COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US cohort

Introduction Infection with SARS-CoV-2 is typically compared with influenza to contextualize its health risks. SARS-CoV-2 has been linked with coagulation disturbances including arterial thrombosis, leading to considerable interest in antithrombotic therapy for Coronavirus Disease 2019 (COVID-19). However, the independent thromboembolic risk of SARS-CoV-2 infection compared with influenza remains incompletely understood. We evaluated the adjusted risks of thromboembolic events after a diagnosis of COVID-19 compared with influenza in a large retrospective cohort. Methods We used a US-based electronic health record (EHR) dataset linked with insurance claims to identify adults diagnosed with COVID-19 between April 1, 2020 and October 31, 2020. We identified influenza patients diagnosed between October 1, 2018 and April 31, 2019. Primary outcomes [venous composite of pulmonary embolism (PE) and acute deep vein thrombosis (DVT); arterial composite of ischemic stroke and myocardial infarction (MI)] and secondary outcomes were assessed 90 days post-diagnosis. Propensity scores (PS) were calculated using demographic, clinical, and medication variables. PS-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression. Results There were 417,975 COVID-19 patients (median age 57y, 61% women), and 345,934 influenza patients (median age 47y, 66% women). Compared with influenza, patients with COVID-19 had higher venous thromboembolic risk (HR 1.53, 95% CI 1.38–1.70), but not arterial thromboembolic risk (HR 1.02, 95% CI 0.95–1.10). Secondary analyses demonstrated similar risk for ischemic stroke (HR 1.11, 95% CI 0.98–1.25) and MI (HR 0.93, 95% CI 0.85–1.03) and higher risk for DVT (HR 1.36, 95% CI 1.19–1.56) and PE (HR 1.82, 95% CI 1.57–2.10) in patients with COVID-19. Conclusion In a large retrospective US cohort, COVID-19 was independently associated with higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared with influenza. These findings may inform crucial knowledge gaps regarding the specific thromboembolic risks of COVID-19.

Electrocardiographic diagnosis of atrial cardiomyopathy to predict atrial contractile dysfunction, thrombogenesis and adverse cardiovascular outcomes

Thromboembolism and stroke are dreaded complications in atrial fibrillation (AF). Established risk stratification models identify susceptible patients, but their discriminative properties are poor. Atrial cardiomyopathy (ACM) is associated to thromboembolism and stroke in smaller studies, but the modalities used for ACM-diagnosis (MRI and endocardial mapping) are unsuitable for widespread population screening. We aimed to investigate an ECG-based diagnosis of ACM using amplified p-wave analysis (APWA) for stratification of thromboembolic risk and cardiovascular outcome. In this case–control study, ACM-staging was performed using APWA on digital 12-lead sinus rhythm-ECGs in patients with LAA-thrombus and a propensity-score-matched control-cohort. Left atrial contractile function and thrombi were evaluated by transesophageal echocardiography (TEE). Outcome for MACCE including death was assessed using official registries and structured phone interviews. Left-atrial appendage [LAA]-thrombi and appropriate sinus rhythm-ECGs for ACM-staging were found in 109 of 4086 patients that were matched 1:1 to control patients without thrombus (218 patients in total). Both cohorts were comparable regarding cardiovascular risk factors, anticoagulants and CHA2DS2-VASC-score. ACM-stages 1 to 3 (equivalent to no, moderate and extensive ACM) were found in 63 (57.8%), 36 (33.0%) and 10 (9.2%) of patients without and 3 (2.8%), 23 (21.1%) and 83 (76.1%) of patients with LAA-thrombi. Atrial contractile function decreased from ACM-stages 1 to 3 (LAA-flow velocities 38 ± 16 cm/s, 31 ± 15 cm/s and 21 ± 12 cm/s; p < 0.0001), while the likelihood for LAA-thrombus increased (2.8%, 21.1% and 76.1%, p < 0.001). Multivariable analysis confirmed an independent odds ratio for LAA-thrombus of 24.6 (p < 0.001) per ACM-stage. Two-year survival free of stroke/TIA, hospitalization for heart failure, myocardial infarction or all-cause death was strongly reduced in ACM-stage 3 (53.8%) compared to no or moderate ACM (82.8% and 84.7%, respectively; p < 0.0001). Electrocardiographic diagnosis of ACM identifies patients with atrial contractile dysfunction and atrial thrombi at risk for adverse cardiovascular outcomes and death.

Tmprss6-ASO as a tool for the treatment of Polycythemia Vera mice

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm resulting from an acquired driver mutation in the JAK2 gene of hematopoietic stem and progenitor cells resulting in the overproduction of mature erythrocytes and abnormally high hematocrit, in turn leading to thromboembolic complications. Therapeutic phlebotomy is the most common treatment to reduce the hematocrit levels and consequently decrease thromboembolic risk. Here we demonstrate that, by using the iron restrictive properties of the antisense oligonucleotides against Tmprss6 mRNA, we can increase hepcidin to achieve effects equivalent to therapeutic phlebotomy. We provide evidence that this less invasive approach could represent an additional therapeutic tool for the treatment of PV patients.

