Bimekizumab safety in patients with moderate-to-severe plaque psoriasis: Analysis of pooled data from up to three years of treatment in Phase 2 and 3 clinical trials

Background: Bimekizumab (BKZ) is a monoclonal IgG1 antibody used in the treatment of psoriasis which selectively inhibits interleukin (IL)-17F in addition to IL-17A.1,2 Data pooled over two years have indicated that BKZ is generally well-tolerated.3 We report three-year BKZ pooled safety data in patients with moderate-to-severe plaque psoriasis. Method(s): Safety data were evaluated for all patients who received one or more dose BKZ in four Phase 3 trials (BE SURE [NCT03412747], BE VIVID [NCT03370133], BE READY [NCT03410992], and their ongoing open-label extension BE BRIGHT open-label extension [NCT03598790;data cut-off : 10/23/2021]) and four Phase 2 trials (BE ABLE 1 [NCT02905006], BE ABLE 2 [NCT03010527], PS0016 [NCT03025542], PS0018 [NCT03230292]). Safety data were evaluated separately for patients receiving BKZ dosed 320mg every four weeks (Q4W) or every eight weeks (Q8W). Exposureadjusted incidence rates (EAIRs) for treatmentemergent adverse events (TEAEs) are the incidence of new cases per 100 patient-years (PY). Result(s): Total BKZ exposure was 4,245.3 PY (N=1,789) across Phase 2/3 trials, and 3,876.4 PY (N=1,495) in Phase 3 trials. TEAEs occurred at a rate of 186.1 across Phase 2/3 trials, serious TEAEs at 5.6, and TEAEs leading to discontinuation at 3.5. Eighteen deaths occurred (0.4/100 PY), all unrelated to study treatment except one (relationship unknown). TEAEs occurred less frequently in Q8W- than Q4W-treated patients in Phase 3 trials. Consistent with previous reports, most common TEAEs (EAIR) in Phase 2/3 trials were nasopharyngitis (15.3), oral candidiasis (10.2), and upper respiratory tract infection (7.1).3 EAIR of serious infections was 1.2. Most frequently reported were serious coronavirus infections (0.2). There were no cases of active tuberculosis. EAIR of oral candidiasis was 10.2, decreased vs two-year data (12.6),3 and was less common with BKZ Q8W vs Q4W. The vast majority of oral candidiasis events were mild or moderate (99.4%);none were serious. EAIRs of hepatic events (4.0) and elevated liver enzymes (3.4) were decreased vs. two-year data (4.3 and 3.6, respectively).3 EAIRs for inflammatory bowel disease (0.1), adjudicated major adverse cardiac events (0.6), and adjudicated suicidal ideation and behavior (0.1) were low. EAIRs for other safety topics of interest were also low and were similar to or lower than two-year EAIRs.3 Conclusion(s): BKZ was well-tolerated over three years. No safety signals were identified;EAIRs of TEAEs did not increase compared with data from two years.3.

Immediate and Contributory Causes of Death in Patients Hospitalized with Covid-19

Background: Accurate determination of the immediate and contributory causes of death in patients with COVID-19 is important for optimal care and instituting mitigation strategies. Method(s): All deaths in Qatar between March 1, 2020 and August 31, 2022 flagged for likely relationship to COVID-19 by were evaluated by two independent reviewers trained to determine and assign the most likely immediate underlying cause of death. Each decedent's electronic medical records was comprehensively reviewed, and the cause of death was assigned based on the most plausible underlying event that triggered the event(s) that led to death based on clinical documentation and a review of laboratory, microbiology, pathology, and radiology data. After cause assignment, each case was categorized into major diagnostic groups by organ system, syndrome, or disease classification. Result(s): Among 749 deaths flagged for likely association with COVID-19, the most common admitting diagnoses were respiratory tract infection (91%) and major adverse cardiac event (MACE, 2.3%). The most common immediate cause of death was COVID pneumonia (66.2%), followed by MACE (7.1%), hospital associated pneumonia (HAP, 6.8%), bacteremia (6.3%), disseminated fungal infection (DFI, 5.2%), and thromboembolism (4.5%). The median length of hospital stay was 23 days (IQR 14,38). COVID pneumonia remained the predominant cause irrespective of the time from admission, though the proportion dropped with increasing length of stay in the hospital. Other than COVID pneumonia, MACE was the predominant cause of death in first two weeks but declined thereafter. No death occurred due to bacteremia, HAP, or DFI in the first week after hospitalization, but became increasing common with increased length of stay in the hospital accounting for 9%, 12%, and 10% of all deaths after 4 weeks in the hospital respectively. The majority of deaths (86%) occurred in the intensive care unit setting. COVID pneumonia accounted for approximately two-thirds of deaths in each setting. MACE and HAP were approximately equally represented in both settings while bacteremia and disseminated fungal infection were more common in the intensive care unit setting. Conclusion(s): Nearly one-third of patients with COVID infection die of non- COVID causes, some of which are preventable. Mitigation strategies should be instituted to reduce the risk of such deaths. (Figure Presented).

