Major Thromboembolic Events Research Articles

P0664 Effectiveness and safety of upadacitinib in ulcerative colitis in clinical practice: results from the U-REAL-UC study from ENEIDA

Abstract Background Upadacitinib (UPA) has shown promising results in the pivotal trials, which require validation in clinical practice. Primary aim:To assess the durability of UPA treatment in patients with ulcerative colitis (UC). Secondary aims:To assess the short and long-term effectiveness, dose optimization and response to dosage adjustments, the impact of extraintestinal manifestations (EIM) and immunomediated diseases (IMIDs), and the tolerability of UPA in UC in a real-world setting Methods Adult patients who started UPA for UC treatment at least 8 weeks prior to data collection and were part of the prospectively maintained ENEIDA registry of GETECCU were included. Patients on concomitant biologic agents or with a history of colectomy were excluded. Patients were followed-up from the first UPA dose until treatment discontinuation or the last visit. Effectiveness analysis was restricted to patients with active disease [Partial Mayo Score (PMS)>2] at UPA initiation. Clinical effectiveness was measured using PMS, and concomitant steroid use was assessed at each visit. Patients who discontinued UPA before their last visit were considered not in remission at subsequent time points (negative imputation) Results The study included 168 patients, 89% with active disease (Table 1); 48% had been previously exposed to JAK inhibitors (JAKi) and 31% to all approved therapeutic targets. Dosage details are summarized in Table 2. A total of 29 patients discontinued treatment during a median follow-up time of 4.3 months.The incidence rate of UPA discontinuation was 27% per patient-year of follow-up (Fig. 1), with no significant differences related to prior JAKi exposure (Fig. 2).The main reason for UPA discontinuation was loss of response (34%), with colectomy being the main subsequent treatment (21%). No predictive factors for UPA discontinuation were identified (Fig. 1). At week 8, 67% of patients were in steroid-free clinical remission (SFCR) (Fig. 3).Prior exposure to JAKi affected short-term effectiveness (Table 3). Among 100 patients in SFCR at week 8, 13 (13%) lost response (31% per patient-year), and 10 (77%) of these had dose escalation, with 4 (90%) regaining SFCR. Of 31 patients (18%) with active EIM/IMIDs at the start of UPA, 15 (48%) showed improvement.Adverse events occurred in 45 patients (27%) with hypercholesterolemia being the most common, but no major cardiovascular or thromboembolic events were reported Conclusion This study, the largest of its kind in clinical practice, confirms the short- and long-term benefits and the safety profile of UPA for UC. Although prior JAKi exposure reduced short-term effectiveness, it did not impact drug survival, indicating that UPA could be a viable option even for patients who have experienced JAKi failure

Treatment-Emergent Major Adverse Cardiovascular and Thromboembolic Events were Infrequent During Clinical Trials of Pegloticase.

Long-term maintenance of serum urate (SU) levels <6 mg/dl reduces gout flare frequency. However, urate-lowering therapy (ULT) initiation can induce gout flare. The incidence of thromboembolic (TE) and cardiovascular (CV) events has been shown to increase in the 30 and 120 days following gout flare, respectively; therefore, the question of ULT initiation increasing patient risk for CV/TE events has been raised. Here, we investigate CV/TE event incidence following pegloticase initiation in clinical trials. This post hoc analysis of pooled data from 4 trials examined treatment-emergent gout flare and CV/TE events in patients with uncontrolled gout. Studies included two phase 3 trials (NCT00325195), the MIRROR open-label trial (NCT03635957), and the MIRROR randomized controlled trial (NCT03994731). Per protocol, pegloticase (8 mg) was administered every 2 (all trials) or 4 weeks (phase 3 trials); data from the first 24 weeks of therapy were included in this analysis. Some MIRROR patients received methotrexate (15 mg/week) as co-therapy. Based on prior studies, the high-risk window for CV/TE events was defined as 120 days following flare onset. Overall, 5/328 (1.5%) patients experienced ≥1 CV/TE event during pegloticase treatment, including 3/244 (1.2%) patients who received on-label (biweekly) dosing (35.4 events/1000 person-years). All events occurred within the 120-day gout flare exposure window. CV/TE event incidence during pegloticase treatment was similar to the general gout population (31.7 events/1000 person-years). These findings suggest that pegloticase initiation does not put patients at a higher risk for CV/TE events.

Tranexamic Acid Within 4.5 Hours of Intracerebral Hemorrhage With the CTA Spot Sign: Systematic Review and Individual Patient Meta-analysis.

