Validation of an acute respiratory infection phenotyping algorithm to support robust computerised medical record-based respiratory sentinel surveillance, England, 2023.

IntroductionRespiratory sentinel surveillance systems leveraging computerised medical records (CMR) use phenotyping algorithms to identify cases of interest, such as acute respiratory infection (ARI). The Oxford-Royal College of General Practitioners Research and Surveillance Centre (RSC) is the English primary care-based sentinel surveillance network.AimThis study describes and validates the RSC's new ARI phenotyping algorithm.MethodsWe developed the phenotyping algorithm using a framework aligned with international interoperability standards. We validated our algorithm by comparing ARI events identified during the 2022/23 influenza season in England through use of both old and new algorithms. We compared clinical codes commonly used for recording ARI.ResultsThe new algorithm identified an additional 860,039 cases and excluded 52,258, resulting in a net increase of 807,781 cases (33.84%) of ARI compared to the old algorithm, with totals of 3,194,224 cases versus 2,386,443 cases. Of the 860,039 newly identified cases, the majority (63.7%) were due to identification of symptom codes suggestive of an ARI diagnosis not detected by the old algorithm. The 52,258 cases incorrectly identified by the old algorithm were due to inadvertent identification of chronic, recurrent, non-infectious and other non-ARI disease.ConclusionWe developed a new ARI phenotyping algorithm that more accurately identifies cases of ARI from the CMR. This will benefit public health by providing more accurate surveillance reports to public health authorities. This new algorithm can serve as a blueprint for other CMR-based surveillance systems wishing to develop similar phenotyping algorithms.

Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study.

BACKGROUND: Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care. METHODS: We did a multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales. Participants aged 18 or older referred with non-specific symptoms or symptoms potentially due to gynaecological, lung, or upper or lower gastrointestinal cancers were included and gave a blood sample when they attended for urgent investigation. Participants were excluded if they had a history of or had received treatment for an invasive or haematological malignancy diagnosed within the preceding 3 years, were taking cytotoxic or demethylating agents that might interfere with the test, or had participated in another study of a GRAIL MCED test. Patients were followed until diagnostic resolution or up to 9 months. Cell-free DNA was isolated and the MCED test performed blinded to the clinical outcome. MCED predictions were compared with the diagnosis obtained by standard care to establish the primary outcomes of overall positive and negative predictive value, sensitivity, and specificity. Outcomes were assessed in participants with a valid MCED test result and diagnostic resolution. SYMPLIFY is registered with ISRCTN (ISRCTN10226380) and has completed follow-up at all sites. FINDINGS: 6238 participants were recruited between July 7 and Nov 30, 2021, across 44 hospital sites. 387 were excluded due to staff being unable to draw blood, sample errors, participant withdrawal, or identification of ineligibility after enrolment. Of 5851 clinically evaluable participants, 376 had no MCED test result and 14 had no information as to final diagnosis, resulting in 5461 included in the final cohort for analysis with an evaluable MCED test result and diagnostic outcome (368 [6·7%] with a cancer diagnosis and 5093 [93·3%] without a cancer diagnosis). The median age of participants was 61·9 years (IQR 53·4-73·0), 3609 (66·1%) were female and 1852 (33·9%) were male. The MCED test detected a cancer signal in 323 cases, in whom 244 cancer was diagnosed, yielding a positive predictive value of 75·5% (95% CI 70·5-80·1), negative predictive value of 97·6% (97·1-98·0), sensitivity of 66·3% (61·2-71·1), and specificity of 98·4% (98·1-98·8). Sensitivity increased with increasing age and cancer stage, from 24·2% (95% CI 16·0-34·1) in stage I to 95·3% (88·5-98·7) in stage IV. For cases in which a cancer signal was detected among patients with cancer, the MCED test's prediction of the site of origin was accurate in 85·2% (95% CI 79·8-89·3) of cases. Sensitivity 80·4% (95% CI 66·1-90·6) and negative predictive value 99·1% (98·2-99·6) were highest for patients with symptoms mandating investigation for upper gastrointestinal cancer. INTERPRETATION: This first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms. FUNDING: GRAIL Bio UK.

