Invasive Endotyping in Patients With Angina and No Obstructive Coronary Artery Disease: A Randomized Controlled Trial.

BACKGROUND: We investigated the usefulness of invasive coronary function testing to diagnose the cause of angina in patients with no obstructive coronary arteries. METHODS: Outpatients referred for coronary computed tomography angiography in 3 hospitals in the United Kingdom were prospectively screened. After coronary computed tomography angiography, patients with unobstructed coronary arteries, and who consented, underwent invasive endotyping. The diagnostic assessments included coronary angiography, fractional flow reserve (patient excluded if ≤0.80), and, for those without obstructive coronary artery disease, coronary flow reserve (abnormal <2.0), index of microvascular resistance (abnormal ≥25), and intracoronary infusion of acetylcholine (0.182, 1.82, and 18.2 µg/mL; 2 mL/min for 2 minutes) to assess for microvascular and coronary spasm. Participants were randomly assigned to disclosure of the results of the coronary function tests to the invasive cardiologist (intervention group) or nondisclosure (control group, blinded). In the control group, a diagnosis of vasomotor angina was based on medical history, noninvasive tests, and coronary angiography. The primary outcome was the between-group difference in the reclassification rate of the initial diagnosis on the basis of coronary computed tomography angiography versus the final diagnosis after invasive endotyping. The Seattle Angina Questionnaire summary score and Treatment Satisfaction Questionnaire for Medication were secondary outcomes. RESULTS: Of 322 eligible patients, 250 (77.6%) underwent invasive endotyping; 19 (7.6%) had obstructive coronary disease, 127 (55.0%) had microvascular angina, 27 (11.7%) had vasospastic angina, 17 (7.4%) had both, and 60 (26.0%) had no abnormality. A total of 231 patients (mean age, 55.7 years; 64.5% women) were randomly assigned and followed up (median duration, 19.9 [12.6-26.9] months). The clinician diagnosed vasomotor angina in 51 (44.3%) patients in the intervention group and in 55 (47.4%) patients in the control group. After randomization, patients in the intervention group were 4-fold (odds ratio, 4.05 [95% CI, 2.32-7.24]; P<0.001) more likely to be diagnosed with a coronary vasomotor disorder; the frequency of this diagnosis increased to 76.5%. The frequency of normal coronary function (ie, no vasomotor disorder) was not different between the groups before randomization (51.3% versus 50.9%) but was reduced in the intervention group after randomization (23.5% versus 50.9%, P<0.001). At 6 and 12 months, the Seattle Angina Questionnaire summary score in the intervention versus control groups was 59.2±24.2 (2.3±16.2 change from baseline) versus 60.4±23.9 (4.6±16.4 change) and 63.7±23.5 (4.7±14.7 change) versus 66.0±19.3 (7.9±17.1 change), respectively, and not different between groups (global P=0.36). Compared with the control group, global treatment satisfaction was higher in the intervention group at 12 months (69.9±22.8 versus 61.7±26.9, P=0.013). CONCLUSIONS: For patients with angina and no obstructive coronary arteries, a diagnosis informed by invasive functional assessment had no effect on long-term angina burden, whereas treatment satisfaction improved. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03477890.

The metabolomic signature of weight loss and remission in the Diabetes Remission Clinical Trial (DiRECT).

AIMS/HYPOTHESIS: High-throughput metabolomics technologies in a variety of study designs have demonstrated a consistent metabolomic signature of overweight and type 2 diabetes. However, the extent to which these metabolomic patterns can be reversed with weight loss and diabetes remission has been weakly investigated. We aimed to characterise the metabolomic consequences of a weight-loss intervention in individuals with type 2 diabetes. METHODS: We analysed 574 fasted serum samples collected within an existing RCT (the Diabetes Remission Clinical Trial [DiRECT]) (N=298). In the trial, participating primary care practices were randomly assigned (1:1) to provide either a weight management programme (intervention) or best-practice care by guidelines (control) treatment to individuals with type 2 diabetes. Here, metabolomics analysis was performed on samples collected at baseline and 12 months using both untargeted MS and targeted 1H-NMR spectroscopy. Multivariable regression models were fitted to evaluate the effect of the intervention on metabolite levels. RESULTS: Decreases in branched-chain amino acids, sugars and LDL triglycerides, and increases in sphingolipids, plasmalogens and metabolites related to fatty acid metabolism were associated with the intervention (Holm-corrected p<0.05). In individuals who lost more than 9 kg between baseline and 12 months, those who achieved diabetes remission saw greater reductions in glucose, fructose and mannose, compared with those who did not achieve remission. CONCLUSIONS/INTERPRETATION: We have characterised the metabolomic effects of an integrated weight management programme previously shown to deliver weight loss and diabetes remission. A large proportion of the metabolome appears to be modifiable. Patterns of change were largely and strikingly opposite to perturbances previously documented with the development of type 2 diabetes. DATA AVAILABILITY: The data used for analysis are available on a research data repository ( https://researchdata.gla.ac.uk/ ) with access given to researchers subject to appropriate data sharing agreements. Metabolite data preparation, data pre-processing, statistical analyses and figure generation were performed in R Studio v.1.0.143 using R v.4.0.2. The R code for this study has been made publicly available on GitHub at: https://github.com/lauracorbin/metabolomics_of_direct .

