BACKGROUND AND OBJECTIVES:The management of anticoagulation after ischemic stroke while on direct oral anticoagulants (DOACs) is controversial. We performed an aggregate-data meta-analysis to compare anticoagulation strategies against each other to define the effect of switch to warfarin, switch to another DOAC, change in dosage, and add-on antiplatelet for the prevention of recurrent stroke, intracranial hemorrhage (ICH), any stroke, and mortality. METHODS:The study protocol was deposited with PROSPERO (CRD42025639057). We systematically searched MEDLINE, Scopus, and the Cochrane Library-all studies reporting on anticoagulation strategies after a stroke while on DOAC up to January 31, 2025. We included randomized controlled clinical studies and cohort studies with sample size ≥50 that (1) enrolled adult patients who experienced ischemic stroke while on DOACs, (2) assessed modifications to anticoagulation therapy, and (3) reported on at least one of the outcomes. Main outcome was recurrent ischemic stroke; secondary outcomes were ICH, all-cause mortality, and any stroke. We pooled estimates by random-effects modelling, reporting risk ratio (RR) with 95% CIs comparing anticoagulation strategies against each other. RESULTS:We retrieved 2,171 results, with 8 observational studies reaching quantitative synthesis (n = 14,307 patients, mean age = 75 years, 48% female). Switching to warfarin was associated with a higher risk of ischemic stroke compared with keeping the same DOAC (RR 1.80, 95% CI 1.42-2.29, I2 = 0%, nstudies = 5) or changing DOAC dosage (RR 1.72, 95% CI 1.20-2.45, I2 = 0%, nstudies = 4). Switching to warfarin was also associated with higher ICH rates compared with keeping the same DOAC (RR 2.90, 95% CI 2.01-4.18, I2 = 0%, nstudies = 5) and DOAC-to-DOAC switch (RR 3.25, 95% CI 2.13-4.96, I2 = 0%; nstudies = 5). Keeping the same DOAC and switching to another DOAC, independently from mechanism, had similar rates of primary and secondary outcomes. DISCUSSION:Our meta-analysis indicates that switching to warfarin after a stroke while on DOAC seems less effective and safe in stroke recurrence prevention, ICH, and mortality compared with DOAC-based strategies.

Current data regarding the effect of intravenous thrombolysis (IVT) in patients with acute ischaemic stroke (AIS) with concomitant malignancy remain unclear. This study aimed to evaluate the efficacy and safety of IVT in patients with AIS and concomitant active cancer. The ITACA-stroke study was a retrospective observational study based on prospective registries of a multicentre international collaboration. Patients with a diagnosis of active cancer and AIS, treated or not with IVT, were enrolled. Multivariable logistic regression analysis was performed to identify independent predictors for functional outcomes (mortality and good functional outcome) and haemorrhagic events at 90 days. A propensity score matching (PSM) analysis compared IVT and no-IVT patients. A total of 521 patients were included, 225 were treated with IVT and 296 were not treated with IVT. IVT was directly correlated with good functional outcome (OR: 2.56, 95

Objectives: The optimal management of acute ischemic stroke (AIS) in patients with oral anticoagulation (OA) is challenging. Our study aimed to analyze the clinical characteristics and outcome of AIS in patients with OA for nonvalvular atrial fibrillation (NVAF). Methods: We retrospectively analyzed data on NVAF patients with AIS on direct oral anticoagulants (DOAC) or vitamin K antagonists (VKA) admitted to our Stroke Unit from 2017 to 2022. Ninety-day modified Rankin Scale (mRS), 90-day, and 12-month stroke recurrences were recorded. Results: A total of 169 patients (53.2% female, mean age 82.8±6.7 y), 117 (69.2%) on DOAC, and 52 on VKA (30.8%), were enrolled. Mean age, in-hospital mortality, and 90-day mRS ≥4 were significantly higher in VKA patients. 63.4% of VKA patients had subtherapeutic INR, whereas 47.1% of DOAC patients were on low-dose (14.2% off-label). Large vessel occlusion and embolic etiology were more frequent in VKA patients (34.6% vs. 26.4%, P=0.358; 92.3% vs. 74.3%, P=0.007, respectively), whereas lacunar strokes were more frequent in DOAC patients (19.8% vs. 12.2%, P=0.366). Among patients on VKA before AIS 86.4% were switched to DOAC, whereas a DOAC-to-VKA and a DOAC-to-DOAC switch were done in 25.4% and 11.7%, respectively. Stroke recurrence occurred in 6.4% of patients at 90 days and 10.7% at 12 months. Anticoagulant switching was not associated with stroke recurrences. Conclusions: In our study, nonembolic etiology was more frequent in DOAC patients and anticoagulant switching did not reduce the risk of stroke recurrence. Prospective multicentric studies are warranted.

Subclinical atrial fibrillation (SAF) represents the most prevalent underlying etiology detected after an embolic stroke of undetermined source (ESUS). Investigating SAF is strongly recommended during the diagnostic work-up. The efficacy of oral anticoagulant (OAC) therapy in reducing the risk of stroke recurrence post-SAF detection remains a conundrum. Thus, our study aimed to analyze the management of secondary antithrombotic prophylaxis and the rate of 12-month stroke recurrence in real-life ESUS patients. We retrospectively analyzed clinical, radiographic, and echocardiographic findings of patients with ESUS who underwent non-implantable 2-week electrocardiogram (ECG) monitoring after discharge. Episodes of SAF of any duration were considered diagnostic. Antithrombotic treatment at hospital discharge and after ECG monitoring, as well as 12-month recurrence, were registered. We compared the rate of stroke recurrence between patients with and without detection of SAF. One hundred and fifty-nine patients (75 females) with a median age of 73.5 (interquartile range [IQR] = 66.75 – 79) years represented the study population. At hospital discharge, 96.9% of patients received antiplatelet therapy as secondary antithrombotic prophylaxis. SAF was detected in 82 patients (51.5%), and OAC was prescribed in 98.6% of them. The median time from stroke onset to OAC prescription was 143 (IQR = 94 – 178) days. Overall, 12-month stroke recurrence occurred in eight patients (5%). The stroke recurrence rate was lower in patients prescribed OAC compared with those not prescribed it, although the difference was not significant (3.7% vs. 6.25%; P = 0.7202). In our study, OACs prescribed post-SAF detection in patients with ESUS reduced, but not significantly, the risk of stroke recurrence. Future research and prospective multicenter studies are warranted.