Adverse events following first and second dose COVID-19 vaccination in England, October 2020 to September 2021: a national vaccine surveillance platform self-controlled case series study.

BackgroundPost-authorisation vaccine safety surveillance is well established for reporting common adverse events of interest (AEIs) following influenza vaccines, but not for COVID-19 vaccines.AimTo estimate the incidence of AEIs presenting to primary care following COVID-19 vaccination in England, and report safety profile differences between vaccine brands.MethodsWe used a self-controlled case series design to estimate relative incidence (RI) of AEIs reported to the national sentinel network, the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub. We compared AEIs (overall and by clinical category) 7 days pre- and post-vaccination to background levels between 1 October 2020 and 12 September 2021.ResultsWithin 7,952,861 records, 781,200 individuals (9.82%) presented to general practice with 1,482,273 AEIs, 4.85% within 7 days post-vaccination. Overall, medically attended AEIs decreased post-vaccination against background levels. There was a 3-7% decrease in incidence within 7 days after both doses of Comirnaty (RI: 0.93; 95% CI: 0.91-0.94 and RI: 0.96; 95% CI: 0.94-0.98, respectively) and Vaxzevria (RI: 0.97; 95% CI: 0.95-0.98). A 20% increase was observed after one dose of Spikevax (RI: 1.20; 95% CI: 1.00-1.44). Fewer AEIs were reported as age increased. Types of AEIs, e.g. increased neurological and psychiatric conditions, varied between brands following two doses of Comirnaty (RI: 1.41; 95% CI: 1.28-1.56) and Vaxzevria (RI: 1.07; 95% CI: 0.97-1.78).ConclusionCOVID-19 vaccines are associated with a small decrease in medically attended AEI incidence. Sentinel networks could routinely report common AEI rates, contributing to reporting vaccine safety.

Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study.

BACKGROUND: The BNT162b2 mRNA (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca) COVID-19 vaccines have shown high efficacy against disease in phase 3 clinical trials and are now being used in national vaccination programmes in the UK and several other countries. Studying the real-world effects of these vaccines is an urgent requirement. The aim of our study was to investigate the association between the mass roll-out of the first doses of these COVID-19 vaccines and hospital admissions for COVID-19. METHODS: We did a prospective cohort study using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19-EAVE II-database comprising linked vaccination, primary care, real-time reverse transcription-PCR testing, and hospital admission patient records for 5·4 million people in Scotland (about 99% of the population) registered at 940 general practices. Individuals who had previously tested positive were excluded from the analysis. A time-dependent Cox model and Poisson regression models with inverse propensity weights were fitted to estimate effectiveness against COVID-19 hospital admission (defined as 1-adjusted rate ratio) following the first dose of vaccine. FINDINGS: Between Dec 8, 2020, and Feb 22, 2021, a total of 1 331 993 people were vaccinated over the study period. The mean age of those vaccinated was 65·0 years (SD 16·2). The first dose of the BNT162b2 mRNA vaccine was associated with a vaccine effect of 91% (95% CI 85-94) for reduced COVID-19 hospital admission at 28-34 days post-vaccination. Vaccine effect at the same time interval for the ChAdOx1 vaccine was 88% (95% CI 75-94). Results of combined vaccine effects against hospital admission due to COVID-19 were similar when restricting the analysis to those aged 80 years and older (83%, 95% CI 72-89 at 28-34 days post-vaccination). INTERPRETATION: Mass roll-out of the first doses of the BNT162b2 mRNA and ChAdOx1 vaccines was associated with substantial reductions in the risk of hospital admission due to COVID-19 in Scotland. There remains the possibility that some of the observed effects might have been due to residual confounding. FUNDING: UK Research and Innovation (Medical Research Council), Research and Innovation Industrial Strategy Challenge Fund, Health Data Research UK.

A randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (the ExACT study).