Myocardial Involvement After Hospitalization for COVID-19 Complicated by Troponin Elevation: A Prospective, Multicenter, Observational Study.

BACKGROUND: Acute myocardial injury in hospitalized patients with coronavirus disease 2019 (COVID-19) has a poor prognosis. Its associations and pathogenesis are unclear. Our aim was to assess the presence, nature, and extent of myocardial damage in hospitalized patients with troponin elevation. METHODS: Across 25 hospitals in the United Kingdom, 342 patients with COVID-19 and an elevated troponin level (COVID+/troponin+) were enrolled between June 2020 and March 2021 and had a magnetic resonance imaging scan within 28 days of discharge. Two prospective control groups were recruited, comprising 64 patients with COVID-19 and normal troponin levels (COVID+/troponin-) and 113 patients without COVID-19 or elevated troponin level matched by age and cardiovascular comorbidities (COVID-/comorbidity+). Regression modeling was performed to identify predictors of major adverse cardiovascular events at 12 months. RESULTS: Of the 519 included patients, 356 (69%) were men, with a median (interquartile range) age of 61.0 years (53.8, 68.8). The frequency of any heart abnormality, defined as left or right ventricular impairment, scar, or pericardial disease, was 2-fold greater in cases (61% [207/342]) compared with controls (36% [COVID+/troponin-] versus 31% [COVID-/comorbidity+]; P<0.001 for both). More cases than controls had ventricular impairment (17.2% versus 3.1% and 7.1%) or scar (42% versus 7% and 23%; P<0.001 for both). The myocardial injury pattern was different, with cases more likely than controls to have infarction (13% versus 2% and 7%; P<0.01) or microinfarction (9% versus 0% and 1%; P<0.001), but there was no difference in nonischemic scar (13% versus 5% and 14%; P=0.10). Using the Lake Louise magnetic resonance imaging criteria, the prevalence of probable recent myocarditis was 6.7% (23/342) in cases compared with 1.7% (2/113) in controls without COVID-19 (P=0.045). During follow-up, 4 patients died and 34 experienced a subsequent major adverse cardiovascular event (10.2%), which was similar to controls (6.1%; P=0.70). Myocardial scar, but not previous COVID-19 infection or troponin, was an independent predictor of major adverse cardiovascular events (odds ratio, 2.25 [95% CI, 1.12-4.57]; P=0.02). CONCLUSIONS: Compared with contemporary controls, patients with COVID-19 and elevated cardiac troponin level have more ventricular impairment and myocardial scar in early convalescence. However, the proportion with myocarditis was low and scar pathogenesis was diverse, including a newly described pattern of microinfarction. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: 58667920.

Dropout from exercise trials among cancer survivors-An individual patient data meta-analysis from the POLARIS study.

INTRODUCTION: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. METHODS: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. RESULTS: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI >28.4 kg/m2 , performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI >28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. CONCLUSIONS: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects.

Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics.

BACKGROUND AND AIMS: To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. METHODS AND RESULTS: A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. CONCLUSION: In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04860011.

Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial.

