Co-primary Endpoints Research Articles

BIOM-12. ALLIANCE A071401: GENOMICALLY GUIDED PHASE II TRIAL OF ABEMACICLIB IN PATIENTS WITH GRADE 2/3 MENINGIOMAS HARBORING SOMATIC NF2 OR CDK PATHWAY ALTERATIONS

Abstract BACKGROUND Patients with meningiomas that have progressed after surgery and/or radiation have limited treatments. Loss of NF2 and CDKN2A/B are common in higher-grade meningiomas and promote meningioma progression. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance A071401, a genomically-driven phase II trial in recurrent or progressive meningiomas. METHODS Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR); the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided ≥85% power to detect a PFS6 ≥41.5% (vs. null 15%; alpha=0.02), and ≥89% power to detect RR ≥20% (vs. null 2.5%; alpha=0.021). RESULTS Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received abemaciclib. The observed PFS6 rate in the first 24 evaluable pts was 54% (95% CI 33-75%), thus the study met PFS6 endpoint. Of all 35 evaluable pts, median PFS was 7.6 months (95% CI 3.6-17.1 months), estimated 6-month PFS was 55% (95% CI 40-75%) and estimated 6-month OS was 88% (95% CI 77-100%). No objective responses were observed. Of the 36 pts who started treatment, two had a grade 4 adverse event at least possibly related to treatment which included ALT elevation(1), AST elevation(1) and vomiting(1). Patients with NF2 alterations (n=24) had favorable PFS6 outcomes (58%, 95% CI 37-78%) compared to those with CDK (n=4, 25%, 95% CI 1-81%) and CDK+NF2 alterations (n=7, 29% 95% CI 4-71%), (Fisher’s Exact p=0.036). CONCLUSIONS Abemaciclib was well-tolerated and resulted in improved PFS6, meeting the trial’s co-primary endpoint. Abemaciclib warrants further investigation for the treatment of patients with progressive meningiomas.

CTNI-24. WF-1801: SINGLE ARM PILOT STUDY OF RAMIPRIL FOR PREVENTION OF RADIATION-INDUCED COGNITIVE DECLINE IN GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIOTHERAPY

Abstract BACKGROUND Patients with glioblastoma (GBM) experience cognitive decline after chemoradiation. Radiation therapy (RT) to the brain creates chronic inflammation believed to contribute to cognitive decline. Ramipril counteracts neuroinflammatory changes in pre-clinical models when given during RT. METHODS This prospective single arm study (WF-1801) coordinated by the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base assessed feasibility, tolerability, and potential efficacy of using ramipril in patients with GBM. Eligibility and treatment paradigms mirrored NRG/RTOG 0825 allowing for outcomes from the placebo arm to be used for comparison. Participants took ramipril during 6 weeks of chemoradiation with temozolomide and for 3 months after RT. Patients completed cognitive testing (HVLT-R, TMT, and COWA) and patient-reported outcomes at baseline, RT completion, and 1 and 4 months after RT. Co-primary endpoints were retention rate (compliance with 75% doses and completion of cognitive testing) and change in cognitive composite score 1 month after RT. RESULTS 75 participants were accrued between 3/25/2019 and 11/14/23: 65% were male, 89% White, median age 63 years. The NRG/RTOG 0825 placebo cohort (n=247) was younger (median 57, p<0.0001) with more White participants (95%, p=0.04). The overall retention rate in WF-1801 was 48% (one-sided 95% CI: 38%-100%); 61% completed >=75% of doses; 57% completed cognitive testing at all time points. The median (range) change in cognitive composite score 1 month after RT was 0.01 (-82.6, 13.0) reflecting an improvement from baseline. However, this was not significantly different from the NRG/RTOG 0825 placebo group median of 0.10 (-48.2, 8.6); p=0.49. CONCLUSION The overall retention rate fell short of our pre-specified endpoint of > 65%; however, medication compliance was high and well-tolerated in retained patients. Future investigations could identify patient subsets who may benefit more from concurrent ramipril. WF-1801 (NCT03475186) funded by UG1CA189824. NRG/RTOG-0825 (NCT00884741) funded by U10CA180868 and U10CA021661.

