Phenogrouping heart failure with preserved or mildly reduced ejection fraction using electronic health record data.

BACKGROUND: Heart failure (HF) with preserved or mildly reduced ejection fraction includes a heterogenous group of patients. Reclassification into distinct phenogroups to enable targeted interventions is a priority. This study aimed to identify distinct phenogroups, and compare phenogroup characteristics and outcomes, from electronic health record data. METHODS: 2,187 patients admitted to five UK hospitals with a diagnosis of HF and a left ventricular ejection fraction ≥ 40% were identified from the NIHR Health Informatics Collaborative database. Partition-based, model-based, and density-based machine learning clustering techniques were applied. Cox Proportional Hazards and Fine-Gray competing risks models were used to compare outcomes (all-cause mortality and hospitalisation for HF) across phenogroups. RESULTS: Three phenogroups were identified: (1) Younger, predominantly female patients with high prevalence of cardiometabolic and coronary disease; (2) More frail patients, with higher rates of lung disease and atrial fibrillation; (3) Patients characterised by systemic inflammation and high rates of diabetes and renal dysfunction. Survival profiles were distinct, with an increasing risk of all-cause mortality from phenogroups 1 to 3 (p < 0.001). Phenogroup membership significantly improved survival prediction compared to conventional factors. Phenogroups were not predictive of hospitalisation for HF. CONCLUSIONS: Applying unsupervised machine learning to routinely collected electronic health record data identified phenogroups with distinct clinical characteristics and unique survival profiles.

Invasive versus non-invasive management of older patients with non-ST elevation myocardial infarction (SENIOR-NSTEMI): a cohort study based on routine clinical data.

BACKGROUND: Previous trials suggest lower long-term risk of mortality after invasive rather than non-invasive management of patients with non-ST elevation myocardial infarction (NSTEMI), but the trials excluded very elderly patients. We aimed to estimate the effect of invasive versus non-invasive management within 3 days of peak troponin concentration on the survival of patients aged 80 years or older with NSTEMI. METHODS: Routine clinical data for this study were obtained from five collaborating hospitals hosting NIHR Biomedical Research Centres in the UK (all tertiary centres with emergency departments). Eligible patients were 80 years old or older when they underwent troponin measurements and were diagnosed with NSTEMI between 2010 (2008 for University College Hospital) and 2017. Propensity scores (patients' estimated probability of receiving invasive management) based on pretreatment variables were derived using logistic regression; patients with high probabilities of non-invasive or invasive management were excluded. Patients who died within 3 days of peak troponin concentration without receiving invasive management were assigned to the invasive or non-invasive management groups based on their propensity scores, to mitigate immortal time bias. We estimated mortality hazard ratios comparing invasive with non-invasive management, and compared the rate of hospital admissions for heart failure. FINDINGS: Of the 1976 patients with NSTEMI, 101 died within 3 days of their peak troponin concentration and 375 were excluded because of extreme propensity scores. The remaining 1500 patients had a median age of 86 (IQR 82-89) years of whom (845 [56%] received non-invasive management. During median follow-up of 3·0 (IQR 1·2-4·8) years, 613 (41%) patients died. The adjusted cumulative 5-year mortality was 36% in the invasive management group and 55% in the non-invasive management group (adjusted hazard ratio 0·68, 95% CI 0·55-0·84). Invasive management was associated with lower incidence of hospital admissions for heart failure (adjusted rate ratio compared with non-invasive management 0·67, 95% CI 0·48-0·93). INTERPRETATION: The survival advantage of invasive compared with non-invasive management appears to extend to patients with NSTEMI who are aged 80 years or older. FUNDING: NIHR Imperial Biomedical Research Centre, as part of the NIHR Health Informatics Collaborative.

Diagnostic and prognostic value of an ejection fraction adjusted for myocardial remodeling.