The antifibrinolytic agent tranexamic acid has been tested in intracerebral hemorrhage trials with overall neutral results. Ongoing contrast extravasation on CT angiography (spot sign) can identify individuals with ongoing bleeding who may benefit from anti-fibrinolytic therapy. We aimed to investigate the effect of tranexamic acid on hematoma growth in patients with spot signs treated within 4.5 hours of onset. We conducted a systematic review and individual patient meta-analysis, which we report according to the Preferred Reporting Items for Systematic Review and Meta-analyses of Individual Participant Data guidelines. PubMed and Embase were searched from inception to May 29, 2023, using the terms ((stroke) AND (randomised OR randomized) AND (tranexamic acid) AND (haemorrhage OR hemorrhage)). We included randomized trials comparing tranexamic acid with placebo in participants with primary intracerebral hemorrhage who had a spot sign and who had follow-up imaging within the required timeframe. Individual patient data were provided by each study and were integrated by the coordinating center. Data were pooled using a random-effects model. The primary endpoint was hematoma growth within 24 hours, defined as ≥33% relative or ≥6 mL absolute hematoma expansion compared with baseline, analyzed using mixed-effects-modified Poisson regression with robust standard errors, adjusted for baseline hematoma volume. Safety outcomes were mortality and major thromboembolic events within 90 days. Of 197 studies identified, 3 were eligible, contributing 162 participants for the primary analysis (60 female and 102 male). Hematoma growth occurred in 36 of 74 (49%) participants treated with tranexamic acid, compared with 48 of 88 (55%) participants treated with placebo (adjusted risk ratio 0.86, 95% CI 0.84-0.89, p < 0.001). Adjusted median absolute hematoma growth was 1.60 mL (95% CI 0.77-2.43) lower with tranexamic acid vs placebo. No differences in functional outcome or safety were observed. Tranexamic acid modestly reduced hematoma growth in patients with CT angiography spot signs treated within 4.5 hours of onset. Given the trials in the meta-analysis were individually neutral, these results require further validation before clinical application.

Risk of major adverse cardiovascular events and venous thromboembolic events between patients with psoriasis or psoriatic arthritis on tumor necrosis factor inhibitors, interleukin 17 inhibitors, interleukin 12/23 inhibitors, and interleukin 23 inhibitors: An emulated target trial analysis.

The risk of major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) in patients with psoriatic disease receiving biologics is not fully understood. This study aimed to investigate whether novel biologic therapies (interleukin 17 inhibitor [IL-17i], interleukin 12/23 inhibitor [IL-12/23i], and interleukin 23 inhibitor [IL-23i]) for biologic-naïve patients with psoriasis or psoriatic arthritis (PsA) are associated with differences in the risks of MACE and VTE compared with those with tumor necrosis factor inhibitors (TNFis). An emulated target trial was designed by a nationwide cohort using data from the TriNetX Research Network. Biologic-naïve patients with psoriasis or PsA receiving biologics between 2014 and 2022 were enrolled. Treatment groups were determined by patients' first prescription of biologics. Three propensity-matched cohorts were established, namely, IL-17i versus TNFi, IL-12/23i versus TNFi, and IL-23i versus TNFi. The incidence rate and incidence rate ratios were estimated. A total of 32,098 biologic-naïve patients with psoriasis or PsA treated with biologics were included. All enrollees were further categorized into 4 cohorts (20,314 in the TNFi cohort, 5073 in the IL-17i cohort, 3573 in the IL-12/23i cohort, and 3138 in the IL-23i cohort). No significant difference in the risks of MACE and VTE between biologics existed among patients with psoriatic disease. In the subgroup analyses for either psoriasis or PsA, no significant difference in the risks of MACE or VTE was noted among all comparisons in the subgroup. Among patients with preexisting hyperlipidemia and diabetes mellitus, the risks of MACE and VTE among patients using new biologics (IL-17i, IL-12/23i, or IL-23i) were lower than those using TNFi. The data lack psoriasis severity. Among patients with psoriasis or PsA, no significant risk differences in MACE and VTE were detected between those with IL-17i, IL-12/23i, and IL-23i and those with TNFi. These findings can serve as a reference to health care providers and patients when making clinical decisions, thereby also providing evidence for future pharmacovigilance research.

Safety of enoxaparin in patients implanted with continuous flow left ventricular assist devices.

