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Background Cardiac troponin is commonly raised in patients with malignancy and may aid clinicians in risk prediction. The prognostic significance of raised troponin in these patients with known malignancies remains unclear. Purpose We sought to investigate the relation between troponin and mortality in a large, well characterised cohort of patients undergoing cardiac troponin testing with a concomitant malignancy. Methods A retrospective cohort study was carried out using the National Institute for Health Research Health Informatics Collaborative Cardiovascular dataset of all consecutive patients who had a troponin measured at five hospitals between 2010 and 2017. Patients with a primary inpatient diagnosis of malignancy who had at least one cTn measurement during their hospital stay were identified. Patients were classified into solid tumour or haematological malignancy subgroups. Survival analyses were performed using multivariate Cox regression analyses and Kaplan-Meier plots. Cox regression analyses were adjusted for age, gender, C-reactive protein, haemoglobin, platelet count, white cell count, acute coronary syndrome, diabetes mellitus, heart failure, chronic kidney disease, chronic obstructive pulmonary disease, atrial fibrillation and angiography. The peak cTn level (highest level measured), standardised to the upper limit of normal (ULN), was used for all analyses. Results 5571 patients undergoing troponin testing had a primary diagnosis of malignancy and comprised of twenty-one different cancer types. 4649 patients were diagnosed with solid tumours and 922 patients were diagnosed with haematological malignancies. Patients with raised troponin had a higher burden of cardiovascular comorbidities compared to patients with a troponin level below the ULN. The median follow-up in the cohort was 14 months (interquartile range 2–39 months). At 1-year follow-up, 2495 (42%) of patients died. Figure 1 shows Kaplan-Meier plots for patients stratified by troponin level. Patients with a troponin level ≥1xULN had a higher risk of death compared to patients with a troponin level Conclusion A raised troponin was associated with an increased mortality risk in patients with malignancy regardless of cancer subtype. Stratification of mortality risk using troponin may help guide clinicians in making management decisions for patients with malignancy. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NIHR Imperial Biomedical Research Centre, as part of the NIHR Health Informatics Collaborative, and 2) British Heart Foundation

Background A positive cardiac troponin (cTn) is an independent predictor of short-term mortality in individuals presenting with acute pulmonary embolism (PE). However, there is limited evidence regarding the impact age has on the association between cTn levels and mortality in patients with PE. Purpose The aim of our study was to investigate the relationship between cTn level, age, and all-cause mortality, in hospitalised patients diagnosed with an acute PE. Methods A retrospective cohort study using the National Institute for Health Research Health Informatics Collaborative Cardiovascular dataset of all consecutive patients who had a troponin measured at five hospitals between 2010 and 2017. Patients admitted to hospital with a primary diagnosis of PE with at least one cTn measurement were included. We modelled the relation between peak troponin level and all-cause mortality using multivariable adjusted restricted cubic spline Cox regression analyses. Effect estimates were adjusted for age, gender, high-sensitivity troponin assay, C-reactive protein, haemoglobin, platelet count, white cell count, creatinine, sodium, potassium, diabetes, hypertension, hypercholesterolaemia, acute coronary syndrome, atrial fibrillation, heart failure, acute kidney injury, chronic kidney disease, obstructive lung disease, inflammatory disorders, pneumonia and malignancy. The peak cTn level (highest level measured), standardised to the upper limit of normal (ULN), was used for all analyses. Results 1,477 patients with at least one cTn measurement and a diagnosis of acute PE were included. During a median follow-up of 34.8 months, there were 290 (19.6%) deaths. Elevated cTn (>1xULN) was associated with a hazard ratio (HR) of 3.29 (95% confidence interval [CI] 1.95–5.53) for 30-day mortality and 2.12 (95% CI 1.63–2.75) for 3-year mortality. Higher cTn levels were progressively associated with a higher mortality risk, reaching a maximum HR of 2.59 (95% CI 1.64–4.09) at 141xULN (Figure 1). Younger patients ( Conclusion Elevated cTn, at all ages, is associated with an increased mortality risk in patients presenting with PE, with increasing cTn levels conferring a progressively worse long-term prognosis. Elevated cTn, no matter how small, needs to be taken seriously, particularly in young patients with an acute PE. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): 1) NIHR Imperial Biomedical Research Centre, as part of the NIHR Health Informatics Collaborative, and 2) British Heart Foundation