Introduction: The best therapeutic strategy for patients with mechanical heart valves (MHVs) having acute ischemic stroke during treatment with vitamin K antagonists (VKAs) remain unclear. Being so, we compared the outcomes for: (i) full dose heparin along with VKA (bridging therapy group) and (ii) restarting VKA without heparin (nonbridging group). Patients and methods: For this multicenter observational cohort study, data on consecutive acute ischemic stroke patients with MHV was retrospectively collected from prospective registries. Propensity score matching (PSM) was adopted to adjust for any treatment allocation confounders. The primary outcome was the composite of stroke, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding at 90 days. Results: Overall, 255 out of 603 patients (41.3%) received bridging therapy: 36 (14.1%) had combined outcome, compared with 28 (8.0%) in the nonbridging group (adjusted OR 1.83; 95% CI 1.05-3.18; p = 0.03). Within the bridging group, 13 patients (5.1%) compared to 12 (3.4%) in the nonbridging group had an ischemic outcome (adjusted OR 1.71; 95% CI 0.84-3.47; p = 0.2); major bleedings were recorded in 23 (9.0%) in the bridging group and 16 (4.6%) in the nonbridging group (adjusted OR 1.88; 95% CI 0.95-3.73; p = 0.07). After PSM, 36 (14.2%) of the 254 bridging patients had combined outcome, compared with 23 (9.1%) of 254 patients in the nonbridging group (OR 1.66; 95% CI 0.95-2.85; p = 0.07). Conclusion: Acute ischemic stroke patients with MHV undergoing bridging therapy had a marginally higher risk of ischemic or hemorrhagic events, compared to nonbridging patients.

BACKGROUND:Subclinical paroxysmal atrial fibrillation (AF) is one of the main occult causative mechanisms of embolic stroke of undetermined source (ESUS). Aim of this study was to identify AF predictors, and to develop a score to predict the probability of AF detection in ESUS.METHODS:We retrospectively analyzed ESUS patients undergoing 2-week external electrocardiographic monitoring. Patients with and without AF detection were compared. On the basis of multivariate analysis, predictors of AF were identified and used to develop a predictive score, which was then compared with other existing literature scores.RESULTS:Eighty-two patients, 48 females, mean age±SD 72±10 years, were included. In 36 patients (43.9%) AF was detected. The frequency of age 75 years or above and arterial hypertension, and the median CHA 2 DS 2 -VASc score were significantly higher in patients with AF compared with those without. National Institutes of Health Stroke Scale (NIHSS) score ≥8 was the only independent variable associated with AF detection. We derived the Empoli ESUS-AF (E 2 AF) score (NIHSS ≥8 5 points, arterial hypertension 3 points, age 75 years or above 2 points, age 65 to 74 years 1 point, history of coronary/peripheral artery disease 1 point, left atrial enlargement 1 point, posterior lesion 1 point, cortical or cortical-subcortical lesion 1 point), whose predictive power in detecting AF was good (area under the curve: 0.746, 95% confidence interval: 0.638-0.836) and higher than that of CHA 2 DS 2 -VASc and other scores.CONCLUSIONS:In our study NIHSS score ≥8 was the only independent predictor of post-ESUS-AF detection. The E 2 AF score appears to have a good predictive power for detecting AF. External validations are required.

Subclinical atrial fibrillation (SAF) is the primary underlying cause of cryptogenic stroke (CS) or embolic stroke of undetermined source (ESUS), particularly in patients over 65 years of age. Therefore, it is strongly recommended screening for SAF in these patients. The development of tools designed to determine the priority of SAF screening is essential for optimizing the diagnostic workup. The aim of our study was to investigate the clinical predictive scores available for SAF detection in patients with CS or ESUS. We gathered data from articles published on the PubMed database from January 1, 2000, to January 31, 2023. Our search yielded eight scores for CS and three for ESUS. SAF diagnosis was established using various methods: 12-lead ECG or 24-h ECG monitoring during 1-year follow-up in three scores; 72-h non-implantable ECG monitoring in two scores; 2 or 3-week non-implantable ECG monitoring in three scores; and implantable ECG monitoring in one score. In two scores, ECG monitoring was performed using a non-implantable and/or implantable loop recorder. Overall, the rate of SAF detection was approximately 6% when using devices for monitoring lasting no more than 72 h and increased to nearly 22% employing 2 or 3-week non-implantable or implantable devices. SAF was defined differently in various scores; five scores considered any episode, even if shorter than 30 s, while six scores required episodes to last at least 30 s. Advanced age was included as a variable in 10 of 11 scores, whereas left atrial enlargement, premature atrial beats, and brain computed tomography characteristics were features in four scores. The area under the curve values of these scores ranged from 0.72 to 0.94. In conclusion, it is still challenging to put the currently available clinical scores to use due to a lack of validation. To provide more comprehensive guidance, it is essential to conduct large prospective multicenter trials in the future.

BACKGROUND:Few data exists on predictive factors of hemorrhagic transformation (HT) in real-world acute ischemic stroke patients. The aims of this study were: (i) to identify predictive variables of HT (ii) to develop a score for predicting HT.METHODS:We retrospectively analyzed the clinical, radiographic, and laboratory data of patients with acute ischemic stroke consecutively admitted to our Stroke Unit along two years. Patients with HT were compared with those without HT. A multivariate logistic regression analysis was performed to identify independent predictors of HT on CT scan at 24 hours to develop a practical score.RESULTS:The study population consisted of 564 patients with mean age 77.5±11.8 years. Fifty-two patients (9.2%) showed HT on brain CT at 24 hours (4.9% symptomatic). NIHSS score ≥8 at Stroke Unit admission (3 points), cardioembolic etiology (2 points), acute revascularization by systemic thrombolysis and/or mechanical thrombectomy (1 point), history of previous TIA/stroke (1 point), and major vessel occlusion (1 point) were found independent risk factors of HT and were included in the score (Hemorrhagic Transformation Empoli score (HTE)). The predictive power of HTE score was good with an AUC of 0.785 (95% CI: 0.749-0.818). Compared with 5 HT predictive scores proposed in the literature (THRIVE, SPAN-100, MSS, GRASPS, SITS-SIC), the HTE score significantly better predicted HT.CONCLUSIONS:NIHSS score ≥8 at Stroke Unit admission, cardioembolism, urgent revascularization, previous TIA/stroke, and major vessel occlusion were independent predictors of HT. The HTE score has a good predictive power for HT. Prospective studies are warranted.

