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Several countries affected by the COVID-19 pandemic have reported a substantial drop in the number of patients attending the emergency department with acute coronary syndromes and a reduced number of cardiac procedures. We aimed to understand the scale, nature, and duration of changes to admissions for different types of acute coronary syndrome in England and to evaluate whether in-hospital management of patients has been affected as a result of the COVID-19 pandemic. We analysed data on hospital admissions in England for types of acute coronary syndrome from Jan 1, 2019, to May 24, 2020, that were recorded in the Secondary Uses Service Admitted Patient Care database. Admissions were classified as ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), myocardial infarction of unknown type, or other acute coronary syndromes (including unstable angina). We identified revascularisation procedures undertaken during these admissions (ie, coronary angiography without percutaneous coronary intervention [PCI], PCI, and coronary artery bypass graft surgery). We calculated the numbers of weekly admissions and procedures undertaken; percentage reductions in weekly admissions and across subgroups were also calculated, with 95% CIs. Hospital admissions for acute coronary syndrome declined from mid-February, 2020, falling from a 2019 baseline rate of 3017 admissions per week to 1813 per week by the end of March, 2020, a reduction of 40% (95% CI 37–43). This decline was partly reversed during April and May, 2020, such that by the last week of May, 2020, there were 2522 admissions, representing a 16% (95% CI 13–20) reduction from baseline. During the period of declining admissions, there were reductions in the numbers of admissions for all types of acute coronary syndrome, including both STEMI and NSTEMI, but relative and absolute reductions were larger for NSTEMI, with 1267 admissions per week in 2019 and 733 per week by the end of March, 2020, a percent reduction of 42% (95% CI 38–46). In parallel, reductions were recorded in the number of PCI procedures for patients with both STEMI (438 PCI procedures per week in 2019 vs 346 by the end of March, 2020; percent reduction 21%, 95% CI 12–29) and NSTEMI (383 PCI procedures per week in 2019 vs 240 by the end of March, 2020; percent reduction 37%, 29–45). The median length of stay among patients with acute coronary syndrome fell from 4 days (IQR 2–9) in 2019 to 3 days (1–5) by the end of March, 2020. Compared with the weekly average in 2019, there was a substantial reduction in the weekly numbers of patients with acute coronary syndrome who were admitted to hospital in England by the end of March, 2020, which had been partly reversed by the end of May, 2020. The reduced number of admissions during this period is likely to have resulted in increases in out-of-hospital deaths and long-term complications of myocardial infarction and missed opportunities to offer secondary prevention treatment for patients with coronary heart disease. The full extent of the effect of COVID-19 on the management of patients with acute coronary syndrome will continue to be assessed by updating these analyses. UK Medical Research Council, British Heart Foundation, Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.

Background Ascertainment of heart failure (HF) hospitalizations in cardiovascular trials is costly and complex, involving processes that could be streamlined by using routinely collected healthcare data (RCD). The utility of coded RCD for HF outcome ascertainment in randomized trials requires assessment. We systematically reviewed studies assessing RCD-based HF outcome ascertainment against “gold standard” (GS) methods to study the feasibility of using such methods in clinical trials. Methods Studies assessing International Classification of Disease (ICD) coded RCD-based HF outcome ascertainment against GS methods and reporting at least one agreement statistic were identified by searching MEDLINE and Embase from inception to May 2021. Data on study characteristics, details of RCD and GS data sources and definitions, and test statistics were reviewed. Summary sensitivities and specificities for studies ascertaining acute and prevalent HF were estimated using a bivariate random effects meta-analysis. Heterogeneity was evaluated using I 2 statistics and hierarchical summary receiver operating characteristic (HSROC) curves. Results A total of 58 studies of 48,643 GS-adjudicated HF events were included in this review. Strategies used to improve case identification included the use of broader coding definitions, combining multiple data sources, and using machine learning algorithms to search free text data, but these methods were not always successful and at times reduced specificity in individual studies. Meta-analysis of 17 acute HF studies showed that RCD algorithms have high specificity (96.2%, 95% confidence interval [CI] 91.5–98.3), but lacked sensitivity (63.5%, 95% CI 51.3–74.1) with similar results for 21 prevalent HF studies. There was considerable heterogeneity between studies. Conclusions RCD can correctly identify HF outcomes but may miss approximately one-third of events. Methods used to improve case identification should also focus on minimizing false positives.