Introduction Acute stroke accounts for significant morbidity and mortality globally. The role of troponin for risk stratification in stroke is unclear. Purpose The aims of this study were to assess the relationship between peak troponin and mortality in patients with ischaemic stroke, haemorrhagic stroke, or subarachnoid haemorrhage and to compare this with the predictive value of first troponin or dynamic troponin change. Methods A retrospective cohort study was carried out using the National Institute for Health Research Health Informatics Collaborative Cardiovascular dataset of all consecutive patients who had a troponin measured at five hospitals between 2010 and 2017. Patients with at least one troponin measurement and a primary diagnosis of ischaemic stroke, haemorrhagic stroke or subarachnoid haemorrhage during a hospital admission were included. The main exposure variables were first and peak troponin, and dynamic troponin change, and the main outcome was all-cause mortality. Results were analysed using multivariable adjusted restricted cubic spline Cox regression. Survival analyses were adjusted for troponin assay, assay sensitivity (standard or highly sensitive), number of troponin measurements, age, sex, C-reactive protein level, white blood cell count, platelet count, haemoglobin, estimated glomerular filtration rate, angiography during admission, acute coronary syndrome during admission, and cardiovascular history (history of diabetes mellitus, myocardial infarction, heart failure, hypertension, stroke or atrial fibrillation). Receiver Operator Characteristic (ROC) curves were used to assess the predictive value of each exposure variable. Results 4,712 patients were included in the analysis (ischaemic stroke: 3,346; haemorrhagic stroke: 718; subarachnoid haemorrhage: 648). Peak troponin was above the upper limit of normal in 47.4% of ischaemic stroke patients, 52.8% of haemorrhagic stroke patients, and 57.1% of subarachnoid haemorrhage patients. Patients with elevated peak troponin were older and had more cardiovascular risk factors. A direct positive relationship was seen between peak troponin level and mortality hazard ratio in all three stroke subtypes (Figure 1). This relationship was consistent when considering dynamic troponin fold change for ischaemic or haemorrhagic stroke. For all three stroke subtypes, there was no added predictive value of peak troponin or dynamic troponin change over first troponin in predicting mortality (Figure 2). Conclusions A positive peak troponin was associated with increased mortality in patients presenting with ischaemic stroke, haemorrhagic stroke, or subarachnoid haemorrhage. Overall, serial troponin measurements may not improve mortality prediction beyond a single measurement. These findings may have implications for risk stratification of patients with acute stroke syndromes. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NIHR Imperial Biomedical Research Centre, as part of the NIHR Health Informatics Collaborative, and 2) British Heart Foundation

Background Current evidence suggests a direct relationship between the magnitude of troponin elevation and mortality, albeit over a limited range of troponin levels, and clinicians generally work under the impression that higher troponins signify higher mortality in all age groups. Purpose The objective was to use big data to determine the relationship between the full spectrum of troponin level and mortality in patients in whom troponin testing has been performed for clinical purposes. Methods As part of the National Institute for Health Research Health Informatics Collaborative project, all troponin values measured during the study period (2010 to 2017) were assembled from five cardiovascular centres. Troponin concentrations were standardised as a multiple of each laboratory's 99th-percentile of the upper limit of normal (ULN). All patients were followed up until death or censoring on 1st April 2017. To model the relation between peak troponin level and all-cause mortality we used restricted cubic spline Cox regression analysis. Splines were adjusted for patient age, gender, haemoglobin, creatinine, white cell count and C-reactive protein. Results 257,948 patients underwent troponin assessment. During a median follow-up of 1,198 (IQR, 514–1,866) days, there were 55,850 (21.7%) deaths. Using multivariable-adjusted restricted cubic spline Cox regression analysis, an inverted-U shaped relationship was observed between peak troponin level and mortality in all patients (Figure 1A). Among patients who were admitted to hospital, the recorded diagnostic code was acute coronary syndrome (ACS) in 14,468 patients and non-ACS in 120,049 patients. The revascularisation rate within 3 months was 61.0% (n=8,820) in ACS versus 4.0% (n=4,793) in non-ACS patients. There was a very different rate of revascularisation across the spectrum of troponin. The rate was only 1.4% for troponins below 1 xULN, and 6.1% between 1 and 10 xULN. Beyond 10 xULN, rate of revascularisation rose rapidly to over 85% for greater than 10,000 xULN (Figure 1B). Stratifying patients by revascularisation, the restricted cubic spline Cox regression curve showed a progressive increase in mortality within both the revascularised and non-revascularised strata, even to very high peak troponin levels (Figure 1C). Overall, revascularisation was associated with lower hazard ratios across all troponin levels. A similar pattern was seen when patients were stratified by the presence or absence of ACS diagnosis. Figure 1. Troponin level and mortality Conclusions An elevated troponin, even slightly above the ULN should be taken seriously. The inverted-U shaped mortality relationship with troponin occurred because patients with the highest troponin formed a different clinical subgroup who underwent different clinical management with a high revascularisation rate. These data on troponin level and mortality may help to inform clinical practice decisions and guide future risk stratification algorithms for patients with elevated troponin. Acknowledgement/Funding Funded by NIHR Imperial Biomedical Research Centre (BRC) using NIHR Health Informatics Collaborative data service, supported by OUH, GSTT & UCLH BRCs