Masotti, Luca MD; Grifoni, Elisa MD; Baglini, Alessia MD; Sivieri, Irene MD; Mannini, Marianna MD; Iandoli, Gina MD; Madonia, Elisa Maria MD; Cosentino, Eleonora MD; Micheletti, Irene MD; Signorini, Ira MD; Cioni, Elisa MD; Sansone, Teresa MD; Pelagalli, Giulia MD; Baldini, Mariella MD; Giannoni, Sara MD; Bertini, Elisabetta MD; Di Donato, Ilaria MD Author Information

Dear editorCytokine antagonists are now concrete therapeutic options in patients with severe SARS-CoV2 respiratory failure. The Interleukin-6 (IL-6) inhibitor tocilizumab (TCZ) has shown to significantly reduce the 30-day mortality risk and the risk of mechanical ventilation, without increasing the risk of infection and/or adverse events [[1]Luo L. Luo T. Du M. Mei H. Hu Y. Efficacy and safety of tocilizumab in hospitalized COVID-19 patients: a systematic review and meta-analysis.J Infect. 2021; (00557-0): S0163-S4453https://doi.org/10.1016/j.jinf.2021.11.013Abstract Full Text Full Text PDF Scopus (7) Google Scholar]. However, 30-day mortality in patients treated with TCZ remain of about 25% [[1]Luo L. Luo T. Du M. Mei H. Hu Y. Efficacy and safety of tocilizumab in hospitalized COVID-19 patients: a systematic review and meta-analysis.J Infect. 2021; (00557-0): S0163-S4453https://doi.org/10.1016/j.jinf.2021.11.013Abstract Full Text Full Text PDF Scopus (7) Google Scholar]. Predictors of tocilizumab failure in SARs-CoV2 patients are uncertain. To tail treatment on single patient based on his or her inflammatory status could improve the rate of success, as highlighted by Levi M in a recent issue of European Journal of Internal Medicine [[2]Levi M. Tocilizumab in severe COVID-19: a promise fulfilled.Eur J Intern Med. 2022; 95: 38-39https://doi.org/10.1016/j.ejim.2021.11.015Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. Evidence shows that the response to TCZ in this context is associated with restoration of thrombo-inflammation biomarkers after its administration [[3]Di Nisio M. Potere N. Candeloro M. et al.Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19.Eur J Intern Med. 2021; 83: 34-38https://doi.org/10.1016/j.ejim.2020.10.020Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar], while persistence of high biomarkers after TCZ administration seems to be associated with poor outcome [[4]Lakatos B. Szabo B.G. Bobek I. et al.Laboratory parameters predicting mortality of adult in-patients with COVID-19 associated cytokine release syndrome treated with high-dose tocilizumab.Acta Microbiol Immunol Hung. 2021; https://doi.org/10.1556/030.2021.01526Crossref Scopus (6) Google Scholar]. Recently, Emre Eskazan A. et al. found that platelets count ≤ 147 × 109/L, procalcitonin ≥ 0.35 ng/mL, room air oxygen saturation ≤ 91.5%, D-Dimer ≥ 2520 microg/L and time from symptoms to TCZ administration > 12 days are independent variables associated with 28-day mortality. Therefore they proposed the CERRAHPASA score, ranging from 0 to 107 points, as a prognostic tool aimed to predict 28-day mortality in severe COVID-19 treated by TCZ with an area under receiver operating characteristics curve (AUROC) of 0.954 (95% CI: 0.908–0.999) [[5]Eşkazan A.E. Balkan İ.İ. Demirbaş K.C. et al.Tocilizumab in COVID-19: the Cerrahpaşa-PREDICT score.J Infect Chemother. 2021; 27: 1329-1335https://doi.org/10.1016/j.jiac.2021.05.007Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. In another study, Mussini C et al. identified sex, paO2/FiO2 ratio (P/F) after 96 h from TCZ administration, platelets count and C-reactive protein (CRP) as independent risk factors for TCZ failure and associated with 28-day mortality and mechanical ventilation [[6]Mussini C. Cozzi-Lepri A. Menozzi M. et al.Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection.PLoS One. 2021; 16e0247275https://doi.org/10.1371/journal.pone.0247275Crossref Scopus (3) Google Scholar]. Combining these variables, the Authors proposed a predictive score with an AUROC of 0.80 [[6]Mussini C. Cozzi-Lepri A. Menozzi M. et al.Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection.PLoS One. 2021; 16e0247275https://doi.org/10.1371/journal.pone.0247275Crossref Scopus (3) Google Scholar]. External validations of CERRAHPASA score and the score proposed by Mussini C et al. lack, therefore we retrospectively analyzed data records of patients admitted in non intensive wards of our hospital and suffering from severe respiratory failure who were treated by TCZ aimed to provide evidence about this issue and to evaluate whether these scores were superior to biomarkers of thrombo-inflammation measured after a time ranging from 72 to 96 h from TCZ administration. Our study population was composed by one hundred and seven patients (77 males and 30 females) with mean age ± SD 64.5 ± 12.8 years. Seventeen patients (15.8%) died during hospital stay, while ten patients received oro-tracheal intubation. Mean age and mean procalcitonin values at hospital arrival in patients who died were significantly higher compared with that of survivors, while mean room air oxygen saturation at hospital arrival was significantly lower in patients who died compared with patients who did not. No difference between groups was found in sex and in the means of P/F ratio at hospital admission and at the time of TCZ administration, time from symptoms onset to TCZ administration, mean CERRAHPASA and MUSSINI scores, mean Neutrophils to Lymphocytes (Neu/Lym) ratio, D-Dimer and CRP at hospital admission (Table 1). After 72–96 h from TCZ administration, mean values of CRP were significantly lower compared with those at hospital admission, both in died patients and in survivors, while no significant difference was found in mean Neu/Lym ratio and D-Dimer values between hospital admission and after 72–96 h from TCZ. At this time, mean Neu/Lym ratio was significantly higher in patients who died compared with that of survivors, while no significant difference between died patients and survivors was found for D-Dimer and CRP values (Table 2). Predictive power of CERRAHPASA and MUSSINI scores as mortality prognosticators were low with an AUROC of 0.517 (95%CI: 0,417–0,615) and 0.613 (95% CI: 0.495–0.723) respectively (difference between areas 0.0668, p = 0.5575). No difference was found in the predictive power of CERRAHPASA score when compared with those of Neu/Lym ratio, D-Dimer and CRP measured at hospital admission, while the predictive power of CERRAHPASA score was significantly lower compared with those of Neu/Lym ratio (AUROC 0.802, 95%CI: 0,713 to 0,873; difference between areas 0.285, 95% CI: 0.120–0.451, p = 0.0007) and D-Dimer (AUROC 0.697, 95%CI: 0,600–0,783; difference between areas 0.181, 95% CI: 0.00162–0.360, p = 0.0480), but not CRP (AUROC 0.579, 95% CI: 0.479–0.674; difference between areas 0.0621, 95% CI: −0.121–0.245, p = 0.5049) measured after 72–96 h from TCZ administration. No significative difference was found between MUSSINI score and biomarkers measured after 72–96 h from TCZ administration, despite Neu/Lym ratio and D-Dimer showed higher predictive power compared with MUSSINI score. At this time, the predictive power of Neu/Lym ratio was significantly higher compared with that of CRP (difference between AUROCS 0.223, 95% CI: 0.0921–0.354, p = 0.0008) (Table 3).Table 1Characteristic of study population.TotalDeadAlivepNumber1071790F/M30/775/1225/651.000Mean age ± SD (years)64.5 ± 12.874.0 ± 9.062.7 ± 12.70.0002Mean room air oxygen saturation (%) ± SD91.0 ± 4.388.6 ± 6.491.5 ± 3.60.0095Mean P/F at hospital admission ± SD260.0 ± 71.4246.0 ± 73.0264.2 ± 71.00.3420Mean P/F at the TCZ administration ± SD134.8 ± 36.2120.3 ± 38.8137.2 ± 35.40.0728Mean time from symptoms to TCZ administration ± SD (days)7.9 ± 3.27.9 ± 2.77.9 ± 3.31.000Mean Neu/Lym ratio ± SD at hospital admission13.8 ± 38.113.7 ± 23.113.9 ± 40.50.9841Mean Neu/Lym ratio ± SD after 72–96 h from TCZ8.49 ± 10.818.6 ± 20.46.5 ± 6.2<0.0001Mean d-Dimer ± SD at hospital admission (microg/L)1212.3 ± 2577.41123.8 ± 677.61228.9 ± 2797.30.8784Mean d-Dimer ± SD after 72–96 h from TCZ (microg/L)2906.35 ± 6554.02787.5 ± 3346.82928.8 ± 7010.20.9356Mean CRP ± SD at hospital admission (mg/dL)8.72 ± 5.349.0 ± 6.08.6 ± 5.20.7771Mean CRP ± SD after 72–96 h from TCZ (mg/dL)1.24 ± 1.491.34 ± 1.351.22 ± 1.520.7621Mean procalcitonin ± SD at hospital admission (ng/mL)0.28 ± 0.730.78 ± 1.710.20 ± 0.330.0045Mean platelets count ± SD at hospital admission x 10^3/μL207.1 ± 79.8182.6 ± 73.4211.8 ± 80.50.1679Mean CERRAHPASA score19.9 ± 18.022.0 ± 19.319.5 ± 17.90.6020Mean MUSSINI score10.2 ± 3.911.5 ± 3.610.1 ± 3.90.1727 Open table in a new tab Table 2Comparison of thrombo-inflammation biomarkers at hospital arrival and after Tocilizumab administration.TotalDeadSurvivorsAt hospital admissionAfter 72-96 h from TCZ administrationpAt hospital admissionAfter 72–96 h from TCZ administrationpAt hospital admissionAfter 72–96 h from TCZ administrationpMean Neu/Lym ratio ± SD13.8 ± 38.18.49 ± 10.80.255513.7 ± 23.118.6 ± 20.4p = 0.367813.9 ± 40.56.5 ± 6.2p = 0.0953Mean d-Dimer ± SD (microg/L)1212.3 ± 2577.42906.35 ± 6554.00.29741123.8 ± 677.62787.5 ± 3346.8p = 0.05851228.9 ± 2797.32928.8 ± 7010.2p = 0.3283Mean CRP ± SD (mg/dL)8.72 ± 5.341.24 ± 1.49<0.00019.0 ± 6.01.34 ± 1.35p < 0.00018.6 ± 5.21.22 ± 1.52P < 0.0001 Open table in a new tab Table 3Predictive power of CERRAHPASA and MUSSINI scores compared with thrombo-inflammation biomarkers measured after 72–96 h from TCZ administration.At hospital admissionAfter 72–96 h from TCZ administrationVariableAUROCStandard Error95% CIAUROCStandard Error95% CICERRAHPASA score0,5170,07340,417–0,615MUSSINI score0.6130.09130.495–0.723D-DIMER0.5780.08280,478–0,6730,6970,06260,600–0,783C-reactive protein0.5050.08480,406–0,6030,5790,06720,479–0,674Neu-Lym ratio0.5050.07840,406–0,6040,8020,05600,713–0,873 Open table in a new tab Predicting the response to TCZ in SARS-CoV2 patients suffering from severe respiratory failure is of utmost importance in clinical practice. Despite CERRAHPASA and MUSSINI scores promise to be good prediction tools, in our study population their predictive power resulted low and lower compared with those of Neu/Lym ratio and D-Dimer measured after 72–96 h from TCZ administration.Monitoring thrombo-inflammation biomarkers after TCZ administration could be useful for risk stratification of patients treated by TCZ. Further prospective studies are warranted. Dear editorCytokine antagonists are now concrete therapeutic options in patients with severe SARS-CoV2 respiratory failure. The Interleukin-6 (IL-6) inhibitor tocilizumab (TCZ) has shown to significantly reduce the 30-day mortality risk and the risk of mechanical ventilation, without increasing the risk of infection and/or adverse events [[1]Luo L. Luo T. Du M. Mei H. Hu Y. Efficacy and safety of tocilizumab in hospitalized COVID-19 patients: a systematic review and meta-analysis.J Infect. 2021; (00557-0): S0163-S4453https://doi.org/10.1016/j.jinf.2021.11.013Abstract Full Text Full Text PDF Scopus (7) Google Scholar]. However, 30-day mortality in patients treated with TCZ remain of about 25% [[1]Luo L. Luo T. Du M. Mei H. Hu Y. Efficacy and safety of tocilizumab in hospitalized COVID-19 patients: a systematic review and meta-analysis.J Infect. 2021; (00557-0): S0163-S4453https://doi.org/10.1016/j.jinf.2021.11.013Abstract Full Text Full Text PDF Scopus (7) Google Scholar]. Predictors of tocilizumab failure in SARs-CoV2 patients are uncertain. To tail treatment on single patient based on his or her inflammatory status could improve the rate of success, as highlighted by Levi M in a recent issue of European Journal of Internal Medicine [[2]Levi M. Tocilizumab in severe COVID-19: a promise fulfilled.Eur J Intern Med. 2022; 95: 38-39https://doi.org/10.1016/j.ejim.2021.11.015Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. Evidence shows that the response to TCZ in this context is associated with restoration of thrombo-inflammation biomarkers after its administration [[3]Di Nisio M. Potere N. Candeloro M. et al.Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19.Eur J Intern Med. 2021; 83: 34-38https://doi.org/10.1016/j.ejim.2020.10.020Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar], while persistence of high biomarkers after TCZ administration seems to be associated with poor outcome [[4]Lakatos B. Szabo B.G. Bobek I. et al.Laboratory parameters predicting mortality of adult in-patients with COVID-19 associated cytokine release syndrome treated with high-dose tocilizumab.Acta Microbiol Immunol Hung. 2021; https://doi.org/10.1556/030.2021.01526Crossref Scopus (6) Google Scholar]. Recently, Emre Eskazan A. et al. found that platelets count ≤ 147 × 109/L, procalcitonin ≥ 0.35 ng/mL, room air oxygen saturation ≤ 91.5%, D-Dimer ≥ 2520 microg/L and time from symptoms to TCZ administration > 12 days are independent variables associated with 28-day mortality. Therefore they proposed the CERRAHPASA score, ranging from 0 to 107 points, as a prognostic tool aimed to predict 28-day mortality in severe COVID-19 treated by TCZ with an area under receiver operating characteristics curve (AUROC) of 0.954 (95% CI: 0.908–0.999) [[5]Eşkazan A.E. Balkan İ.İ. Demirbaş K.C. et al.Tocilizumab in COVID-19: the Cerrahpaşa-PREDICT score.J Infect Chemother. 2021; 27: 1329-1335https://doi.org/10.1016/j.jiac.2021.05.007Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. In another study, Mussini C et al. identified sex, paO2/FiO2 ratio (P/F) after 96 h from TCZ administration, platelets count and C-reactive protein (CRP) as independent risk factors for TCZ failure and associated with 28-day mortality and mechanical ventilation [[6]Mussini C. Cozzi-Lepri A. Menozzi M. et al.Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection.PLoS One. 2021; 16e0247275https://doi.org/10.1371/journal.pone.0247275Crossref Scopus (3) Google Scholar]. Combining these variables, the Authors proposed a predictive score with an AUROC of 0.80 [[6]Mussini C. Cozzi-Lepri A. Menozzi M. et al.Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection.PLoS One. 2021; 16e0247275https://doi.org/10.1371/journal.pone.0247275Crossref Scopus (3) Google Scholar]. External validations of CERRAHPASA score and the score proposed by Mussini C et al. lack, therefore we retrospectively analyzed data records of patients admitted in non intensive wards of our hospital and suffering from severe respiratory failure who were treated by TCZ aimed to provide evidence about this issue and to evaluate whether these scores were superior to biomarkers of thrombo-inflammation measured after a time ranging from 72 to 96 h from TCZ administration. Our study population was composed by one hundred and seven patients (77 males and 30 females) with mean age ± SD 64.5 ± 12.8 years. Seventeen patients (15.8%) died during hospital stay, while ten patients received oro-tracheal intubation. Mean age and mean procalcitonin values at hospital arrival in patients who died were significantly higher compared with that of survivors, while mean room air oxygen saturation at hospital arrival was significantly lower in patients who died compared with patients who did not. No difference between groups was found in sex and in the means of P/F ratio at hospital admission and at the time of TCZ administration, time from symptoms onset to TCZ administration, mean CERRAHPASA and MUSSINI scores, mean Neutrophils to Lymphocytes (Neu/Lym) ratio, D-Dimer and CRP at hospital admission (Table 1). After 72–96 h from TCZ administration, mean values of CRP were significantly lower compared with those at hospital admission, both in died patients and in survivors, while no significant difference was found in mean Neu/Lym ratio and D-Dimer values between hospital admission and after 72–96 h from TCZ. At this time, mean Neu/Lym ratio was significantly higher in patients who died compared with that of survivors, while no significant difference between died patients and survivors was found for D-Dimer and CRP values (Table 2). Predictive power of CERRAHPASA and MUSSINI scores as mortality prognosticators were low with an AUROC of 0.517 (95%CI: 0,417–0,615) and 0.613 (95% CI: 0.495–0.723) respectively (difference between areas 0.0668, p = 0.5575). No difference was found in the predictive power of CERRAHPASA score when compared with those of Neu/Lym ratio, D-Dimer and CRP measured at hospital admission, while the predictive power of CERRAHPASA score was significantly lower compared with those of Neu/Lym ratio (AUROC 0.802, 95%CI: 0,713 to 0,873; difference between areas 0.285, 95% CI: 0.120–0.451, p = 0.0007) and D-Dimer (AUROC 0.697, 95%CI: 0,600–0,783; difference between areas 0.181, 95% CI: 0.00162–0.360, p = 0.0480), but not CRP (AUROC 0.579, 95% CI: 0.479–0.674; difference between areas 0.0621, 95% CI: −0.121–0.245, p = 0.5049) measured after 72–96 h from TCZ administration. No significative difference was found between MUSSINI score and biomarkers measured after 72–96 h from TCZ administration, despite Neu/Lym ratio and D-Dimer showed higher predictive power compared with MUSSINI score. At this time, the predictive power of Neu/Lym ratio was significantly higher compared with that of CRP (difference between AUROCS 0.223, 95% CI: 0.0921–0.354, p = 0.0008) (Table 3).Table 1Characteristic of study population.TotalDeadAlivepNumber1071790F/M30/775/1225/651.000Mean age ± SD (years)64.5 ± 12.874.0 ± 9.062.7 ± 12.70.0002Mean room air oxygen saturation (%) ± SD91.0 ± 4.388.6 ± 6.491.5 ± 3.60.0095Mean P/F at hospital admission ± SD260.0 ± 71.4246.0 ± 73.0264.2 ± 71.00.3420Mean P/F at the TCZ administration ± SD134.8 ± 36.2120.3 ± 38.8137.2 ± 35.40.0728Mean time from symptoms to TCZ administration ± SD (days)7.9 ± 3.27.9 ± 2.77.9 ± 3.31.000Mean Neu/Lym ratio ± SD at hospital admission13.8 ± 38.113.7 ± 23.113.9 ± 40.50.9841Mean Neu/Lym ratio ± SD after 72–96 h from TCZ8.49 ± 10.818.6 ± 20.46.5 ± 6.2<0.0001Mean d-Dimer ± SD at hospital admission (microg/L)1212.3 ± 2577.41123.8 ± 677.61228.9 ± 2797.30.8784Mean d-Dimer ± SD after 72–96 h from TCZ (microg/L)2906.35 ± 6554.02787.5 ± 3346.82928.8 ± 7010.20.9356Mean CRP ± SD at hospital admission (mg/dL)8.72 ± 5.349.0 ± 6.08.6 ± 5.20.7771Mean CRP ± SD after 72–96 h from TCZ (mg/dL)1.24 ± 1.491.34 ± 1.351.22 ± 1.520.7621Mean procalcitonin ± SD at hospital admission (ng/mL)0.28 ± 0.730.78 ± 1.710.20 ± 0.330.0045Mean platelets count ± SD at hospital admission x 10^3/μL207.1 ± 79.8182.6 ± 73.4211.8 ± 80.50.1679Mean CERRAHPASA score19.9 ± 18.022.0 ± 19.319.5 ± 17.90.6020Mean MUSSINI score10.2 ± 3.911.5 ± 3.610.1 ± 3.90.1727 Open table in a new tab Table 2Comparison of thrombo-inflammation biomarkers at hospital arrival and after Tocilizumab administration.TotalDeadSurvivorsAt hospital admissionAfter 72-96 h from TCZ administrationpAt hospital admissionAfter 72–96 h from TCZ administrationpAt hospital admissionAfter 72–96 h from TCZ administrationpMean Neu/Lym ratio ± SD13.8 ± 38.18.49 ± 10.80.255513.7 ± 23.118.6 ± 20.4p = 0.367813.9 ± 40.56.5 ± 6.2p = 0.0953Mean d-Dimer ± SD (microg/L)1212.3 ± 2577.42906.35 ± 6554.00.29741123.8 ± 677.62787.5 ± 3346.8p = 0.05851228.9 ± 2797.32928.8 ± 7010.2p = 0.3283Mean CRP ± SD (mg/dL)8.72 ± 5.341.24 ± 1.49<0.00019.0 ± 6.01.34 ± 1.35p < 0.00018.6 ± 5.21.22 ± 1.52P < 0.0001 Open table in a new tab Table 3Predictive power of CERRAHPASA and MUSSINI scores compared with thrombo-inflammation biomarkers measured after 72–96 h from TCZ administration.At hospital admissionAfter 72–96 h from TCZ administrationVariableAUROCStandard Error95% CIAUROCStandard Error95% CICERRAHPASA score0,5170,07340,417–0,615MUSSINI score0.6130.09130.495–0.723D-DIMER0.5780.08280,478–0,6730,6970,06260,600–0,783C-reactive protein0.5050.08480,406–0,6030,5790,06720,479–0,674Neu-Lym ratio0.5050.07840,406–0,6040,8020,05600,713–0,873 Open table in a new tab Predicting the response to TCZ in SARS-CoV2 patients suffering from severe respiratory failure is of utmost importance in clinical practice. Despite CERRAHPASA and MUSSINI scores promise to be good prediction tools, in our study population their predictive power resulted low and lower compared with those of Neu/Lym ratio and D-Dimer measured after 72–96 h from TCZ administration.Monitoring thrombo-inflammation biomarkers after TCZ administration could be useful for risk stratification of patients treated by TCZ. Further prospective studies are warranted. Cytokine antagonists are now concrete therapeutic options in patients with severe SARS-CoV2 respiratory failure. The Interleukin-6 (IL-6) inhibitor tocilizumab (TCZ) has shown to significantly reduce the 30-day mortality risk and the risk of mechanical ventilation, without increasing the risk of infection and/or adverse events [[1]Luo L. Luo T. Du M. Mei H. Hu Y. Efficacy and safety of tocilizumab in hospitalized COVID-19 patients: a systematic review and meta-analysis.J Infect. 2021; (00557-0): S0163-S4453https://doi.org/10.1016/j.jinf.2021.11.013Abstract Full Text Full Text PDF Scopus (7) Google Scholar]. However, 30-day mortality in patients treated with TCZ remain of about 25% [[1]Luo L. Luo T. Du M. Mei H. Hu Y. Efficacy and safety of tocilizumab in hospitalized COVID-19 patients: a systematic review and meta-analysis.J Infect. 2021; (00557-0): S0163-S4453https://doi.org/10.1016/j.jinf.2021.11.013Abstract Full Text Full Text PDF Scopus (7) Google Scholar]. Predictors of tocilizumab failure in SARs-CoV2 patients are uncertain. To tail treatment on single patient based on his or her inflammatory status could improve the rate of success, as highlighted by Levi M in a recent issue of European Journal of Internal Medicine [[2]Levi M. Tocilizumab in severe COVID-19: a promise fulfilled.Eur J Intern Med. 2022; 95: 38-39https://doi.org/10.1016/j.ejim.2021.11.015Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. Evidence shows that the response to TCZ in this context is associated with restoration of thrombo-inflammation biomarkers after its administration [[3]Di Nisio M. Potere N. Candeloro M. et al.Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19.Eur J Intern Med. 2021; 83: 34-38https://doi.org/10.1016/j.ejim.2020.10.020Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar], while persistence of high biomarkers after TCZ administration seems to be associated with poor outcome [[4]Lakatos B. Szabo B.G. Bobek I. et al.Laboratory parameters predicting mortality of adult in-patients with COVID-19 associated cytokine release syndrome treated with high-dose tocilizumab.Acta Microbiol Immunol Hung. 2021; https://doi.org/10.1556/030.2021.01526Crossref Scopus (6) Google Scholar]. Recently, Emre Eskazan A. et al. found that platelets count ≤ 147 × 109/L, procalcitonin ≥ 0.35 ng/mL, room air oxygen saturation ≤ 91.5%, D-Dimer ≥ 2520 microg/L and time from symptoms to TCZ administration > 12 days are independent variables associated with 28-day mortality. Therefore they proposed the CERRAHPASA score, ranging from 0 to 107 points, as a prognostic tool aimed to predict 28-day mortality in severe COVID-19 treated by TCZ with an area under receiver operating characteristics curve (AUROC) of 0.954 (95% CI: 0.908–0.999) [[5]Eşkazan A.E. Balkan İ.İ. Demirbaş K.C. et al.Tocilizumab in COVID-19: the Cerrahpaşa-PREDICT score.J Infect Chemother. 2021; 27: 1329-1335https://doi.org/10.1016/j.jiac.2021.05.007Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. In another study, Mussini C et al. identified sex, paO2/FiO2 ratio (P/F) after 96 h from TCZ administration, platelets count and C-reactive protein (CRP) as independent risk factors for TCZ failure and associated with 28-day mortality and mechanical ventilation [[6]Mussini C. Cozzi-Lepri A. Menozzi M. et al.Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection.PLoS One. 2021; 16e0247275https://doi.org/10.1371/journal.pone.0247275Crossref Scopus (3) Google Scholar]. Combining these variables, the Authors proposed a predictive score with an AUROC of 0.80 [[6]Mussini C. Cozzi-Lepri A. Menozzi M. et al.Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection.PLoS One. 2021; 16e0247275https://doi.org/10.1371/journal.pone.0247275Crossref Scopus (3) Google Scholar]. External validations of CERRAHPASA score and the score proposed by Mussini C et al. lack, therefore we retrospectively analyzed data records of patients admitted in non intensive wards of our hospital and suffering from severe respiratory failure who were treated by TCZ aimed to provide evidence about this issue and to evaluate whether these scores were superior to biomarkers of thrombo-inflammation measured after a time ranging from 72 to 96 h from TCZ administration. Our study population was composed by one hundred and seven patients (77 males and 30 females) with mean age ± SD 64.5 ± 12.8 years. Seventeen patients (15.8%) died during hospital stay, while ten patients received oro-tracheal intubation. Mean age and mean procalcitonin values at hospital arrival in patients who died were significantly higher compared with that of survivors, while mean room air oxygen saturation at hospital arrival was significantly lower in patients who died compared with patients who did not. No difference between groups was found in sex and in the means of P/F ratio at hospital admission and at the time of TCZ administration, time from symptoms onset to TCZ administration, mean CERRAHPASA and MUSSINI scores, mean Neutrophils to Lymphocytes (Neu/Lym) ratio, D-Dimer and CRP at hospital admission (Table 1). After 72–96 h from TCZ administration, mean values of CRP were significantly lower compared with those at hospital admission, both in died patients and in survivors, while no significant difference was found in mean Neu/Lym ratio and D-Dimer values between hospital admission and after 72–96 h from TCZ. At this time, mean Neu/Lym ratio was significantly higher in patients who died compared with that of survivors, while no significant difference between died patients and survivors was found for D-Dimer and CRP values (Table 2). Predictive power of CERRAHPASA and MUSSINI scores as mortality prognosticators were low with an AUROC of 0.517 (95%CI: 0,417–0,615) and 0.613 (95% CI: 0.495–0.723) respectively (difference between areas 0.0668, p = 0.5575). No difference was found in the predictive power of CERRAHPASA score when compared with those of Neu/Lym ratio, D-Dimer and CRP measured at hospital admission, while the predictive power of CERRAHPASA score was significantly lower compared with those of Neu/Lym ratio (AUROC 0.802, 95%CI: 0,713 to 0,873; difference between areas 0.285, 95% CI: 0.120–0.451, p = 0.0007) and D-Dimer (AUROC 0.697, 95%CI: 0,600–0,783; difference between areas 0.181, 95% CI: 0.00162–0.360, p = 0.0480), but not CRP (AUROC 0.579, 95% CI: 0.479–0.674; difference between areas 0.0621, 95% CI: −0.121–0.245, p = 0.5049) measured after 72–96 h from TCZ administration. No significative difference was found between MUSSINI score and biomarkers measured after 72–96 h from TCZ administration, despite Neu/Lym ratio and D-Dimer showed higher predictive power compared with MUSSINI score. At this time, the predictive power of Neu/Lym ratio was significantly higher compared with that of CRP (difference between AUROCS 0.223, 95% CI: 0.0921–0.354, p = 0.0008) (Table 3). Predicting the response to TCZ in SARS-CoV2 patients suffering from severe respiratory failure is of utmost importance in clinical practice. Despite CERRAHPASA and MUSSINI scores promise to be good prediction tools, in our study population their predictive power resulted low and lower compared with those of Neu/Lym ratio and D-Dimer measured after 72–96 h from TCZ administration. Monitoring thrombo-inflammation biomarkers after TCZ administration could be useful for risk stratification of patients treated by TCZ. Further prospective studies are warranted. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

