Completion and reporting of COVID-19 clinical trials registered on ClinicalTrials.gov during the first 6 months of the pandemic: cohort study

Background
Early in the COVID-19 pandemic, numerous clinical trials were initiated. Although concerns were raised regarding the quality of the trials, the eventual research output yielded from the trials remains unknown. The objective of this study was to include all clinical trials registered on ClinicalTrials.gov during the first 6 months of the pandemic and assess if and where their results had been reported, their completion and discontinuation rates, achieved enrolment and changes made to the primary outcome after trial registration.

Methods
We included all interventional studies related to COVID-19 first registered on ClinicalTrials.gov between 1 January 2020 and 1 July 2020. We systematically searched for trial results, reported through 15 May 2023, in scientific publications, preprints and ClinicalTrials.gov. We assessed the achieved trial enrolment, trial discontinuation (reaching

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Novembre 2024

Trajectories of functional limitations, health-related quality of life and societal costs in individuals with long COVID: a population-based longitudinal cohort study

Objectives
To examine trajectories of functional limitations, fatigue, health-related quality of life (HRQL) and societal costs of patients referred to long COVID clinics.

Design
A population-based longitudinal cohort study using real-time user data.

Setting
35 specialised long COVID clinics in the UK.

Participants
4087 adults diagnosed with long COVID in primary or secondary care deemed suitable for rehabilitation and registered in the Living With Covid Recovery (LWCR) programme between 4 August 2020 and 5 August 2022.

Main outcome measures
Generalised linear mixed models were fitted to estimate trajectories of functional limitations, using the Work and Social Adjustment Scale (WSAS); scores of ≥20 indicate moderately severe limitations. Other outcomes included fatigue using the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) reversed score (scores of ≥22 indicate impairment), HRQL using the EQ-5D-5L, and long COVID-related societal costs, encompassing healthcare costs and productivity losses.

Results
The mean WSAS score at 6 months after registration in the LWCR was 19.1 (95% CI 18.6, 19.6), with 46% of the participants (95% CI 40.3%, 52.4%) reporting a WSAS score above 20 (moderately severe or worse impairment). The mean change in the WSAS score over the 6-month period was –0.86 (95% CI –1.32, –0.41). The mean reversed FACIT-F score at 6 months was 29.1 (95% CI 22.7, 35.5) compared with 32.0 (95% CI 31.7, 32.3) at baseline. The mean EQ-5D-5L score remained relatively constant between baseline (0.63, 95% CI 0.62, 0.64) and 6 months (0.64, 95% CI 0.59, 0.69). The monthly societal cost per patient related to long COVID at 6 months was £931, mostly driven by the costs associated with working days lost.

Conclusions
Individuals referred to long COVID clinics in the UK reported small improvements in functional limitations, fatigue, HRQL and ability to work within 6 months of registering in the LWCR programme.

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Novembre 2024

COVID-19 Therapeutics for Nonhospitalized Older Adults

This Viewpoint summarizes the factors contributing to increased risk of severe outcomes and hospitalization associated with COVID-19 among older adults, stresses the importance of assessing COVID-19 risk before infection occurs, calls for all immunocompromised older adults to be considered for COVID-19 treatment, and details 3 recommended COVID-19 therapies.

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Novembre 2024

Abstract 4142129: The Role of Neutrophil to Lymphocyte Ratio and Right Ventricular Dysfunction in Indonesian Patients with COVID-19