Effects of Implementing a Heart Failure Order Set to Optimize Guideline-Directed Medical Therapy and Diuresis in Patients with Acute Heart Failure

Background: Utilization of guideline-directed medical therapy in patients hospitalized for acute heart failure is suboptimal during the hospitalization and after discharge. An inpatient heart failure order set may be a convenient and useful intervention to improve heart failure therapy in the inpatient setting. Methods: This is a retrospective study that assessed the use of an inpatient heart failure order set on pharmacologic therapy in patients hospitalized for acute heart failure from May to August 2022. Patients with heart failure with an ejection fraction less than 50% were included in the analysis. The co-primary endpoints were maintenance or optimization of guideline-directed medical therapy during the hospitalization. Results: Maintenance of guideline-directed medical therapy was significantly greater when providers used the heart failure order set (OR 2.35, 95% CI 1.03-5.33, P = .041). Optimization of guideline-directed medical therapy was also statistically greater with use of the order set (OR 11.31, 95% CI 4.37-29.31, P < .001). Conclusions: An inpatient heart failure order set may be an effective strategy to improve heart failure pharmacotherapy in patients hospitalized with acute heart failure.

Renal Effects of Combination Phosphodiesterase V Inhibition and Low-Dose B-Type Natriuretic Peptide in Acute Heart Failure: A Randomized Clinical Trial.

Cardiorenal dysfunction with impaired cyclic GMP (cGMP) response is common in patients presenting with acute heart failure (HF). Type V phosphodiesterase (PDEV) is known to be upregulated in HF and may explain the dysfunction of renal response. The aim of this study was to determine whether B-type natriuretic peptide (BNP) alone or in combination with PDEV inhibition improves renal function and increases urinary sodium and cGMP excretion in acute HF. This open-label study included 67 patients hospitalized with acute HF and renal dysfunction. Patients were randomized to standard care, low-dose intravenous BNP (0.005 µg/kg per minute), or combination BNP/PDEV inhibition with sildenafil (25 mg q12 hours) for 48 hours. The coprimary end points were the percent change in estimated glomerular filtration rate and blood urea nitrogen from baseline to 48 hours. Treatment with BNP and BNP/PDEV inhibitor significantly increased plasma cGMP at 24 hours (+25.6% [+9.8%, +84.7%] and +60.8% [+32.3%, +103.8%] for BNP and BNP/PDEV versus -13.5% [-29.1%, +14.2%] with standard care; P=0.001). However, there was no significant change in estimated glomerular filtration rate 0 (-10.8%, +12.7%) for standard care versus 0 (-15.3%, +11.8%) for the BNP group versus -8.8% (-14.3%, +8.3%) for the BNP/PDEV group (P=0.60) or blood urea nitrogen -1.4% (-10.7%, +12.0%) for standard care versus -5.9% (-14.6%, +9.4%) for the BNP group versus +6.9% (-5.3%, +18.8%) for the BNP/PDEV group (P=0.38) between groups. Hypotension was more common in the BNP/PDEV inhibitor group. BNP and combination BNP/PDEV inhibition increased plasma cGMP in patients with acute HF but did not improve renal function or urinary sodium/cGMP excretion. Our study does not support the use of intravenous low-dose BNP with or without PDEV inhibition to enhance renal function in patients admitted with acute HF. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00972569.

Brodalumab is Effective for Psoriasis Patients with Difficult-to-treat Body Regions: Results from an Observational Clinical Study.

Brodalumab, a human monoclonal antibody that selectively inhibits the interleukin (IL)-17 receptor subunit A, has been approved for the treatment of moderate-to-severe plaque psoriasis. The treatment benefit of brodalumab has been clearly demonstrated in multiple clinical studies. However, data on effectiveness for difficult-to-treat body regions, especially in everyday clinical practice, are still limited. In this exploratory observational clinical study, psoriasis patients suffering from nail and scalp involvement who received brodalumab during routine clinical care were enrolled at 7 centers in Germany. Patients were observed over 60 weeks. The co-primary endpoints were 75% improvement in Psoriasis Scalp Severity Index (PSSI75) at week 12 and 75% improvement in Nail Psoriasis Severity Index (NAPSI75) at week 24. Secondary endpoints included assessment of general skin and disease outcomes, quality-of-life, and patient satisfaction with treatment. Eighty-seven patients were included. Mean age was 46.8 years, 70.1% patients were male, and mean body mass index was 28.9 kg/m². The co-primary endpoints were achieved by more than 90% of patients who met criteria for effectiveness analyses (n=62): 93.6% of patients achieved PSSI75 at week 12 and 90.3% of patients achieved NAPSI75 at week 24. Median body surface area involvement improved from 14% at baseline to 1.5% and 1% at weeks 12 and 24, respectively. Median Dermatology Life Quality Index scores improved from 16 at baseline to 2 and 1 at weeks 12 and 24, respectively. Improvements were maintained in the majority of patients throughout the 60-week study. Brodalumab was well tolerated and patients were highly satisfied with treatment. Outcomes assessed in this study, including assessments of scalp and nail symptoms, improved following initiation of brodalumab therapy. This study of psoriasis patients in a real-world setting supports the long-term clinical effectiveness of brodalumab on difficult-to-treat body regions.