Introduction: Ejection fraction (EF) is widely used to evaluate heart function during heart failure (HF) due to its simplicity compared but it may misrepresent cardiac function during ventricular hypertrophy, especially in heart failure with preserved EF (HFpEF). To resolve this shortcoming, we evaluate a correction factor to EF, which is equivalent to computing EF at the mid-wall layer (without the need for mid-layer identification) rather than at the endocardial surface, and thus better complements other complex metrics. Method: The retrospective cohort data was studied, consisting of 2,752 individuals (56.5% male, age 69.3 ± 16.4 years) admitted with a request of a troponin test and undergoing echocardiography as part of their clinical assessment across three centres. Cox-proportional regression models were constructed to compare the adjusted EF (EFa) to EF in evaluating risk of heart failure admissions. Result: Comparing HFpEF patients to non-HF cases, there was no significant difference in EF (62.3 ± 7.6% vs. 64.2 ± 6.2%, p = 0.79), but there was a significant difference in EFa (56.6 ± 6.4% vs. 61.8 ± 9.9%, p = 0.0007). Both low EF and low EFa were associated with a high HF readmission risk. However, in the cohort with a normal EF (EF ≥ 50%), models using EFa were significantly more associative with HF readmissions within 3 years, where the leave one out cross validation ROC analysis showed a 18.6% reduction in errors, and Net Classification Index (NRI) analysis showed that risk increment classification of events increased by 12.2%, while risk decrement classification of non-events decreased by 16.6%. Conclusion: EFa is associated with HF readmission in patients with a normal EF.

Prognostic Significance of Ventricular Arrhythmias in 13 444 Patients With Acute Coronary Syndrome: A Retrospective Cohort Study Based on Routine Clinical Data (NIHR Health Informatics Collaborative VA-ACS Study).

Background A minority of acute coronary syndrome (ACS) cases are associated with ventricular arrhythmias (VA) and/or cardiac arrest (CA). We investigated the effect of VA/CA at the time of ACS on long-term outcomes. Methods and Results We analyzed routine clinical data from 5 National Health Service trusts in the United Kingdom, collected between 2010 and 2017 by the National Institute for Health Research Health Informatics Collaborative. A total of 13 444 patients with ACS, 376 (2.8%) of whom had concurrent VA, survived to hospital discharge and were followed up for a median of 3.42 years. Patients with VA or CA at index presentation had significantly increased risks of subsequent VA during follow-up (VA group: adjusted hazard ratio [HR], 4.15 [95% CI, 2.42-7.09]; CA group: adjusted HR, 2.60 [95% CI, 1.23-5.48]). Patients who suffered a CA in the context of ACS and survived to discharge also had a 36% increase in long-term mortality (adjusted HR, 1.36 [95% CI, 1.04-1.78]), although the concurrent diagnosis of VA alone during ACS did not affect all-cause mortality (adjusted HR, 1.03 [95% CI, 0.80-1.33]). Conclusions Patients who develop VA or CA during ACS who survive to discharge have increased risks of subsequent VA, whereas those who have CA during ACS also have an increase in long-term mortality. These individuals may represent a subgroup at greater risk of subsequent arrhythmic events as a result of intrinsically lower thresholds for developing VA.

Implications of elevated troponin on time-to-surgery in non-ST elevation myocardial infarction (NIHR Health Informatics Collaborative: TROP-CABG study).

Implications of elevated troponin on time-to-surgery in non-ST elevation myocardial infarction(NIHR Health Informatics Collaborative:TROP-CABG study). Benedetto et al. BACKGROUND: The optimal timing of coronary artery bypass grafting (CABG) in patients with non-ST elevation myocardial infarction (NSTEMI) and the utility of pre-operative troponin levels in decision-making remains unclear. We investigated (a) the association between peak pre-operative troponin and survival post-CABG in a large cohort of NSTEMI patients and (b) the interaction between troponin and time-to-surgery. METHODS AND RESULTS: Our cohort consisted of 1746 patients (1684 NSTEMI; 62 unstable angina) (mean age 69 ± 11 years,21% female) with recorded troponins that had CABG at five United Kingdom centers between 2010 and 2017. Time-segmented Cox regression was used to investigate the interaction of peak troponin and time-to-surgery on early (within 30 days) and late (beyond 30 days) survival. Average interval from peak troponin to surgery was 9 ± 15 days, with 1466 (84.0%) patients having CABG during the same admission. Sixty patients died within 30-days and another 211 died after a mean follow-up of 4 ± 2 years (30-day survival 0.97 ± 0.004 and 5-year survival 0.83 ± 0.01). Peak troponin was a strong predictor of early survival (adjusted P = 0.002) with a significant interaction with time-to-surgery (P interaction = 0.007). For peak troponin levels <100 times the upper limit of normal, there was no improvement in early survival with longer time-to-surgery. However, in patients with higher troponins, early survival increased progressively with a longer time-to-surgery, till day 10. Peak troponin did not influence survival beyond 30 days (adjusted P = 0.64). CONCLUSIONS: Peak troponin in NSTEMI patients undergoing CABG was a significant predictor of early mortality, strongly influenced the time-to-surgery and may prove to be a clinically useful biomarker in the management of these patients.