Venous thromboembolism (VTE) is prevalent and impactful, with a risk of death, morbidity and recurrence. Post-thrombotic syndrome (PTS) is a common consequence and associated with impaired quality of life (QoL). The ExACT study was a non-blinded, prospective, multicentred randomised controlled trial comparing extended versus limited duration anticoagulation following a first unprovoked VTE (proximal deep vein thrombosis or pulmonary embolism). Adults were eligible if they had completed ≥3 months anticoagulation (remaining anticoagulated). The primary outcome was time to first recurrent VTE from randomisation. The secondary outcomes included PTS severity, bleeding, QoL and D-dimers. Two-hundred and eighty-one patients were recruited, randomised and followed up for 24 months (mean age 63, male:female 2:1). There was a significant reduction in recurrent VTE for patients receiving extended anticoagulation [2·75 vs. 13·54 events/100 patient years, adjusted hazard ratio (aHR) 0·20 (95% confidence interval (CI): 0·09 to 0·46, P < 0·001)] with a non-significant increase in major bleeding [3·54 vs. 1·18 events/100 patient years, aHR 2·99 (95% CI: 0·81-11·05, P = 0·10)]. Outcomes of PTS and QoL were no different between groups. D-dimer results (on anticoagulation) did not predict VTE recurrence. In conclusion, extended anticoagulation reduced VTE recurrence but did not reduce PTS or improve QoL and was associated with a non-significant increase in bleeding. Results also suggest very limited clinical utility of D-dimer testing on anticoagulated patients.

Survival following a diagnosis of heart failure in primary care.

Background: Heart failure is a common long term condition affecting around 900 000 people in the UK and patients commonly present to primary care. The prognosis of patients with a code of heart failure in their primary care record is unknown. Objective: The study sought to determine the overall survival rates for patients with heart failure in a primary care population from the time of diagnosis. Methods: Survival analysis was carried out using UK primary care records from The Health Improvement Network (THIN) between 1 January 1998 and 31 December 2012. Patients age 45 or over with a first diagnostic label of heart failure were matched by age, sex and practice to people without heart failure. Outcome was death in the heart failure and no heart failure cohorts. Kaplan-Meier curves were used to compare survival. Age-specific survival rates at 1, 5 and 10 years were determined for men and women with heart failure. Survival rates by year of diagnosis and case definition were also calculated. Results: During the study period, 54313 patients had a first diagnostic code of heart failure. Overall survival rates for the heart failure group were 81.3% (95%CI 80.9-81.6), 51.5% (95%CI 51.0-52.0) and 29.5% (95%CI 28.9-30.2) at 1, 5 and 10 years respectively and did not change over time. Conclusions: In a primary care population, the survival of patients diagnosed with heart failure did not improved over time. Further research is needed to explain these trends and to find strategies to improve outlook.

Management of chronic heart failure in general practice in Australia.

BACKGROUND: Chronic heart failure is a common clinical syndrome associated with high healthcare system use. OBJECTIVE: The aim of this study was to explore the management of chronic heart failure in Australian general practice. METHODS: Data from the Bettering the Evaluation and Care of Health program were used to determine the prevalence of chronic heart failure, use of natriuretic peptide testing, prescribing patterns, hospitalisation rates and referrals to community-based heart failure management programs in three study periods between 2010 and 2015. RESULTS: Data on 8989 patients from 308 general practitioners were analysed. Of these patients, 324 had chronic heart failure (prevalence 3.6%; 95% confidence interval [CI]: 3.1-4.2), 44% (95% CI: 34.5-53.6) of whom had been hospitalised for the condition. The mean number of prescribed heart failure medication agents was 2.26 (95% CI: 2.13-2.39) per patient. Discharge under community heart failure programs was not routine. DISCUSSION: Chronic heart failure is a significant burden in general practice. Strategies to optimise management and avoid hospitalisation, where possible, are needed.

Heart failure and major haemorrhage in people with atrial fibrillation.