Clinical Course and Short-Term Follow-up of SARS-CoV-2 Vaccine-Related Myocarditis in Children and Adolescents within the Prospective German Registry for Suspected Myocarditis "MYKKE

Background: Several studies described occurrence of myocarditis after SARS-CoV-2 vaccination in pediatric patients. Weaimed to characterize the clinical course of myocarditis following SARS-CoV2 vaccination including follow-up data within the prospective German registry for suspected myocarditis in children and adolescents "MYKKE." Method: Patients younger than 18 years with suspected myocarditis and onset of symptoms within 21 days followingSARS-CoV2 vaccination were enrolled within the MYKKE registry. The suspect of myocarditis is valid in patients with clinical symptoms and diagnostic findings typically seen in myocarditis. Clinical data are monitored at initial admission and duringshort-term and long-term follow-up. Result(s): Between July 2021 and August 2022, a total of 48 patients with a median age of 16.2 years (IQR: 15.2-16.8)were enrolled by 13 centers, 88% male. Onset of symptoms occurred at a median of 3 days (IQR: 2-7) after vaccine administration, most frequently after the second dose (52%). Most common symptoms at initial admission were anginapectoris (81%), fatigue (56%), dyspnea (24%) and documented arrhythmias (17%). Initial ECG abnormalities included ST-elevation (48%) and T-wave inversion (23%). Elevated Tropon in was observed in 32 patients (67%) and in 19 cases (40%)NT-proBNP was above the normal range with a median level of 171 pg/mL (IQR: 32-501). 11 (23%) patients presentedwith mildly reduced systolic function at initial echocardiography or cardiac MRI. In 40 patients cardiac MRI and/orendomyocardial biopsy was performed (83%) and diagnosis of myocarditis could be verified in 27 cases (68%). Thirty-nine patients underwent short-term follow-up with a median of 2.8 months (IQR: 1.9-3.9) after discharge. 19 patients (49%)presented with either clinical symptoms (n = 9) and/or diagnostic abnormalities (n = 16) at follow-up. 12 patients (38%)still had medical treatment. Except for one patient with malign arrhythmias (ventricular tachycardia), no major cardiac adverse events were observed during initial admission and follow-up. Conclusion(s): Our data confirm that SARS-CoV-2 vaccine-related myocarditis is characterized by a mild disease course. However, after short-term follow-up a considerable number of patients still presented with symptoms and/or diagnostic abnormalities. Data on long-term follow-up are awaited.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) complicating myocarditis

Myocarditis can lead to myocardial infarction in the absence of coronary artery obstruction. We report a case of probable myocarditis, complicated by myocardial infarction with non-obstructive coronary arteries. A 19-year-old man presented with chest pain typical of myocarditis. He was a smoker but was otherwise well. Electrocardiogram revealed diffuse ST-elevation and echocardiography revealed a thin, akinetic apex. Troponin-T levels on admission were raised leading to an initial diagnosis of myocarditis being made. However, late gadolinium enhancement study on cardiac magnetic resonance imaging demonstrated transmural enhancement typical of ischaemia. Coronary angiogram was normal, leading to a likely diagnosis of myocardial infarction with non-obstructive coronary arteries. It is important to highlight that coronary assessment remains important when working up for myocarditis, as myocardial infarction with non-obstructive coronary arteries can often complicate myocarditis in cases of normal angiography. Another important lesson was on how cardiac magnetic resonance imaging provided vital evidence to support underlying ischaemia despite normal coronary angiogram, leading to a diagnosis of myocardial infarction with non-obstructive coronary arteries. Myocardial infarction with non-obstructive coronary arteries remains a broad 'umbrella' term and cardiac magnetic resonance imaging, as well as more invasive coronary imaging techniques during angiography, can further assist in its diagnosis. Our case provides a reminder that myocardial infarction with non-obstructive coronary arteries, although increasingly recognised, remains under-diagnosed and can often overlap with peri-myocarditis, highlighting the need to employ multi-modality imaging in guiding management.Copyright © The Author(s) 2021.

The arrhythmic events and short-term cardiovascular outcomes in patients hospitalized with COVID-19 infection in Taiwan

Objective: The aim of this study is to investigate the arrhythmic events and short-term cardiovascular (CV) outcomes in patients hospitalized with COVID-19 infection in a single Taiwan tertiary center. Method(s): A retrospective study was carried out on 186 confirmed COVID-19 infection patients admitted to our hospital between May, 2021 and September, 2021. We investigate their CV symptoms, vital signs, laboratory examinations, arrhythmic events, and major adverse cardiovascular events (MACE), including ischemic stroke or systemic embolism, myocardial infarction, CV death, and heart failure (HF) during hospitalization. Result(s): During the hospitalization, 29.6% of patients had an elevation of cardiac enzymes, 67.2% had an elevation of d-dimer level, and 7.5% had abnormal NT-pro BNP level. The most common recorded arrhythmia is sinus tachycardia (22%), followed by atrial arrhythmia (12.4%, including atrial fibrillation 7.0%), sinus bradycardia (3.2%), ventricular arrhythmia (1.6%), and paroxysmal supraventricular tachycardia (1.1%). A total of 68 patients (36.6%) had arrhythmic events during hospitalization. During the mean follow-up of 2.8 months, 17 patients (9.1%) developed MACE, including 6 ischemic strokes, one pulmonary embolism, one peripheral artery occlusive disease, 3 HF, and 7 CV death. The total mortality rate is 19.9%. The hospitalized patients with arrhythmic events were associated with a higher incidence of intubation (32% vs 15%, p = 0.0062), MACE (22% vs 2%, p < 0.001), and mortality (37% vs 10%, p < 0.001) than those without arrhythmic events. Conclusion(s): The patients hospitalized with COVID-19 infection were associated with higher CV manifestations and arrhythmic events in Taiwan. Those patients with arrhythmic events were associated with higher morbidity and mortality.