Circulation, Volume 150, Issue Suppl_1, Page A4142129-A4142129, November 12, 2024. Background:The clinical impact of neutrophil to lymphocyte ratio (NLR) and right ventricular (RV) dysfunction on clinical outcomes in COVID-19 have not been studied in the often-underrepresented Indonesian population.Aim:To investigate the role of NLR and RV dysfunction in Indonesian patients hospitalized for COVID-19.Methods:A retrospective cohort study was conducted at a COVID-19 referral hospital in Indonesia. We included all adult patients hospitalized with COVID-19 between April 2020 – April 2021 who had transthoracic echocardiography (TTE) during admission. Clinical data were extracted from electronic medical records. TTE variables were defined according to the American Society of Echocardiography criteria. All statistical analyses were conducted using the SPSS software. This study was approved by the IRB at Universitas Indonesia (#2022-01-135).Results:A total of 488 patients were included – 29 with and 459 without RV dysfunction. The mean age of the population was 54.8 (SD ± 13.5), and 42% were females. Receiver operating curve analysis and Youden’s J statistics were used to determine the optimal NLR cut-off (Figure 1). An NLR > 4.79 was considered elevated, and had a sensitivity of 70.6% and a specificity of 80.6% in predicting severe – critical COVID-19. A high NLR (OR: 3.38, P = 0.02) and LV systolic dysfunction (OR: 9.76, P < 0.01) were independently associated with RV dysfunction. In multivariate cox regression analysis, older age (HR: 1.02, P = 0.01), obesity (HR: 1.85, P < 0.01), chronic kidney disease (HR: 1.69, P = 0.01), high NLR (HR: 2.75, P < 0.01), and RV dysfunction (HR: 2.07, P = 0.02) increased the risk of 30-day mortality.Conclusions:In Indonesian patients hospitalized with COVID-19, A high NLR is predictive of severe – critical COVID-19 and is associated with RV dysfunction. A high NLR at admission and RV dysfunction independently increase the risk of 30-day mortality in hospitalized Indonesian adults with COVID-19.

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Novembre 2024

Abstract 4145096: Postural Orthostatic Tachycardia Syndrome and Inappropriate Sinus Tachycardia – Two Distinct Phenotypes in Post-COVID-19 Cardiovascular Dysautonomia: Prevalence, Overlap and Clinical Characteristics

Circulation, Volume 150, Issue Suppl_1, Page A4145096-A4145096, November 12, 2024. Introduction:Postural orthostatic tachycardia syndrome (POTS) and Inappropriate sinus tachycardia (IST) are common manifestations of cardiovascular dysautonomia (CVAD) in patients with post-COVID-19 syndrome. Studies regarding differences between post-COVID-19 POTS and post-COVID-19 IST have been sparse and based on small patient series.Aims:To examine clinical differences between POTS and IST in patients with post-COVID-19 syndrome.Methods:A cross-sectional observational study based on a dataset of patients diagnosed with post-COVID-19 syndrome and POTS/IST, at Karolinska University Hospital, Stockholm in 2020-2023, was performed. Data was retrieved using patients’ medical records. ANOVA, chi-square tests and Fisher’s exact tests were used for analysis.Results:A total of 200 patients diagnosed with post-COVID POTS/IST (ICD-10 codes, I.498 + U.099) were included (female, 85%) and divided into a POTS-group (n=110) and IST-group (n=90). Sixty-one patients (31%) met the diagnostic criteria of both and were included in the IST-group. The mean ages were 38 years for the POTS-group and 42 years for the IST-group (p=0.027). Hypertension was more common within the IST-group (p

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Novembre 2024

Abstract 4140201: Disparities in Defibrillator Implantations during COVID-19: Insights from the NCDR registry

Circulation, Volume 150, Issue Suppl_1, Page A4140201-A4140201, November 12, 2024. Introduction:While implantable cardiac defibrillators (ICD) decrease sudden cardiac death, disparities in ICD use remain. The COVID-19 pandemic created strains on the US healthcare system that may have exacerbated these disparities.Methods:Using the US NCDR registry of primary and secondary prevention ICD implants, we compared sex, racial and ethnic disparities for 239,014 patients, aged 19-90 years, grouped into three time intervals from 2016 to 2022: Pre-COVID, COVID and Post-COVID. Centers without consistent reporting were excluded, as were patients with incomplete sex, race or ethnicity data. ICD implantation rates were compared using a Poisson regression model with interaction tests for sex, race and ethnicity by time window to see if disparities changed within this period. Implant rates by indication were also assessed.Results:Overall ICD implants decreased over the study period (Figure 1) with an average monthly rate of 3271 in the first three months of 2016 declining to 2334 in the last three months of 2022 (p=0.017). Disparities in ICD implantation for women, racial and ethnic minorities were observed pre-COVID and persisted (Table 1). Average ICD implant rates during these time periods varied by race with predominance in White patients. While gaps in ICD implant persisted, the disparities did not worsen during COVID-19 by sex, race or ethnicity (p-value for interactions were 0.79; 0.47; and 0.095, respectively). There was a more significant decrease in primary prevention ICD compared to secondary prevention ICD (p