BACKGROUND: Heart failure (HF) is not included in atrial fibrillation (AF) bleeding risk prediction scores, reflecting uncertainty regarding its importance as a risk factor for major haemorrhage. We aimed to report the relative risk of first major haemorrhage in people with HF and AF compared with people with AF without HF ('AF only'). METHODS: English primary care cohort study of 2 178 162 people aged ≥45 years in the Clinical Practice Research Datalink from January 2000 to December 2018, linked to secondary care and mortality databases. We used traditional survival analysis and competing risks methods, accounting for all-cause mortality and anticoagulation. RESULTS: Over 7.56 years median follow-up, 60 270 people were diagnosed with HF and AF of whom 4996 (8.3%) had a major haemorrhage and 36 170 died (60.0%), compared with 8256 (6.4%) and 34 375 (27.2%), respectively, among 126 251 people with AF only. Less than half those with AF were prescribed an anticoagulant (45.6% from 2014 onwards), although 75.7% were prescribed an antiplatelet or anticoagulant. In a fully adjusted Cox model, the HR for major haemorrhage was higher among people with HF and AF (2.52, 95% CI 2.44 to 2.61) than AF only (1.87, 95% CI 1.82 to 1.92), even in a subgroup analysis of people prescribed anticoagulation. However, in a Fine and Gray competing risk model, the HR of major haemorrhage was similar for people with AF only (1.82, 95% CI 1.77 to 1.87) or HF and AF (1.71, 95% CI 1.66 to 1.78). CONCLUSIONS: People with HF and AF are at increased risk of major haemorrhage compared with those with AF only and current prediction scores may underestimate the risk of haemorrhage in HF and AF. However, people with HF and AF are more likely to die than have a major haemorrhage and therefore an individual's expected prognosis should be carefully considered when predicting future bleeding risk.

Outcomes for older people with screening detected versus existing chronic kidney disease: Cohort study with data linkage.

BACKGROUND: Chronic Kidney Disease (CKD) is a common health problem, associated with increased risk of cardiovascular disease (CVD), end stage kidney disease (ESKD), and premature death. A third of people aged≥70 years have CKD, many of whom are undiagnosed, but little is known about the value of screening. AIM: To compare the risk of adverse health outcomes between people with an existing diagnosis of CKD and those identified on screening. To identify factors associated with mortality in CKD. DESIGN & SETTING: Prospective cohort study of 892 primary care patients aged≥60 years with CKD (existing and screening detected) in Oxfordshire, with data linkage to civil death registry and secondary care. METHOD: Hazard Ratios (HR) and 95% Confidence Intervals (CI) were estimated using Cox proportional-hazard models to compare the risk of all-cause mortality, hospitalisation, CVD, ESKD separately, and as a composite between CKD groups, as well as to identify factors associated with mortality. RESULTS: After a median follow-up of 3-5 years, 49 people died, 493 were hospitalised, 57 had an incident CVD event, and 0 had an ESKD event. There was no difference in the composite outcome between those existing CKD and those identified on screening (HR 0.94, CI 0.67-1.33). Older age (HR 1.10, CI 1.06-1.15), male sex (HR 2.31, CI 1.26-4.24), and heart failure (HR 5.18, CI 2.45-10.97) were associated with increased risk of death. CONCLUSION: Screening older people for CKD may be of value, as their risk of short-term mortality, hospitalisation, and CVD is comparable to people routinely diagnosed. Larger studies with longer follow-up in more diverse and representative populations of older adults are needed to corroborate these findings.

Ivermectin for COVID-19 in adults in the community (PRINCIPLE): An open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials. METHODS: In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 µg/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n = 2157), usual care (n = 3256), and other treatments (n = 3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1·15 [95% Bayesian credible interval, 1·07 to 1·23], median decrease 2.06 days [1·00 to 3·06]), probability of meaningful effect (pre-specified hazard ratio ≥1.2) 0·192). COVID-19-related hospitalisations/deaths (odds ratio 1·02 [0·63 to 1·62]; estimated percentage difference 0% [-1% to 0·6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74·3% and 71·2% respectively (RR = 1·05, [1·02 to 1·08]) and also at 3 and 12 months. INTERPRETATION: Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted. FUNDING: UKRI/National Institute of Health Research (MC_PC_19079).