Haematological Indices Predictive Role In Post Contrast Induced Acute Kidney Injury

Contrast-induced acute kidney injury (CI-AKI) is a frequent complication in cardiac patients after percutaneous coronary intervention (PCI). Thus, the early prediction of such cases is essential to improve outcomes and prevent complications. Hemogram-derived indices provide a cheap, easy, and non-invasive test. Systemic immune inflammation index (SII) is a novel marker that can be calculated easily from a complete blood count test. It can be an important indicator in determining the balance between systemic inflammation and immune status and can predict CI-AKI better than neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR).Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Routine Periodic Fasting Is Associated with a Lower Risk of Inpatient Hospitalization for the Primary Diagnosis of Heart Failure Following Covid-19 Diagnosis

Background Intermittent fasting modulates inflammation and reduces cardiometabolic risks, even without weight loss. Many Utahns (30%) engage in routine periodic fasting, primarily for religious purposes (1 day/month for?>40 years). Periodic fasting is associated with greater longevity, lower incidence of heart failure (HF) and diabetes, and lower COVID-19 severity. This study evaluated the association of periodic fasting with inpatient hospitalization (hosp.) for the primary diagnosis of HF after COVID-19 diagnosis. Methods Patients undergoing cardiac catheterization at Intermountain Healthcare from 2/2013-3/2020 were enrolled in the INSPIRE registry (NCT02450006) and provided survey data for periodic fasting (n=5,795). Between March 6, 2020 and April 8, 2022, COVID-19 was diagnosed in N=464 (1852 COVID-negative, 3466 no test, 13 fasted routinely <5 years). Subjects were followed to April 17, 2022 for HF hosp., mortality, MI, revascularization, and stroke. Results Periodic fasting was reported by 135 (29.1%) of the 464 subjects and they had fasted routinely for 42.7+/-19.0 years (min: 7 years, max: 82 years). HF hosp. (n=65, 14.0%) was found in 8.1% of fasters and 16.4% of non-fasters (HR=0.45, 95% CI=0.24, 0.87;p=0.017). Fasting was retained in multivariable analyses (adjusted HR=0.44, CI=0.23, 0.84;p=0.013). Age, diabetes, prior MI, TIA, and prior HF diagnosis also predicted HF hosp. Qualitative but non-significantly lower risk for fasting vs non-fasters was found for mortality (3.7% vs 5.8%), MI (0% vs 1.2%), and revasc. (1.5% vs 2.7%), but not stroke (1.5% vs 1.5%). Composites were significant: HF hosp./mortality, n=74 (10.4% vs 18.2%, adj. HR=0.55, CI=0.30, 0.99;p=0.047) and major adverse cardiovascular events (MACE: HF hosp., mortality, MI, revasc., stroke), n=86 (12.6% vs 21.0%, adj. HR=0.58, CI=0.34, 1.00;p=0.0504). Conclusion Routine periodic fasting was associated with a lower risk of HF hosp., HF hosp./mortality, and MACE in patients at high risk due to COVID-19 diagnosis. This supports and expands on previous studies that reported fasting may reduce the risk of incident HF and reduce the risk of severe COVID-19. Further study of fasting and heart failure is indicated. Prevention and Health PromotionCopyright © 2023 American College of Cardiology Foundation

CRT-100.96 Effect of COVID-19 Pandemic on Six-Month Mortality and Clinical Outcomes of Patients With ST-Elevation Myocardial Infarction

Background: The coronavirus disease 2019 (COVID-19) infection has changed everyday clinical practice with a shortage of solid data about its implications on ST-elevation myocardial infarction (STEMI) patients. Aim: To evaluate the impact of COVID-19 on six-month clinical outcomes of patients with STEMI and determine the mortality predictors after STEMI during the COVID-19 pandemic. Methods: This prospective observational study was conducted on consecutive STEMI patients with confirmed COVID-19 infection who were presented to our hospital between April and October 2021. A total of 74 COVID-19 patients were included (group I) and were compared to 148 STEMI patients with matched baseline clinical parameters to the COVID-19 cases (group II). We compared the two cohorts' rates of major adverse cardiovascular events (MACEs;composite of death from any cause, recurrent MI, target-vessel revascularization, and stroke) at six months. Results: COVID-19 STEMI patients were more likely to present with angina equivalent symptoms, had higher Killip class at admission, and higher levels of high-sensitive cardiac Troponin T and serum C-reactive Protein. The six-month rates of MACEs were significantly higher in STEMI patients with COVID-19 compared to non- COVID-19 patients (41.9% vs. 16.9%, respectively;P<0.001) and were mainly due to higher in-hospital mortality (20.3% vs. 6.1%, respectively;P=0.001). The independent predictors of Six-month mortality in STEMI patients during the COVID-19 pandemic were the absence of ST resolution, low systolic blood and higher Killip class on admission, presence of severe MR and atrial fibrillation, and anterior wall STEMI. Conclusion: STEMI patients with superimposed COVID -19 infection had worse clinical outcomes with almost three times higher in-hospital mortality and six-month MACEs.