Uptake of gonadotrophin-releasing hormone agonists for prevention of premature ovarian insufficiency in women undergoing chemotherapy: an Australian single-centre study.

Treatment-related premature ovarian insufficiency (POI) can result in early-onset menopause and infertility. To assess the prevalence of goserelin use for POI prevention in women with cancer since it was listed by the Australian Pharmaceutical Benefits Scheme in 2018 for this indication. This retrospective study included women aged 18-45 years who received curative-intent alkylating chemotherapy for a malignancy between August 2020 and December 2022 at the Peter MacCallum Cancer Centre. The co-primary end-points were (i) documentation of a discussion with the patient regarding goserelin for POI prevention and (ii) prescription of goserelin for POI prevention prior to chemotherapy commencement. Sixty-six patients were eligible. Fifty patients (76%) had a documented discussion regarding goserelin for POI prevention and 53 patients (80%) were prescribed goserelin for POI prevention. Nulliparous women were more likely to have a discussion regarding goserelin (P = 0.004). Younger women, nulliparous women and those referred to a fertility service were more likely to have been prescribed goserelin for POI prevention (P = 0.003, P = 0.001 and P = 0.002 respectively). Twenty-one of 53 patients (40%) who received goserelin had the first dose administered ≥7 days before chemotherapy commencement. One-quarter of eligible patients did not have a documented discussion regarding goserelin, despite the negative consequences of POI. Efforts are needed to increase the discussion and use of goserelin in all premenopausal women regardless of their fertility interests and to ensure timely administration in those who choose to receive it.

Balancing Fertility Preservation and Treatment Efficacy in (Neo)adjuvant Therapy for Adolescent and Young Adult Breast Cancer Patients: a Narrative Review.

Adolescent and young adult (AYA) breast cancer survivors face a significant risk of infertility due to the gonadotoxic effects of (neo)adjuvant therapy, which complicates their ability to conceive post-treatment. While (neo)adjuvant therapy primarily aims to improve recurrence-free and overall survival, fertility preservation strategies should also be considered for young patients. This narrative review explores recent advancements in fertility preservation techniques, such as oocyte, embryo, and ovarian tissue cryopreservation, and evaluates the feasibility of modifying breast cancer (neo)adjuvant therapy to preserve fertility without compromising survival outcomes. Our review highlights that clinical trials with co-primary endpoints of oncological safety and fertility preservation are limited, and substituting standard treatment regimens solely for fertility preservation is currently not recommended. Nevertheless, new clinical studies have emerged that either exclude highly ovarian-toxic agents, such as cyclophosphamide, or omit adjuvant therapy altogether, even if fertility preservation is not their primary endpoint. Unfortunately, many of these trials have not evaluated ovarian toxicity. Notably, since 2020, major oncology organizations, including the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO) have advocated for the routine assessment of ovarian toxicity in all clinical trials. The review underscores the importance of incorporating ovarian toxicity as a standard endpoint in future trials involving premenopausal breast cancer patients to identify treatment regimens that can effectively balance fertility preservation with treatment efficacy.

Preventing Allogeneic Stem Cell Transplant-Related Cardiovascular Dysfunction: ALLO-Active Trial.

