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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.

Choosing optimal outcome measures maximizes statistical power, accelerates discovery and improves reliability in early-phase trials. We devised and evaluated a modification to a pragmatic measure of oxygenation function, the S / F ratio. Because of the ceiling effect in oxyhaemoglobin saturation, S / F ratio ceases to reflect pulmonary oxygenation function at high S p O 2 values. We found that the correlation of S / F with the reference standard ( P a O 2 / F I O 2 ratio) improves substantially when excluding S p O 2 > 0.94 and refer to this measure as S / F 94 . Using observational data from 39,765 hospitalised COVID-19 patients, we demonstrate that S / F 94 is predictive of mortality, and compare the sample sizes required for trials using four different outcome measures. We show that a significant difference in outcome could be detected with the smallest sample size using S / F 94 . We demonstrate that S / F 94 is an effective intermediate outcome measure in COVID-19. It is a non-invasive measurement, representative of disease severity and provides greater statistical power. There is a need for an accurate measure of pulmonary oxygenation function that can be used as an intermediate endpoint in pragmatic clinical trials, to increase statistical power and efficiency. Here, the authors show that the S/F94, a modification of the S/F ratio, is a simple, meaningful and effective intermediate outcome measure.

Angiotensin receptor blockers (ARBs) and β blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments. In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus β blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus β blocker; and indirectly, β blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva. We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference –0·07 [95% CI –0·12 to –0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with β-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with β blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase –0·08 [SE 0·03] in ARB groups vs –0·11 [SE 0·02] in β-blocker groups; absolute difference 0·03 [95% CI –0·05 to 0·10]; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between β blockers and control was –0·09 (95% CI –0·18 to 0·00; p=0·042). In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a β blocker. The effects of β blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and β blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery. Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.

Background: Randomised trials have shown that statin therapy reduces the risk of major vascular events (ie, heart attacks, strokes and coronary revascularisation procedures) without any increase in the risk of nonvascular causes of death or of site-specific cancer, but does produce a small increase in the risk of muscle pain or weakness, diabetes and, possibly, haemorrhagic stroke. Although statins are widely prescribed, there are concerns that they might have a range of other side effects. This DPhil addresses these concerns through an individual-participant-data meta-analysis of all recorded adverse events (AEs) in all large, long-term, randomised, double-blind trials of statin therapy, taking into consideration the substantial challenges related to multiple hypotheses testing (MHT). Methods: Double-blind randomised trials of statin therapy with at least 1,000 participants and a scheduled treatment duration of at least 2 years were included. Individual participant data on all AEs reported in 19 trials of statin vs placebo (123,940 randomised participants) and 4 trials of a more intensive versus a less intensive statin regimen (30,724 randomised participants) were analysed. A literature review identified potentially relevant MHT methods and simulation studies were done to assess their expected performance (ie, control of false positive [FP] and false negative results). Adverse event data were organised and coded according to a common medical dictionary based upon the Medical Dictionary for Regulatory Activities (MedDRA). Under the selected strategy, inverse-variance-weighted meta-analyses of the effects on all AEs were performed using time-to-event analyses for the first occurrence of each outcome among participants randomly assigned into each trial. Results: The literature review identified 6,569 eligible papers, of which 337 were included for full text review. Five MHT methods (Holm, Hochberg, Hommel, Benjamini & Hochberg and Mehrotra & Adewale) were selected as the most appropriate based on their statistical control of type I and II error rates. Simulation analyses identified the Mehrotra & Adewale method, which controls the false discovery rate (FDR), as the most suitable as it resulted in a low expected number of FP results whilst maintaining reasonable statistical power to detect any real effects of statin therapy. Blinded (ie, using a 'shuffled' treatment allocation) meta-analyses of the trials of statin vs placebo were first done, which confirmed that no correction for MHT resulted in 179 (4.4%) FP findings while the Mehrotra & Adewale MHT method led to zero FPs. Unblinded analyses (ie, using the actual treatment allocation) of all non-lipid-related AEs then confirmed the already known beneficial effects of statins on major vascular events. They also showed that statin therapy was FDR-significantly associated with a reduced risk of having an arteriogram or an angiogram procedure. Subsequent analyses which ignored the already known beneficial or harmful effects of statin therapy, very rare outcomes and irrelevant overlap in tests, identified two new benefits of statin therapy: reductions in the risk of peripheral embolism and thrombosis (361 [0.6%] vs 451 [0.7%], rate ratio [RR] 0.72, 95% confidence interval [CI]: 0.61−0.83, p=0.0012), and carotid endarterectomy (47 [<0.1%] vs 83 [0.1%], RR 0.57, 95% CI: 0.40−0.80, p= 0.0013). However, statins were also FDR-significantly associated with an increased risk of hepatobiliary investigations (1,349 [2.2%] vs 1,025 [1.7%], RR 1.32, 95% CI: 1.22-1.43, p<0.0001) and the extremely rare outcome parosmia (18 vs 2, p=0.00036). The meta-analyses of the 4 trials of more vs less statin revealed that more intensive statin therapy was associated with an FDR-significantly reduced risk of coronary artery disorders (3,518 [22.9%] vs 3,779 [24.6%], RR 0.92, 95% CI: 0.88−0.96, p= 0.00025), general system disorders (5,098 [33.1%] vs 5,682 [37.1%],RR 0.87, 95% CI: 0.84−0.91, p<0.0001), any surgical and medical procedures (4,067 [26.4%] vs 4,333 [28.3%],RR 0.93, 95% CI: 0.89−0.97, p= 0.00059) and the rare AE of renal therapeutic procedures (30 [0.2%] vs 57 [0.4%], RR 0.54, 95% CI: 0.35−0.82, p= 0.0038). More intensive statin regimens were also FDR-significantly associated with an increased risk of hepatobiliary investigations (502 [3.3%] vs 253 [1.6%], RR 1.95, 95% CI: 1.69-2.25, p<0.0001) and high blood creatine phosphokinase (223 [1.4%] vs 146 [1.0%], RR 1.51, 95% CI: 1.24−1.86, p<0.0001). Conclusion: These findings highlight the importance of using appropriate statistical methods to control for multiple testing. The results confirmed the already known benefits of statin therapy while identifying some new potential benefits and harms. However, the nature and frequency of the newly detected harms confirm that the benefits of statin therapy greatly outweigh the potential harms.

