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ObjectiveTo evaluate the effect of colchicine and high-intensity rosuvastatin in addition to standard of care on the progression of COVID-19 disease in hospitalised patients.DesignA pragmatic, open-label, multicentre, randomised controlled trial conducted from October 2020 to September 2021. Follow-up was conducted at 30 and 60 days. The electronic medical record was used at all stages of the trial including screening, enrolment, randomisation, event ascertainment and follow-up.SettingFour centres in the Yale New Haven Health System.ParticipantsNon-critically ill hospitalised patients with COVID-19.InterventionsPatients were randomised 1:1 to either colchicine plus high-intensity rosuvastatin in addition to standard of care versus standard of care alone. Assigned treatment was continued for the duration of index hospitalisation or 30 days, whichever was shorter.Primary and secondary outcome measuresThe prespecified primary endpoint was progression to severe COVID-19 disease (new high-flow or non-invasive ventilation, mechanical ventilation, need for vasopressors, renal replacement therapy or extracorporeal membrane oxygenation, or death) or arterial/venous thromboembolic events (ischaemic stroke, myocardial infarction, deep venous thrombosis or pulmonary embolism) evaluated at 30 days.ResultsAmong the 250 patients randomised in this trial (125 to each arm), the median age was 61 years, 44% were women, 15% were Black and 26% were Hispanic/Latino. As part of the standard of care, patients received remdesivir (87%), dexamethasone (92%), tocilizumab (18%), baricitinib (2%), prophylactic/therapeutic anticoagulation (98%) and aspirin (91%). The trial was terminated early by the data and safety monitoring board for futility. No patients were lost to follow-up due to electronic medical record follow-up. There was no significant difference in the primary endpoint at 30 days between the active arm and standard of care arm (15.2% vs 8.8%, respectively, p=0.17).ConclusionsIn this small, open-label, randomised trial of non-critically ill hospitalised patients with COVID-19, the combination of colchicine and rosuvastatin in addition to standard of care did not appear to reduce the risk of progression of COVID-19 disease or thromboembolic events, although the trial was underpowered due to a lower-than-expected event rate. The trial leveraged the power of electronic medical records for efficiency and improved follow-up and demonstrates the utility of incorporating electronic medical records into future trials.Trial registrationNCT04472611.

Background Despite improvement in the standard of care (SOC) for hospitalized COVID-19 patients, rates of morbidity and mortality remain high. There continues to be a need for easily available and cost-effective treatments. Colchicine and rosuvastatin are both safe and well-studied medications with anti-inflammatory and other pleiotropic effects that may provide additional benefits to hospitalized COVID-19 patients. Methods and results The Colchicine/Statin for the Prevention of COVID-19 Complications (COLSTAT) trial is a pragmatic, open-label, multicenter, randomized trial comparing the combination of colchicine and rosuvastatin in addition to SOC to SOC alone in hospitalized COVID-19 patients. Four centers in the Yale New Haven Health network will enroll a total of 466 patients with 1:1 randomization. The trial will utilize the electronic health record (Epic® Systems, Verona, Wisconsin, USA) at all stages including screening, randomization, intervention, event ascertainment, and follow-up. The primary endpoint is the 30-day composite of progression to severe COVID-19 disease as defined by the World Health Organization ordinal scale of clinical improvement and arterial/venous thromboembolic events. The secondary powered endpoint is the 30-day composite of death, respiratory failure requiring intubation, and myocardial injury. Conclusions The COLSTAT trial will provide evidence on the efficacy of repurposing colchicine and rosuvastatin for the treatment of hospitalized COVID-19 patients. Moreover, it is designed to be a pragmatic trial that will demonstrate the power of using electronic health records to improve efficiency and enrollment in clinical trials in an adapting landscape. Clinical Trial Registration: NCT04472611 ( https://clinicaltrials.gov/ct2/show/NCT04472611 ).

Introduction: Hydroxychloroquine (HCQ) is known to cause QTc prolongation, however its association with other ECG changes and how those are related to markers of myocardial injury in COVID-19 patients (pts) are not well described. Hypothesis: To study ECG changes in COVID-19 pts with or without troponin (Tn) elevation >3X normal (Tn +/-), who were or were not treated with HCQ (+/-). Methods: This is an observational study of pts admitted with COVID-19. All had at least 3 ECGs during admission; on day 1, day 2-3 and day 4-6. Pre-admission and final ECGs were included when available. Pts were excluded if they had atrial fibrillation, paced QRS, QRS>120msec, STEMI, or end stage renal disease. QRS, QTc, PR, P wave duration, QRS amplitude and the sum of T wave deflections in both limb and precordial leads were measured. Data were collected on medical history, illness severity, electrolytes, and medications within the 12-hour window of each ECG. Results: A total of 116 pts were included: 85 HCQ+ (40% Tn+) and 31 HCQ- (48% Tn+). There were no differences between the two groups in baseline characteristics, illness severity or mortality. Significant QTc prolongation was noted only in the HCQ+ group (p Conclusions: HCQ related ECG effects extend beyond QTc prolongation. These are most notable in pts with evidence of myocardial injury.