Long-term cardiovascular outcomes in Covid-19 survivors among non-vaccinated population: a retrospective cohort study from the trinetx us collaborative networks

Background: The long-term cardiovascular outcomes in COVID-19 survivors remain largely unclear. The aim of this study was to investigate the long-term cardiovascular outcomes in COVID-19 survivors. Method(s): This study used the data from the US Collaborative Network in TriNetX. From a cohort of more than 42 million records between January 1, 2019 and March 31, 2022, a total of 4 131 717 participants who underwent SARS-CoV- 2 testing were recruited. Study population then divided into two groups based on COVID-19 test results. To avoid reverse causality, the follow-up initiated 30 days after the test, and continued until 12 months. Hazard ratios (HRs) and 95% Confidence intervals (CIs) of the incidental cardiovascular outcomes were calculated between propensity score-matched patients with versus without SARS-CoV- 2 infection. Subgroup analyses on sex, and age group were also conducted. Sensitivity analyses were performed using different network, or stratified by hospitalization to explore the difference of geography and severity of COVID-19 infection. Result(s): The COVID-19 survivors were associated with increased risks of cerebrovascular diseases, such as stroke (HR [95% CI] = 1.618 [1.545-1.694]), arrhythmia related disorders, such as atrial fibrillation (HR [95% CI] = 2.407 [2.296-2.523]), inflammatory heart disease, such as myocarditis (HR [95% CI] = 4.406 [2.890-6.716]), ischemic heart disease (IHD), like ischemic cardiomyopathy (HR [95% CI] = 2.811 [2.477-3.190]), other cardiac disorders, such as heart failure (HR [95% CI] = 2.296 [2.200-2.396]) and thromboembolic disorders (e.g. pulmonary embolism: HR [95% CI] = 2.648 [2.443-2.870]). The risks of two composite endpoints, major adverse cardiovascular event (HR [95% CI] = 1.871 [1.816-1.927]) and any cardiovascular outcome (HR [95% CI] = 1.552 [1.526-1.578]), were also higher in the COVID-19 survivors than in the controls. Moreover, the survival probability of the COVID-19 survivors dramatically decreased in all the cardiovascular outcomes. The risks of cardiovascular outcomes were evident in both male and female COVID-19 survivors. Furthermore, the risk of mortality was higher in the elderly COVID-19 survivors (age >= 65 years) than in the young ones. Sensitivity analyses presented roughly similar results globally. Furthermore, the impact of COVID-19 on cardio-related outcomes appeared to be more pronounced in inpatients than in outpatients. Conclusion(s): The 12-month risk of incidental cardiovascular diseases is substantially higher in the COVID-19 survivors than the non-COVID- 19 controls. Clinicians and patients with a history of COVID-19 should pay attention to their cardiovascular health in long term.

Timely PCI Shows Beneficial Long-Term Outcomes in Late Presentation With STEMI: A Systematic Review and Meta-Analysis Between 2012 and 2022

Introduction: Approximately 8-40% of ST-elevation Myocardial Infarction (STEMI) present later than 12 hours after symptom onset. Current ACC/AHA guidelines recommend primary percutaneous coronary intervention (PCI) for STEMI after 12 hours of symptom onset only in the setting of cardiogenic shock or severe acute heart failure, (Class Ia, LOE B) or persistent ischemic symptoms (Class IIa, LOE B). There are limited data comparing long-term outcomes among patients with a late STEMI presentation managed with PCI versus medical therapy (MT). Objective(s): To compare long-term outcomes among patients treated with PCI versus MT who have late presentation of STEMI Methods: We followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to extract data from PubMed/Medline, Cochrane, Embase, and Clinicaltrials.gov databases by using the search terms "late" or "delayed" or ">12 hours" presentation with STEMI from 01/2012 through 12/2022. Included studies reported at least one of the following outcomes: all-cause mortality, reinfarction, heart failure, major adverse cardiac events (MACE), and stroke. Studies reporting delays in PCI due to COVID-19 positive status or COVID-19 enforced protocols were excluded to prevent the impact of pragmatic barriers on treatment. Relative risk (RR) was calculated using random effects model if heterogeneity was >50%, otherwise, fixed effects model was used Results: Seven studies (n=11,576, delayed PCI n=6,248, and medical therapy n=5,319) were included in our analysis. The median follow-up was 12 months (1-60 months). Overall, among patients with STEMI and PCI >12 hour after presentation had lower incidence of MACE (27% vs. 30%, RR 0.85, 95% CI 0.76-0.69, I2=30%, p=0.007) compared to MT alone, which was driven by a significantly reduced all-cause mortality with PCI (4.4% vs. 17%, RR 0.38, 95% CI 0.17-0.85, I2=95%, p=0.01). No significant differences were observed in the incidence of recurrent MI and heart failure hospitalizations. Conclusion(s): Our study suggests favorable outcomes of PCI in STEMI with presentation >12 hours compared with medical therapy. Further prospective studies are needed to validate our findings.

