Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study) (preprint)

Background: Significant clinical similarities have been observed between the recently described Long-Haul COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, brain-fog, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design: A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.

COVID-19 testing avoidance among patients with cardiovascular disease (preprint)

Background: Rapid coronavirus 2019 (COVID-19) testing in symptomatic cases is extremely important for preventing the spread of COVID-19 infection and early therapeutic intervention. In contrast, whether symptomatic patients are tested depends largely on their health literacy, interpretation, and knowledge of COVID-19. We aimed to investigate the rate of COVID-19 testing avoidance despite having common cold symptoms in patients with cardiovascular disease and examine factors related to testing avoidance. Methods: A large-scale epidemiological questionnaire survey, the Japan COVID-19 and Society Internet Survey 2022 (JACSIS), was conducted online from April to May 2022. The rate of COVID-19 testing avoidance was investigated in patients aged 20 to 80 years with cardiovascular risk factors (hypertension, dyslipidemia, or diabetes) or a history of cardiovascular disease (angina, myocardial infarction, or stroke), only those exhibiting common cold symptoms during the 2 months in the survey. Results: Of the 1,565 eligible patients, 58% (909 patients) did not undergo COVID-19 testing. Multivariate analysis revealed that older age, obesity, non-walking regularly, long sedentary time, eating alone, frequent snacking, and having received 4 COVID-19 vaccinations were independently associated with testing avoidance. Conclusions: In the chronic phase of the COVID-19 pandemic, prompt COVID-19 testing at the time of symptomatic disease is important, and strategies to reduce testing hesitancy should be considered.

Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study) (preprint)

Background:  Significant clinical similarities have been observed between the recently described ‘Long-Haul’ COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog”, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design:  A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction.  A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction.  Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade. Trial registration:ClinicalTrials.gov, ID:NCT05481177 Registered on 29 July 2022.

Coronary calcium scoring as first-line test to detect and exclude coronary artery disease in patients presenting to the general practitioner with stable chest pain: protocol of the cluster-randomised CONCRETE trial.

INTRODUCTION: Identifying and excluding coronary artery disease (CAD) in patients with atypical angina pectoris (AP) and non-specific thoracic complaints is a challenge for general practitioners (GPs). A diagnostic and prognostic tool could help GPs in determining the likelihood of CAD and guide patient management. Studies in outpatient settings have shown that the CT-based coronary calcium score (CCS) has high accuracy for diagnosis and exclusion of CAD. However, the CT CCS test has not been tested in a primary care setting. In the COroNary Calcium scoring as fiRst-linE Test to dEtect and exclude coronary artery disease in GPs patients with stable chest pain (CONCRETE) study, the impact of direct access of GPs to CT CCS will be investigated. We hypothesise that this will allow for early diagnosis of CAD and treatment, more efficient referral to the cardiologist and a reduction of healthcare-related costs. METHODS AND ANALYSIS: CONCRETE is a pragmatic multicentre trial with a cluster randomised design, in which direct GP access to the CT CCS test is compared with standard of care. In both arms, at least 40 GP offices, and circa 800 patients with atypical AP and non-specific thoracic complaints will be included. To determine the increase in detection and treatment rate of CAD in GP offices, the CVRM registration rate is derived from the GPs electronic registration system. Individual patients' data regarding cardiovascular risk factors, expressed chest pain complaints, quality of life, downstream testing and CAD diagnosis will be collected through questionnaires and the electronic GP dossier. ETHICS AND DISSEMINATION: CONCRETE has been approved by the Medical Ethical Committee of the University Medical Center of Groningen. TRIAL REGISTRATION NUMBER: NTR 7475; Pre-results.