The objective of this study is to determine the incidence of major bleeding events in patients implanted with continuous flow left ventricular assist devices (CF-LVADs) bridged with enoxaparin (LMWH) compared to intravenous unfractionated heparin (IV UFH) for a subtherapeutic INR on warfarin. A single-center, retrospective, cohort study was conducted including patients with CF-LVADs implanted between January 1, 2012 and July 1, 2020 who received at least one inpatient dose or outpatient prescription for LMWH or IV UFH at least 60 days after CF-LVAD implantation. The primary endpoint was the incidence of major bleeding. In total, 176 orders were screened and 90 orders in 62 unique patients were included. Major bleeding and thromboembolic events occurred in 1 (2.5%) versus 4 (10.0%) orders (p = 0.36) and 3 (7.5%) versus 1 (2.5%) orders (p = 0.62) in the LMWH and IV UFH groups, respectively. One patient had a fatal thromboembolic event in each group. More patients receiving IV UFH had minor bleeding events (10 [25.0%] vs. 3 [7.5%]; p = 0.03). There was no difference between bleeding and thromboembolic events in patients implanted with CF-LVADs prescribed LMWH or IV UFH for bridging of subtherapeutic INRs. Larger prospective randomized data are needed to validate these findings.

Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis refractory to biologic therapy: 2-year clinical and radiographic results from the open-label extension of the SELECT-AXIS 2 study

BackgroundThe efficacy and safety of upadacitinib in patients with ankylosing spondylitis (AS) and inadequate response/intolerance to biologic disease-modifying antirheumatic drugs (bDMARD-IR) were evaluated through 1 year in the SELECT-AXIS 2 study. Here, we assess 2-year efficacy, safety, and imaging outcomes in SELECT-AXIS 2.MethodsPatients who received continuous upadacitinib, and those who switched from placebo to upadacitinib at week 14, could enter the open-label extension (OLE). Efficacy endpoints included Assessment of SpondyloArthritis international Society (ASAS) and Axial Spondyloarthritis Disease Activity Score (ASDAS) responses, and changes from baseline in measures of disease activity, back pain, function, and quality of life. Radiographic progression was evaluated using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). As observed (AO) and AO with non-responder imputation (AO-NRI) analyses were used for binary endpoints; AO with mixed-effects model for repeated measures (AO-MMRM) for continuous endpoints; and AO-analysis of covariance for mSASSS. Treatment-emergent adverse events (TEAEs) in patients receiving ≥ 1 upadacitinib dose through week 104 are presented as events (E)/100 patient-years (PY). Subgroup analyses were performed by prior tumor necrosis factor/interleukin-17 inhibitor exposure and bDMARD lack of efficacy/intolerance.ResultsOf 420 patients who entered the bDMARD-IR AS study, 409 entered the OLE, and 331 (continuous upadacitinib, n = 163; placebo to upadacitinib, n = 168) completed week 104. Improvements in efficacy measures were sustained through the OLE, with similar response rates between the continuous upadacitinib and placebo to upadacitinib groups at week 104. At week 104, 64.9% and 61.7% of patients, respectively, had achieved ASAS 40% response (AO-NRI). Mean changes from baseline were similar between the two groups at week 104 across measures (ASDAS: -2.1 and -2.0; total back pain: -4.9 and -4.6, respectively; AO-MMRM). Over 93.0% of patients showed no radiographic progression (mSASSS mean change from baseline < 2) at week 104. The overall TEAE rate was 165.2 E/100 PY, with low rates of major adverse cardiovascular and venous thromboembolic events (0.3 E/100 PY each).ConclusionsUpadacitinib efficacy, including very low rates of radiographic progression, was demonstrated through 104 weeks in treatment-refractory patients with active AS. Treatment was well tolerated, with no newly identified safety signals.Trial registrationNCT04169373.

Optimal anticoagulation strategy for left ventricular assist device patients undergoing thoracentesis: a retrospective study