BACKGROUND: Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension. METHODS: The TIME study is a prospective, pragmatic, decentralised, parallel-group study in the UK, that recruited adults (aged ≥18 years) with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned (1:1), without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning (0600-1000 h) or in the evening (2000-0000 h). Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete. FINDINGS: Between Dec 17, 2011, and June 5, 2018, 24 610 individuals were screened and 21 104 were randomly assigned to evening (n=10 503) or morning (n=10 601) dosing groups. Mean age at study entry was 65·1 years (SD 9·3); 12 136 (57·5%) participants were men; 8968 (42·5%) were women; 19 101 (90·5%) were White; 98 (0·5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 4·9-5·7), and 529 (5·0%) of 10 503 participants assigned to evening treatment and 318 (3·0%) of 10 601 assigned to morning treatment had withdrawn from all follow-up. A primary endpoint event occurred in 362 (3·4%) participants assigned to evening treatment (0·69 events [95% CI 0·62-0·76] per 100 patient-years) and 390 (3·7%) assigned to morning treatment (0·72 events [95% CI 0·65-0·79] per 100 patient-years; unadjusted hazard ratio 0·95 [95% CI 0·83-1·10]; p=0·53). No safety concerns were identified. INTERPRETATION: Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects. FUNDING: British Heart Foundation.

The coronary microvascular angina cardiovascular magnetic resonance imaging trial: Rationale and design.

BACKGROUND: Coronary microvascular dysfunction may cause myocardial ischemia with no obstructive coronary artery disease (INOCA). If functional testing is not performed INOCA may pass undetected. Stress perfusion cardiovascular MRI (CMR) quantifies myocardial blood flow (MBF) but the clinical utility of stress CMR in the management of patients with suspected angina with no obstructive coronary arteries (ANOCA) is uncertain. OBJECTIVES: First, to undertake a diagnostic study using stress CMR in patients with ANOCA following invasive coronary angiography and, second, in a nested, double-blind, randomized, controlled trial to assess the effect of disclosure on the final diagnosis and health status in the longer term. DESIGN: All-comers referred for clinically indicated coronary angiography for the investigation of suspected coronary artery disease will be screened in 3 regional centers in the United Kingdom. Following invasive coronary angiography, patients with ANOCA who provide informed consent will undergo noninvasive endotyping using stress CMR within 3 months of the angiogram. DIAGNOSTIC STUDY: Stress perfusion CMR imaging to assess the prevalence of coronary microvascular dysfunction and clinically significant incidental findings in patients with ANOCA. The primary outcome is the between-group difference in the reclassification rate of the initial diagnosis based on invasive angiography versus the final diagnosis after CMR imaging. RANDOMIZED, CONTROLLED TRIAL: Participants will be randomized to inclusion (intervention group) or exclusion (control group) of myocardial blood flow to inform the final diagnosis. The primary outcome of the clinical trial is the mean within-subject change in the Seattle Angina Questionnaire summary score (SAQSS) at 6 months. Secondary outcome assessments include the EUROQOL EQ-5D-5L questionnaire, the Brief Illness Perception Questionnaire (Brief-IPQ), the Treatment Satisfaction Questionnaire (TSQM-9), the Patient Health Questionnaire-4 (PHQ-4), the Duke Activity Status Index (DASI), the International Physical Activity Questionnaire- Short Form (IPAQ-SF), the Montreal Cognitive Assessment (MOCA) and the 8-item Productivity Cost Questionnaire (iPCQ). Health and economic outcomes will be assessed using electronic healthcare records. VALUE: To clarify if routine stress perfusion CMR imaging reclassifies the final diagnosis in patients with ANOCA and whether this strategy improves symptoms, health-related quality of life and health economic outcomes. CLINICALTRIALS: GOV: NCT04805814.

Physical activity, inactivity and sleep during the Diabetes Remission Clinical Trial (DiRECT).

AIMS: As sustained weight loss is vital for achieving remission of type 2 diabetes, we explored whether randomisation to weight loss plus maintenance in the DiRECT trial was associated with physical activity, inactivity or sleep. METHODS: Participants were randomised to either a dietary weight management programme or best-practice care. The weight management group were encouraged to increase daily physical activity to their sustainable maximum. Objective measurement was achieved using a wrist-worn GENEActiv accelerometer for 7 days at baseline, 12 and 24 months in both groups. RESULTS: Despite average weight loss of 10 kg at 12 months in the intervention (n = 66) group, there were no differences in total physical activity or inactivity compared with the control (n = 104) at any time point. However, in our exploratory analysis, those who lost more than 10% of their baseline body weight performed on average 11 mins/day more light activity than the <10% group at 24 months (p = 0.033) and had significantly lower bouts of Inactivity30min (interaction, p = 0.005) across 12 and 24 months. At 24 months, the ≥10% group had higher daily acceleration (38.5 ± 12.1 vs. 33.2 ± 11.1 mg, p = 0.020), and higher accelerations in the most active 5-hour period (59.4 ± 21.8 vs. 50.6 ± 18.3 mg, p = 0.023). Wakefulness after sleep onset decreased in the intervention group compared with the control group and also in the ≥10% weight loss group at 12 and 24 months. CONCLUSIONS: Randomisation to a successful intensive weight loss intervention, including regular physical activity encouragement, was not associated with increased physical activity although sleep parameters improved. Physical activity was greater, and night-time waking reduced in those who maintained >10% weight loss at 12 and 24 months. TRIAL REGISTRATION ISRCTN03267836.