Association of COVID-19 with arterial and venous vascular diseases: a population-wide cohort study of 48 million adults in England and Wales (preprint)

Importance: The long-term effects of COVID-19 on the incidence of vascular diseases are unclear. Objective: To quantify the association between time since diagnosis of COVID-19 and vascular disease, overall and by age, sex, ethnicity, and pre-existing disease. Design: Cohort study based on population-wide linked electronic health records, with follow up from January 1st to December 7th 2020. Setting and participants: Adults registered with an NHS general practice in England or Wales and alive on January 1st 2020. Exposures: Time since diagnosis of COVID-19 (categorised as 0-6 days, 1-2 weeks, 3-4, 5-8, 9-12, 13-26 and 27-49 weeks since diagnosis), with and without hospitalisation within 28 days of diagnosis. Main outcomes and measures: Primary outcomes were arterial thromboses (mainly acute myocardial infarction and ischaemic stroke) and venous thromboembolic events (VTE, mainly pulmonary embolism and lower limb deep vein thrombosis). We also studied other vascular events (transient ischaemic attack, haemorrhagic stroke, heart failure and angina). Hazard ratios were adjusted for demographic characteristics, previous disease diagnoses, comorbidities and medications. Results: Among 48 million adults, 130,930 were and 1,315,471 were not hospitalised within 28 days of COVID-19. In England, there were 259,742 first arterial thromboses and 60,066 first VTE during 41.6 million person-years follow-up. Adjusted hazard ratios (aHRs) for first arterial thrombosis compared with no COVID-19 declined rapidly from 21.7 (95% CI 21.0-22.4) to 3.87 (3.58-4.19) in weeks 1 and 2 after COVID-19, 2.80 (2.61-3.01) during weeks 3-4 then to 1.34 (1.21-1.48) during weeks 27-49. aHRs for first VTE declined from 33.2 (31.3-35.2) and 8.52 (7.59-9.58) in weeks 1 and 2 to 7.95 (7.28-8.68) and 4.26 (3.86-4.69) during weeks 3-4 and 5-8, then 2.20 (1.99-2.44) and 1.80 (1.50-2.17) during weeks 13-26 and 27-49 respectively. aHRs were higher, for longer after diagnosis, after hospitalised than non-hospitalised COVID-19. aHRs were also higher among people of Black and Asian than White ethnicity and among people without than with a previous event. Across the whole population estimated increases in risk of arterial thromboses and VTEs were 2.5% and 0.6% respectively 49 weeks after COVID-19, corresponding to 7,197 and 3,517 additional events respectively after 1.4 million COVID-19 diagnoses. Conclusions and Relevance: High rates of vascular disease early after COVID-19 diagnosis decline more rapidly for arterial thromboses than VTEs but rates remain elevated up to 49 weeks after COVID-19. These results support continued policies to avoid COVID-19 infection with effective COVID-19 vaccines and use of secondary preventive agents in high-risk patients.

Impact of the COVID-19 Pandemic on Percutaneous Coronary Intervention in England: Insights From the British Cardiovascular Intervention Society PCI Database Cohort.

BACKGROUND: The objective of the study was to evaluate changes in percutaneous coronary intervention (PCI) practice in England by analyzing procedural numbers, changes in the clinical presentation, and characteristics of patients and their clinical outcomes during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: We conducted a retrospective cohort study of all patients who underwent PCI in England between January 2017 and April 2020 in the British Cardiovascular Intervention Society database. RESULTS: Forty-four hospitals reported PCI procedures for 126 491 patients. There were ≈700 procedures performed each week before the lockdown. After the March 23, 2020 lockdown (11th/12th week in 2020), there was a 49% fall in the number of PCI procedures after the 12th week in 2020. The decrease was greatest in PCI procedures performed for stable angina (66%), followed by non-ST-segment-elevation myocardial infarction (45%), and ST-segment-elevation myocardial infarction (33%). Patients after the lockdown were younger (64.5 versus 65.5 years, P<0.001) and less likely to have diabetes (20.4% versus 24.6%, P<0.001), hypertension (52.0% versus 56.8%, P=0.001), previous myocardial infarction (23.5% versus 26.7%, P=0.008), previous PCI (24.3% versus 28.3%, P=0.001), or previous coronary artery bypass graft (4.6% versus 7.2%, P<0.001) compared with before the lockdown. CONCLUSIONS: The lockdown in England has resulted in a significant decline in PCI procedures. Fewer patients underwent PCI for stable angina. This enabled greater capacity for urgent and emergency cases, and a reduced length of stay was seen for such patients. Significant changes in the characteristics of patients towards a lower risk phenotype were observed, particularly for non-ST-segment-elevation myocardial infarction, reflecting a more conservative approach to this cohort.