Allogeneic stem cell transplantation (allo-SCT) is an efficacious treatment for hematologic malignancies but can be complicated by cardiac dysfunction and exercise intolerance impacting quality of life and longevity. We conducted a randomized controlled trial testing whether a multicomponent activity intervention could attenuate reductions in cardiorespiratory fitness and exercise cardiac function (co-primary end points) in adults undergoing allo-SCT. Sixty-two adults scheduled for allo-SCT were randomized to a 4-month activity program (n=30) or usual care (UC; n=32). Activity comprised multicomponent exercise training (3 days/week) and sedentary time reduction (≥30 min/day) program and was delivered throughout hospitalization (≈4 weeks) and for 12 weeks after discharge. Physiological assessments conducted before admission and at 12 weeks after discharge included cardiopulmonary exercise testing to quantify peak oxygen uptake ([Formula: see text]), exercise cardiac magnetic resonance imaging for peak cardiac volume (CIpeak) and stroke volume (SVIpeak) index, echocardiography-derived left ventricular ejection fraction and global longitudinal strain, and cardiac biomarkers (cTn-I [troponin-I] and BNP [B-type natriuretic peptide]). Fifty-two participants (84%) completed follow-up (25 activity and 27 UC); median (interquartile range [IQR]) adherence to the activity program was 74% (41-96%). There was a marked decline in [Formula: see text] in the UC program (-3.4 mL‧kg-1‧min-1 [95% CI, -4.9 to -1.8]) that was attenuated with activity (-0.9 mL‧kg-1‧min-1 [95% CI, -2.5 to 0.8]; interaction P=0.029). Activity preserved exercise cardiac function, with preservation of CIpeak (0.30 L‧min-1‧m-2 [95% CI, -0.34 to 0.41]) and SVIpeak (0.6 mL/m2 [95% CI, -1.3 to 2.5]), both of which declined with UC (CIpeak, -0.68 L‧min-1‧m-2 [95% CI, -1.3 to -0.32]; interaction P=0.008; SVIpeak, -2.7 mL/m2 [95% CI, -4.6 to -0.9]; interaction P=0.014). There were no treatment effects of activity on cardiac biomarkers or echocardiographic indices. Multicomponent activity intervention during and after allo-SCT is beneficial for preserving patient cardiorespiratory fitness and exercise cardiac function. These results may have important implications for cardiovascular morbidity and mortality after allo-SCT. URL: https://anzctr.org.au/; Unique identifier: ACTRN12619000741189.

Novel versus Established Cryoballoon Ablation System for Atrial fibrillation: A Systematic Review and Meta-Analysis

BackgroundRecently a novel cryoballoon ablation (CBA) system (POLARx) for the treatment of atrial fibrillation (AF) has been introduced. ObjectiveWe aimed at systematically reviewing the efficacy and safety of the POLARx to the ArcticFront system. MethodsStructured systematic database search for articles published between 2021 and 2024 reporting the efficacy and/or safety of the POLARx system for AF ablation. The co-primary endpoints were the long-term efficacy and safety of the POLARx system ResultsOf the 24 studies with 5364 patients (weighted mean age 62.4 years) included, 15 compared the POLARx system (1746 patients) to the ArcticFront system (2282 patients). Despite significantly lower temperatures at isolation (POLARx -46.3°C, ArcticFront -31.6°C, p <0.01) and nadir temperatures (POLARx -56.5°C ArcticFront -47.8°C p <0.01), the POLARx system did not show a better acute (98.9% and 99.2% successfully ablated patients, 99.5% and 99.8% successfully ablated pulmonary veins in the POLARx and ArcticFront group, respectively) or long-term efficacy (After a weighted mean follow-up of 12.6 months, the success rate was 69.5% with POLARx and 60.2% with ArcticFront (p = 0.98)). While most complications were similar between the POLARx and ArcticFront group, the incidence of phrenic nerve palsies in the pooled cohorts (all POLARx vs all ArcticFront control patients) differed (2.7% vs. 1.6% in the POLARx vs. ArcticFront group, respectively, OR 1.79 [1.14-2.83], p-value = 0.01). ConclusionThe novel POLARx system provided similar efficiency and acute/long-term efficacy, but showed a higher incidence of phrenic nerve palsies compared to the ArcticFront system.

Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial

Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis. ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed. Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group. Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug. Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".

Tofacitinib Safety and Effectiveness in Canadian Patients with Rheumatoid Arthritis by Cardiovascular Risk Enrichment: Subanalysis of the CANTORAL Study.