Background Cardioembolism in paroxysmal atrial fibrillation (PAF) is a preventable cause of transient ischaemic attack (TIA) or ischaemic stroke, however, due its transient nature, a short-duration Holter monitor may miss a significant proportion of events. Methods We conducted an open-label randomised controlled trial of cardiac monitoring after a TIA or ischaemic stroke comparing a 14-day ECG monitoring patch with short-duration Holter monitoring for the detection of PAF. The primary outcome was the detection of one or more episodes of ECG-documented PAF lasting at least 30 seconds within 90 days in each of the study arms. A budget impact analysis from the healthcare perspective was performed to assess the theoretical economic implications of the patch-based service versus Holter monitoring. Based on the AF detection rates found in this study, Hospital Episode Statistics data for the incidence of stroke and TIA (October 2016-September 2017) and National Health Service reference costs, the cost-effectiveness of the patch-based service versus Holter monitoring was calculated. The Sentinel Stroke National Audit Programme estimate of £13,452 was used as the mean year one direct medical cost of a stroke. Results From February 2016 through February 2017, 43 (76.8%) of the 56 patients assigned to the patch-based monitoring group and 47 (78.3%) of the 60 patients assigned to the short-duration Holter monitoring group had successful monitor placement with 90 days of follow-up (Figure 1). Of the 26 protocol failures between the two groups, 23 (88.5%) were due to patient refusal for outpatient short-duration Holter monitor placement, whilst only 1 (3.8%) was due to unsuccessful patch placement. The rate of detection of PAF at 90 days was 16.3% in the patch-based monitoring group (7 patients) compared to 2.1% in the short-duration Holter monitoring group (1 patient), with an odds ratio of 8.9 (95% CI 1.1–76.0; P=0.026). Implementation of the patch-based service at our hospital would result in 10.8 more strokes avoided per year compared to current practice with short-duration Holter monitoring. This would equate to a yearly saving in direct medical costs of £57,481, increasing to £106,342 over 5 years. When social care costs are included, incremental savings of £154,716 can be achieved in the first year and £410,449 at 5 years. In addition, an analysis of the potential reduction in outpatient follow-up appointment costs resulted in a further saving of £56,149, giving a total potential saving of £113,630 over the first year with the use of the patch-based service compared to short-duration Holter monitoring, increasing to £162,491 over 5 years. Figure 1. Study participant flowchart Conclusions Early, prolonged, patch-based monitoring after an index stroke or TIA is superior to short-duration Holter monitoring in the detection of PAF and likely cost-effective for preventing recurrent strokes. Acknowledgement/Funding Bristol-Myers Squibb-Pfizer alliance (Grant Number CV185-475)

Background Many of the data points required to support translational research are collected as a matter of routine, and should be available within electronic patient records. Variations in clinical and data recording practice can mean that the extraction and standardisation of this data, with the aim of producing a large-scale, research-ready dataset, presents a number of challenges. Purpose We set out to create a large-scale, research-ready dataset to support translational research in cardiovascular medicine, using routinely-collected data from five large university-hospital partnerships. As an initial focus, we selected those data points that would support an investigation of the relationship between test results and outcomes in acute coronary syndrome (ACS). Methods The National Institute of Health Research (NIHR) Health Informatics Collaborative (HIC) is a programme of infrastructure development aimed at increasing the quality and availability of routinely-collected data for collaborative, translational research. Eighteen university-hospital partnerships signed the data sharing agreement, and are working to facilitate the sharing and re-use of data across centres, for approved research purposes. With support from the Directors of the NIHR Biomedical Research Centres (BRCs) within five of the largest partnerships, we established a clinical data collaboration, specifying a dataset and selecting an initial research question (Figure 1). The NIHR HIC team worked to extract data against this specification. With approval from an ethics committee, and from the information governance teams at each contributing centre, data was processed by one of the centres for standardisation and analysis. Results The specified dataset represented a longitudinal record for patients presenting with a suspected ACS, characterised by a request for a troponin test (Figure 1). The dataset included 156 data points, grouped into demographics, cardiovascular risk factor profile, emergency department attendance and inpatient episodes, blood tests, echocardiography and mortality. Data was extracted from the records of patients for whom a troponin test was requested between 2010 and 2017. A total of 257,948 records were standardised and analysed. The collaboration has been successful, and an initial version of the combined dataset has been created. The size of the dataset has yielded new insights into the relationship between test results and outcomes, and publications are in preparation. An expanded dataset of over 800 data points has been agreed for the next phase of the collaboration, and three other centres have joined. Figure 1. NIHR HIC dataset generation Conclusion It is perfectly feasible – in terms of governance and technology – to re-use routinely-collected data for collaborative, translational research in cardiovascular medicine. The resulting dataset will be large and complex enough to require big data tools and techniques, and will yield the kind of insights afforded only by big data in medicine. Acknowledgement/Funding Funded by NIHR Imperial Biomedical Research Centre (BRC) using NIHR Health Informatics Collaborative data service, supported by OUH, GSTT & UCLH BRCs

