulmonary vein isolation showed the most pronounced survival benefit.

Prognostic model for atrial fibrillation after cardiac surgery: a UK cohort study.

OBJECTIVE: To develop a validated clinical prognostic model to determine the risk of atrial fibrillation after cardiac surgery as part of the PARADISE project (NIHR131227). METHODS: Prospective cohort study with linked electronic health records from a cohort of 5.6 million people in the United Kingdom Clinical Practice Research Datalink from 1998 to 2016. For model development, we considered a priori candidate predictors including demographics, medical history, medications, and clinical biomarkers. We evaluated associations between covariates and the AF incidence at the end of follow-up using logistic regression with the least absolute shrinkage and selection operator. The model was validated internally with the bootstrap method; subsequent performance was examined by discrimination quantified with the c-statistic and calibration assessed by calibration plots. The study follows TRIPOD guidelines. RESULTS: Between 1998 and 2016, 33,464 patients received cardiac surgery among the 5,601,803 eligible individuals. The final model included 13-predictors at baseline: age, year of index surgery, elevated CHA2DS2-VASc score, congestive heart failure, hypertension, acute coronary syndromes, mitral valve disease, ventricular tachycardia, valve surgery, receiving two combined procedures (e.g., valve replacement + coronary artery bypass grafting), or three combined procedures in the index procedure, statin use, and ethnicity other than white or black (statins and ethnicity were protective). This model had an optimism-corrected C-statistic of 0.68 both for the derivation and validation cohort. Calibration was good. CONCLUSIONS: We developed a model to identify a group of individuals at high risk of AF and adverse outcomes who could benefit from long-term arrhythmia monitoring, risk factor management, rhythm control and/or thromboprophylaxis.

Multimorbidity patterns and risk of hospitalisation in children: A population cohort study of 3.6 million children in England, with illustrative examples from childhood cancer survivors.

Background: Population-level estimates of hospitalisation risk in children are currently limited. The study aims to characterise morbidity patterns in all children, focusing on childhood cancer survivors versus children without cancer. Methods: Employing hospital records of children aged <19 years between 1997 to 2018 in England, we characterised morbidity patterns in childhood cancer survivors compared with children without cancer. The follow-up began on the 5th anniversary of the index hospitalisation and the primary outcome was the incidence of comorbidities. Findings: We identified 3,559,439 eligible participants having 12,740,666 hospital admissions, with a mean age at study entry of 11.2 years. We identified 32,221 patients who survived for at least 5 years since their initial cancer diagnosis. During the follow-up period and within the whole population of 3.6 million children, the leading conditions for admission were (i) metabolic, endocrine, digestive renal and genitourinary conditions (84,749, 2.5%), (ii) neurological (35,833, 1.0%) and (iii) musculoskeletal or skin conditions (23,574, 0.7%), fever, acute respiratory and sepsis (22,604, 0.7%). Stratified analyses revealed that females and children from socioeconomically deprived areas had a higher cumulative incidence for morbidities requiring hospitalisation (p < 0.001). At baseline (5 years after the initial cancer diagnosis or initial hospitalisation for survivors and population comparisons, respectively), cancer survivors experienced a higher prevalence of individual conditions and multimorbidity (≥ 2 morbidities) compared with children without cancer. Cox regression analyses showed that survivors had at least a 4-fold increase in the risk of hospitalisation for conditions such as chronic eye conditions (hazard ration (HR):4.0, 95% confidence interval (CI): 3.5-4.7), fever requiring hospitalisation (HR: 4.4, 95% CI: 3.8-5.0), subsequent neoplasms (HR: 5.7, 95% CI:5.0-6.5), immunological disorders (HR: 6.5, 95% CI:4.5-9.3) and metabolic conditions (HR: 7.1, 95% CI:5.9-8.5). Interpretation: The overall morbidity burden among children was low in general; however, childhood cancer survivors experienced a higher prevalence and subsequent risk of hospitalisation for a range of morbidities. Targeted policies may be required to promote awareness on health vulnerabilities and gender disparity and to improve advocacy for healthcare in deprived communities. Funding: Wellcome Trust, National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre and Academy of Medical Sciences. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Increased burden of cardiovascular disease in people with liver disease: unequal geographical variations, risk factors and excess years of life lost.