IMPACT: Advanced cardiac magnetic resonance imaging techniques can help to protect cancer patients from cardiotoxicity from immunotherapy with a more sensitive assessment of cardiac function with strain imaging for detection of abnormal cardiac function in the setting of normal left ventricular ejection fraction. OBJECTIVES/GOALS: Immune checkpoint inhibitors (ICI) are associated with fatal cardiotoxicity. Cardiac magnetic resonance (CMR) imaging can assess ICI-associated cardiotoxicity, but the utility of CMR strain imaging is unknown. We present a study of patients with ICI-associated cardiotoxicity evaluated with fast strain-encoded (fast-SENC) CMR. METHODS/STUDY POPULATION: This prospective study was approved by the institutional IRB and informed consent was obtained from 15 patients (5 patients with ICI-associated cardiotoxicity, 10 controls patients) between August 2018 and January 2020. All patients with ICI-associated cardiotoxicity had abnormal troponin values and evidence of cardiotoxicity on T2-weighted and/or delayed enhancement CMR images. All patients underwent standard CMR assessment with steady state free precession cine images, T2-weighted imaging, and delayed gadolinium enhancement imaging. Additionally, free-breathing SENC images were obtained and then processed by a team of blinded cardiovascular imaging specialists using Myostrain software (Morrisville, USA). RESULTS/ANTICIPATED RESULTS: Left ventricular ejection fraction (LVEF) was normal in both groups (ï,³53%). Global longitudinal LV strain was significantly depressed in the ICI cardiotoxicity group versus controls (-12.8 ±3.2% vs. -16.6 ±1.9%, p=0.028). The average global circumferential LV strain was mildly abnormal (defined as strain > -17) in the ICI cardiotoxicity group and trended towards a higher value compared with controls (-16.0 ±2.6% vs -17.8 ±1.7%, p=0.103). The average number of dysfunctional segments (defined as strain > -10) was significantly higher in the ICI cardiotoxicity group (6.8 ±4.2 vs. 1.0 ±1.7, p=0.017). The proportion of abnormal myocardium was higher in the ICI cardiotoxicity group (66 ±21% vs. 45 ±18%, p=0.050), as well as the proportion of myocardium found to be dysfunctional (26 ±22% vs. 3.0 ±6.0%, p=0.041). DISCUSSION/SIGNIFICANCE OF FINDINGS: Despite having preserved LVEF, patients who met criteria for ICI-associated cardiotoxicity had both global and regional abnormal LV strain. Fast-SENC imaging may provide a sensitive tool for detection of early cardiotoxicity in this population. This study is limited by its small cohort and a larger prospective study would be of value.

BackgroundImmune checkpoint inhibitors (ICIs) are highly effective in treating cancer; however, cardiotoxicity can occur, including myocarditis. Cardiac magnetic resonance (CMR) imaging is useful for evaluation of myocarditis, although it has not been well studied in ICI cardiotoxicity.MethodsWe identified patients referred for CMR evaluation of ICI cardiotoxicity from September 2015 through September 2019. We assessed structural and functional parameters, feature tracking (FT) left ventricular and atrial strain, T2- weighted ratios and quantitative late gadolinium enhancement (LGE). We also applied the Updated Lake Louise Criteria for diagnosis of myocarditis.ResultsOf the 20 patients referred, the median left ventricular ejection fraction (LVEF) was 52.5% ± 19.1 and 50% had a normal LVEF (≥53%). FT strain analysis revealed an average abnormal global longitudinal strain (GLS) of −9.8%± 4.2%. In patients with a normal LVEF, the average GLS remained depressed at −12.3%± 2.4%. In all patients, GLS demonstrated a significant negative correlation with LVEF (rs= −0.64, p 0.002). Sixteen patients (80%) had presence of LGE (14 non-ischemic pattern and 2 ischemic). Percent LGE did not correlate with any CMR parameters and notably did not correlate with LVEF (rs= −0.29, p = 0.22) or GLS (rs= 0.10, p = 0.67), highlighting the value of tissue characterization beyond functional assessment. Nine patients (45%) met full Updated Lake Louise Criteria and 85% met at least one criterion, suggestive of myocarditis in the correct clinical context. Thirteen patients (65%) were treated for ICI-associated myocarditis and, of these, 54% (n = 7) had recovery of LVEF to normal. There was no correlation between LVEF (p = 0.47), GLS (0.89), or % LGE (0.15) and recovery of LVEF with treatment.ConclusionIn patients with suspected ICI cardiotoxicity, CMR is an important diagnostic tool, even in the absence of overt left ventricular dysfunction, as abnormalities in left ventricular strain, T2 signal and LGE can identifying disease.