Post-COVID-19 illness and associations with sex and gender.

BACKGROUND: Post-COVID-19 syndromes have associated with female sex, but the pathophysiological basis is uncertain. AIM: There are sex differences in myocardial inflammation identified using cardiac magnetic resonance (CMR) in post-COVID-19 patients, and in patient reported health outcomes following COVID-19 infection. DESIGN: This prospective study investigated the time-course of multiorgan injury in survivors of COVID-19 during convalescence. METHODS: Clinical information, blood biomarkers, and patient reported outcome measures were prospectively acquired at enrolment (visit 1) and 28-60 days post-discharge (visit 2). Chest computed tomography (CT) and CMR were performed at visit 2. Follow-up was carried out for serious adverse events, including death and rehospitalization. RESULTS: Sixty-nine (43%) of 159 patients recruited were female. During the index admission, females had a lower peak C-reactive protein (74 mg/l (21,163) versus 123 mg/l (70, 192) p = 0.008) and peak ferritin (229 µg/l (103, 551) versus 514 µg/l (228, 1122) p < 0.001). Using the Modified Lake-Louise criteria, females were more likely to have definite evidence of myocardial inflammation (54% (37/68) versus 33% (30/90) p = 0.003). At enrolment and 28-60 days post-discharge, enhanced illness perception, higher levels of anxiety and depression and lower predicted maximal oxygen utilization occurred more commonly in women. The mean (SD, range) duration of follow-up after hospital discharge was 450 (88) days (range 290, 627 days). Compared to men, women had lower rates of cardiovascular hospitalization (0% versus 8% (7/90); p = 0.018). CONCLUSIONS: Women demonstrated worse patient reported outcome measures at index admission and 28-60 days follow-up though cardiovascular hospitalization was lower.

More time in a community setting: A service evaluation of the impact of intrathecal drug delivery systems on place of care of patients with cancer pain.

BACKGROUND: Intrathecal Drug Delivery Systems are underutilised in the management of refractory cancer pain despite evidence of their efficacy. Not all patients who are offered this treatment modality accept it. There is no current evidence that indicates if the use of intrathecal drug delivery systems impacts on place of care for patients with cancer related pain. AIMS: This service evaluation compared place of care, place of death and morphine equivalent daily dose at end of life for patients in whom Intrathecal Drug Delivery was successfully established versus those who chose comprehensive medical management. SETTING/PARTICIPANTS: A retrospective longitudinal cohort study of 45 patients with cancer pain comparing those who had ongoing analgesia successfully delivered via an implanted Intrathecal Drug Delivery System (n = 28) with those who continued to receive comprehensive medical management (n = 17). RESULTS: There was a markedly greater time spent in the community in the intrathecal group than the medical management group (median 126.5vs 25.5 days; p = 0.002) and a lower morphine equivalent daily dose at end of life (median 127.5vs 440.0 p = 0.022). CONCLUSION: In patients with advanced cancer, the successful establishment of intrathecal analgesia is associated with more time in the community and a lower morphine equivalent daily dose at end of life. The study has low numbers, and the sample was retrospectively selected. Nevertheless, these findings suggest the initial investment of time in an inpatient setting may be beneficial. Further research is required, using larger, prospective studies of patient outcomes in this setting.

European Society of Cardiology: cardiovascular disease statistics 2021.