BACKGROUND: People with liver disease are at increased risk of developing cardiovascular disease (CVD), however, there has yet been an investigation of incidence burden, risk, and premature mortality across a wide range of liver conditions and cardiovascular outcomes. METHODS: We employed population-wide electronic health records (EHRs; from 1998 to 2020) consisting of almost 4 million adults to assess regional variations in disease burden of five liver conditions, alcoholic liver disease (ALD), autoimmune liver disease, chronic hepatitis B infection (HBV), chronic hepatitis C infection (HCV) and NAFLD, in England. We analysed regional differences in incidence rates for 17 manifestations of CVD in people with or without liver disease. The associations between biomarkers and comorbidities and risk of CVD in patients with liver disease were estimated using Cox models. For each liver condition, we estimated excess years of life lost (YLL) attributable to CVD (i.e., difference in YLL between people with or without CVD). RESULTS: The age-standardised incidence rate for any liver disease was 114.5 per 100,000 person years. The highest incidence was observed in NAFLD (85.5), followed by ALD (24.7), HCV (6.0), HBV (4.1) and autoimmune liver disease (3.7). Regionally, the North West and North East regions consistently exhibited high incidence burden. Age-specific incidence rate analyses revealed that the peak incidence for liver disease of non-viral aetiology is reached in individuals aged 50-59 years. Patients with liver disease had a two-fold higher incidence burden of CVD (2634.6 per 100,000 persons) compared to individuals without liver disease (1339.7 per 100,000 persons). When comparing across liver diseases, atrial fibrillation was the most common initial CVD presentation while hypertrophic cardiomyopathy was the least common. We noted strong positive associations between body mass index and current smoking and risk of CVD. Patients who also had diabetes, hypertension, proteinuric kidney disease, chronic kidney disease, diverticular disease and gastro-oesophageal reflex disorders had a higher risk of CVD, as do patients with low albumin, raised C-reactive protein and raised International Normalized Ratio levels. All types of CVD were associated with shorter life expectancies. When evaluating excess YLLs by age of CVD onset and by liver disease type, differences in YLLs, when comparing across CVD types, were more pronounced at younger ages. CONCLUSIONS: We developed a public online app ( https://lailab.shinyapps.io/cvd_in_liver_disease/ ) to showcase results interactively. We provide a blueprint that revealed previously underappreciated clinical factors related to the risk of CVD, which differed in the magnitude of effects across liver diseases. We found significant geographical variations in the burden of liver disease and CVD, highlighting the need to devise local solutions. Targeted policies and regional initiatives addressing underserved communities might help improve equity of access to CVD screening and treatment.

A population-based study of 92 clinically recognized risk factors for heart failure: co-occurrence, prognosis and preventive potential.

AIMS: Primary prevention strategies for heart failure (HF) have had limited success, possibly due to a wide range of underlying risk factors (RFs). Systematic evaluations of the prognostic burden and preventive potential across this wide range of risk factors are lacking. We aimed at estimating evidence, prevalence and co-occurrence for primary prevention and impact on prognosis of RFs for incident HF. METHODS AND RESULTS: We systematically reviewed trials and observational evidence of primary HF prevention across 92 putative aetiologic RFs for HF identified from US and European clinical practice guidelines. We identified 170 885 individuals aged ≥30 years with incident HF from 1997 to 2017, using linked primary and secondary care UK electronic health records (EHR) and rule-based phenotypes (ICD-10, Read Version 2, OPCS-4 procedure and medication codes) for each of 92 RFs. Only 10/92 factors had high quality observational evidence for association with incident HF; 7 had effective randomized controlled trial (RCT)-based interventions for HF prevention (RCT-HF), and 6 for cardiovascular disease prevention, but not HF (RCT-CVD), and the remainder had no RCT-based preventive interventions (RCT-0). We were able to map 91/92 risk factors to EHR using 5961 terms, and 88/91 factors were represented by at least one patient. In the 5 years prior to HF diagnosis, 44.3% had ≥4 RFs. By RCT evidence, the most common RCT-HF RFs were hypertension (48.5%), stable angina (34.9%), unstable angina (16.8%), myocardial infarction (15.8%), and diabetes (15.1%); RCT-CVD RFs were smoking (46.4%) and obesity (29.9%); and RCT-0 RFs were atrial arrhythmias (17.2%), cancer (16.5%), heavy alcohol intake (14.9%). Mortality at 1 year varied across all 91 factors (lowest: pregnancy-related hormonal disorder 4.2%; highest: phaeochromocytoma 73.7%). Among new HF cases, 28.5% had no RCT-HF RFs and 38.6% had no RCT-CVD RFs. 15.6% had either no RF or only RCT-0 RFs. CONCLUSION: One in six individuals with HF have no recorded RFs or RFs without trials. We provide a systematic map of primary preventive opportunities across a wide range of RFs for HF, demonstrating a high burden of co-occurrence and the need for trials tackling multiple RFs.