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Novembre 2024

Abstract 4119613: Evaluation of Gender, Racial and Ethnic Differences in Time to PCI in the Pre and Post Covid-19 Era

Circulation, Volume 150, Issue Suppl_1, Page A4119613-A4119613, November 12, 2024. Introduction:Percutaneous Coronary Intervention (PCI) is recommended for reperfusion of patients presenting with ST-segment myocardial infarction (STEMI) within 90 minutes. In this study, we sought to identify differences in PCI timing based on gender, race and ethnicity in the pre- and post-COVID era.Methods:We collected retrospective data on 760 patients admitted with STEMI at our quaternary academic medical center from 2018-2022. We defined our binary outcome as time to PCI less than 90 minutes, and adjusted for transfers from outside hospitals. We utilized univariate logistic regression analysis to analyze the association of demographic, clinical, and cardiac catheterization details on our outcome. We then utilized multivariate logistic regression analysis to determine the association of our covariates of interests with time to PCI. The logistic regression model was adjusted for collinearity which were deemed not significant.Results:Among our study population, COVID did not significantly impact whether or not a patient had a diagnostic cardiac catheterization on univariate analysis (OR 2.68, 95% CI 0.61-18.40, p=0.23). However, the post-COVID era was significantly associated with a delayed time to PCI on multivariate analysis [OR 1.62, 95% CI 1.04-2.55, p=0.035) [Figure 1]. In addition, females were 1.8x more likely to have a delayed PCI than males on multivariate regression [OR 1.80, 95% CI 1.10-2.95, p= 0.019) [Figure 1]. Interestingly, on multivariate analysis, females were more likely to have delayed reperfusion in the pre-COVID era (OR 2.92, 1.29-6.77,p= 0.01) but not the post-COVID era (OR 1.54, 0.78-3.06,p=0.2134). Patients in the post-COVID era had increased risk of having their culprit coronary not revascularized on multivariate analysis (OR 2.85, 1.2-8.03, p= 0.03).Conclusions:At our center, COVID did not significantly impact cardiac catheterization rates. However, COVID was significantly associated with delayed reperfusion timing and not revascularizing culprit vessels. Females were much more likely to have a delayed PCI than males in the pre-COVID era which was not seen following COVID-19.

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Novembre 2024

Abstract 4145068: Machine learning analysis of serum proteome in the diagnosis of COVID-19 myocarditis

Circulation, Volume 150, Issue Suppl_1, Page A4145068-A4145068, November 12, 2024. Background:The COVID-19 global pandemic was the third leading cause of mortality in the US in 2020 and is associated with numerous complications, including myocarditis. Diagnosis of COVID-19 myocarditis can involve costly and invasive procedures. In addition, asymptomatic myocarditis could place people at risk for arrhythmias and sudden cardiac death.Objective:To use machine learning (ML) of serum proteomics to distinguish asymptomatic COVID-19 positive volunteers with and without myocarditis.Approach and Results:In 2020, for a cohort of 20 previously healthy 18–23-year-old individuals diagnosed with COVID-19 two weeks after the diagnosis, CMR was performed to assess for evidence of cardiac inflammation and serum samples were obtained the same day (10 were diagnosed as myocarditis positive and 10 negative) We performed proteomic analysis using the SomaScan proteomics assay from SomaLogic. The data were passed through an initial feature selection process of 1000 rounds of bootstrapped multivariate logistic regression using L1-regularization to introduce sparser feature utilization. The top 25 features (largest absolute log-odds) were utilized for a final logistic regression analysis. The feature selection step was optimized to have an average receiver operating characteristic area under the curve (ROCAUC) of 83.29% over 1000 iterations, but the final model utilizing only 25 proteins achieved an average ROCAUC of 99.58%. This method produced 22 proteins with significant odds-ratios for COVID-19 myocarditis (OR 95%CI excluding 1), of particular interest are those involved in inflammatory control and injury response mechanisms. Increases in the heat shock protein DNAJB11 (1.19 [1.10, 1.27]) and calponin-2 (1.17 [1.10, 1.25]), as well as decreases IL1RN (0.88 [0.83, 0.93]) were associated in increased likelihood of CMR diagnosed myocarditis (Fig 1A). Furthermore, a UMAP projection of the data using the 22 significant features yielded a clear visual distinction between those with and without COVID-19 myocarditis via CMR (Fig 1B).Conclusion:Utilizing ML on serum proteomic screenings of asymptomatic young COVID-19 patients, we can differentiate between those with CMR myocarditis positive and negative patients.