Abstract Background Although morbidity and mortality from COVID-19 have been widely reported, the indirect effects of the pandemic beyond 2020 on other major diseases and health service activity have not been well described. Methods and results Analyses used national administrative electronic hospital records in England, Scotland, and Wales for 2016–21. Admissions and procedures during the pandemic (2020–21) related to six major cardiovascular conditions [acute coronary syndrome (ACS), heart failure (HF), stroke/transient ischaemic attack (TIA), peripheral arterial disease (PAD), aortic aneurysm (AA), and venous thromboembolism(VTE)] were compared with the annual average in the pre-pandemic period (2016–19). Differences were assessed by time period and urgency of care. In 2020, there were 31 064 (−6%) fewer hospital admissions [14 506 (−4%) fewer emergencies, 16 560 (−23%) fewer elective admissions] compared with 2016–19 for the six major cardiovascular diseases (CVDs) combined. The proportional reduction in admissions was similar in all three countries. Overall, hospital admissions returned to pre-pandemic levels in 2021. Elective admissions remained substantially below expected levels for almost all conditions in all three countries [−10 996 (−15%) fewer admissions]. However, these reductions were offset by higher than expected total emergency admissions [+25 878 (+6%) higher admissions], notably for HF and stroke in England, and for VTE in all three countries. Analyses for procedures showed similar temporal variations to admissions. Conclusion The present study highlights increasing emergency cardiovascular admissions during the pandemic, in the context of a substantial and sustained reduction in elective admissions and procedures. This is likely to increase further the demands on cardiovascular services over the coming years. Graphical Abstract Graphical Abstract Monthly total admissions for CVD as primary diagnosis across subtypes, across three countries in the UK and across pre-pandemic (2016–2019) and pandemic (2020–2021) periods. Key question: What is the impact in 2020 and 2021 of the COVID-19 pandemic on hospital admissions and procedures for six major CVDs in England, Scotland, and Wales?