AIMS: This report from the European Society of Cardiology (ESC) Atlas Project updates and expands upon the widely cited 2019 report in presenting cardiovascular disease (CVD) statistics for the 57 ESC member countries. METHODS AND RESULTS: Statistics pertaining to 2019, or the latest available year, are presented. Data sources include the World Health Organization, the Institute for Health Metrics and Evaluation, the World Bank, and novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery. New material in this report includes sociodemographic and environmental determinants of CVD, rheumatic heart disease, out-of-hospital cardiac arrest, left-sided valvular heart disease, the advocacy potential of these CVD statistics, and progress towards World Health Organization (WHO) 2025 targets for non-communicable diseases. Salient observations in this report: (i) Females born in ESC member countries in 2018 are expected to live 80.8 years and males 74.8 years. Life expectancy is longer in high income (81.6 years) compared with middle-income (74.2 years) countries. (ii) In 2018, high-income countries spent, on average, four times more on healthcare than middle-income countries. (iii) The median PM2.5 concentrations in 2019 were over twice as high in middle-income ESC member countries compared with high-income countries and exceeded the EU air quality standard in 14 countries, all middle-income. (iv) In 2016, more than one in five adults across the ESC member countries were obese with similar prevalence in high and low-income countries. The prevalence of obesity has more than doubled over the past 35 years. (v) The burden of CVD falls hardest on middle-income ESC member countries where estimated incidence rates are ∼30% higher compared with high-income countries. This is reflected in disability-adjusted life years due to CVD which are nearly four times as high in middle-income compared with high-income countries. (vi) The incidence of calcific aortic valve disease has increased seven-fold during the last 30 years, with age-standardized rates four times as high in high-income compared with middle-income countries. (vii) Although the total number of CVD deaths across all countries far exceeds the number of cancer deaths for both sexes, there are 15 ESC member countries in which cancer accounts for more deaths than CVD in males and five-member countries in which cancer accounts for more deaths than CVD in females. (viii) The under-resourced status of middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, ablation procedures, device implantation, and cardiac surgical procedures. CONCLUSION: Risk factors and unhealthy behaviours are potentially reversible, and this provides a huge opportunity to address the health inequalities across ESC member countries that are highlighted in this report. It seems clear, however, that efforts to seize this opportunity are falling short and present evidence suggests that most of the WHO NCD targets for 2025 are unlikely to be met across ESC member countries.

AppReminders - a pilot feasibility randomized controlled trial of a memory aid app for people with acquired brain injury.

Mobile phone reminding apps can be used by people with acquired brain injury (ABI) to compensate for memory impairments. This pilot feasibility trial aimed to establish the feasibility of a randomized controlled trial comparing reminder apps in an ABI community treatment setting. Adults with ABI and memory difficulty who completed the three-week baseline were randomized (n = 29) and allocated to Google Calendar or ApplTree app. Those who attended an intervention session (n = 21) watched a 30-minute video tutorial of the app then completed reminder setting assignments to ensure they could use the app. Guidance was given if needed from a clinician or researcher. Those who passed the app assignments (n = 19) completed a three-week follow up. Recruitment was lower than target (n = 50), retention rate was 65.5%, adherence rate was 73.7%. Qualitative feedback highlighted issues that may impact usability of reminding apps introduced within community brain injury rehabilitation. Feasibility results indicate a full trial would require 72 participants to demonstrate the minimally clinically important efficacy difference between apps, should a difference exist. Most participants (19 of 21) given an app could learn to use it with the short tutorial. Design features implemented in ApplTree have potential to improve the uptake and utility of reminding apps.

Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction.

BACKGROUND: Patients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects. METHODS: We performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a ß-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire. RESULTS: From July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m2 (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change. CONCLUSIONS: In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.

Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF).

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain. METHODS: We designed a multicenter, randomized, double-blind, placebo-controlled trial (the SUGAR-DM-HF trial [Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus, or Prediabetes, and Heart Failure]) to investigate the cardiac effects of empagliflozin in patients in New York Heart Association functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomly assigned 1:1 to empagliflozin 10 mg once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The coprimary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area and LV global longitudinal strain both measured using cardiovascular magnetic resonance. Secondary efficacy outcomes included other cardiovascular magnetic resonance measures (LV end-diastolic volume index, LV ejection fraction), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, B-lines on lung ultrasound, and biomarkers (including N-terminal pro-B-type natriuretic peptide). RESULTS: From April 2018 to August 2019, 105 patients were randomly assigned: mean age 68.7 (SD, 11.1) years, 77 (73.3%) male, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LV ejection fraction 32.5% (9.8%), and 81 (77.1%) New York Heart Association II and 24 (22.9%) New York Heart Association III. Patients received standard treatment for HFrEF. In comparison with placebo, empagliflozin reduced LV end-systolic volume index by 6.0 (95% CI, -10.8 to -1.2) mL/m2 (P=0.015). There was no difference in LV global longitudinal strain. Empagliflozin reduced LV end-diastolic volume index by 8.2 (95% CI, -13.7 to -2.6) mL/m2 (P=0.0042) and reduced N-terminal pro-B-type natriuretic peptide by 28% (2%-47%), P=0.038. There were no between-group differences in other cardiovascular magnetic resonance measures, diuretic intensification, Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, or B-lines. CONCLUSIONS: The sodium-glucose cotransporter 2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which sodium-glucose cotransporter 2 inhibitors reduce heart failure hospitalization and mortality in HFrEF. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03485092.