Abstract Background Left ventricular assist devices (LVADs) are associated with thromboembolic risks necessitating anticoagulation, yet balancing these risks with bleeding concerns remains challenging. Current practice involves warfarin with a target INR of 2-3 alongside anti-platelet therapy. However, consensus on anticoagulation management is lacking, particularly during sub-therapeutic INR or procedural settings. Common strategies include bridging anticoagulation with heparin or enoxaparin, temporary cessation of anticoagulation during the procedure or uninterrupted anticoagulation. Purpose To evaluate and compare the incidence of bleeding and thromboembolic events in LVAD patients undergoing thoracentesis, with a focus on determining the optimal anticoagulation strategy during procedures. Methods Retrospective data was collected over one year from LVAD patients undergoing thoracentesis at a large academic center. Patients were categorized into ‘bridge’ (received intravenous heparin for bridging during thoracentesis) and ‘no-bridge’ (did not receive bridging anticoagulation) groups. Warfarin was paused before procedure and resumed after procedure in both groups. Baseline characteristics, including age, sex, race, BMI, LVAD type, and INTERMACS profile, were recorded. Primary outcomes were major bleeding and thromboembolic events within 30 days of warfarin cessation. Statistical analysis used t-test/Wilcoxon for continuous variables and Chi-square/Fisher exact test for categorical variables. A p-value &amp;lt;0.05 was considered significant. Results During the study, twenty LVAD patients underwent thirty-two thoracenteses (nineteen bridge, thirteen no-bridge). The demographics were similar among the two groups. Warfarin was held for an average of 5.5 ± 4.6 days before and resumed 4.1 ± 4.6 days after the procedure in the bridge group and 3.8± 3.2 days before and 1.7 ± 2.5 days after in the no-bridge group. Major bleeding occurred in 73.7% of bridge group cases versus 30.8% of no-bridge group cases (p=0.059). 63.2% of bridge group patients had a bloody pleural effusion on thoracentesis compared to 46.2% of no-bridge group patients (p value= 0.34). Average transfusion requirements were 2.8 units and 2 units in the bridge and the no-bridge groups respectively (p=0.658). Thromboembolic events included a 10.5% ischemic CVA rate in the bridge group, with none in the no-bridge group. No other arterial thromboembolic events, pump thrombosis or DVT/PE were observed in either group. Conclusion In LVAD patients undergoing thoracentesis, a non-bridging strategy does not appear to elevate the risk of thrombosis compared to a bridging approach. Moreover, the incidence of bleeding, while not statistically significant, trended higher in the bridging group.

Apixaban, edoxaban and rivaroxaban but not dabigatran are associated with higher mortality compared to vitamin-K antagonists: A retrospective German claims data analysis.

Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials. Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding. Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all p<0.001) but not for dabigatran (p=0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all p<0.001) and 13.0% for dabigatran versus 12.8% for VKA (p=0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine-Gray regression models on the basis of the entire cohort. In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs.

Systemic effects of anti-VEGF intravitreal injection in patients with age-related macular degeneration: A multi-institutional real-world study.

In individuals aged >50 years, age-related macular degeneration (AMD) is the leading cause of irreversible blindness. Intravitreal injections of antivascular endothelial growth factor (VEGF) agents (bevacizumab, ranibizumab, and aflibercept) show good efficacy and similar incidences of systemic adverse events (SAEs). However, comparative studies between agents are limited. Our study aimed to compare the real-world SAE risks of bevacizumab, ranibizumab, and aflibercept users. This retrospective cohort study identified new bevacizumab, ranibizumab, and aflibercept users in a multi-institutional database in Taiwan between 2014 and 2019. Inverse probability of treatment weights (IPTW) with propensity scores was conducted to achieve homogeneity among groups. The Fine and Gray model was utilized to estimate the subdistribution hazard ratio and 95% confidence interval. This study included 701 bevacizumab, 463 ranibizumab, and 984 aflibercept users. After IPTW, all covariates were well-balanced. All three anti-VEGF agents had a low and comparable number per 100 person-years of major adverse cardiac events, heart failure, thromboembolic events, major bleeding, all-cause admission, and all-cause death (all P > 0.05). No significant differences in long-term change of systolic and diastolic blood pressure, low-density lipoprotein, estimated glomerular filtration rate, and alanine transaminase (all P for interaction > 0.05) were observed among groups. Bevacizumab, ranibizumab, and aflibercept had a good systemic safety profile in this study. All groups showed a low and similar SAE risk and no differences in their long-term change of laboratory data. Therefore, these anti-VEGF agents could be prescribed safely to patients with AMD.

Apixaban vs rivaroxaban in patients with atrial fibrillation at high or low bleeding risk: A population-based cohort study

BackgroundDespite many atrial fibrillation (AF) patients being at risk of bleeding, very limited data are available on bleeding rates of different direct oral anticoagulants based on the spectrum of bleeding risk. ObjectiveWe aimed to compare the risk of major bleeding and thromboembolic events with apixaban vs rivaroxaban for AF patients stratified by bleeding risk. MethodsWe conducted a population-based, retrospective cohort study of all adult patients (66 years or older) with AF in Ontario, Canada, who were treated with apixaban or rivaroxaban between April 1, 2011, and March 31, 2020. Bleeding risk was estimated by the HAS-BLED score, with high bleeding risk defined as a score of ≥3. The primary safety outcome was major bleeding, and the primary efficacy outcome was thromboembolic events. Comparisons were adjusted for baseline comorbidities by inverse probability of treatment weighting. ResultsThis study included 18,156 AF patients with high bleeding risk and 55,186 AF patients with low bleeding risk. Apixaban use was more common in patients with high bleeding risk; 63% of high-risk patients used apixaban compared with 56% of low-risk patients. Apixaban users had lower rates of major bleeding in high-risk patients (2.9% vs 4.2% per year; hazard ratio [HR], 0.69; 95% CI, 0.58–0.81) and in low-risk patients (1.8% vs 2.9% per year; HR, 0.63; 95% CI, 0.56–0.70) compared with rivaroxaban. There were no differences in rates of thromboembolic events, 3.1% vs 3.0% per year (HR, 1.02; 95% CI, 0.86–1.22) in high-risk patients and 1.9% vs 1.9% per year (HR, 1.00; 95% CI, 0.89–1.14) in low-risk patients. ConclusionIn older AF patients with high or low bleeding risk, treatment with apixaban was associated with lower rates of major bleeding with no difference in risk for thromboembolic events compared with rivaroxaban.