Thromboembolic risk factors and predictors of left atrial appendage thrombosis in Far North patients with nonvalvular atrial fibrillation

Aim. To analyze thromboembolic risk factors and identify additional predictors of left atrial appendage (LAA) thrombosis, which are not included in the CHA2DS2VASc scale, in long-term Far North residents with nonvalvular atrial fibrillation (AF).Material and methods. The study included 162 patients (men, 108; women, 54; mean age, 55,3±8,7 years) with non-valvular AF, living in the Far North, and 684 patients (men, 408; women, 276; mean age, 56,9±9,3 years), living in the temperate latitudes, hospitalized for catheter ablation. All patients underwent transthoracic and transesophageal echocardiography. According to transesophageal echocardiography, Far North patients were divided into two groups: group 1 — 21 patients with LAA thrombosis, group 2 — 141 patients without LAA thrombosis.Results. Compared to patients living in the temperate latitudes, Far North patients were younger (p=0,021) and were more likely to have type 2 diabetes (14,2% vs 8,3%, p=0,022), class ³II obesity (29,6% vs 21,1%, p=0,019), persistent AF(47,5% vs 33,2%, p=0,0019), LAA thrombosis (13% vs 6,6%, p=0,006), and severe structural and functional cardiac abnormalities (biatrial and right ventricular enlargement, lower left ventricular ejection fraction). In Far North patients, using logistic regression, independent predictors of LAA thrombosis were identified: an increase in left ventricular mass index (odds ratio (OR), 1,029; 95% confidence interval (CI), 1,011-1,048; p=0,001), persistent AF (OR, 3,521; 95% CI, 1,050-11,800; p=0,041).Conclusion. In Far North patients with nonvalvular AF, scheduled for catheter ablation, compared with patients from temperate latitudes, with a similar profile of cardiovascular diseases at a younger age, type 2 diabetes, grade ³II obesity, persistent AF, and LAA thrombosis were more common. The presence of persistent AF and an increase in left ventricular mass index are independent predictors of LAA thrombosis in Far North patients with nonvalvular AF.

Immunomodulation and Reduction of Thromboembolic Risk in Hospitalized COVID-19 Patients: Systematic Review and Meta-Analysis of Randomized Trials

Background: We aimed to investigate the potential beneficial effect of immunomodulation therapy on the thromboembolic risk in hospitalized COVID-19 patients. Methods: We searched PubMed and Scopus for randomized trials reporting the outcomes of venous thromboembolism (VTE), ischemic stroke or systemic embolism, myocardial infarction, any thromboembolic event, and all-cause mortality in COVID-19 patients treated with immunomodulatory agents. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using the Mantel–Haenszel random effects method. Results: Among 8499 patients hospitalized with COVID-19, 4638 were treated with an immunomodulatory agent, 3861—with usual care only. Among the patients prescribed immunomodulatory agents, there were 1.77 VTEs per 100 patient-months compared to 2.30 among those treated with usual care (OR: 0.84, 95% CI: 0.61–1.16; I2: 0%). Among the patients who received an interleukin 6 (IL-6) antagonist, VTEs were reported in 12 among the 1075 patients compared to 20 among the 848 receiving the usual care (OR: 0.52, 95% CI: 0.22–1.20; I2: 6%). Immunomodulators as an add-on to usual care did not reduce the risk of stroke or systemic embolism (OR: 1.10, 95% CI: 0.50–2.40; I2: 0%) or of myocardial infarction (OR: 1.06, 95% CI: 0.47–2.39; I2: 0%) and there was a nonsignificant reduction in any thromboembolic event (OR: 0.86, 95% CI: 0.65–1.14; I2: 0%). Conclusions: We did not identify a statistically significant effect of immunomodulation on prevention of thromboembolic events in COVID-19. However, given the large effect estimate for VTE prevention, especially in the patients treated with IL-6 antagonists, we cannot exclude a potential effect of immunomodulation.

Efficacy of R2CHA2DS2-VA score for predicting thromboembolism in Thai patients with non-valvular atrial fibrillation