INTRODUCTION:Despite Tocilizumab is now recognized as a concrete therapeutic option in patients with severe SARS-CoV-2 related respiratory failure, literature lacks about factors influencing the response to it in this context. Therefore, the aim of our study was to provide evidence about predictors of poor outcome in Tocilizumab treated patients in the real-world practice.MATERIALS AND METHODS:We retrospectively analyzed clinical, laboratory and chest computer tomography (CCT) data of patients firstly admitted in non Intensive Care Units (ICU) and suffering from severe respiratory failure, who were treated with the IL-6 antagonist Tocilizumab. We compared patients who died and/or required admission to ICU with oro-tracheal intubation (OTI) with those who did not.RESULTS:Two hundreds and eighty-seven patients (29.9% females) with mean age ± SD 64.1 ± 12.6 years were the study population. In-hospital mortality was 18.8%, while the composite endpoint in-hospital mortality and/or ICU admission with OTI occurred in 23.7%. At univariate analysis, patients who died and/or were admitted to ICU with OTI were significantly older and co-morbid, had significantly higher values of creatinine, C-reactive protein (CRP) and procalcitonin and lower lymphocytes count, PaO2/FiO2 ratio (P/F) and room air pulsossimetry oxygen saturation (RAO2S) at hospital admission. Computed tomography ground glass opacities (CT-GGO) involving the pulmonary surface ≥ 50% were found in 55.4% of patients who died and/or were admitted to ICU with OTI and in 21.5% of patients who did not (p=0.0001). At multivariate analysis, age ≥ 65 years (OR 17.3, 95% CI: 3.7-81.0), procalcitonin ≥ 0.14 (OR 9.9, 95%CI: 1.7-56.1), RAO2S ≤ 90% (OR 4.6, 95%CI: 1.2-17.0) and CCT-GGO involvement ≥ 50% (OR 5.1, 95%CI: 1.2-21.0) were independent risk factors associated with death and/or ICU admission with OTI.CONCLUSION:Tocilizumab has shown to improve outcome in patients with severe respiratory failure associated to SARS-CoV-2 related pneumonia. In our multicentre study focusing on Tocilizumab treated severe COVID-19 patients, age ≥ 65 years, procalcitonin ≥ 0.14 ng/mL, RAO2S ≤ 90% and CCT-GGO involvement ≥ 50% were independent factors associated with poor outcome.