Conservative Versus Operative Treatment of Proximal Humerus Fractures in Older Individuals.

Little is known about the frequency and results of conservative treatment of proximal humerus fractures (PHF) in older individuals. Billing data of the BARMER health insurance carrier for all patients of age ≥ 65 for the years 2005-2021 were retrospectively analyzed with multivariable Cox regression models, taking account of the patients' age, sex, and individual comorbidity profiles. The defined primary endpoints were overall survival (OS), major adverse events (MAE), thromboembolic events (TE), and complications of surgery or of trauma. Multivariable p-values for the effect of treatment on all primary endpoints were jointly adjusted using the Bonferroni-Holm method. Of 81 909 patients, 54% were treated conservatively. Conservative treatment was more common in those who received their diagnosis as outpatients (79.5%, vs. 37.2% for inpatients). Operative treatment was associated with significantly longer overall survival (long-term hazard ratio [HR] 0.89, 95% confidence interval [0.86; 0.91]), fewer MAE (0.90 [0.88; 0.92]), and fewer TE (0.89 [0.87; 0.92]), but more complications due to surgery or trauma (1.66 [1,.4; 1.78]; all p < 0.001). By 6 months after diagnosis, 3.1% of the patients who were initially treated conservatively had undergone surgery. Risk factors for failure of conservative treatment were alcohol abuse, obesity, cancer, diabetes mellitus, Parkinson disease, and osteoporosis. The conservative treatment of PHF is associated with a lower overall rate of complications due to surgery or trauma, but also with more MAE, more TE, and higher mortality. These findings underline the need for individualized and risk-adjusted treatment recommendations.

Comparative effectiveness and safety of apixaban and rivaroxaban in older patients with atrial fibrillation: A population-based cohort study

BackgroundThere are no clinical trials with a head-to-head comparison between the 2 most commonly used oral anticoagulants (apixaban and rivaroxaban) in patients with atrial fibrillation (AF). The comparative efficacy and safety between these drugs remain unclear, especially in older patients who are at the highest risk for stroke and bleeding. ObjectiveThe purpose of this study was to compare the risk of major bleeding and thromboembolic events between apixaban and rivaroxaban in older patients with AF. MethodsWe conducted a population-based retrospective cohort study of all adult patients (66 years or older) with AF in Ontario, Canada, who were treated with apixaban or rivaroxaban between April 1, 2011, and March 31, 2020. The primary safety outcome was major bleeding, and the primary efficacy outcome was thromboembolic events. Secondary outcomes included any bleeding. Rates and hazard ratios (HRs) were adjusted for baseline comorbidities with inverse probability of treatment weighting. ResultsThis study included 42,617 patients with AF treated with apixaban and 30,725 patients treated with rivaroxaban. After inverse probability of treatment weighting using the propensity score, patients in the apixaban and rivaroxaban groups were well balanced for baseline values of demographic characteristics, comorbidities, and medications; both groups had a similar mean age of 77.4 years, and 49.9% were female. At 1 year, the apixaban group had a lower risk for both major bleeding with an absolute risk reduction at 1 year of 1.1% (2.1% vs 3.2%; HR 0.65; 95% confidence interval [CI] 0.59–0.71]) and any bleeding (8.1% vs 10.9%; HR 0.73; 95% CI 0.69–0.77), with no difference in the risk for thromboembolic events (2.2% vs 2.2%; HR 1.02; 95% CI 0.92–1.13). ConclusionIn patients with AF, 66 years or older, treatment with apixaban was associated with lower risk for major bleeding, with no difference in the risk for thromboembolic events compared with rivaroxaban.

Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial

Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. Australian Government Medical Research Future Fund.

Risk of Major Adverse Cardiovascular Events and Venous Thromboembolism with JAK Inhibitors versus TNF Inhibitors in Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis.