Favipiravir for COVID-19 in adults in the community in PRINCIPLE, an open-label, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: Evidence for the effect of favipiravir treatment of acute COVID-19 on recovery, hospital admissions and longer-term outcomes in community settings is limited. METHODS: In this multicentre. open-label, multi-arm, adaptive platform randomised controlled trial participants aged ≥18 years in the community with a positive test for SARS-CoV-2 and symptoms lasting ≤14 days were randomised to: usual care; usual care plus favipiravir tablets (loading dose of 3600 mg in divided doses on day one, then 800 mg twice a day for four days); or, usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Recovery at six months was the primary longer-term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis model included 8811 SARS-CoV-2 positive mostly COVID vaccinated participants, randomised to favipiravir (n = 1829), usual care (n = 3256), and other treatments (n = 3726). Time to self-reported recovery was shorter in the favipiravir group than usual care (estimated hazard ratio 1·23 [95% credible interval 1·14 to 1·33]), a reduction of 2·98 days [1·99 to 3·94] from 16 days in median time to self-reported recovery for favipiravir versus usual care alone. COVID-19 related hospitalisations/deaths were similar (estimated odds ratio 0·99 [0·61 to 1·61]; estimated difference 0% [-0·9% to 0·6%]). 14 serious adverse events occurred in the favipiravir group and 4 in usual care. By six months, the proportion feeling fully recovered was 74·9% for favipiravir versus 71·3% for usual care (RR = 1·05, [1·02 to 1·08]). INTERPRETATION: In this open-label trial in a largely vaccinated population with COVID-19 in the community, favipiravir did not reduce hospital admissions, but shortened time to recovery and had a marginal positive impact on long term outcomes.

Face masks while exercising trial (MERIT): a cross-over randomised controlled study.

OBJECTIVES: Physical exertion is a high-risk activity for aerosol emission of respiratory pathogens. We aimed to determine the safety and tolerability of healthy young adults wearing different types of face mask during moderate-to-high intensity exercise. DESIGN: Cross-over randomised controlled study, completed between June 2021 and January 2022. PARTICIPANTS: Volunteers aged 18-35 years, who exercised regularly and had no significant pre-existing health conditions. INTERVENTIONS: Comparison of wearing a surgical, cloth and filtering face piece (FFP3) mask to no mask during 4×15 min bouts of exercise. Exercise was running outdoors or indoor rowing at moderate-to-high intensity, with consistency of distance travelled between bouts confirmed using a smartphone application (Strava). Each participant completed each bout in random order. OUTCOMES: The primary outcome was change in oxygen saturations. Secondary outcomes were change in heart rate, perceived impact of face mask wearing during exercise and willingness to wear a face mask for future exercise. RESULTS: All 72 volunteers (mean age 23.9) completed the study. Changes in oxygen saturations did not exceed the prespecified non-inferiority margin (2% difference) with any mask type compared with no mask. At the end of exercise, the estimated average difference in oxygen saturations for cloth mask was -0.07% (95% CI -0.39% to 0.25%), for surgical 0.28% (-0.04% to 0.60%) and for FFP3 -0.21% (-0.53% to 0.11%). The corresponding estimated average difference in heart rate for cloth mask was -1.20 bpm (95% CI -4.56 to 2.15), for surgical 0.36 bpm (95% CI -3.01 to 3.73) and for FFP3 0.52 bpm (95% CI -2.85 to 3.89). Wearing a face mask caused additional symptoms such as breathlessness (n=13, 18%) and dizziness (n=7, 10%). 33 participants broadly supported face mask wearing during exercise, particularly indoors, but 22 were opposed. CONCLUSION: This study adds to previous findings (mostly from non-randomised studies) that exercising at moderate-to-high intensity wearing a face mask appears to be safe in healthy, young adults. TRIAL REGISTRATION NUMBER: NCT04932226.

Body mass index and survival in people with heart failure.