ORAL Surveillance, a post-authorisation safety study of patients with rheumatoid arthritis (RA) enriched for cardiovascular (CV) risk, demonstrated increased risk of major adverse CV events (MACE) and malignancies (excluding non-melanoma skin cancer [NMSC]) for tofacitinib versus tumour necrosis factor inhibitors (TNFi). This analysis of a real-world Canadian observational study evaluated tofacitinib safety/effectiveness in patients meeting or not meeting CV risk criteria. CANTORAL included patients with moderate-to-severe RA initiating tofacitinib (10/2017-07/2020; N = 504). Interim data (data-cut: 07/2021) were stratified as CV risk-enriched (CV+ ; patients ≥ 50 years with ≥ 1 additional CV risk factor) or not CV risk-enriched (CV-; ≥ 50years without additional CV risk factors and 18-49 years with/without CV risk factors). Safety and persistence were evaluated to month (M) 36. Effectiveness outcomes to M18 included Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA)/remission (CANTORAL co-primary endpoints) and Disease Activity Score in 28 joints, C-reactive protein (DAS28-4[CRP]) < 3.2/ < 2.6. Overall, 272/232 patients were included in CV+ /CV- cohorts (full analysis set) (435/356 patient-years [safety analysis set]). Incidence rates (events/100 patient-years) in CV+ /CV- cohorts were 138.5/112.5 for treatment-emergent adverse events (AEs); 17.0/5.6for serious AEs; 1.2/0.3for deaths; 5.5/1.7 for serious infections; 1.4/1.1 for herpes zoster; 1.6/0.0for MACE; 2.1/0.3for malignancies (excluding NMSC); 0.7/0.6 for NMSC; 0.5/0.0 for venous thromboembolic events. Persistence was generally comparable between cohorts. In CV+ /CV- cohorts, at M6, CDAI LDA and remission rates were 51.5%/54.6% and 12.0%/19.6%; DAS28-4(CRP) < 3.2/ < 2.6 rates were 44.0%/39.3% and 31.5%/28.8%, respectively; effectiveness was generally maintained to M18. In concordance with studies of background risk, AEs were more common in patients with CV risk enrichment, particularly those aged ≥ 65 years. Tofacitinib effectiveness/persistence were generally similar regardless of CV risk enrichment. These findings support individualised treatment benefit-risk assessment, including CV assessment/management, to optimise RA outcomes.

Interleukin-6, C-Reactive Protein, and Recurrence After Stroke: A Time-Course Analysis of Individual-Participant Data.

Inflammation promotes atherogenesis. Randomized controlled trials of anti-inflammatory therapies for prevention after stroke have not yet demonstrated clear benefit. IL-6 (interleukin-6) and hsCRP (high-sensitivity C-reactive protein) are independently associated with major adverse cardiovascular events poststroke and may guide patient selection in future randomized controlled trials. Optimal timing of hsCRP/IL-6 measurement poststroke is unknown, as early blood levels may be confounded by the inflammatory response to brain infarction. Using individual-participant data from a systematic review, we performed a time-course analysis to investigate the association between hsCRP/IL-6 and recurrent events stratified by timing of sampling. The prespecified coprimary end points after sample measurement were: (1) recurrent major adverse cardiovascular events (first major coronary event, recurrent stroke, or vascular death) and (2) recurrent stroke (ischemic, hemorrhagic, or unspecified). The poststroke dynamics of IL-6/hsCRP were analyzed by plotting their median (interquartile interval) concentrations within each tenth of the sampling timeframe. Acute/postacute phases were defined for each biomarker according to the shape of this relationship. There were data for 9798 patients from 11 studies (19 891 person-years follow-up, 10 observational cohorts, and 1 randomized trial). Each marker was measured once. IL-6 was markedly elevated <24 hours poststroke compared with postacute levels (≥24 hours; 11.6 versus 3.02 pg/mL; P<0.001). HsCRP was elevated for 10 days. IL-6 was associated with recurrent major adverse cardiovascular events in the postacute phase (≥24 hours; risk ratio, 1.30 [CI, 1.19-1.41], per unit logeIL-6), but not in the acute phase (<24 hours; risk ratio, 1.10 [CI, 0.98-1.25]; Pinteraction=0.03). After adjustment for risk factors/medication, the association remained for postacute IL-6 when analyzed per logeunit (risk ratio, 1.16 [CI, 1.05-1.66]) and per quarter increase (risk ratio, 1.55 [CI, 1.19-2.02]; Q4 versus Q1), but not if measured acutely. Similar findings were observed for recurrent stroke. There was no evidence of time-dependent interaction with hsCRP. Timing of sample measurement after stroke modifies the association with recurrent major adverse cardiovascular events for IL-6 but not hsCRP. These data inform future randomized controlled trial designs incorporating biomarker-based selection of patients for anti-inflammatory therapies.