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Novembre 2024

Abstract 4145229: Outcomes among hospitalized patients with stress-induced cardiomyopathy and concomitant Coronavirus Disease 2019 (COVID-19) infection: Insight from the US National Inpatient Sample

Circulation, Volume 150, Issue Suppl_1, Page A4145229-A4145229, November 12, 2024. Background:Stress-induced cardiomyopathy (CM) is a form of acute transient left ventricular dysfunction triggered by underlying physiological stress which often leads to increased morbidity and mortality. Coronavirus disease 2019 (COVID-19) is thought to cause stress-induced CM due to overwhelming systemic inflammation. There is paucity of data regarding the impact of COVID-19 on in-hospital outcomes of patients with stress-induced CM. The purpose of this study is to investigate in-hospital outcomes, including mortality and cardiogenic shock, of patients with concomitant COVID-19 and stress-induced CM.Methods:We queried the 2020 USA National Inpatient Sample (NIS) Database in conducting this retrospective cohort study. We identified hospitalized adult patients ≥ 18 years old with stress-induced CM and concomitant COVID-19 using ICD-10 CM codes. We used a survey multivariable logistic and linear regression analysis to calculate adjusted odds ratios (aORs) for outcomes of interest. A p value of

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Novembre 2024

Abstract 4113573: Long Noncoding RNAs to Predict COVID-19 Neuro-Cardio-Vascular Outcomes

Circulation, Volume 150, Issue Suppl_1, Page A4113573-A4113573, November 12, 2024. Introduction/Background:Cardiovascular and neurological diseases develop in a significant proportion of COVID-19 patients. Minimally invasive tools to predict outcome after SARS-CoV-2 infection would enable personalized healthcare, potentially easing the disease burden. We showed that blood levels of the long noncoding RNA lymphoid enhancer-binding factor-1 antisense 1 (LEF1-AS1) predict COVID-19 in-hospital mortality.Hypothesis:LEF1-AS1 is associated with long-term clinical outcomes of COVID-19.Aim:Test the capacity of LEF1-AS1 to predict neuro-cardio-vascular outcomes post-SARS-CoV-2 infection.Methods/Approach:We enrolled 104 primo-infected COVID-19 patients aged 18+ recruited from April to December 2020 in the PrediCOVID national cohort for which 12-month follow-up data were available (Ethics Committee approvals 202003/07 and 202310/02-SU-202003/07). Whole blood samples were collected at baseline and expression levels of LEF1-AS1 were assessed by quantitative PCR.Results/Data:Of the 104 patients, 35 had at least one neurological symptom and one cardiovascular symptom at month 12. Levels of LEF1-AS1 at baseline were lower (p=0.019) in patients who developed neurological and cardiovascular symptoms as compared to patients who did not. Lower LEF1-AS1 was associated with symptoms development with an odds ratio of 0.48 (95% CI 0.28-0.83) from logistic regression model adjusted for age, sex, comorbidities and disease severity at baseline. Addition of LEF1-AS1 to a clinical model including age, sex, comorbidities and baseline severity yielded an incremental predictive value as attested by an increased AUC from 0.79 to 0.83 (likelihood ratio test p=0.005), a net reclassification index of 0.54 (p=0.007) and an integrated discrimination improvement of 0.08 (p=0.009).Conclusion:Blood levels of LEF1-AS1 predict 12-month neurological and cardiovascular outcomes of COVID-19 patients. This needs to be validated in larger populations.

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Novembre 2024

Abstract 4146592: Device-Recorded Physical Activity and Atrial Fibrillation Burden: A Natural History Experiment from the COVID-19 Pandemic in the TRIM-AF Clinical Trial