Background There is no data specific to the addition of renal dysfunction and age 50–64 years as risk parameters to the CHA2DS2-VA score, which is known as the R2CHA2DS2-VA score, among NVAF patients. Accordingly, the aim of this study was to validate the R2CHA2DS2-VA score for predicting thromboembolism in Thai NVAF patients. Methods Thai NVAF patients were prospectively enrolled in a nationwide multicenter registry from 27 hospitals during 2014–2020. Each component of the CHA2DS2-VA and R2CHA2DS2-VA scores was scored and recorded. The main outcomes were thromboembolism, including ischemic stroke, transient ischemic attack (TIA), and/or systemic embolism. The annual incidence rate of thromboembolism among patients in each R2CHA2DS2-VA and CHA2DS2-VA risk score category is shown as hazard ratio (HR) and 95% confidence interval (95% CI). The performance of the R2CHA2DS2-VA and CHA2DS2-VA scores was demonstrated using c-statistics. Net reclassification index was calculated. Calibration plat was used to assess agreement between observed probabilities and predicted probabilities of both scoring system. Results A total of 3402 patients were enrolled during 2014–2020. The average age of patients was 67.38 ± 11.27 years. Of those, 46.9% had renal disease, 30.7% had a history of heart failure, and 17.1% had previous stroke or TIA. The average R2CHA2DS2-VA and CHA2DS2-VA scores were 3.92 ± 1.92 and 2.98 ± 1.43, respectively. Annual thromboembolic risk increased with incremental increase in R2CHA2DS2-VA and CHA2DS2-VA scores. Oral anticoagulants had benefit in stroke prevention in NVAF patients with an R2CHA2DS2-VA score of 2 or more (adjusted HR: 0.630, 95% CI 0.413–0.962, p = 0.032). The c-statistics were 0.630 (95% CI 0.61–0.65) and 0.627 (95% CI 0.61–0.64), for R2CHA2DS2-VA and CHA2DS2-VA scores respectively. NRI was 2.2%. The slope and R2 of the calibration plot were 0.73 and 0.905 for R2CHA2DS2-VA and 0.70 and 0.846 for CHA2DS2-VA score respectively. Conclusions R2CHA2DS2-VA score was found to be at least as good as CHA2DS2-VA score for predicting thromboembolism in Thai patients with NVAF. Similar to CHA2DS2-VA score, thromboembolism increased with incremental increase in R2CHA2DS2-VA score.

Atrial High‐Rate Episode Duration Thresholds and Thromboembolic Risk: A Systematic Review and Meta‐Analysis

Background Available evidence supports an association between atrial high‐rate episode (AHRE) burden and thromboembolic risk, but the necessary extent and duration of AHREs to increase the thromboembolic risk remain to be defined. The aim of this systematic review and meta‐analysis was to identify the thromboembolic risk associated with various AHRE thresholds. Methods and Results We searched PubMed and Scopus until January 9, 2020, for literature reporting AHRE duration and thromboembolic risk in patients with implantable electronic devices. The outcome assessed was stroke or systemic embolism. Risk estimates were reported as hazard ratio (HR) or relative risk alongside 95% CIs. We used the Paule‐Mandel estimator, and heterogeneity was calculated with I 2 index. Among 27 studies including 61 919 patients, 23 studies reported rates according to the duration of the longest AHRE and 4 studies reported rates according to the cumulative day‐level AHRE duration. In patients with cardiac implantable devices, AHREs lasting ≥30 seconds significantly increased the risk of stroke or systemic embolism (HR, 4.41; 95% CI, 2.32–8.39; I 2 , 5.5%), which remained consistent for the thresholds of 5 minutes and 6 and 24 hours. Patients with previous stroke or transient ischemic attack and AHREs lasting ≥2 minutes had a marginally increased risk of recurrent stroke or transient ischemic attack. The risk of stroke or systemic embolism was higher in patients with cumulative AHRE ≥24 hours compared with those of shorter duration or no AHRE (HR, 1.25; 95% CI, 1.04–1.52; I 2 , 0%). Conclusions This systematic review and meta‐analysis suggests that single AHRE episodes ≥30 seconds and cumulative AHRE duration ≥24 hours are associated with increased risk of stroke or systemic embolism.

COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US cohort

Introduction Infection with SARS-CoV-2 is typically compared with influenza to contextualize its health risks. SARS-CoV-2 has been linked with coagulation disturbances including arterial thrombosis, leading to considerable interest in antithrombotic therapy for Coronavirus Disease 2019 (COVID-19). However, the independent thromboembolic risk of SARS-CoV-2 infection compared with influenza remains incompletely understood. We evaluated the adjusted risks of thromboembolic events after a diagnosis of COVID-19 compared with influenza in a large retrospective cohort. Methods We used a US-based electronic health record (EHR) dataset linked with insurance claims to identify adults diagnosed with COVID-19 between April 1, 2020 and October 31, 2020. We identified influenza patients diagnosed between October 1, 2018 and April 31, 2019. Primary outcomes [venous composite of pulmonary embolism (PE) and acute deep vein thrombosis (DVT); arterial composite of ischemic stroke and myocardial infarction (MI)] and secondary outcomes were assessed 90 days post-diagnosis. Propensity scores (PS) were calculated using demographic, clinical, and medication variables. PS-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression. Results There were 417,975 COVID-19 patients (median age 57y, 61% women), and 345,934 influenza patients (median age 47y, 66% women). Compared with influenza, patients with COVID-19 had higher venous thromboembolic risk (HR 1.53, 95% CI 1.38-1.70), but not arterial thromboembolic risk (HR 1.02, 95% CI 0.95-1.10). Secondary analyses demonstrated similar risk for ischemic stroke (HR 1.11, 95% CI 0.98-1.25) and MI (HR 0.93, 95% CI 0.85-1.03) and higher risk for DVT (HR 1.36, 95% CI 1.19-1.56) and PE (HR 1.82, 95% CI 1.57-2.10) in patients with COVID-19. Conclusion In a large retrospective US cohort, COVID-19 was independently associated with higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared with influenza. These findings may inform crucial knowledge gaps regarding the specific thromboembolic risks of COVID-19.