Background The incremental long-term prognostic value of high-sensitivity C-reactive protein (hsCRP) above troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndromes (ACS) is unknown. Purpose We hypothesised that a mildly elevated hsCRP is associated with mortality risk in patients with suspected ACS, independent of troponin level. Methods We used the National Institute for Health Research Health Informatics Collaborative data of 257,948 patients who had a troponin measured at 5 cardiac centres. We excluded patients with clinically abnormal white cell counts and hsCRP >15 mg/L to try limiting the population to those without overt infections, malignancies or systemic inflammatory conditions that may confound our analyses. Patients were divided into four hsCRP groups ( Results There were 102,337 patients included in the analysis (hsCRP In Cox regression analysis with time-dependent covariates, even mildly raised hsCRP was an independent predictor of mortality over time, after adjusting for age, gender, haemoglobin, white cell count, platelet count, creatinine and troponin positivity. There was a positive and graded relationship between hsCRP level and mortality at baseline, which remained at 3-years (hazard ratio (95% CI) of 1.32 (1.18–1.48) for those with hsCRP 2.0–4.9mg/L, and 1.40 (1.26–1.57), and 2.00 (1.75–2.28) for those with hsCRP 5–9.9 mg/L and 10–15 mg/L, respectively. We explored whether inclusion of hsCRP could better reclassify the population into at-risk mortality groups. The association with 30-day, 1-year and 3-year mortality was assessed using three different risk models (model 1: age, gender, haemoglobin, creatinine; model 2: model 1 plus troponin (positivity versus negativity); model 3: model 2 plus hsCRP groups. For cumulative mortality at each time point, each successive model was better able to discriminate risk than its precursor (p0.8 at 30 days, 1-year and 3-year mortality, surpassing the use of troponin on its own. Figure 1. Kaplan-Meier mortality curves Conclusions These multi-centre, real-world data from a large cohort of patients with suspected ACS identify hsCRP as a clinically meaningful prognostic marker in addition to troponin levels and point to its potential utility in selecting patients for novel treatments targeting inflammation. Acknowledgement/Funding Funded by NIHR Imperial Biomedical Research Centre (BRC) using NIHR Health Informatics Collaborative data service, supported by OUH, GSTT & UCLH BRCs

Background Life threatening arrhythmias (LTA) can trigger sudden cardiac death, or provoke implantable cardioverter defibrillator (ICD) discharges that escalate morbidity and mortality. Longitudinal myofibrils predominate in the subendocardium which is uniquely sensitive to arrhythmogenic triggers. Objectives To test the hypothesis that mitral annular systolic velocity (S'), a tissue Doppler index of LV long-axis systolic function, might predict lethal arrhythmias irrespective of LVEF. Methods We analysed data from diverse ICD and cardiac resynchronization therapy defibrillator (CRT-D) patients at 2 London centres. Channelopathies were excluded. S' was averaged from medial and lateral mitral annuli velocities. Primary outcome was time to sustained ventricular tachycardia (VT) or fibrillation (VF) needing device therapy. Results In 302 patients (mean age 68 years, LVEF 32%, 77% male, 52% ischemic, 35% primary prevention, and 53% CRT-D), median S' was 5.1 (IQR: 4.0–6.2) cm/s and lower in CRT-D than ICD subjects. After a median follow-up of 15 months, 56 (19%) subjects had LTA and those who did had a lower S' than those who did not (4.6±1.4 cm/s vs. 5.4±1.7 cm/s, P=0.003-Fig A). Each 1cm/s lower S' correlated to a 43% increased risk of LTA (HR: 0.70, 95% CI: 0.57–0.87, P=0.001) independently of age, gender, β-blocker use, centre, ICD use and LVEF. Adding S' to the baseline model improved net reclassification (P=0.02) implying incremental utility (Fig B). An S' ≤5.6cm/s was the best cut-off, conferring a 2.4-fold higher LTA risk than an S'>5.6 cm/s (95% CI: 1.17–4.37, P=0.02–Fig C). Conclusion A lower S' forecasts an enhanced probability of LTA in cardiac device recipients irrespective of LVEF, and could be used to titrate medical, device and ablative therapies to mitigate future arrhythmic risk.