Role of Vaccination in the COVID-19 Nationwide Cohort (N3C) of Solid Organ Transplant Recipients

Purpose: Immunosuppressed solid organ transplant (SOT) patients have been repeatedly challenged in the COVID-19 pandemic with significant morbidities and mortality following infection and a suppressed immune response to vaccination. The aim of this study was to assess the impact on COVID-19 morbidity and mortality in the presence and absence of vaccination. Method(s): We studied adult (>18 years) patients from across the United States identified using the National COVID Cohort Collaborative (N3C) Enclave from Dec 10, 2020-Oct 12, 2021. Using multivariable logistic regression, we determined the odds of developing COVID-19 infection in the 6 months after full vaccination (defined as a breakthrough (BT) infection) in SOT recipients relative to nonimmunosuppressed (non-IS) patients. In SOT patients with BT COVID-19 infection, we then used multivariable logistic regression to determine the association of full and partial vaccination status with major adverse cardiac events, mortality, and additional secondary outcomes in the 90 days following COVID-19 diagnosis relative to unvaccinated/unconfirmed vaccination status SOT recipients). Result(s): Over the study period, 16,075 SOT patients were diagnosed with COVID-19 (515 were partially vaccinated, and 1,868 were fully vaccinated). Relative to non- IS, SOT was associated with an increased odds of BT COVID-19 infection in the 6 months post vaccine, that varied by organ type (i.e. OR 1.97, 95% CI 1.75-2.25 for kidney;OR 2.30, 95% CI 1.70-3.06 for lung), Table 1. In SOT patients who experienced BT COVID-19, full vaccination was associated with a small reduction in adverse outcomes relative to unvaccinated/unconfirmed vaccination status (OR 0.91, 95% CI 0.89-0.93 for MARCE;OR 0.92, 95% CI 0.90-0.93 for death;OR 0.90, 95% CI 0.88-0.92 for hospitalization), Table 2. Conclusion(s): SOT patients are at a ~2-fold increased odds of BT COVID-19 infection after vaccination compared with non-IS patients. Vaccination in SOT patients, regardless of product, has a small but significant reduction in the risk of adverse outcomes after a diagnosis of COVID-19, however SOT recipients remain at high risk and should continue to use caution even after vaccination. (Table Presented).

Long-term safety of risankizumab in patients with psoriatic disease: Findings from integrated analyses of 17 clinical trials in psoriasis and 4 in psoriatic arthritis

Objective: To report long-term risankizumab safety in patients with psoriatic disease. Method: Risankizumab safety data to March 25, 2021 were pooled from 17 phase 1–3 clinical trials in plaque psoriasis (PsO) and 4 phase 2/3 trials in psoriatic arthritis (PsA). Adverse events (AEs) of safety interest were reported for patients receiving ≥1 dose risankizumab. Results: Among 3197 patients with PsO (9982.6 patient years’ [PY] exposure;median (range) treatment duration, 3.7 years [1 day–6.9 years]) and 1542 patients with PsA (1594.9 PY;1.0 year [84 days–2.0 years]), rates of treatment-emergent AEs (158.3 and 160.8 events (E)/100PY), serious AEs (7.6 and 8.4 E/100PY) and AEs leading to discontinuation (1.9 and 2.3 E/100PY) were similar. Nasopharyngitis (PsO 14.5 E/100PY, PsA 7.9 E/100PY) and upper respiratory infection (PsO 7.8 E/100PY, PsA 5.6 E/100PY) were the most common infections;sepsis and pneumonia for PsO (0.1 E/100PY each) and COVID-19 for PsA (0.4 E/100PY) were the most common serious infections. Rates of opportunistic fungal infections were <0.1 and 0.1 E/100PY in PsO/PsA patients. Rates of nonmelanoma skin cancer (NMSC) were 0.7 and 0.4 E/100PY, and malignant tumors excluding NMSC were 0.6 and 0.3 E/100PY in PsO/PsA patients. Rates of major adverse cardiovascular events were 0.5 and 0.4 E/100PY in PsO/PsA patients. Conclusion: Rates of AEs of safety interest remained low in this largest and longest safety reporting for risankizumab to date, supporting the safety of risankizumab for the long-term treatment of patients with psoriatic disease.

Is It Time to Revisit Remdesivir Use for Severe COVID-19?

How to cite this article: Taggarsi DA. Is It Time to Revisit Remdesivir Use for Severe COVID-19? Indian J Crit Care Med 2022;26(9):983-984.

CARDIOVASCULAR EVENT, VENOUS THROMBOEMBOLIZM, and INFECTION RISK with TOFACITINIB in RHEUMATOID ARTHRITIS PATIENTS AGED ≥ 60 YEARS

Background: Tofacitinib is a targeted synthetic DMARD that selectively inhibits Janus kinase (JAK) and is approved for the treatment of RA by the FDA in 2012. In recent years, an important safety concern related to incidence of adverse events after treatment with tofacitinib has emerged. Objectives: To evaluate the risk of major adverse cardiovascular events (MACE), venous thromboembolism (pulmonary embolism or deep vein thrombosis), serious infections requiring hospitalization, and herpes zoster with tofacitinib in RA patients aged ≥ 60 years. Methods: HUR-BIO (Hacettepe University Rheumatology Biologic Registry) is a single center biological and targeted synthetic DMARD registry since 2005. We analyzed RA patients aged ≥ 60 years receiving tofacitinib who had at least 1 control visit registered in the HURBIO database. Phone calls were made with these patients for the current health status information until the end of January 2022. The data of the patients who lost the follow-up in our clinic were obtained from the personal health record system of the Republic of Turkey Ministry of Health by patients' permission. The coprimary end points were adjudicated MACE, VTE, serious infections, and herpes zoster. These events were identi-fed using patients' medical records. Crude incidence rates were expressed in patients with frst events per 100 patient-years, with two-sided 95% confdence intervals. Results: A total of 132 RA patients (109, 82.6% female) aged ≥ 60 years received tofacitinib at a dose of 5 mg twice daily. The median (25-75% percentiles) age was 67 (63-73) years and median duration under tofacitinib was 18 (5-33) months. Approximately 70% of patients were biologically naive. During a median follow-up of 1. 5 years, the incidences of serious infection requiring hospitalization and herpes zoster were higher (5.5% [95%CI 3.12-9.86] and 3.4% [1.67-7.17], respectively) while there was no increase in the incidences of MACE and VTE. The causes for hospitalization were as follows: COVID-19 (n=4), pneumonia (n=3), soft-tissue infection (n=3), and GIS infection (n=1). Tw o of these patients deceased. Conclusion: Older patients with RA are at increased infection risk because of age and comorbid conditions. Although adverse events are reported with 10 mg tofacitinib twice daily, clinicians should be careful against the risk of infection at a dose of 5 mg twice daily, especially in elderly patients.

