Dynamic assessment of CHA2DS2-VASc and HAS-BLED scores for predicting ischemic stroke and major bleeding in atrial fibrillation patients.

INTRODUCTION AND OBJECTIVES: Stroke and bleeding risks in atrial fibrillation (AF) are often assessed at baseline to predict outcomes years later. We investigated whether dynamic changes in CHA2DS2-VASc and HAS-BLED scores over time modify risk prediction. METHODS: We included patients with AF who were stable while taking vitamin K antagonists. During a 6-year follow-up, all ischemic strokes/transient ischemic attacks (TIAs) and major bleeding events were recorded. CHA2DS2-VASc and HAS-BLED were recalculated every 2-years and tested for clinical outcomes at 2-year periods. RESULTS: We included 1361 patients (mean CHA2DS2-VASc and HAS-BLED 4.0±1.7 and 2.9±1.2). During the follow-up, 156 (11.5%) patients had an ischemic stroke/TIA and 269 (19.8%) had a major bleeding event. Compared with the baseline CHA2DS2-VASc, the CHA2DS2-VASc recalculated at 2 years had higher predictive ability for ischemic stroke/TIA during the period from 2 to 4 years. Integrated discrimination improvement (IDI) and net reclassification improvement (NRI) showed improvements in sensitivity and better reclassification. The CHA2DS2-VASc recalculated at 4 years had better predictive performance than the baseline CHA2DS2-VASc during the period from 4 to 6 years, with an improvement in IDI and an enhancement of the reclassification. The recalculated HAS-BLED at 2-years had higher predictive ability than the baseline score for major bleeding during the period from 2 to 4 years, with significant improvements in sensitivity and reclassification. A slight enhancement in sensitivity was observed with the HAS-BLED score recalculated at 4 years compared with the baseline score. CONCLUSIONS: In AF patients, stroke and bleeding risks are dynamic and change over time. The CHA2DS2-VASc and HAS-BLED scores should be regularly reassessed, particularly for accurate stroke risk prediction.

NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy.

Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1ß release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1ß release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.

Reducing bleeding risk in patients on oral anticoagulation therapy.

INTRODUCTION: Oral anticoagulation (OAC) significantly mitigates thromboembolism risks in atrial fibrillation (AF) and venous thromboembolism (VTE) patients yet concern about major bleeding events persist. In fact, clinically relevant hemorrhages can be life-threatening. Bleeding risk is dynamic and influenced by factors such as age, new comorbidities, and drug therapies, and should not be assessed solely based on static baseline factors. AREAS COVERED: We comprehensively review the bleeding risk associated with OAC therapy. Emphasizing the importance of assessing both thromboembolic and bleeding risks, we present clinical tools for estimating stroke and systemic embolism (SSE) and bleeding risk in AF and VTE patients. We also address overlapping risk factors and the dynamic nature of bleeding risk. EXPERT OPINION: The OAC management is undergoing constant transformation, motivated by the primary objective of mitigating thromboembolism and bleeding hazards, thereby amplifying patient safety throughout the course of treatment. The future of OAC embraces personalized approaches and innovative therapies, driven by advanced pathophysiological insights and technological progress. This holds promise for improving patient outcomes and revolutionizing anticoagulation practices.

Remdesivir or Nirmatrelvir/Ritonavir Therapy for Omicron SARS-CoV-2 Infection in Hematological Patients and Cell Therapy Recipients.

BACKGROUND: Scarce data exist that analyze the outcomes of hematological patients with SARS-CoV-2 infection during the Omicron variant period who received treatment with remdesivir or nirmatrelvir/ritonavir. METHODS: This study aims to address this issue by using a retrospective observational registry, created by the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group, spanning from 27 December 2021 to 30 April 2023. RESULTS: This study included 466 patients, 243 (52%) who were treated with remdesivir and 223 (48%) with nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was primarily used for mild cases, resulting in a lower COVID-19-related mortality rate (1.3%), while remdesivir was preferred for moderate to severe cases (40%), exhibiting a higher mortality rate (9%). A multivariate analysis in the remdesivir cohort showed that male gender (odds ratio (OR) 0.35, p = 0.042) correlated with a lower mortality risk, while corticosteroid use (OR 9.4, p < 0.001) and co-infection (OR 2.8, p = 0.047) were linked to a higher mortality risk. Prolonged virus shedding was common, with 52% of patients shedding the virus for more than 25 days. In patients treated with remdesivir, factors associated with prolonged shedding included B-cell malignancy as well as underlying disease, severe disease, a later onset of and shorter duration of remdesivir treatment and a higher baseline viral load. Nirmatrelvir/ritonavir demonstrated a comparable safety profile to remdesivir, despite a higher risk of drug interactions. CONCLUSIONS: Nirmatrelvir/ritonavir proved to be a safe and effective option for treating mild cases in the outpatient setting, while remdesivir was preferred for severe cases, where corticosteroids and co-infection significantly predicted worse outcomes. Despite antiviral therapy, prolonged shedding remains a matter of concern.