The aim of this study was to compare the risk of major cardiovascular events (MACE) and venous thromboembolic events (VTE) between tumour necrosis factor (TNF) and Janus kinase (JAK) inhibitors in patients with rheumatoid arthritis (RA). We researched PubMed, Scopus, Cochrane Library, and clinicaltrials.gov until December of 2023 for randomised controlled trials (RCTs) and observational studies. The outcomes studied were MACE (stroke, heart attack, myocardial infarction, sudden cardiac death) and VTE (deep vein thrombosis, pulmonary embolism). We pooled data using random effects model. Risk for the reported outcomes was expressed as odds ratio (OR) with a 95% confidential interval (CI). We performed a subgroup analysis based on study design. We identified 23 studies, 20 of which compared the odds for MACE and 14 the odds for VTE between JAK and TNF inhibitors in RA patients. Ten studies were RCTs and the rest were observational. Regarding MACE risk we pooled data from a total of 215,278 patients (52,243 were treated with JAK inhibitors, while the rest 163,035 were under TNF inhibitors). Compared with TNF inhibitors, the OR for JAK inhibitors in regards with MACE risk was 0.87 (0.64-1.17, p<0.01). Regarding VTE, a total of 176,951 patients were analysed (41,375 JAK inhibitors users and 135,576 TNF inhibitors users). The OR for VTE for JAK inhibitors compared with TNF inhibitors was 1.28 (0.89-1.84, p<0.01). According to our results, there is no statistically significant difference for MACE or VTE in RA patients who receive either JAK or TNF inhibitors.

Major bleeding in patients with atrial fibrillation treated with apixaban versus warfarin in combination with amiodarone: nationwide cohort study

BackgroundAmiodarone is an established treatment for atrial fibrillation (AF) but might interfere with the metabolism of apixaban or warfarin. Therefore, the aim was to investigate the occurrence of major bleeding...

Twice-daily rivaroxaban after percutaneous left atrial appendage closure for atrial fibrillation.

Background and aim: Rivaroxaban is an emerging oral anticoagulant for postoperative anticoagulation after percutaneous left atrial appendage closure (LAAC). Because a once-daily dosing regimen of rivaroxaban causes fluctuations in the drug plasma concentration, we studied the feasibility and safety of twice-daily rivaroxaban as a postoperative anticoagulation regimen for patients with atrial fibrillation (AF) undergoing LAAC. Methods: This study involved patients with AF who underwent LAAC and took rivaroxaban postoperatively. A total of 326 patients who received a standard total dose (15 or 20mg) of rivaroxaban based on their creatinine clearance rate were divided into the twice-daily (BID) rivaroxaban group (n = 208) and once-daily (QD) rivaroxaban group (n = 118) according to their anticoagulation strategy. Transesophageal echocardiography was recommended at 3-6months postoperatively to check for device-related thrombosis (DRT). Clinical outcomes were evaluated during postoperative anticoagulation. Results: The median CHA2DS2-VASc score (4 [3, 5] vs. 4 [3, 5], p = 0.28) and HAS-BLED score (2 [2, 3] vs. 2 [2, 3], p = 0.48) were not significantly different between the groups. During the anticoagulation period (4.1 ± 0.7 vs. 4.1 ± 0.9 months, p = 0.58), 148 (71.2%) patients in the BID group and 75 (63.6%) in the QD group underwent follow-up transesophageal echocardiography. There were no statistically significant differences between the two groups in terms of DRT (1.4% vs. 2.7%, p = 0.60), minor bleeding (8.2% vs. 11.0%, p = 0.39), thromboembolic events (1.0% vs. 0.8%, p = 1.00), major bleeding (0.5% vs. 0.8%, p = 1.00), or death. Conclusion: A short course of twice-daily rivaroxaban following LAAC is a feasible alternative regimen with a low rate of major bleeding events, DRT, and thromboembolic events for patients with AF.

P943 Real world Effectiveness and safety of tofacitinib in patients with Ulcerative Colitis: 6 months follow-up of the French TOFAST study