Circulation, Volume 150, Issue Suppl_1, Page A4146592-A4146592, November 12, 2024. Introduction:Low physical activity (PA) has been identified as a risk factor for development of atrial fibrillation (AF). However, the effect of changes in PA on directly recorded AF burden has not been well studied. The COVID-19 pandemic offered an opportunity to observe whether changes in activity were correlated with changes in AF burden. To determine if reduced PA is associated with higher AF burden, we assessed daily PA and AF burden data from patients with cardiac implantable electronic devices (CIEDs) enrolled in a prospective clinical trial, Targeting Risk Interventions and Metformin for Atrial Fibrillation (TRIM-AF, NCT03603912).Methods:Daily AF burden and activity were determined from implantable cardiac devices with atrial leads. The pandemic lockdown period was analyzed for up to 1 year. Pre-pandemic periods were matched by month to pandemic periods. To test the potential confounding of aging, pre-pre-pandemic periods were matched by month to pre-pandemic periods. To reduce the confounding of study interventions, matched periods were taken on one side of the study enrollment date. For PA and AF burden, Gaussian linear mixed models and a Bayesian mixed effect model were fitted and adjusted for age, sex, and device manufacturers. A Gaussian model was used to correlate daily activity minutes and AF%. Time splines were added to adjust for non-linear time effects. Outcomes are reported as mean activity minutes and daily AF%.Results:Comparing Pandemic vs. Pre-periods (N=82 periods; 55 male, 27 female), daily activity minutes decreased by a mean of 13.16±1.06 minutes/day, and daily AF burden increased by 16% [5%-26%]. Comparing Pre vs. Pre-Pre-Pandemic periods (N=60 periods; 41 male, 19 female), mean activity decreased by 2.28±1.13 mins/day, and AF burden increased by 57% [50%-64%]. A significant negative correlation between activity and AF burden was demonstrated (coefficient -2.0, 95% CI -2.4, -1.6). A decrease in 2.0 activity minutes was associated with a 10% increase in AF burden.Conclusions:This natural history analysis of PA and AF burden demonstrated decreases in activity and increases in AF burden with time and the pandemic. Activity and AF burden were significantly negatively correlated.

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Novembre 2024

Abstract 4143985: Post-acute Sequelae of COVID-19 (PASC) is Related to Endothelial Dysfunction and Elevated Asymmetric-dimethylarginine

Circulation, Volume 150, Issue Suppl_1, Page A4143985-A4143985, November 12, 2024. Introduction:Endothelial dysfunction can trigger the development and progression of cardiovascular disease. We hypothesize that cardiovascular PASC is induced by persistent endothelial dysfunction mediated via asymmetric-dimethylarginine (ADMA, the endogenous inhibitor of endothelial nitric oxide synthase). ADMA levels rise in response to viral infections, but it is usually degraded by the enzyme DDAH1, which is inhibited by chronic inflammation and oxidative stress. This study aims to determine whether cardiovascular PASC is associated with endothelial dysfunction and to clarify the role of ADMA in this relationship.Methods:We recruited subjects who had been previously infected and developed cardiovascular symptoms (PASC+), those who had been infected but did not have PASC (PASC-), and those who had never been infected (controls) (n=20 each). Groups were matched for age, sex, and BMI and underwent blood draws and fat biopsies. Vascular function was assessedin-vivovia ultrasound imaging andex-vivoin fat-isolated arterioles.Results:Compared to PASC- and controls, PASC+ subjects exhibited 80% higher serum levels of ADMA and 40% reduced nitric oxide levels. DDAH1 activity was elevated in the PASC+, suggesting a compensatory mechanism for the elevated ADMA levels. However, PASC+ obese subjects exhibited substantially lower DDAH1 activity than non-obese subjects, which was associated with lower insulin sensitivity and higher ADMA levels. Compared to the other two groups, the PASC+ group exhibited lower brachial artery vasoreactivity, while nitroglycerin-induced dilation did not differ statistically, suggesting impaired endothelial function. In the PASC+ group, microvascular recruitment in response to reactive hyperemia was diminished, as was the ex vivo measured flow-induced arteriolar dilation and NO generation. Left ventricle (LV) dysfunction was observed in 80% of the PASC+ group, as opposed to 5% of the PASC- and controls. The LV ejection fraction and global longitudinal strain (GLS) were substantially reduced in the PASC+ group, which was correlated with higher ADMA, C-reactive protein, and troponin-1, as well as lower NO and vascular function. Obese PASC+ subjects had the highest ADMA and the lowest endothelial-dependent vasodilation and insulin sensitivity.Conclusion:Cardiovascular PASC symptoms are related to persistent endothelial dysfunction and elevated ADMA levels, which may be further exacerbated by obesity and reduced DDAH1 activity.

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Novembre 2024