EFFICACY and SAFETY of UPADACITINIB in PATIENTS with ACTIVE ANKYLOSING SPONDYLITIS REFRACTORY to BIOLOGIC THERAPY: A DOUBLEBLIND, RANDOMIZED, PLACEBO-CONTROLLED PHASE 3 TRIAL

Background: Upadacitinib (UPA) was shown to be safe and effective through 2 years in patients (pts) with active ankylosing spondylitis (AS) naïve to biologic disease-modifying antirheumatic drugs (bDMARDs) in the pivotal phase 2/3 SELECT-AXIS 1 trial.1,2 Objectives: To assess the efficacy and safety of UPA in pts with active AS with an inadequate response (IR) to bDMARDs. Methods: SELECT-AXIS 2 (NCT04169373) was conducted under a master protocol and includes two separate studies (one for AS bDMARD-IR and one for non-radiographic axial spondyloarthritis [nr-axSpA]). The AS bDMARD-IR study is a randomized, double-blind, placebo (PBO)-controlled, phase 3 trial that enrolled adults ≥18 years with AS who met modifed New York criteria, had BAS-DAI and pt's assessment of total back pain scores ≥4 (numeric rating scale 0-10) at study entry, and had an IR to one or two bDMARDs (TNF inhibitor or IL-17 inhibitor). Pts were randomized 1:1 to receive oral UPA 15 mg once daily (QD) or PBO during the 14-week (wk) double-blind treatment period. The primary endpoint was ASAS40 response at wk 14. Multiplicity-controlled secondary endpoints evaluated at wk 14 were improvements from baseline in disease activity (ASDAS [CRP], ASDAS ID [<1.3], ASDAS LDA [<2.1], BASDAI50, ASAS20, and ASAS PR), pain (total and nocturnal back pain), function (BASFI), objective measure of infammation (SPARCC MRI score of the spine), spinal mobility (BASMI), enthesitis (MASES), and quality of life (ASQoL and ASAS HI). Non-responder imputation incorporating multiple imputation (NRI-MI) was used to handle intercurrent events and missing data for binary endpoints. Cochran-Mantel-Haenszel (CMH) test and mixed-effect model for repeated measures (MMRM) were used for analyzing binary and continuous endpoints, respectively. Treatment-emergent adverse events (TEAEs) assessed through wk 14 are reported for pts who had ≥1 dose of study drug. Results: All 420 randomized pts with active AS received assigned treatment (UPA 15 mg, n=211;PBO, n=209);409 (97%) received study drug through wk 14. Baseline demographic and disease characteristics were generally similar between treatment groups and refective of an active AS bDMARD-IR population (74% male;mean age 42.4 years;mean disease duration 7. 7 years;83% HLA-B27 positive;mean BASDAI 6.8). Signifcantly more pts achieved the primary endpoint of ASAS40 response at wk 14 with UPA vs PBO (45% vs 18%;P<0.0001;Figure 1);UPA showed onset of effect in ASAS40 as early as wk 4 (nominal P≤0.05). All multiplicity-controlled secondary endpoints met statistical signifcance for UPA vs PBO at wk 14 across multiple clinical domains of AS (P<0.0001;Figure 1). The rate of TEAEs was similar between treatment groups through wk 14 (UPA, 41%;PBO, 37%). TEAEs led to discontinuation in 3 (1.4%) pts treated with PBO and none with UPA. Serious infections occurred with UPA (2.4%) but not with PBO and included 4 events of COVID-19 and 1 event of uveitis. Additional events of uveitis were reported in 3 (1.4%) pts treated with PBO. Infammatory bowel disease (IBD) occurred in 1 (0.5%) pt on UPA and none on PBO. No malignancy, major adverse cardiovascular events, venous thromboembolic events, or death were reported with UPA;1 event of malignancy was observed with PBO. Conclusion: UPA 15 mg QD was signifcantly more effective than PBO over 14 wks of treatment in pts with active AS and IR to bDMARDs. No new safety risks were identifed with UPA compared with its known safety profile.3,4 These fndings are consistent with and complementary to those of SELECT-AXIS 1 (bDMARD-naïve AS population),1,2 and support the use of UPA in pts with active AS, including those who had a previous IR to bDMARD therapy.