Atrial fibrillation epidemiology, disparity and healthcare contacts: a population-wide study of 5.6 million individuals.

Background: We aimed to evaluate atrial fibrillation occurrence, reasons for healthcare visits, mortality, causes of death and examined patterns by relative deprivation in the UK. Methods: To study the atrial fibrillation (AF) incidence, mortality and case-fatality, we implemented a prospective cohort study with the linked electronic health records of 5.6 million population in the United Kingdom Clinical Practice Research Datalink from 1998 to 2016. A matched case-control study was used to investigate causes of hospitalisation and death comparing individuals with and without incident AF. Results: During a median follow-up of 10.3 years, 199,433(3.6%) patients developed incident AF. Increased risk of hospitalisation for heart failure, cardiovascular conditions and infection was present among patients who later developed AF. Following an AF diagnosis, patients were frequently admitted to the hospital for heart failure, lower respiratory tract infection, chronic obstructive pulmonary disease and ischemic heart disease. One in 5 AF patients died during the first year after diagnosis, and the mortality increased to 42.7% at the fifth year. The excess deaths in AF cases compared to controls may result from cardiovascular diseases, infection and metabolic disorders. Individuals from areas with higher deprivation in socioeconomic and living status had both higher AF incidence and fatality. Interpretation: We observed an elevated risk of hospitalisation for cardiovascular or respiratory diseases among incident AF patients, and the considerable disparity in AF burden by socioeconomic deprivation informs priorities for prevention and provision of patient care. Funding: The study was supported by the GlaxoSmithKline, University College London Hospital and National Institute for Health Research. The funders did not have any role in study design, data collection, data analysis, interpretation, and writing of the report.

Lessons from countries implementing find, test, trace, isolation and support policies in the rapid response of the COVID-19 pandemic: a systematic review.

OBJECTIVE: To systematically learn lessons from the experiences of countries implementing find, test, trace, isolate, support (FTTIS) in the first wave of the COVID-19 pandemic. DESIGN, DATA SOURCES AND ELIGIBILITY CRITERIA: We searched MEDLINE (PubMed), Cochrane Library, SCOPUS and JSTOR, initially between 31 May 2019 and 21 January 2021. Research articles and reviews on the use of contact tracing, testing, self-isolation and quarantine for COVID-19 management were included in the review. DATA EXTRACTION AND SYNTHESIS: We extracted information including study objective, design, methods, main findings and implications. These were tabulated and a narrative synthesis was undertaken given the diverse research designs, methods and implications. RESULTS: We identified and included 118 eligible studies. We identified the core elements of an effective find, test, trace, isolate, support (FTTIS) system needed to interrupt the spread of a novel infectious disease, where treatment or vaccination was not yet available, as pertained in the initial stages of the COVID-19 pandemic. We report methods used to shorten case finding time, improve accuracy and efficiency of tests, coordinate stakeholders and actors involved in an FTTIS system, support individuals isolating and make appropriate use of digital tools. CONCLUSIONS: We identified in our systematic review the key components of an FTTIS system. These include border controls, restricted entry, inbound traveller quarantine and comprehensive case finding; repeated testing to minimise false diagnoses and pooled testing in resource-limited circumstances; extended quarantine period and the use of digital tools for contact tracing and self-isolation. Support for mental or physical health and livelihoods is needed for individuals undergoing self-isolation/quarantine. An integrated system with rolling-wave planning can best use effective FTTIS tools to respond to the fast-changing COVID-19 pandemic. Results of the review may inform countries considering implementing these measures.