Abstract Background TOFAST is an observational, prospective, multicenter cohort study aiming to describe the real-life clinical benefit of tofacitinib in moderate-to-severe Ulcerative Colitis (UC). Methods We report the results of the interim analysis after 6 months of follow-up, describing patient's characteristics, effectiveness, including change in daily PRO2 scores [RB and stool frequency (SF)] during the first 14 days and the median time to relief, and safety. Clinical response was defined as a decrease in partial Mayo score (PMS) (≥ 3 points and ≥30%) from inclusion with a concomitant decrease in rectal bleeding (RB) subscore ≥ 1 point (absolute subscore of 0 or 1). Clinical remission was defined as PMS ≤2 with no subscore &amp;gt;1. Symptomatic relief was reported by patients as the time in days from initiation of tofacitinib to improvement of their symptoms. Safety has been been reported as the % of Adverse Events (AE), serious AE and AE of special interest. Results 88 patients were included in the safety analysis (one patient was excluded from the effectiveness analysis as he did not meet the eligibility criteria) with a median exposure duration of 11.7 [Q1; Q3: 6.0; 22.1] months. Of these patients, 67 completed a 6-month follow-up visit by 15/07/2023 and were included in the effectiveness analysis. At inclusion 59.8% of patients were male with a mean (± SD) age of 37.5 ±13.2 years, a median disease duration of 5.9 years [Q1; Q3: 2.7; 13.1]. 46.5% of patients had pancolitis. The mean total Mayo Score was 8.1 ±2.4. 94.3% of patients had previously received at least one anti-TNF agent, 67.8% vedolizumab and 35.6% ustekinumab. Tofacitinib was initiated at 10 mg b.i.d, in combination with corticosteroids for 35.6% of patients. At 6 months, 53 (77.9%) patients were still treated with tofacitinib, 58.5% at 10 mg BID dose. Corticosteroids were ongoing in 22.9% of patients. Clinical response and remission were observed in 64.2% and 61.2% of patients, respectively. For the 68 (78.2%), patients who reported improvement the median time to relief was 7 days [Q1; Q3: 3.5 ;14.5]. PRO2 scores normalization during the first 14 days is shown in the figure. 84.1% of patients reported at least one adverse event (AE) and 21.6% reported at least one serious AE. Seventeen (19.3%) infections and 3 (3.4%) cases of herpes zoster were observed as well as one non-invasive low-grade urothelial carcinoma. No major cardiovascular or venous thromboembolic event, nor malignancy or death were observed (Table). Conclusion In this real-life cohort of patients with refractory UC, tofacitinib induced a clinical response and remission in over 60% of patients, with symptoms relief observed as early as the first two weeks. AEs were consistent with the known tofacitinib safety profile.

Comparison of Fibrinogen Concentrate and Cryoprecipitate on Major Thromboembolic Events after Living Donor Liver Transplantation

(1) Background: Liver transplantation (LT) is associated with significant hemorrhage and massive transfusions. Fibrinogen replacement has a key role in treating massive bleeding during LT and hypofibrinogenemia is treated by fibrinogen concentrate or cryoprecipitate. However, these two products are known to be associated with major thromboembolism events (MTEs). We aimed to compare the effect of fibrinogen concentrate and cryoprecipitate on MTEs in living donor LT (LDLT) recipients. (2) Methods: We analyzed 206 patients who underwent LDLT between January 2021 and March 2022. The patients were divided into two groups according to fibrinogen concentrate or cryoprecipitate use. We compared the incidence of MTEs between the two groups. In addition, we performed multiple logistic regression analyses to identify the risk factors for MTEs. (3) Results: There was no significant difference in the incidence of MTEs (16 [14.7%] vs. 14 [14.4%], p = 1.000) between the cryoprecipitate group and fibrinogen concentrate group. In the multivariate analysis, cryoprecipitate (OR 2.09, 95%CI 0.85–5.11, p = 0.107) and fibrinogen concentrate (OR 2.05, 95%CI 0.82–5.12, p = 0.126) were not significantly associated with MTEs. (4) Conclusions: there was no significant difference in the incidence of MTEs between cryoprecipitate and fibrinogen concentrate in LDLT recipients.

Cardiovascular Safety of Ozanimod in Patients With Ulcerative Colitis: True North and Open-Label Extension Analyses