AIMS: In people with heart failure (HF), a high body mass index (BMI) has been linked with better outcomes ('obesity paradox'), but there is limited evidence in community populations across long-term follow-up. We aimed to examine the association between BMI and long-term survival in patients with HF in a large primary care cohort. METHODS: We included patients with incident HF aged ≥45 years from the Clinical Practice Research Datalink (2000-2017). We used Kaplan-Meier curves, Cox regression and penalised spline methods to assess the association of pre-diagnostic BMI, based on WHO classification, with all-cause mortality. RESULTS: There were 47 531 participants with HF (median age 78.0 years (IQR 70-84), 45.8% female, 79.0% white ethnicity, median BMI 27.1 (IQR 23.9-31.0)) and 25 013 (52.6%) died during follow-up. Compared with healthy weight, people with overweight (HR 0.78, 95% CI 0.75 to 0.81, risk difference (RD) -4.1%), obesity class I (HR 0.76, 95% CI 0.73 to 0.80, RD -4.5%) and class II (HR 0.76, 95% CI 0.71 to 0.81, RD -4.5%) were at decreased risk of death, whereas people with underweight were at increased risk (HR 1.59, 95% CI 1.45 to 1.75, RD 11.2%). In those underweight, this risk was greater among men than women (p value for interaction=0.02). Class III obesity was associated with increased risk of all-cause mortality compared with overweight (HR 1.23, 95% CI 1.17 to 1.29). CONCLUSION: The U-shaped relationship between BMI and long-term all-cause mortality suggests a personalised approach to identifying optimal weight may be needed for patients with HF in primary care. Underweight people have the poorest prognosis and should be recognised as high-risk.

Effectiveness of exhaled nitric oxide for the prediction of non-invasive left atrial pressure in older people: a cross-sectional cohort study.

BACKGROUND: During left-sided heart failure (HF), left atrial and pulmonary venous pressure increase, which may lead to pulmonary congestion. Previous cohort studies, examining participants with symptomatic HF or rheumatic heart disease, suggest a relationship between increased left atrial pressure (LAP) and fractional exhaled nitric oxide (FeNO). AIM: To examine the strength of association between FeNO and echocardiographic assessment of LAP by the E/e' ratio, to determine if FeNO could be used to identify those with elevated LAP. DESIGN & SETTING: This cross-sectional cohort study examined a subset of the OxVALVE cohort aged ≥65 years. Data collection was undertaken in primary care practices in central England. METHOD: Each participant underwent a focused cardiovascular history and clinical examination. Standard transthoracic echocardiographic (TTE) assessment was performed on all participants, with the E/e' ratio calculated to obtain a validated surrogate of LAP. FeNO was measured in 227 participants. RESULTS: FeNO was higher in males compared with females and no different in participants with asthma, chronic obstructive pulmonary disease (COPD), or those using inhaled steroids. Participants with a high E/e' (>14) were older, with a higher proportion of females than males. There was no relationship between E/e' and FeNO, either when measured as a continuous variable or in the group with high E/e'. CONCLUSION: FeNO was not found to be an accurate predictor of elevated LAP in a primary care setting.

Natriuretic peptide testing and heart failure diagnosis in primary care: diagnostic accuracy study.

BACKGROUND: Natriuretic peptide (NP) testing is recommended for patients presenting to primary care with symptoms of chronic heart failure (HF) to prioritise referral for diagnosis. AIM: To report NP test performance at European Society of Cardiology (ESC) and National Institute for Health and Care Excellence (NICE) guideline referral thresholds. DESIGN AND SETTING: Diagnostic accuracy study using linked primary and secondary care data (2004 to 2018). METHOD: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of NP testing for HF diagnosis was assessed. RESULTS: In total, 229 580 patients had an NP test and 21 102 (9.2%) were diagnosed with HF within 6 months. The ESC NT-proBNP threshold ≥125 pg/mL had a sensitivity of 94.6% (95% confidence interval [CI] = 94.2 to 95.0) and specificity of 50.0% (95% CI = 49.7 to 50.3), compared with sensitivity of 81.7% (95% CI = 81.0 to 82.3) and specificity of 80.3% (95% CI = 80.0 to 80.5) for the NICE NT-proBNP ≥400 pg/mL threshold. PPVs for an NT-proBNP test were 16.4% (95% CI = 16.1 to 16.6) and 30.0% (95% CI = 29.6 to 30.5) for ESC and NICE thresholds, respectively. For both guidelines, nearly all patients with an NT-proBNP level below the threshold did not have HF (NPV: ESC 98.9%, 95% CI = 98.8 to 99.0 and NICE 97.7%, 95% CI = 97.6 to 97.8). CONCLUSION: At the higher NICE chronic HF guideline NP thresholds, one in five cases are initially missed in primary care but the lower ESC thresholds require more diagnostic assessments. NP is a reliable 'rule-out' test at both cut-points. The optimal NP threshold will depend on the priorities and capacity of the healthcare system.

