Citations

Abstract Introduction Non-vitamin-K oral anticoagulants (NOACs) were recommended in preference to oral vitamin K antagonists (VKAs) in the 2020 updated guidelines for stroke prevention in atrial fibrillation (AF), from the European Society of Cardiology (ESC). Rivaroxaban is a NOAC that is approved in many countries worldwide for reducing the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). Purpose To explore the baseline characteristics, dosing and 2-year outcomes of patients with AF treated with rivaroxaban. Methods RIVaroxaban Evaluation in Real Life setting (RIVER) is a prospective international, multicenter registry of patients with newly diagnosed non-valvular AF treated with rivaroxaban for the prevention of thromboembolic stroke and at least one investigator-determined risk factor for stroke. Results A total of 5043 patients were enrolled into RIVER between January 2015 and June 2017. Mean (SD) age at diagnosis was 69.5 (11.0) years and 55.7% were males. Caucasian patients represented the largest proportion of patients in RIVER (80.3%), followed by Asians (5.5%) and hispanic/latino (3.7%). Almost all patients (98.5%) were prescribed a single daily dose of rivaroxaban, most commonly 20 mg (77.3%) and 15 mg (20.4%), while a 10 mg dose was prescribed in only 2.3% of patients. During the 2-year follow-up, the rates (95% CI) of all-cause mortality, stroke/SE, and major bleeding were 2.75 (2.43 to 3.12), 0.89 (0.72; 1.11), and 1.26 (1.05 to 1.52) per 100 person years, respectively (Figure 1). The most common cardiovascular cause of death was congestive heart failure (30.4%) and myocardial infarction (11.4%). Leading non-cardiovascular causes of death were malignancy (27.4%), respiratory failure (18.9%) and infections/sepsis (13.2%). Over 2 years, 710 (14.1%) of patients discontinued rivaroxaban. The corresponding proportions at 6 months and 1 year were 7.8% and 10.8%, respectively. Out of all the patients who discontinued, 62 (8.7%) restarted rivaroxaban during their follow-up (Table 1). Conclusion During 2 years of follow up in the international, prospective RIVER registry, rivaroxaban treatment for AF was associated with low rates of stroke or major bleeding. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Abstract Introduction Rivaroxaban is recommended as an option for anticoagulation in patients with nonvalvular atrial fibrillation (AF) with one or more risk factors for stroke. The approved/recommended rivaroxaban dose for stroke prevention in patients with atrial fibrillation (AF) is solely based on renal function: 20 mg once daily (od) for patients with a creatinine clearance [CrCl] ≥50 ml/min and 15 mg od in patients with CrCl 15–49 mL/min). Purpose To assess the patterns of rivaroxaban prescription as per the creatinine clearances levels and to assess the impact of the rivaroxaban dosing on the rate of events at 2-year follow-up in patients with AF. Methods RIVaroxaban Evaluation in Real Life setting (RIVER) is a prospective international registry of patients with newly diagnosed non-valvular AF treated with rivaroxaban for the prevention of thromboembolic stroke and at least one investigator-determined risk factor for stroke. Adjusted hazard ratios (HRs) were obtained through Cox proportional-hazard model. Results Among 3402 patients with normal renal function (CrCl ≥50 mL/min), 82.1% were prescribed the recommended rivaroxaban dose of 20 mg (od) at baseline. Among 524 patients with moderate or severe renal impairment (CrCl 15–50 mL/min), 55.3% patients received rivaroxaban 15 mg (od), 39.9% received 20 mg (od) and 4.2% 10 mg (od). Non-recommended dosing was rare in patients younger than 70 (13.5%) but more frequent in older patients (28.8%). Non-recommended low dosing was more frequent in Asians (38.9%), compared to non-Asian patients (13.8%). Regarding clinical outcomes, adjusted hazards ratios (HR, presented with 95% confidence intervals) showed that the non-recommended low dosing (<20 mg od) was associated with higher risk of non-cardiovascular mortality (HR 2.09 (1.16–3.77)) in patients with normal renal function. The non-recommended high dosing (>15 mg od) was associated with lower risk of all-cause mortality (HR 0.63 (0.42–0.93)) and cardiovascular mortality (HR 0.32 (0.13–0.77)) and higher risk of major bleeding (HR 2.86 (1.49–5.50)) in patients with moderate to severe renal impairment (figure 1 and 2). Conclusion In patients with normal renal function, non-recommended low dose rivaroxaban was associated with increased cardiovascular mortality without reducing the risk of major bleeding compared to recommended dosing. In patients with CrCl <50 ml/min, non-recommended high dose rivaroxaban was associated with reduced cardiovascular mortality but at the cost of increased major bleeding. These observational data largely support the reduction of rivaroxaban dosing according to renal function but educational strategies are needed to ensure that rivaroxaban is used appropriately. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK, which sponsors the RIVER registry. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