Why We Are Losing the War Against COVID-19 on the Data Front and How to Reverse the Situation.

With over 117 million COVID-19-positive cases declared and the death count approaching 3 million, we would expect that the highly digitalized health systems of high-income countries would have collected, processed, and analyzed large quantities of clinical data from patients with COVID-19. Those data should have served to answer important clinical questions such as: what are the risk factors for becoming infected? What are good clinical variables to predict prognosis? What kinds of patients are more likely to survive mechanical ventilation? Are there clinical subphenotypes of the disease? All these, and many more, are crucial questions to improve our clinical strategies against the epidemic and save as many lives as possible. One might assume that in the era of big data and machine learning, there would be an army of scientists crunching petabytes of clinical data to answer these questions. However, nothing could be further from the truth. Our health systems have proven to be completely unprepared to generate, in a timely manner, a flow of clinical data that could feed these analyses. Despite gigabytes of data being generated every day, the vast quantity is locked in secure hospital data servers and is not being made available for analysis. Routinely collected clinical data are, by and large, regarded as a tool to inform decisions about individual patients, and not as a key resource to answer clinical questions through statistical analysis. The initiatives to extract COVID-19 clinical data are often promoted by private groups of individuals and not by health systems, and are uncoordinated and inefficient. The consequence is that we have more clinical data on COVID-19 than on any other epidemic in history, but we have failed to analyze this information quickly enough to make a difference. In this viewpoint, we expose this situation and suggest concrete ideas that health systems could implement to dynamically analyze their routine clinical data, becoming learning health systems and reversing the current situation.

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

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.

Diagnosis and treatment for hyperuricemia and gout: a systematic review of clinical practice guidelines and consensus statements.

OBJECTIVES: Despite the publication of hundreds of trials on gout and hyperuricemia, management of these conditions remains suboptimal. We aimed to assess the quality and consistency of guidance documents for gout and hyperuricemia. DESIGN: Systematic review and quality assessment using the appraisal of guidelines for research and evaluation (AGREE) II methodology. DATA SOURCES: PubMed and EMBASE (27 October 2016), two Chinese academic databases, eight guideline databases, and Google and Google scholar (July 2017). ELIGIBILITY CRITERIA: We included the latest version of international and national/regional clinical practice guidelines and consensus statements for diagnosis and/or treatment of hyperuricemia and gout, published in English or Chinese. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened searched items and extracted data. Four reviewers independently scored documents using AGREE II. Recommendations from all documents were tabulated and visualised in a coloured grid. RESULTS: Twenty-four guidance documents (16 clinical practice guidelines and 8 consensus statements) published between 2003 and 2017 were included. Included documents performed well in the domains of scope and purpose (median 85.4%, range 66.7%-100.0%) and clarity of presentation (median 79.2%, range 48.6%-98.6%), but unsatisfactory in applicability (median 10.9%, range 0.0%-66.7%) and editorial independence (median 28.1%, range 0.0%-83.3%). The 2017 British Society of Rheumatology guideline received the highest scores. Recommendations were concordant on the target serum uric acid level for long-term control, on some indications for urate-lowering therapy (ULT), and on the first-line drugs for ULT and for acute attack. Substantially inconsistent recommendations were provided for many items, especially for the timing of initiation of ULT and for treatment for asymptomatic hyperuricemia. CONCLUSIONS: Methodological quality needs improvement in guidance documents on gout and hyperuricemia. Evidence for certain clinical questions is lacking, despite numerous trials in this field. Promoting standard guidance development methods and synthesising high-quality clinical evidence are potential approaches to reduce recommendation inconsistencies. PROSPERO REGISTRATION NUMBER: CRD42016046104.