Reliable assessment of the effects of an intervention usually requires large randomised trials but such studies are becoming increasingly complex and costly to run. ‘Streamlined’ trials are needed in which every aspect of the trial design and conduct is simplified, retaining only those elements needed to answer the research question and ensure the safety of the individual participants. In this review we discuss how the trial ‘A Study of Cardiovascular Events iN Diabetes’ (ASCEND) was streamlined. The study included a two-by-two factorial design: it assessed the effects of low-dose aspirin and, separately, supplementation with n-3 fatty acids on serious vascular events in 15,480 people with diabetes but no overt cardiovascular disease. Other key streamlined design features, such as mail-based recruitment and follow-up, mainly by post, with no in-person visits and use of a run-in period, are also described. We go on to discuss the success of the study and other studies that have employed a similar mail-based approach, and the type of clinical trials that are suitable for mail-based design. Finally, we consider the limitations of the study, and how these could be circumvented in future studies. ASCEND randomised large numbers of eligible participants, achieved good adherence rates and almost complete follow-up at a fraction of the cost of traditional clinic-based trials. Such studies are necessary if researchers are to address the important clinical questions most relevant to improving health.

Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607. 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74–0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76–1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60–0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68–0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13). Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.

Background: Exogenous tracer-based methods of measuring glomerular filtration rate (GFR) are difficult to perform, whilst creatinine-based estimation formulae are inaccurate. Methods: We assessed a new technique of measuring iohexol clearance using timed dried capillary blood spots. A reference GFR was measured in 81 subjects (GFR 15-124 ml/min/1.73 m2) by iohexol clearance using three venous samples (2, 3 and 4 h after an intravenous bolus). GFR was estimated by six test methods; iohexol clearance using (i) 3 blood spots (2, 3, 4 h); (ii) 2 blood spots (2, 4 h) and (iii) 1 blood spot (4 h); (iv) the Modification of Diet in Renal Disease (MDRD) formula; (v) the Cockcroft-Gault formula, and (vi) a formula estimating GFR from serum cystatin C concentration. For each test method the bias and precision were calculated as the mean and standard deviation (SD) of the 'GFR differences' (test method GFR - reference GFR). Results: The limits of agreement (bias ±1.96 × SD; in ml/min/1.73 m2) were: (i) 1.1 ± 15.1 for 3-spot iohexol clearance; (ii) 0.6 ± 14.9 for 2-spot iohexol clearance; (iii) 4.5 ± 21.2 for 1-spot iohexol clearance; (iv) -15.7 ± 33.3 for the MDRD formula; (v) -9.6 ± 32.9 for the Cockcroft-Gault formula, and (vi) -12.1 ± 31.7 for the Cystatin C formula. The accuracy of all six test methods was similar among individuals with GFR <60 ml/min/ 1.73 m2; however, in individuals with GFR ≥60 ml/min/ 1.73 m2, the MDRD, Cockcroft-Gault and Cystatin C formulae were all imprecise and systematically underestimated GFR. Conclusions: Blood spot iohexol clearance provides a potentially practical method of estimating GFR accurately in large-scale epidemiological studies especially among individuals without established chronic kidney disease. Copyright © 2007 S. Karger AG, Basel