AbstractData regarding the use of corticosteroids for treatment of acute respiratory distress syndrome (ARDS) are conflicting. As the coronavirus disease 2019 (COVID‐19) pandemic progresses, more literature supporting the use of corticosteroids for COVID‐19 and non‐COVID‐19 ARDS have emerged. Glucocorticoids are proposed to attenuate the inflammatory response and prevent progression to the fibroproliferative phase of ARDS through their multiple mechanisms and anti‐inflammatory properties. The purpose of this systematic review was to comprehensively evaluate the literature surrounding corticosteroid use in ARDS (non‐COVID‐19 and COVID‐19) in addition to a narrative review of clinical considerations of corticosteroid use in these patient populations. OVID Medline and EMBASE were searched. Randomized controlled trials evaluating the use of corticosteroids for COVID‐19 and non‐COVID‐19 ARDS in adult patients on mortality outcomes were included. Risk of bias was assessed with the Risk of Bias 2.0 tool. There were 388 studies identified, 15 of which met the inclusion criteria that included a total of 8877 patients. The studies included in our review reported a mortality benefit in 6/15 (40%) studies with benefit being seen at varying time points of mortality follow‐up (ICU survival, hospital, and 28 and 60 days) in the COVID‐19 and non‐COVID‐19 ARDS studies. The two non‐COVID19 trials assessing lung injury score improvements found that corticosteroids led to significant improvements with corticosteroid use. The number of mechanical ventilation‐free days significantly were found to be increased with the use of corticosteroids in all four studies that assessed this outcome. Corticosteroids are associated with improvements in mortality and ventilator‐free days in critically ill patients with both COVID‐19 and non‐COVID‐19 ARDS, and evidence suggests their use should be encouraged in these settings. However, due to substantial differences in the corticosteroid regimens utilized in these trials, questions still remain regarding the optimal corticosteroid agent, dose, and duration in patients with ARDS.

ABSTRACT Background Nephrolithiasis in allograft kidneys is rare, but this diagnosis may lead to allograft complications and patient morbidity. Previous studies that have evaluated nephrolithiasis posttransplant have focused on surgical stone management, with limited data on urine metabolic risk factors and the presence of stones after follow-up. Methods We retrospectively evaluated kidney transplant recipients who were diagnosed with transplant nephrolithiasis between 2009 and 2019. Computed tomography and ultrasound imaging were used to confirm stone presence. Results The incidence of allograft kidney stone formation was 0.86% of 6548 kidney transplant recipients. Of the 56 cases identified, 17 (30%) had a pretransplant history of nephrolithiasis. Only four (7%) patients received a known kidney stone at the time of allograft implantation. Of the 56 cases, 34 had a 24-h supersaturation study. The urine supersaturation study showed 32 patients (94%) had a urine citrate of <450 mg excreted in 24 h (median 124.5 mg/24 h, reference range >500 mg/24 h), along with 22 patients (61%) having a urine oxalate excretion of ≥30 mg in 24 h (median 34.4 mg/24 h, reference range <30 mg/24 h). Calcium oxalate composition was most common (91% with >1 supersaturation for calcium oxalate crystals), with normal median urine calcium levels (median urine calcium 103.5 mg/24 h, reference range <200 mg/24 h). After a 4-year follow-up, 50% (n = 28) required surgical intervention and 43 (77%) patients continued to have evidence of transplant nephrolithiasis on imaging. Conclusions This is the largest study of transplant nephrolithiasis confirming that hypocitraturia and hyperoxaluria were the most significant urine metabolic risk factors associated with allograft nephrolithiasis and that hyperoxaluria was the most prevalent driver for calcium oxalate stone composition. Our study is first to show low stone-free rates at the last follow-up and a significant proportion requiring surgical intervention.