LONG-TERM SAFETY of RISANKIZUMAB in PATIENTS with PSORIATIC DISEASE: FINDINGS from INTEGRATED ANALYSES of 17 CLINICAL TRIALS in PSORIASIS and 4 in PSORIATIC ARTHRITIS

Background: Risankizumab, an interleukin-23 inhibitor, was efficacious and well tolerated in phase 2 and 3 clinical studies in patients with psoriatic disease. Objectives: To report long-term risankizumab safety in patients with psoriatic disease. Methods: Risankizumab safety data to March 25, 2021 were pooled from 17 phase 1-3 clinical trials in plaque psoriasis (PsO) and 4 phase 2/3 trials in pso-riatic arthritis (PsA). Adverse events (AEs) of safety interest were reported for patients receiving ≥1 dose risankizumab. Results: Among 3197 patients with PsO (9982.6 patient years' [PY] exposure;median (range) treatment duration, 3.7 years [1 day-6.9 years]) and 1542 patients with PsA (1594.9 PY;1. 0 year [84 days-2.0 years]), rates of treatment-emergent AEs (158.3 and 160.8 events (E)/100PY), serious AEs (7.6 and 8.4 E/100PY) and AEs leading to discontinuation (1.9 and 2.3 E/100PY) were similar. Nasopharyn-gitis (PsO 14.5 E/100PY, PsA 7. 9 E/100PY) and upper respiratory infection (PsO 7. 8 E/100PY, PsA 5.6 E/100PY) were the most common infections;sepsis and pneumonia for PsO (0.1 E/100PY each) and COVID-19 for PsA (0.4 E/100PY) were the most common serious infections. Rates of opportunistic fungal infections were <0.1 and 0.1 E/100PY in PsO/PsA patients. Rates of non-melanoma skin cancer (NMSC) were 0.7 and 0.4 E/100PY, and malignant tumors excluding NMSC were 0.6 and 0.3 E/100PY in PsO/PsA patients. Rates of major adverse cardiovascular events were 0.5 and 0.4 E/100PY in PsO/PsA patients. Conclusion: Rates of AEs of safety interest remained low in this largest and longest safety reporting for risankizumab to date, supporting the safety of risankizumab for the long-term treatment of patients with psoriatic disease.

IDF21-0311 Pre-Admission, Diabetic Glycemic Control on 60-Day Mortality and Major Adverse Cardiovascular Events from COVID-19

Background: Patients with diabetes mellitus (DM) are at increased risk for intubation, death, and other complications from COVID-19. However, the importance of a patient’s glycemic control preceding the COVID-19 infection is less well understood. Method: From March to November 2020, data from adult patients with confirmed COVID-19 admitted to Rush University System for Health (RUSH) was studied. Patients with both a pre-existing history of diabetes mellitus (DM) and a hemoglobin A1c (HbA1c) measurement during their hospitalization were included. Based on their HbA1c, patients were then divided into 4 groups: adequate glycemic control (≤ 6.5), mild elevation (6.5 – 7.4), intermediate elevation (7.5 – 8.4), and severe elevation (≥ 8.5). Multivariable logistic regression, adjusted for age, body mass index, and pre-existing history of atrial fibrillation, coronary artery disease, hypertension, and chronic obstructive pulmonary disorder, was performed with glycemic control group as a predictor for 60-day mortality and severe COVID-19, which was a composite of 60-day mortality or requiring the intensive care unit, non-invasive positive pressure ventilation, or mechanical ventilation. Major adverse cardiac events (MACE) were defined as nonfatal myocardial injury, nonfatal stroke, or cardiovascular death. Results: Of the 1682 patients admitted, 774 had pre-existing DM, and 534 had HbA1c measurement during their hospitalization. The median HbA1c value was 8.0% (interquartile range 6.6% – 9.9%). In our entire cohort, 75 (14.0%) and 280 (52.4%) patients suffered 60-day mortality and severe COVID-19 infection, respectively. When adjusting for baseline characteristics and comorbidities, patients with mild (adjusted odds ratio [aOR] 2.39 [CI 1.04 – 5.83];p < 0.05) and intermediate (aOR 3.59 [CI 1.49 – 9.12];p < 0.01) HbA1c elevation were at increased risk of 60-day mortality compared to those with adequate glycemic control;no statistically significant difference was present in those with severe elevation (aOR 2.19 [CI 0.95 – 5.44];p = 0.08). Furthermore, only the mild HbA1c elevation group was at increased risk for severe COVID-19 infection (aOR 1.88 [CI 1.06 – 3.38];p < 0.05). Those with intermediate (aOR 1.77 [CI 0.94 – 3.33];p = 0.08) or severe (aOR 1.57 [CI 0.92 – 2.70];p = 0.10) HbA1c elevation were not at higher risk for severe COVID-19 infection. When comparing other 60-day outcomes, there was no difference between the glycemic groups in MACE, life-threatening arrhythmia, deep venous thrombosis, acute renal failure requiring renal replacement therapy, and pulmonary embolism (Table 1). Discussion: In our cohort, patients with DM with an HbA1c of 6.5 – 8.4 were at increased risk of 60-day mortality, while those with an HbA1c of 6.5 – 7.4 were at an increased risk of severe COVID-19 infection.