Simulation training for invasive cardiovascular procedures: the Heart-SIMS-1 study

Abstract Introduction Interventional cardiology training has a long learning curve and exposes patients and clinicians to undesirable procedural risks. We aim to assess whether mentored simulation-based training with three dimensional (3D) printed models can improve the procedural skills and safety performance of beginners in coronary diagnostic procedures. Methods Twenty-nine final-year medical students from a single centre were lectured in the basic principles of invasive coronary angiography (ICA) for one-hour, and then randomized to conventional training or simulation training. Conventional training (n=15) consisted in watching a 20-minute video demonstrating all ICA steps in a 3D-printed coronary simulator. Simulation training (n=14) offered the same explanations in a hands-on training session with the 3D-printed model, in pairs, for 20 minutes. The co-primary endpoint was efficacy and safety of performing a simulated ICA in the 3D-printed simulator, installed under sterile drapes, in a conventional angiography suite. Efficacy and safety were graded by a blinded investigator using a pre-specified performance checklist, including the identification of procedural "red flags", graded 0-100%. The secondary endpoint was theoretical knowledge, assessed in a 25-question multiple-choice quiz, graded 0-100%. Results All participants completed the training and evaluation phases. Both elements of the co-primary endpoint were superior in the simulation group: efficacy score of 91.5 ± 3.8 vs 64.6 ± 8.3% and safety score 100.0 (100.0-100.0) vs 62.5 (20.8-79.2) %, p&amp;lt;0.001. The median number of "red flags" were 2 (1-4) in conventional and 0 (0-0) in simulation training recipients (p&amp;lt;0.001). Secondary endpoint was higher in simulation training: 85.7 ± 9.0 vs 76.8 ± 12.7% (p=0.039). Conclusion Mentored simulation-based training of medical students in ICA with 3D-printed models resulted in improved performance regarding efficacy, procedural safety, and theoretical knowledge.ResultsSimulation and evaluation setup

Treatment of Post-COVID-19 POTS by inhibiting FcRn: a phase 2 randomized, placebo controlled, double-blind, proof of concept study with efgartigimod

Abstract Background While the underlying pathophysiology is unknown, post–COVID-19 postural orthostatic tachycardia syndrome (POTS) may be related to immune dysfunction and autoimmunity precipitated by SARS-CoV-2 infection. Various autoantibodies, including those targeting G-protein coupled receptors (GPCRs), have been observed in patients with POTS. Binding of these autoantibodies to adrenergic receptors, which are prototypical GPCRs, has been hypothesized to modulate receptor activity, increase sympathetic tone, and cause tachycardia. Moreover, IgG anti-GPCR autoantibodies, acting as partial agonists, are thought to decrease the effect of peripheral vasomotor control, leading to an increased sympathetic response to upright posture that can result in postural tachycardia in the absence of hypotension. Purpose We hypothesize that a reduction in autoantibody levels by efgartigimod, a FcRn-antagonist, will ameliorate the underlying immune-mediated pathogenesis and lead to clinical improvements in patients who developed POTS following COVID-19 infection. We propose a phase II multicenter, randomized, placebo-controlled, double-blind, proof-of-mechanism study initiated to evaluate the safety and efficacy of efgartigimod in adults with post–COVID-19 POTS. Methods Adult patients diagnosed with new-onset of POTS following SARS-CoV-2 infection are eligible for participation in the study. Prior COVID-19 must be confirmed by documentation of historical PCR test, and POTS diagnosis must meet consensus criteria. Study subjects must have moderate to severe autonomic symptoms (COMPASS-31 score ≥ 35 points at screening). Approximately 42 patients will be randomly allocated (2:1) to receive weekly intravenous efgartigimod or placebo for 24 weeks. At the end of the treatment period, participants who complete the study may roll over into an open-label extension (OLE). The co-primary endpoints are change from baseline to week 24 in the COMPASS-31 and Malmo POTS Symptom Score as well as safety and tolerability outcomes. Key secondary endpoints include assessments of disease activity, fatigue, cognitive function, walking capacity and quantitative autonomic testing. Additional exploratory endpoints include intraepidermal small fiber densities (optional), sudomotor innervation (optional) and peripheral blood biomarkers to define histopathological and immune determinants associated with treatment response. Conclusions This phase II study of efgartigimod will evaluate the effect of FcRn inhibition on disease pathology and the potential for therapeutic benefit in patients with post–COVID-19 POTS.