Patterns of Multimorbidity and Risk of Severe SARS-CoV-2 Infection: an observational study in the U.K. (preprint)

Background Pre-existing comorbidities have been linked to SARS-CoV-2 infection but evidence is sparse on the importance and pattern of multimorbidity (2 or more conditions) and severity of infection indicated by hospitalisation or mortality. We aimed to use a multimorbidity index developed specifically for COVID-19 to investigate the association between multimorbidity and risk of severe SARS-CoV-2 infection. Methods We used data from the UK Biobank linked to laboratory confirmed test results for SARS-CoV-2 infection and mortality data from Public Health England between March 16 and July 26, 2020. By reviewing the current literature on COVID-19 we derived a multimorbidity index including: 1) angina; 2) asthma; 3) atrial fibrillation; 4) cancer; 5) chronic kidney disease; 6) chronic obstructive pulmonary disease; 7) diabetes mellitus; 8) heart failure; 9) hypertension; 10) myocardial infarction; 11) peripheral vascular disease; 12) stroke. Adjusted logistic regression models were used to assess the association between multimorbidity and risk of severe SARS-CoV-2 infection (hospitalisation or death). Potential effect modifiers of the association were assessed: age, sex, ethnicity, deprivation, smoking status, body mass index, air pollution, 25-hydroxyvitamin D, cardiorespiratory fitness, high sensitivity C-reactive protein. Results Among 360,283 participants, the median age was 68 [range, 48-85] years, most were White (94.5%), and 1,706 had severe SARS-CoV-2 infection. The prevalence of multimorbidity was more than double in those with severe SARS-CoV-2 infection (25%) compared to those without (11%), and clusters of several multimorbidities were more common in those with severe SARS-CoV-2 infection. The most common clusters with severe SARS-CoV-2 infection were stroke with hypertension (79% of those with stroke had hypertension); diabetes and hypertension (72%); and chronic kidney disease and hypertension (68%). Multimorbidity was independently associated with a greater risk of severe SARS-CoV-2 infection (adjusted odds ratio 1.91 [95% confidence interval 1.70, 2.15] compared to no multimorbidity). The risk remained consistent across potential effect modifiers, except for greater risk among men. Conclusion The risk of severe SARS-CoV-2 infection is higher in individuals with multimorbidity, indicating the need to target research and resources in people with SARS-CoV-2 infection and multimorbidity.

Clinical Course And Risk Factors For In-hospital Death In Critical COVID-19 In Wuhan, China (preprint)