Overestimation of anticoagulant benefit in patients with atrial fibrillation and low life expectancy: evidence from 12 randomized trials.

Background: Patients with atrial fibrillation (AF) have a high rate of all-cause mortality that is only partially attributable to vascular outcomes. While the competing risk of death may affect expected anticoagulant benefit, guidelines do not account for it. We sought to determine if using a competing risks framework materially affects the guideline-endorsed estimate of absolute risk reduction attributable to anticoagulants. Methods: We conducted a secondary analysis of 12 RCTs that randomized patients with AF to oral anticoagulants or either placebo or antiplatelets. For each participant, we estimated the absolute risk reduction (ARR) of anticoagulants to prevent stroke or systemic embolism using two methods. First, we estimated the ARR using a guideline-endorsed model (CHA 2 DS 2 -VASc) and then again using a Competing Risk Model that uses the same inputs as CHA 2 DS 2 -VASc but accounts for the competing risk of death and allows for non-linear growth in benefit over time. We compared the absolute and relative differences in estimated benefit and whether the differences in estimated benefit varied by life expectancy. Results: 7933 participants had a median life expectancy of 8 years (IQR 6, 12), determined by comorbidity-adjusted life tables. 43% were randomized to oral anticoagulation (median age 73 years, 36% women). The guideline-endorsed CHA 2 DS 2 -VASc model estimated a larger ARR than the Competing Risk Model (median ARR at 3 years, 6.9% vs. 5.2%). ARR differences varied by life expectancies: for those with life expectancies in the highest decile, 3-year ARR difference (CHA 2 DS 2 -VASc model - Competing Risk Model 3-year risk) was -1.2% (42% relative underestimation); for those with life expectancies in the lowest decile, 3-year ARR difference was 5.9% (91% relative overestimation). Conclusion: Anticoagulants were exceptionally effective at reduced stroke risk. However, anticoagulant benefits were misestimated with CHA 2 DS 2 -VASc, which does not account for the competing risk of death nor decelerating treatment benefit over time. Overestimation was most pronounced in patients with the lowest life expectancy and when benefit was estimated over a multi-year horizon.

Development of a modified Cambridge Multimorbidity Score for use with SNOMED CT: an observational English primary care sentinel network study.

BACKGROUND: People with multiple health conditions are more likely to have poorer health outcomes and greater care and service needs; a reliable measure of multimorbidity would inform management strategies and resource allocation. AIM: To develop and validate a modified version of the Cambridge Multimorbidity Score in an extended age range, using clinical terms that are routinely used in electronic health records across the world (Systematized Nomenclature of Medicine - Clinical Terms, SNOMED CT). DESIGN AND SETTING: Observational study using diagnosis and prescriptions data from an English primary care sentinel surveillance network between 2014 and 2019. METHOD: In this study new variables describing 37 health conditions were curated and the associations modelled between these and 1-year mortality risk using the Cox proportional hazard model in a development dataset (n = 300 000). Two simplified models were then developed - a 20-condition model as per the original Cambridge Multimorbidity Score and a variable reduction model using backward elimination with Akaike information criterion as the stopping criterion. The results were compared and validated for 1-year mortality in a synchronous validation dataset (n = 150 000), and for 1-year and 5-year mortality in an asynchronous validation dataset (n = 150 000). RESULTS: The final variable reduction model retained 21 conditions, and the conditions mostly overlapped with those in the 20-condition model. The model performed similarly to the 37- and 20-condition models, showing high discrimination and good calibration following recalibration. CONCLUSION: This modified version of the Cambridge Multimorbidity Score allows reliable estimation using clinical terms that can be applied internationally across multiple healthcare settings.