Cardiovascular clinical trials continue to under-represent children, older adults, females and people from ethnic minority groups relative to population disease distribution. Here we describe strategies to foster trial representativeness, with proposed actions at the levels of trial funding, design, conduct and dissemination. In particular, trial representativeness may be increased through broad recruitment strategies and site selection criteria that reflect the diversity of patients in the catchment area, as well as limiting unjustified exclusion criteria and using pragmatic designs that minimize research burden on patients (including embedded and decentralized trials). Trial communications ought to be culturally appropriate; engaging diverse people with lived experience in the co-design of some trial elements may foster this. The demographics of trialists themselves are associated with participant demographics; therefore, trial leadership must be actively diversified. Funding bodies and journals increasingly require the reporting of sociodemographic characteristics of trial participants, and regulatory bodies now provide guidance on increasing trial diversity; these steps may increase the momentum towards change. Although this Perspective focuses on the cardiovascular trial context, many of these strategies could be applied to other fields. Cardiology trials continue to under-represent certain population groups relative to disease distribution; this Perspective outlines strategies to foster representativeness and create a research enterprise that meets the needs of people living with cardiovascular disease.

Background Speech and language changes occur decades before the clinical diagnosis of Alzheimer's disease (AD). Digital tools for frequent speech assessments may have promise for early‐stage AD trials. Here, we present results from the RADAR‐AD study on the use of acoustic speech markers obtained from a story narration task, across AT(N) groups within the syndromic stages of AD. Method Four study groups (Healthy controls (HC), preclinical AD (pre. AD), prodromal AD (pro. AD), and mild AD) were included in this cross‐sectional study of 8 weeks duration. The speech samples were collected using a voice‐based story narration task (Story Time), deployed within the Mezurio smartphone application. Analysis of speech from this task includes data from 159 participants across 12 different European languages (HC = 47, Pre.AD = 31, Pro.AD = 49, Mild AD = 32) collected across 6 different days during the study. To understand the effect of amyloid, tau and syndromic stages of AD on speech, we used a linear mixed‐effect model with participants, stories, and language as random effects and demographic variables as fixed effects and compared to A‐T‐ healthy controls. Result For the preclinical subgroup, articulation rate was statically significant (FDR corrected) and was lower for A+T+ (β=‐0.62; p = .03). This feature was also lower for A+T+ in both prodromal (β=‐0.51; p =.03) and mild‐to‐moderate AD (β=‐0.58; p = .01), but not for the prodromal A+T‐ subgroups. The prodromal subgroups had statistically significant differences in jitter and voiced segments for the A+T‐ subgroup, and articulation rate, speech rate, peaks of loudness, voiced segments, and F2 frequency (sd) for A+T+. Conclusion Our results suggest that subtle tau driven changes in speech fluency begin as early as preclinical stage highlighting the potential utilization of speech markers in improving screening in AD clinical trials. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

Speech and language changes occur decades before the clinical diagnosis of Alzheimer's disease (AD). Digital tools for frequent speech assessments may have promise for early-stage AD trials. Here, we present results from the RADAR-AD study on the use of acoustic speech markers obtained from a story narration task, across AT(N) groups within the syndromic stages of AD. Four study groups (Healthy controls (HC), preclinical AD (pre. AD), prodromal AD (pro. AD), and mild AD) were included in this cross-sectional study of 8 weeks duration. The speech samples were collected using a voice-based story narration task (Story Time), deployed within the Mezurio smartphone application. Analysis of speech from this task includes data from 159 participants across 12 different European languages (HC = 47, Pre.AD = 31, Pro.AD = 49, Mild AD = 32) collected across 6 different days during the study. To understand the effect of amyloid, tau and syndromic stages of AD on speech, we used a linear mixed-effect model with participants, stories, and language as random effects and demographic variables as fixed effects and compared to A-T- healthy controls. For the preclinical subgroup, articulation rate was statically significant (FDR corrected) and was lower for A+T+ (β=-0.62; p = .03). This feature was also lower for A+T+ in both prodromal (β=-0.51; p =.03) and mild-to-moderate AD (β=-0.58; p = .01), but not for the prodromal A+T- subgroups. The prodromal subgroups had statistically significant differences in jitter and voiced segments for the A+T- subgroup, and articulation rate, speech rate, peaks of loudness, voiced segments, and F2 frequency (sd) for A+T+. Our results suggest that subtle tau driven changes in speech fluency begin as early as preclinical stage highlighting the potential utilization of speech markers in improving screening in AD clinical trials. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR-AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.