IMPACT OF SERUM IGG LEVELS AGAINST SARS-COV-2 ON CLINICAL OUTCOMES FOR HOSPITALIZED COVID PATIENTS

BACKGROUND: The SAR-CoV-2 pandemic continues to negatively impact the healthcare system globally with over 800,000 deaths in the United States and millions more worldwide. The cases are rising despite availability of vaccines. For most immunocompetent patients these vaccines will generate a humoral response and also a memory T-cell response. Few if any studies have reported data that measure anti-spike IgG titers and also correlate those titers with clinical outcomes in the instance of breakthrough infection. METHODS: We conducted a pilot prospective observational clinical study enrolling 30 immunocompetent patients who were admitted with a positive SARS-CoV-2 PCR. Leftover blood from admission was used to obtain antispike and anti-nucleocapsid antibody levels. Baseline characteristics were collected and patients were divided into two categories based on anti-spike antibody level and vaccination status. Clinical outcomes including mortality, major adverse cardiac events (MACE), overall length of stay (LOS), ICU LOS, maximum oxygen support needs, and mechanical ventilation needs were analyzed on day 28 in both categories. RESULTS: On analyzing the patients enrolled, the median age was 59 years, 56.67% were female and 73.3% were Caucasian. 6 patients (20%) were asymptomatic, and 63.3% patients had hypertension. Among all patients, the median duration of symptoms was 7 days, and the median LOS was 7 days as well.Anti-spike antibody was detected in 22 patients (73.33%), and the median value was 956. Anti-nucleocapsid antibody was positive only in 9 patients (30%). Three patients (10%) were admitted to ICU, and all 3 were mechanically ventilated. Four patients (13.33%) had a MACE event in those 28 days, and 5 patients (16.67%) died. Comparing vaccinated vs unvaccinated: 3/5 deceased patients were unvaccinated, and 2/3 mechanically ventilated were unvaccinated as well but these were not statistically significant. 0.6% patients were asymptomatic in unvaccinated group versus 33% in the vaccinated group. Among the 7 patients with high oxygen needs (fio2 100%), 5 had undetectable anti-spike antibodies, and one had low value (89.6). 2 out of 3 mechanically ventilated and 3 out of 5 deceased patients had undetectable anti-spike antibodies. CONCLUSIONS: Our pilot study did not show significance in outcomes between vaccinated and unvaccinated patients, but this relation has been verified in multiple larger studies. We also noted patients with undetectable/ low anti- spike antibody levels had increased fio2 needs, ICU admission, and mortality.However, it was not feasible to compare both these findings between groups due to less number of patients. This demands a larger study to better describe these relations.

Doctors With Borders: The Impact Of International Travel Bans on Timorese Citizens Awaiting Cardiac Intervention

Background: In Timor-Leste, cardiac interventions and surgical procedures are largely provided by the East Timor Hearts Fund. Since March 2020, no Timorese patients have been able to travel to Australia for humanitarian cardiac procedures. Methods: We describe patients awaiting cardiac intervention as of March 2020, documenting their outcomes eighteen months later in August 2021. Contact with healthcare facilities (the national hospital, local clinics or online telehealth) was identified. Major adverse cardiac events (MACE;death, heart failure admission or stroke) were documented and demographic characteristics compared between patients experiencing MACE versus those remaining symptomatically stable. Results: In March 2020, 35 patients were waitlisted for cardiac intervention (68.6% female, mean age 26.8 ± 9.4 yrs). Eighteen months later, 9 (25.7%) patients experienced definite MACE, comprising 3 sudden deaths and 14 admissions for decompensated heart failure. A further 10 patients (28.6%) had newly-disconnected phone numbers, implying possible additional deaths. 15 patients attended online telehealth clinics;7 (46.7%) had deteriorating NYHA scores. 14 patients (40.0%) were symptomatically stable. Patients experiencing MACE had been waitlisted a median of 30 months by August 2021 compared to 22 months for stable patients. Conclusions: At least one-quarter and possibly over half of a humanitarian charity’s patient list died or developed severe heart failure following eighteen months’ delay to cardiac intervention during international border closures from COVID-19. Patients attending online telehealth clinics reported high rates of morbidity and deteriorating symptoms. Abrupt border closures leaving a country without access to humanitarian surgery highlight the vulnerabilities of short-term medical mission models.

COMPARISON OF OUTCOMES BETWEEN IN-PERSON AND VIRTUAL TIA CLINIC VISITS

Background and aims: During the COVID-19 pandemic, outpatient services transitioned mostly to virtual care. It is unknown if virtual Urgent TIA Clinic care outcomes are comparable to those of in-person visits. We, therefore, compared the risk of major adverse cardiovascular events (MACE) at 12 months between first virtual and in-person Urgent TIA Clinic visits. Methods: A virtual TIA Clinic was implemented in March 2020 in a Regional Stroke Center as an urgent response to the COVID-19 pandemic. We conducted a retrospective observational study by interrogating prospectively collected data from the London Ontario Stroke Registry. We used 26 epidemiological weeks from 2019 (in-person, prepandemic) and 2020 (virtual, pandemic). We included patients with and without a final diagnosis of stroke or TIA. The primary outcome was MACE (stroke, acute coronary syndromes, heart failure hospitalizations, and cardiovascular death) at 12 months. We applied propensity score weighted Cox regression analyses to control for risk factors, vascular comorbidities, presenting symptoms, diagnostic investigations, and secondary prevention therapies (see table for a comprehensive list), further adjusted for the final diagnosis (cerebrovascular vs. non-cerebrovascular event). Results: We included1153 patients, 700 assessed in-person and 453 virtually. The median age was 70 years, and 53% were females. MACE occurred in 27 (3.9%) in-person and 14 (3.1%) virtual care patients at 12 months, a statistically non-significant difference (adjusted HR 0.95, 95%CI 0.46 to 1.99;P=0.90). Conclusions: We found no differences in MACE at 12 months between in-person and virtual care visits in an Urgent TIA Clinic. (Table Presented).