Background Coronavirus disease 2019 (COVID-19) infection causes acute respiratory insufficiency with severe interstitial pneumonia and extrapulmonary complications; in particular, it may predispose to thromboembolic disease. The reported incidence of thromboembolic complications varies from 5 to 30% of cases. Aim We conducted a multicenter, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe the clinical characteristics of patients at admission and bleeding and thrombotic events occurring during the hospital stay. Results The number of hospitalized patients included in the START-COVID-19 Register was 1,135, and the number of hospitalized patients in ordinary wards included in the study was 1,091, with 653 (59.9%) being males and 71 years (interquartile range 59–82 years) being the median age. During the observation, two (0.2%) patients had acute coronary syndrome episodes and one patient (0.1%) had an ischemic stroke; no other arterial thrombotic events were recorded. Fifty-nine patients had symptomatic venous thromboembolism (VTE) (5.4%) events, 18 (30.5%) deep vein thrombosis (DVT), 39 (66.1%) pulmonary embolism (PE), and 2 (3.4%) DVT+PE. Among patients with DVT, eight (44.4%) were isolated distal DVT and two cases were jugular thrombosis. Among patients with PE, seven (17.9%) events were limited to subsegmental arteries. No fatal PE was recorded. Major bleeding events occurred in nine (1.2%) patients and clinically relevant nonmajor bleeding events in nine (1.2%) patients. All bleeding events occurred among patients receiving thromboprophylaxis, more frequently when treated with subtherapeutic or therapeutic dosages. Conclusion Our findings confirm that patients admitted to ordinary wards for COVID-19 infection are at high risk for thromboembolic events. VTE recorded among these patients is mainly isolated PE, suggesting a peculiar characteristic of VTE in these patients.