The presence and impact of multimorbidity clusters on adverse outcomes across the spectrum of kidney function.

BACKGROUND: Multimorbidity (the presence of two or more chronic conditions) is common amongst people with chronic kidney disease, but it is unclear which conditions cluster together and if this changes as kidney function declines. We explored which clusters of conditions are associated with different estimated glomerular filtration rates (eGFRs) and studied associations between these clusters and adverse outcomes. METHODS: Two population-based cohort studies were used: the Stockholm Creatinine Measurements project (SCREAM, Sweden, 2006-2018) and the Secure Anonymised Information Linkage Databank (SAIL, Wales, 2006-2021). We studied participants in SCREAM (404,681 adults) and SAIL (533,362) whose eGFR declined lower than thresholds (90, 75, 60, 45, 30 and 15 mL/min/1.73m2). Clusters based on 27 chronic conditions were identified. We described the most common chronic condition(s) in each cluster and studied their association with adverse outcomes using Cox proportional hazards models (all-cause mortality (ACM) and major adverse cardiovascular events (MACE)). RESULTS: Chronic conditions became more common and clustered differently across lower eGFR categories. At eGFR 90, 75, and 60 mL/min/1.73m2, most participants were in large clusters with no prominent conditions. At eGFR 15 and 30 mL/min/1.73m2, clusters involving cardiovascular conditions were larger and were at the highest risk of adverse outcomes. At eGFR 30 mL/min/1.73m2, in the heart failure, peripheral vascular disease and diabetes cluster in SCREAM, ACM hazard ratio (HR) is 2.66 (95% confidence interval (CI) 2.31-3.07) and MACE HR is 4.18 (CI 3.65-4.78); in the heart failure and atrial fibrillation cluster in SAIL, ACM HR is 2.23 (CI 2.04 to 2.44) and MACE HR is 3.43 (CI 3.22-3.64). Chronic pain and depression were common and associated with adverse outcomes when combined with physical conditions. At eGFR 30 mL/min/1.73m2, in the chronic pain, heart failure and myocardial infarction cluster in SCREAM, ACM HR is 2.00 (CI 1.62-2.46) and MACE HR is 4.09 (CI 3.39-4.93); in the depression, chronic pain and stroke cluster in SAIL, ACM HR is 1.38 (CI 1.18-1.61) and MACE HR is 1.58 (CI 1.42-1.76). CONCLUSIONS: Patterns of multimorbidity and corresponding risk of adverse outcomes varied with declining eGFR. While diabetes and cardiovascular disease are known high-risk conditions, chronic pain and depression emerged as important conditions and associated with adverse outcomes when combined with physical conditions.

Antibiotic prophylaxis in breast cancer surgery (PAUS trial): randomised clinical double-blind parallel-group multicentre superiority trial.

BACKGROUND: Participants were patients with invasive breast cancer undergoing primary surgery. The aim was to test whether a single dose of amoxicillin-clavulanic acid would reduce wound infection at 30 days postoperatively, and to identify risk factors for infection. METHODS: Participants were randomised to either a single bolus of 1.2 g intravenous amoxicillin-clavulanic acid after the induction of anaesthesia (intervention) or no antibiotic (control). The primary outcome was the incidence of wound infection at 30 days postoperatively. RESULTS: There were 871 evaluable patients. Of these, 438 received prophylactic antibiotic and 433 served as controls. Seventy-one (16.2 per cent) patients in the intervention group developed a wound infection by 30 days, while there were 83 (19.2 per cent) infections in the control group. This was not statistically significant (odds ratio (OR) 0.82, 95 per cent c.i. 0.58 to 1.15; P = 0.250). The risk of infection increased for every 5 kg/m2 of BMI (OR 1.29, 95 per cent c.i. 1.10 to 1.52; P = 0.003). Patients who were preoperative carriers of Staphylococcus aureus had an increased risk of postoperative wound infection; however, there was no benefit of preoperative antibiotics for patients with either a high BMI or who were carriers of S. aureus. CONCLUSION: There was no statistically significant or clinically meaningful reduction in wound infection at 30 days following breast cancer surgery in patients who received a single dose of amoxicillin-clavulanic acid preoperatively. REGISTRATION NUMBER: N0399145605 (National Research Register).