BACKGROUND The risk factors for mortality of COVID-19 classified as critical type have not been well described. OBJECTIVES This study aimed to described the clinical outcomes and further explored risk factors of in-hospital death for COVID-19 classified as critical type. METHODS This was a single-center retrospective cohort study. From February 5, 2020 to March 4, 2020, 98 consecutive patients classified as critical COVID-19 were included in Huo Shen Shan Hospital. The final date of follow-up was March 29, 2020. The primary outcome was all-cause mortality during hospitalization. Multivariable Cox regression model was used to explore the risk factors associated with in-hospital death. RESULTS Of the 98 patients, 43 (43.9%) died in hospital, 37(37.8%) discharged, and 18(18.4%) remained in hospital. The mean age was 68.5 (63, 75) years, and 57 (58.2%) were female. The most common comorbidity was hypertension (68.4%), followed by diabetes (17.3%), angina pectoris (13.3%). Except the sex (Female: 68.8% vs 49.1%, P=0.039) and angina pectoris (20.9% vs 7.3%, P = 0.048), there was no difference in other demographics and comorbidities between non-survivor and survivor groups. The proportion of elevated alanine aminotransferase, creatinine, D-dimer and cardiac injury marker were 59.4%, 35.7%, 87.5% and 42.9%, respectively, and all showed the significant difference between two groups. The acute cardiac injury, acute kidney injury (AKI), and acute respiratory distress syndrome (ARDS) were observed in 42.9%, 27.8% and 26.5% of the patients. Compared with survivor group, non-survivor group had more acute cardiac injury (79.1% vs 14.5%, P<0.0001), AKI (50.0% vs 10.9%, P<0.0001), and ARDS (37.2% vs 18.2%, P=0.034). Multivariable Cox regression showed increasing hazard ratio of in-hospital death associated with acute cardiac injury (HR, 6.57 [95% CI, 1.89-22.79]) and AKI (HR, 2.60 [95% CI, 1.15-5.86]). CONCLUSIONS COVID-19 classified as critical type had a high prevalence of acute cardiac and kidney injury, which were associated with a higher risk of in-hospital mortality.

Epidemiological and clinical characteristics of 1663 hospitalized patients infected with COVID-19 in Wuhan, China: a single-center experience.

BACKGROUND: The COVID-19 outbreak in late December 2019 has quickly emerged into pandemic in 2020. We aimed to describe the epidemiology and clinical characteristics of hospitalized COVID-19 patients, and to investigate the potential risk factors for COVID-19 severity. METHOD: 1663 hospitalized patients with laboratory-confirmed diagnosed COVID-19 from Tongji Hospital between January 14, 2020, and February 28, 2020 were included in the present study. Demographic information, exposure history, medical history, comorbidities, signs and symptoms, chest computed tomography (CT) scanning, severity of COVID-19 and laboratory findings on admission were collected from electronic medical records. Multivariable logistic regression was used to explore the association between potential risk factors with COVID-19 severity. RESULTS: In the present study, the majority (79%) of 1663 COVID-19 patients were aged over 50 years old. A total of 2.8% were medical staff, and an exposure history of Huanan seafood market was document in 0.7%, and 7.4% were family infection. Fever (85.8%), cough (36.0%), fatigue (23.6%) and chest tightness (11.9%) were the most common symptoms in COVID-19 patients. As of February 28, 2020, of the 1663 patients included in this study, 26.0% were discharged, 10.2% were died, and 63.8% remained hospitalized. More than 1/3 of the patients had at least one comorbidity. Most (99.8%) patients had abnormal results Chest CT, and the most common manifestations of chest CT were local patchy shadowing (70.7%) and ground-glass opacity (44.8%). On admission, lymphocytopenia was present in 51.1% of the patients, mononucleosis in 26.6%, and erythrocytopenia in 61.3%. Most of the patients had increased levels of C-reactive protein (80.4%) and D-dimer (64.4%). Compared with non-severe patients, severe patients had more obvious abnormal laboratory results related to inflammation, coagulation disorders, liver and kidney damage (all P < 0.05). Older age (OR = 2.37, 95% CI: 1.47-3.83), leukocytosis (OR = 2.37, 95% CI: 1.47-3.83), and increased creatine kinase (OR = 2.37, 95% CI: 1.47-3.83) on admission were significantly associated with COVID-19 severity. CONCLUSION: Timely medical treatment and clear diagnosis after the onset might be beneficial to control the condition of COVID-19. Severe patients were more likely to be to be elder, and tended to have higher proportion of comorbidities and more prominent laboratory abnormalities. Older age, leukocytosis, and increased creatine kinase might help clinicians to identify severe patients with COVID-19.