Introduction: Searching paroxysmal atrial fibrillation (PAF) is fundamental and strongly recommended in patients suffering from cryptogenic stroke or embolic stroke of undetermined source (ESUS). In the latest years some prediction scores for detecting post-stroke PAF have been proposed, such as Brown-AF and AS5F. However, external validations lack. The aim of the present study was to analyze the predictive power of AS5F and Brown-AF scores and compare them with the CHA2DS2-VASc score. Materials and Methods We analyzed demographic, clinical, trans-thoracic echocardiography and brain computer tomography characteristics of patients with ESUS undergone to two weeks external ECG monitoring after hospital discharge. PAF was considered detected when any evidence of AF and/or atrial flutter occurred at monitoring. For each patient we calculated the Brown-AF, AS5F and CHA2DS2-VASc scores and we analyzed and compared their predictive power by using area under the Receiver Operating Curve (AUROC). Results: Eighty-two consecutive ESUS patients with mean age ± SD 72 ± 10 years were the study population. Overall, PAF was detected in 43.9% of patients. PAF detection increased from 18.75% of patients with Brown ESUS-AF score 0 to 54.3% of patients with Brown ESUS-AF score ≥ 2. PAF was detected in 37.2% of patients with AS5F < 67.5 and 51.2% of patients with AS5F score ≥ 67.5. AUROC of Brown ESUS-AF score in predicting AF detection was 0.642 (95% CI: 0.528-0.745), while AUROC of AS5F was 0.618 (95% CI: 0.504-0.723)(p=0.6872). No difference between predictive power of Brown ESUS-AF and AS5F scores with CHA2DS2-VASc (AUROC 0.671, 95% CI: 0.559-0.771) was found. Conclusion: Both Brown ESUS-AF and AS5F scores could be used as a screening tool for selecting ESUS patients requiring prolonged ECG monitoring aimed to detect PAF. However, in our study their predictive power was quite low and not superior to that of CHA2DS2-VASc score.