Predicting the risk of acute kidney injury in primary care: derivation and validation of STRATIFY-AKI.

BACKGROUND: Antihypertensives reduce the risk of cardiovascular disease but are also associated with harms including acute kidney injury (AKI). Few data exist to guide clinical decision making regarding these risks. AIM: To develop a prediction model estimating the risk of AKI in people potentially indicated for antihypertensive treatment. DESIGN AND SETTING: Observational cohort study using routine primary care data from the Clinical Practice Research Datalink (CPRD) in England. METHOD: People aged ≥40 years, with at least one blood pressure measurement between 130 mmHg and 179 mmHg were included. Outcomes were admission to hospital or death with AKI within 1, 5, and 10 years. The model was derived with data from CPRD GOLD (n = 1 772 618), using a Fine-Gray competing risks approach, with subsequent recalibration using pseudo-values. External validation used data from CPRD Aurum (n = 3 805 322). RESULTS: The mean age of participants was 59.4 years and 52% were female. The final model consisted of 27 predictors and showed good discrimination at 1, 5, and 10 years (C-statistic for 10-year risk 0.821, 95% confidence interval [CI] = 0.818 to 0.823). There was some overprediction at the highest predicted probabilities (ratio of observed to expected event probability for 10-year risk 0.633, 95% CI = 0.621 to 0.645), affecting patients with the highest risk. Most patients (>95%) had a low 1- to 5-year risk of AKI, and at 10 years only 0.1% of the population had a high AKI and low CVD risk. CONCLUSION: This clinical prediction model enables GPs to accurately identify patients at high risk of AKI, which will aid treatment decisions. As the vast majority of patients were at low risk, such a model may provide useful reassurance that most antihypertensive treatment is safe and appropriate while flagging the few for whom this is not the case.

Trends in direct oral anticoagulant (DOAC) prescribing in English primary care (2014-2019).

BACKGROUND: In England, most prescribing of direct-acting oral anticoagulants for atrial fibrillation (AF) is in primary care. However, there remain gaps in our understanding of dosage and disparities in use. We aimed to describe trends in direct oral anticoagulant (DOAC) prescribing, including dose reduction in people with renal impairment and other criteria, and adherence. METHODS: Using English primary care sentinel network data from 2014 to 2019, we assessed appropriate DOAC dose adjustment with creatinine clearance (CrCl). Our primary care sentinel cohort was a subset of 722 general practices, with 6.46 million currently registered patients at the time of this study. RESULTS: Of 6 464 129 people in the cohort, 2.3% were aged ≥18 years with a diagnosis of AF, and 30.8% of these were prescribed vitamin K antagonist and 69.1% DOACs. Appropriate DOAC prescribing following CrCl measures improved between 2014 and 2019; dabigatran from 21.3% (95% CI 15.1% to 28.8%) to 48.7% (95% CI 45.0% to 52.4%); rivaroxaban from 22.1% (95% CI 16.7% to 28.4%) to 49.9% (95% CI 48.5% to 53.3%); edoxaban from 10.0% (95% CI 0.3% to 44.5%) in 2016 to 57.6% (95% CI 54.5% to 60.7%) in 2019; apixaban from 30.8% (95% CI 9.1% to 61.4%) in 2015 to 60.5% (95% CI 57.8% to 63.2%) in 2019.Adherence was highest for factor Xa inhibitors, increasing from 50.1% (95% CI 47.7% to 52.4%) in 2014 to 57.8% (95% CI 57.4% to 58.2%) in 2019. Asian and black/mixed ethnicity was associated with non-adherence (OR 1.81, 95% CI 1.56 to 2.09) as was male gender (OR 1.19, 95% CI 1.15 to 1.22), higher socioeconomic status (OR 1.60, 95% CI 1.52 to 1.68), being an ex-smoker (OR 1.12, 95% CI 1.06 to 1.19) and hypertension (OR 1.07, 95% CI 1.03 to 1.17). CONCLUSIONS: The volume and quality of DOAC prescribing has increased yearly. Future interventions to augment quality of anticoagulant management should target disparities in adherence.