There is little research about antibiotics in breast cancer surgery. Surgeons are not certain whether or not to use antibiotics for their patients. The aim of the Prophylactic Antibiotic Use in Surgery (PAUS) trial was to ask a question, 'Do preoperative antibiotics have any benefit for patients having surgery for breast cancer?' In the PAUS trial patients were given information to decide whether they wished to take part in the trial or not. Participants were randomly placed in one of two groups. Half were given one dose of the amoxicillin­clavulanic acid antibiotic at the time of their operation. The other half had no antibiotic. Neither the patient nor the surgeon knew which group the patient was in. Patients were carefully checked until 30 days after their operation for signs of wound infection. Altogether, 871 patients agreed to take part in the PAUS trial. Of these, 438 patients had the antibiotic and 433 had no antibiotic. The PAUS trial showed that there was no difference in the number of wound infections when comparing the two groups. Seventy-one patients (16.2 per cent) who had been given the antibiotic developed a wound infection by 30 days versus 83 (19.2 per cent) in the group who had not been given the antibiotic. This trial shows that antibiotics may not be needed for breast cancer surgery. PAUS may help to cut down on unnecessary antibiotic use.

Predicting mortality after hospitalisation for COPD using electronic health records.

BACKGROUND: Few prognostic models exist for patients hospitalised with chronic obstructive pulmonary disease (COPD); most are based on small cohorts enroled by specialists in academic centres. Electronic health records (EHRs) provide an opportunity to develop more representative models, although they may not record some variables used in existing models. MATERIALS AND METHODS: for this retrospective cohort study, using EHRs, we identified 17,973 patients with an unplanned hospitalisation for COPD (in any diagnostic position) in the Glasgow area between 2011 and 2017. Patients with known lung cancer were excluded. EHR were linked to prior admissions, community prescribing and laboratory data. A pragmatic, parsimonious multivariable model was developed to predict 90-day mortality. RESULTS: we identified 12 variables strongly related to prognosis, including age, sex, length of index hospitalisation stay, prior diagnosis of cancer (excluding lung cancer) or dementia, prescription of oxygen or digoxin, neutrophil/lymphocyte ratio and serum chloride, urea, creatinine and albumin. The model achieved excellent calibration with reasonable discrimination (area under the curve: 0.806; 95% CI: 0.792-0.820). A risk-score was developed and an electronic risk-calculator is provided. CONCLUSIONS: a small number of variables, including prescriptions and laboratory data obtained from routine EHRs predict 90-day mortality after a hospitalisation for COPD. The risk-calculator provided might prove useful for service-evaluation and audit, to guide clinical management and to risk-stratify and select patients to be invited to participate in clinical research.

Dietary consumption of tea and the risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Tea contains polyphenols such as flavonoids, anthocyanidins, flavanols and phenolic acids which in laboratory studies have reported to promote antioxidant enzyme formation, reduces excess inflammation, slow cancer cell proliferation and promote apoptosis. Evidence from epidemiological studies on the effect of tea consumption on prostate cancer (CaP) incidence has been conflicting. We analysed data from 25 097 men within the intervention arm of the 155 000 participant Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Histologically confirmed cases of prostate cancer were reported in 3088 men (12·3 %) during the median 11·5 year follow-up. Tea consumption was assessed with a FFQ. Baseline characteristics were compared between groups using χ2 and Kruskal-Wallis tests. Cox regression models were used to assess associations between tea intake and CaP incidence. There was no statistical difference between the risk of CaP between men who never drank tea to those who drank tea at any quantity. Amongst tea drinkers, those in the highest third of consumption group had a small but significantly lower risk compared with those in the lowest third (11·2 % v. 13·2 % hazard ratio 1·16; (95 % CI 1·05, 1·29), P = 0·004). This pattern persisted with adjustments for demographics and lifestyle. In conclusion, among tea drinkers, there was a small positive association between drinking tea and a reduced risk of prostate cancer. It does not support starting to drink tea, if men previously did not, to reduce the risk. Further research is needed to establish whether tea is justified for future prospective nutritional intervention studies investigating CaP prevention.