Introduction  Few data exist on the use of edoxaban in cancer-associated venous thromboembolism (VTE) outside of clinical trials. Aim of this study was to evaluate the characteristics and outcomes of these patients in a real world clinical setting. Methods  We retrospectively analyzed the characteristics of patients with cancer-associated VTE who were prescribed edoxaban. Follow-up at 3, 6, and 12 months was performed: VTE recurrences, bleedings, mortality, cancer progression and treatment, edoxaban interruption and its reason were assessed. Results  Fifty-four patients, 38 females (70.4%), mean age 71 ± 14 years, were enrolled. In 38 patients (70.4%), the episode of VTE was the first one, in 28 (51.8%) it was an isolated deep vein thrombosis (DVT), in 13 (24.1%) a pulmonary embolism (PE) associated with DVT, in 13 (24.1%) an isolated PE. Median time between cancer and VTE diagnosis was 6 (interquartile range [IQR] 2-47) months. Median time between VTE diagnosis and edoxaban prescription was 36 (IQR 7-117) days. At 3, 6, and 12 months the incidence of all-cause mortality was 16.6, 22.2, and 38.8%, that of VTE recurrence 1.8, 1.8, and 3.7%, and that of major bleeding 7.4, 9.2, and 12.9%, respectively. No bleeding was fatal. Of the 33 patients alive at 12 months, 32 (96.9%) were still on edoxaban therapy, in seven (21.2%) cancer was in progression. Conclusion  Our study, conducted on a real world population of patients with cancer-associated VTE, confirms the results of randomized controlled clinical trials, and supports the use of edoxaban as effective and safe treatment in this context.

Introduction: Searching paroxysmal atrial fibrillation (PAF) is the cornerstone in post embolic stroke of undetermined source (ESUS) patients. The Brown ESUS-AF score was proposed as a simple and good prognosticator of poststroke PAF detection. Age (≥ 75 years 2 points, 65-74 years 1 point) and moderate-severe left atrial enlargement (LAE, 2 points) are the variables enclosed in the score. External validation of Brown ESUS-AF score was the aim of the present study. Materials and Methods: We analyzed demographic, clinical, trans-thoracic echocardiography and brain computer tomography characteristics of patients with ESUS undergone to two weeks external ECG monitoring after hospital discharge. PAF was considered detected when any evidence of AF and/or atrial flutter occurred at monitoring. Results: Eighty-two consecutive ESUS patients with mean age ± SD 72 ± 10 years were the study population. PAF detection increased from 18.75% of patients with Brown ESUS-AF score 0 to 54.3% of patients with Brown ESUS-AF score ≥ 2. AUC of Brown ESUS-AF score in predicting AF detection was 0.642 (95% CI: 0.528-0.745). No difference between predictive power of Brown ESUS-AF score and CHA2DS2-VASc score was found. Conclusion: Brown ESUS-AF score could be used as a screening tool for selecting ESUS patients requiring prolonged ECG monitoring aimed to detect PAF. However, in our study the predictive power of Brown ESUS-AF score was not superior to that of CHA2DS2-VASc score.

Introduction and aim: Hemorrhagic transformation (HT) is the most feared complication in acute phase of ischemic stroke. Predicting HT is of utmost importance in clinical practice. In the latest years a lot of HT prediction scores have been proposed, but their comparison in real life lack. Therefore, the aim of our study was to provide information about this topic. Materials and Methods: We retrospectively calculated THRIVE, SPAN-100, MSS score, SITS-ICH and GRASPS scores in patients consecutively admitted in our Stroke Unit along two years. To evaluate their predictive power, the area under the curve (AUC) of the Receiver Operating Characteristic (ROC) curve was calculated. Results: Study population was composed by ninety-one patients (51.6% females) with mean age 80.1 ± 11.3 years. Seventy-four (81.3%) patients undergone to systemic intravenous alteplase, seven (7.7%) to mechanical thrombectomy, ten (11%) to systemic intravenous alteplase plus mechanical thrombectomy. Eighteen patients (19.7%) presented HT. MSS score was the best prognosticator of HT, however the predictive power of the five analyzed score was low, ranging from and none of the score resulted significantly superior to the others. Conclusion: Our real-life study showed a low predictive power of a lot of HT prediction scores. Further prospective studies are warranted.

Calprotectin (S100A8/A9) has been identified as a biomarker that can aid in predicting the severity of disease in COVID‐19 patients. This study aims to evaluate the correlation between levels of circulating calprotectin (cCP) and the severity of COVID‐19.

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA 2 DS 2 -VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0–1.3] for each point increase; P =0.05) and hypertension (OR, 2.3 [95% CI, 1.0–5.1]; P =0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0–1.2] for each year increase; P =0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4–14.2]; P =0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4–5.5]; P =0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8–1.7]). Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Background and Purpose- Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non-vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods- Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results- Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95-5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63-9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83-3.16), and CHA2DS2-VASc score (OR, 1.72 for each point increase; 95% CI, 1.58-1.88) were associated with ischemic events. Among the CHA2DS2-VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33-0.61). Conclusions- In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA2DS2-VASc score were associated with increased risk of cerebrovascular events.

Giant Cell Arteritis (GCA) is an immune-mediated vasculitis of large- and medium-sized vessels. Stroke happens in 3% to 7% of the cases, and identifying GCA properly is important because potentially curative treatment exists. We present a case of an 83-year-old woman, in whom suspected GCA was revealed by stroke caused by Vertebral Artery (VA) inflammation. The uncommon stroke localization and the ultrasound findings suggested vasculitic etiology of lesions. 18-Fluorodeoxyglucose-Positron Emission Tomography (18-FDG-PET) confirmed inflamed VA walls. Patient was treated with oral steroids and antiplatelet therapy, with improvement of clinical and ultrasonographic status. In our patient clinical diagnosis of GCA was challenging due to limited classical symptoms. Arguments in favor of arteritis were the symmetric and bilateral involvement of the VA, the sonographic halo sign and atypical stroke localization. Abbreviations: VA: Vertebral Artery; MRI: Magnetic Resonance Imaging; 18-FDG-PET: 18-Fluorodeoxyglucose-Positron Emission Tomography; AICA: Anterior Inferior Cerebellar Artery; PICA: Posterior Inferior Cerebellar Artery; GCA: Giant Cell Arteritis.