Prognostic significance of troponin level in 3121 patients presenting with atrial fibrillation (The NIHR Health Informatics Collaborative TROP-AF study).

Background Patients presenting with atrial fibrillation (AF) often undergo a blood test to measure troponin, but interpretation of the result is impeded by uncertainty about its clinical importance. We investigated the relationship between troponin level, coronary angiography, and all-cause mortality in real-world patients presenting with AF. Methods and Results We used National Institute of Health Research Health Informatics Collaborative data to identify patients admitted between 2010 and 2017 at 5 tertiary centers in the United Kingdom with a primary diagnosis of AF. Peak troponin results were scaled as multiples of the upper limit of normal. A total of 3121 patients were included in the analysis. Over a median follow-up of 1462 (interquartile range, 929-1975) days, there were 586 deaths (18.8%). The adjusted hazard ratio for mortality associated with a positive troponin (value above upper limit of normal) was 1.20 (95% CI, 1.01-1.43; P<0.05). Higher troponin levels were associated with higher risk of mortality, reaching a maximum hazard ratio of 2.6 (95% CI, 1.9-3.4) at ≈250 multiples of the upper limit of normal. There was an exponential relationship between higher troponin levels and increased odds of coronary angiography. The mortality risk was 36% lower in patients undergoing coronary angiography than in those who did not (adjusted hazard ratio, 0.61; 95% CI, 0.42-0.89; P=0.01). Conclusions Increased troponin was associated with increased risk of mortality in patients presenting with AF. The lower hazard ratio in patients undergoing invasive management raises the possibility that the clinical importance of troponin release in AF may be mediated by coronary artery disease, which may be responsive to revascularization.

Association of troponin level and age with mortality in 250 000 patients: cohort study across five UK acute care centres.

OBJECTIVE: To determine the relation between age and troponin level and its prognostic implication. DESIGN: Retrospective cohort study. SETTING: Five cardiovascular centres in the UK National Institute for Health Research Health Informatics Collaborative (UK-NIHR HIC). PARTICIPANTS: 257 948 consecutive patients undergoing troponin testing for any clinical reason between 2010 and 2017. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: 257 948 patients had troponin measured during the study period. Analyses on troponin were performed using the peak troponin level, which was the highest troponin level measured during the patient's hospital stay. Troponin levels were standardised as a multiple of each laboratory's 99th centile of the upper limit of normal (ULN). During a median follow-up of 1198 days (interquartile range 514-1866 days), 55 850 (21.7%) deaths occurred. A positive troponin result (that is, higher than the upper limit of normal) signified a 3.2 higher mortality hazard (95% confidence interval 3.1 to 3.2) over three years. Mortality varied noticeably with age, with a hazard ratio of 10.6 (8.5 to 13.3) in 18-29 year olds and 1.5 (1.4 to 1.6) in those older than 90. A positive troponin result was associated with an approximately 15 percentage points higher absolute three year mortality across all age groups. The excess mortality with a positive troponin result was heavily concentrated in the first few weeks. Results were analysed using multivariable adjusted restricted cubic spline Cox regression. A direct relation was seen between troponin level and mortality in patients without acute coronary syndrome (ACS, n=120 049), whereas an inverted U shaped relation was found in patients with ACS (n=14 468), with a paradoxical decline in mortality at peak troponin levels >70×ULN. In the group with ACS, the inverted U shaped relation persisted after multivariable adjustment in those who were managed invasively; however, a direct positive relation was found between troponin level and mortality in patients managed non-invasively. CONCLUSIONS: A positive troponin result was associated with a clinically important increased mortality, regardless of age, even if the level was only slightly above normal. The excess mortality with a raised troponin was heavily concentrated in the first few weeks. STUDY REGISTRATION: ClinicalTrials.gov NCT03507309.