Evaluating cardiovascular safety of sphingosine 1-phosphate (S1P) receptor modulators is warranted due to S1P receptor expression on cardiomyocytes and vascular endothelial cells. This analysis reports the cardiovascular safety of ozanimod, an S1P receptor modulator, in patients with moderately to severely active ulcerative colitis from the phase 3 True North (TN) and open-label extension (OLE). All patients who received ozanimod in TN (n= 796) and all eligible TN patients who entered the OLE (n= 823) were included. Cardiovascular-related adverse events were evaluated in patients with up to 146 weeks of ozanimod exposure (2219 patient-years), which included 52 weeks during TN. On TN day 1, first-dose ozanimod resulted in a 0.2 beats per minute mean decrease in heart rate from pretreatment to hour 6; 2 patients experienced bradycardia, which resolved without treatment modification. Mean systolic and diastolic blood pressure increases of 5.1 and 2.2 mm Hg, respectively, were observed at TN week 52. No second-degree Mobitz type II atrioventricular block events were reported; 1 third-degree atrioventricular block unrelated to ozanimod occurred in the OLE. Cardiac and vascular treatment-emergent adverse events were infrequent (3.8% [31 of 823] and 8.5% [70 of 823]); no ozanimod-related cardiovascular deaths occurred. The incidences of deep-vein thrombosis (0.2%; 2 of 823), pulmonary embolism (0.2%; 2 of 823), and ischemic stroke (0.4%; 3 of 823) in the OLE were low. No new cardiovascular safety signals were identified, consistent with findings from previous ozanimod studies. There were few major adverse cardiovascular events or thromboembolic events, which were unrelated or unlikely related to ozanimod. Ozanimod has a well-tolerated cardiovascular safety profile when prescribed in accordance with the label. Clinical trial registry website and trial numbers: ClinicalTrials.gov numbers: NCT02435992 and NCT02531126.

Post Hoc Analysis of a Phase 2/3 Study in Japanese Patients with iTTP Treated with Caplacizumab

Introduction Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disease caused by a severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13). Caplacizumab is a von Willebrand factor-directed antibody fragment designed to treat iTTP in conjunction with therapeutic plasma exchange (TPE) and immunosuppressive therapy. Caplacizumab was approved in Europe in 2018, in the United States in 2019, and in Japan in 2022. Methods In the open-label, Phase 2/3 study (NCT04074187), Japanese patients ≥18 years old with a clinical diagnosis of iTTP and ≤1 prior TPE received caplacizumab in combination with TPE and immunosuppression for ≥30 days post-TPE and were followed for 4 weeks after the end of treatment. Patients with persistent ADAMTS13 deficiency (eg, &amp;lt;10%) were allowed treatment extension of up to 8 weeks. This post hoc analysis assessed outcomes including patient characteristics, time to platelet count recovery, time to normalization of all 3 organ damage markers (lactate dehydrogenase, cardiac troponin I, and serum creatinine), safety, time to recovery of ADAMTS13 activity, ADAMTS13 activity at end of treatment, and incidence of ADAMTS13 inhibitor elevation during treatment stratified by iTTP severity. Very severe iTTP at baseline was defined as follows: French severity score ≥3 or severe neurological involvement (eg, coma, seizures, focal deficit), or cardiac involvement (cardiac troponin level &amp;gt;2.5×ULN). Results Overall, 21 patients were enrolled and treated with ≥1 dose of caplacizumab (modified intent-to-treat population [mITT] and safety population). Of these,19 patients had confirmed iTTP (less severe iTTP, n=8; very severe iTTP, n=11; Table). Median (95% confidence interval [CI]) time to platelet count response and median (range) days of TPE was 3.28 (1.69-4.01) and 5.5 (3-15) days in patients with less severe iTTP and 3.49 (1.76-3.98) and 6.0 (4-20) days in patients with very severe iTTP, respectively. Median (95% CI) time to normalization of all 3 organ damage marker levels was 1.73 (0.79-2.94) days in patients with less severe iTTP and 8.66 (2.65-12.55) days in patients with very severe iTTP, which may reflect the fact that patients with very severe iTTP had worse organ damage at baseline. The number of patients experiencing recurrence, ≥1 major thromboembolic event, or TTP-related death in patients with less severe and very severe iTTP was 1 for each subgroup. Two patients in each disease severity subgroup had ≥1 treatment-emergent serious adverse event. Of the 19 patients with confirmed iTTP, median (95% CI) time to recovery of ADAMTS13 activity to ≥10, ≥20, and ≥60% was 14.57 (5.95-24.76),18.49 (5.95-31.75), and 47.51 (18.49-60.94) days, respectively. Patients with ADAMTS13 inhibitor levels ≥2 BU/mL at baseline (n=7) took approximately twice as long to recover ADAMTS13 activity to ≥10, ≥20, and ≥60% versus patients with baseline inhibitor levels &amp;lt;2 BU/mL. Median (range) ADAMTS13 activity level at the end of caplacizumab treatment was 62.0% (29.0%-101.0%). ADAMTS13 inhibitor elevation occurred in 9 patients (Figure). Among them, 7 patients extended caplacizumab treatment. Only 1 patient with inhibitor re-increase experienced a recurrence 2 days after discontinuing caplacizumab due to an adverse event. Conclusions These results suggest that caplacizumab in conjunction with TPE and immunosuppression is effective for patients with iTTP regardless of their baseline severity and may reduce the risk of recurrence due to inhibitor re-increase.