Background Relationships between occlusive clot histopathology, baseline characteristics, imaging findings, revascularization rates, and clinical outcomes of stroke patients with large vessel occlusion (LVO) are not well understood. This study will assess the real-world experience on the efficacy and safety of using the EmboTrap device as the first approach in LVO patients and explore the associations between clot histological characteristics, imaging and clinical findings, revascularization rates, and clinical outcomes. Methods Prospective, global, multicenter, single-arm, imaging core laboratory, and clot analysis central laboratory observational registry. Adult patients (>18 years) with LVO, treated with EmboTrap as the first attempted device, will be eligible for study participation. Results Up to 1000 subjects at 50 international sites may be enrolled. Occlusive clots will be collected from at least 500 subjects. Independent central and imaging core laboratories will perform clot analysis and image adjudication. Statistical analysis will assess the association between imaging and clinical findings, clot characteristics, subject comorbidities, revascularization, and clinical outcomes. Study endpoints are functional independence (modified Rankin Scale score ≤2 at 90 days), expanded Thrombolysis In Cerebral Infarction (eTICI) score ≥2b50 rate, first-pass effect, number of passes, embolization into new territory, symptomatic intracranial hemorrhage, and 90-day mortality. Conclusions The EXCELLENT registry will provide reproducible effectiveness and safety data of EmboTrap for its use for mechanical thrombectomy. Additionally, the study will characterize the blood clots retrieved during mechanical thrombectomy with respect to their composition and histopathological analysis and potential correlations with clinical and imaging findings. Trial registration number NCT03685578 .

Abstract Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

AbstractLangerhans cell histiocytosis (LCH) is a histiocytic neoplasm that can involve the lungs as single system (LCH‐SSL) or multisystem disease (LCH‐MSL). The role of full‐body radiographic staging to determine whether patients have LCH‐SSL or LCH‐MSL is unclear. Long‐term outcomes of LCH‐SSL versus LCH‐MSL and multisystem without lung involvement (LCH‐MSNL) are unknown. A retrospective study of adult LCH patients seen at our center from January 2000 to 2020 was performed. In Part 1, we addressed utility of whole‐body staging imaging among those presenting with isolated pulmonary signs or symptoms. Staging was defined as fluorodeoxyglucose positron emission tomography‐computed tomography (CT) or whole‐body CT obtained within 3 months of diagnosis. In Part 2, we examined the frequency of developing extra‐pulmonary disease over time and mortality in patients with LCH‐SSL. In Part 3, we compared the overall survival of LCH‐SSL, LCH‐MSL, and LCH‐MSNL. Part 1: 240 patients with LCH were identified. A total of 112 (47%) had pulmonary signs or symptoms at presentation. Thirty‐four (30%) underwent radiographic staging and only one showed evidence of extra‐pulmonary disease. Part 2: 108 (45%) were LCH‐SSL. Median follow‐up duration of 4.5 years (95% confidence interval [CI]: 2.9–6.0). None developed extra‐pulmonary disease. Part 3: 5‐year survival: 94% (95% CI: 84%–98%) for LCH‐SSL, 78% (95% CI: 59%–90%) for LCH‐MSL, and 75% (95% CI: 53%–89%) for LCH‐MSNL. LCH patients presenting with isolated pulmonary signs or symptoms rarely have extra‐pulmonary involvement at the time of diagnosis and generally do not develop extra‐pulmonary progression. LCH‐SSL has the best overall survival, while LCH‐MSL and LCH‐MSNL have similar clinical outcomes.

Abstract The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.