E. coli bacteraemia and antimicrobial resistance following antimicrobial prescribing for urinary tract infection in the community.

BACKGROUND: Urinary tract infections are one of the most common infections in primary and secondary care, with the majority of antimicrobial therapy initiated empirically before culture results are available. In some cases, however, over 40% of the bacteria that cause UTIs are resistant to some of the antimicrobials used, yet we do not know how the patient outcome is affected in terms of relapse, treatment failure, progression to more serious illness (bacteraemia) requiring hospitalization, and ultimately death. This study analyzed the current patterns of antimicrobial use for UTI in the community in Scotland, and factors for poor outcomes. OBJECTIVES: To explore antimicrobial use for UTI in the community in Scotland, and the relationship with patient characteristics and antimicrobial resistance in E. coli bloodstream infections and subsequent mortality. METHODS: We included all adult patients in Scotland with a positive blood culture with E. coli growth, receiving at least one UTI-related antimicrobial (amoxicillin, amoxicillin/clavulanic acid, ciprofloxacin, trimethoprim, and nitrofurantoin) between 1st January 2009 and 31st December 2012. Univariate and multivariate logistic regression analysis was performed to understand the impact of age, gender, socioeconomic status, previous community antimicrobial exposure (including long-term use), prior treatment failure, and multi-morbidity, on the occurrence of E. coli bacteraemia, trimethoprim and nitrofurantoin resistance, and mortality. RESULTS: There were 1,093,227 patients aged 16 to 100 years old identified as receiving at least one prescription for the 5 UTI-related antimicrobials during the study period. Antimicrobial use was particularly prevalent in the female elderly population, and 10% study population was on long-term antimicrobials. The greatest predictor for trimethoprim resistance in E. coli bacteraemia was increasing age (OR 7.18, 95% CI 5.70 to 9.04 for the 65 years old and over group), followed by multi-morbidity (OR 5.42, 95% CI 4.82 to 6.09 for Charlson Index 3+). Prior antimicrobial use, along with prior treatment failure, male gender, and higher deprivation were also associated with a greater likelihood of a resistant E. coli bacteraemia. Mortality was significantly associated with both having an E. coli bloodstream infection, and those with resistant growth. CONCLUSION: Increasing age, increasing co-morbidity, lower socioeconomic status, and prior community antibiotic exposure were significantly associated with a resistant E. coli bacteraemia, which leads to increased mortality.

A randomized controlled trial to investigate the effects of intra-dialytic cycling on left ventricular mass.

Cardiovascular disease is the leading cause of death for patients receiving hemodialysis. Since exercise mitigates many risk factors which drive cardiovascular disease for these patients, we assessed effects of a program of intra-dialytic cycling on left ventricular mass and other prognostically relevant measures of cardiovascular disease as evaluated by cardiac MRI (the CYCLE-HD trial). This was a prospective, open-label, single-blinded cluster-randomized controlled trial powered to detect a 15g difference in left ventricular mass measured between patients undergoing a six-month program of intra-dialytic cycling (exercise group) and patients continuing usual care (control group). Pre-specified secondary outcomes included measures of myocardial fibrosis, aortic stiffness, physical functioning, quality of life and ventricular arrhythmias. Outcomes were analyzed as intention-to-treat according to a pre-specified statistical analysis plan. Initially, 130 individuals were recruited and completed baseline assessments (65 each group). Ultimately, 101 patients completed the trial protocol (50 control group and 51 exercise group). The six-month program of intra-dialytic cycling resulted in a significant reduction in left ventricular mass between groups (-11.1g; 95% confidence interval -15.79, -6.43), which remained significant on sensitivity analysis (missing data imputed) (-9.92g; 14.68, -5.16). There were significant reductions in both native T1 mapping and aortic pulse wave velocity between groups favoring the intervention. There was no increase in either ventricular ectopic beats or complex ventricular arrhythmias as a result of exercise with no significant effect on physical function or quality of life. Thus, a six-month program of intradialytic cycling reduces left ventricular mass and is safe, deliverable and well tolerated.