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

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.

Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study.

Importance: The increasing burden due to cancer and other noncommunicable diseases poses a threat to human development, which has resulted in global political commitments reflected in the Sustainable Development Goals as well as the World Health Organization (WHO) Global Action Plan on Non-Communicable Diseases. To determine if these commitments have resulted in improved cancer control, quantitative assessments of the cancer burden are required. Objective: To assess the burden for 29 cancer groups over time to provide a framework for policy discussion, resource allocation, and research focus. Evidence Review: Cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) were evaluated for 195 countries and territories by age and sex using the Global Burden of Disease study estimation methods. Levels and trends were analyzed over time, as well as by the Sociodemographic Index (SDI). Changes in incident cases were categorized by changes due to epidemiological vs demographic transition. Findings: In 2016, there were 17.2 million cancer cases worldwide and 8.9 million deaths. Cancer cases increased by 28% between 2006 and 2016. The smallest increase was seen in high SDI countries. Globally, population aging contributed 17%; population growth, 12%; and changes in age-specific rates, -1% to this change. The most common incident cancer globally for men was prostate cancer (1.4 million cases). The leading cause of cancer deaths and DALYs was tracheal, bronchus, and lung cancer (1.2 million deaths and 25.4 million DALYs). For women, the most common incident cancer and the leading cause of cancer deaths and DALYs was breast cancer (1.7 million incident cases, 535 000 deaths, and 14.9 million DALYs). In 2016, cancer caused 213.2 million DALYs globally for both sexes combined. Between 2006 and 2016, the average annual age-standardized incidence rates for all cancers combined increased in 130 of 195 countries or territories, and the average annual age-standardized death rates decreased within that timeframe in 143 of 195 countries or territories. Conclusions and Relevance: Large disparities exist between countries in cancer incidence, deaths, and associated disability. Scaling up cancer prevention and ensuring universal access to cancer care are required for health equity and to fulfill the global commitments for noncommunicable disease and cancer control.

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.

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.

White cell count in the normal range and short-term and long-term mortality: international comparisons of electronic health record cohorts in England and New Zealand.

OBJECTIVES: Electronic health records offer the opportunity to discover new clinical implications for established blood tests, but international comparisons have been lacking. We tested the association of total white cell count (WBC) with all-cause mortality in England and New Zealand. SETTING: Primary care practices in England (ClinicAl research using LInked Bespoke studies and Electronic health Records (CALIBER)) and New Zealand (PREDICT). DESIGN: Analysis of linked electronic health record data sets: CALIBER (primary care, hospitalisation, mortality and acute coronary syndrome registry) and PREDICT (cardiovascular risk assessments in primary care, hospitalisations, mortality, dispensed medication and laboratory results). PARTICIPANTS: People aged 30-75 years with no prior cardiovascular disease (CALIBER: N=686 475, 92.0% white; PREDICT: N=194 513, 53.5% European, 14.7% Pacific, 13.4% Maori), followed until death, transfer out of practice (in CALIBER) or study end. PRIMARY OUTCOME MEASURE: HRs for mortality were estimated using Cox models adjusted for age, sex, smoking, diabetes, systolic blood pressure, ethnicity and total:high-density lipoprotein (HDL) cholesterol ratio. RESULTS: We found 'J'-shaped associations between WBC and mortality; the second quintile was associated with lowest risk in both cohorts. High WBC within the reference range (8.65-10.05×109/L) was associated with significantly increased mortality compared to the middle quintile (6.25-7.25×109/L); adjusted HR 1.51 (95% CI 1.43 to 1.59) in CALIBER and 1.33 (95% CI 1.06 to 1.65) in PREDICT. WBC outside the reference range was associated with even greater mortality. The association was stronger over the first 6 months of follow-up, but similar across ethnic groups. CONCLUSIONS: Clinically recorded WBC within the range considered 'normal' is associated with mortality in ethnically different populations from two countries, particularly within the first 6 months. Large-scale international comparisons of electronic health record cohorts might yield new insights from widely performed clinical tests. TRIAL REGISTRATION NUMBER: NCT02014610.

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

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.