Post-PCI anticoagulation with unfractionated heparin in acute coronary syndrome: insight from the STOPDAPT-3 trial

Abstract Background The guidelines recommend the post-procedural anticoagulation should be discontinued after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) except for the specific indications.(1) However, these guideline recommendations were not well supported by data, and therefore, post-PCI parental anticoagulation has been commonly implemented in patients with ACS in the previous studies.(2-5) Purpose To clarify the preference and clinical situations of post-PCI unfractionated heparin (UFH) in ACS patients and to explore the influence of post-PCI UFH on cardiovascular and bleeding outcomes. Methods STOPDAPT-3 trial is a randomized controlled trial to demonstrate the efficacy and safety of the aspirin-free prasugrel monotherapy strategy compared to the conventional dual antiplatelet therapy after PCI in patients with high-bleeding risk or ACS.(6) Data on periprocedural heparin use and its doses were vigorously collected. The current study population was the ACS patients enrolled in the STOPDAPT-3 without use of mechanical circulatory support devices. The two co-primary endpoints were the bleeding outcome defined as the BARC 3 or 5 criteria and the cardiovascular outcome defined as a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke. Outcomes were assessed at 30 days from index PCI. Results Among 4088 ACS study patients, 2339 (57.2%) patients received post-PCI UFH. Median dose of UFH was 7.1 (IQR 6.0-8.8) units/kg/hour and the median duration was 25 (IQR 24-48) hours. As many as 57.7% of patients received 10000 units/day of heparin after PCI irrespective of body weight. STEMI patients more frequently received post-PCI UFH compared to NSTE-ACS (72.3% and 38.8%, P&amp;lt;0.001) and the patients with intraprocedural adverse angiographic findings such as thrombus, slow-flow, no-reflow, or final TIMI flow &amp;lt;=2 also more frequently received post-PCI UFH than those without (67.6% and 47.5%, P&amp;lt;0.001). Post-PCI UFH was associated with a significantly increased risk of bleeding endpoint (4.75% and 2.52%, adjusted HR 1.69 [95%CI 1.15-2.46], P=0.007) and a numerically increased risk of cardiovascular endpoint (3.16% and 1.72%, adjusted HR 1.56 [95%CI 0.98-2.46], P=0.06). Even in the patients with intraprocedural adverse angiographic findings, post-PCI UFH did not show a clear benefit for cardiovascular endpoint (3.15% and 1.72%, adjusted HR 1.73 [95%CI 0.88-3.41]. P=0.11). Conclusion(s) Post-PCI anticoagulation with UFH was frequently implemented in ACS patients enrolled in the latest large Japanese clinical trial. Post-PCI UFH use was associated with harm in terms of bleeding without a benefit in reducing cardiovascular events.

Mobile Stroke Unit Management in Patients With Acute Ischemic Stroke Eligible for Intravenous Thrombolysis

Clinical trials have suggested that prehospital management in a mobile stroke unit (MSU) improves functional outcomes in patients with acute ischemic stroke who are potentially eligible for intravenous thrombolysis, but there is a paucity of real-world evidence from routine clinical practice on this topic. To determine the association between prehospital management in an MSU vs standard emergency medical services (EMS) management and the level of global disability at hospital discharge. This was a retrospective, observational, cohort study that included consecutive patients with a final diagnosis of ischemic stroke who received either prehospital management in an MSU or standard EMS management between August 1, 2018, and January 31, 2023. Follow-up ended at hospital discharge. The primary analytic cohort included those who were potentially eligible for IV thrombolysis. A separate, overlapping cohort including all patients regardless of diagnosis was also analyzed. Patient data were obtained from the American Heart Association's Get With The Guidelines-Stroke (GWTG-Stroke) Program, a nationwide, multicenter quality assurance registry. This analysis was completed in May 2024. Prehospital management in an MSU (vs standard EMS management). The primary efficacy end point was the utility-weighted modified Rankin Scale (UW-mRS) score. The secondary efficacy end point was independent ambulation status. The coprimary safety end points were symptomatic intracranial hemorrhage (sICH) and in-hospital mortality. Of 19 433 patients (median [IQR] age, 73 [62-83] years; 9867 female [50.8%]) treated at 106 hospitals, 1237 (6.4%) received prehospital management in an MSU. Prehospital management in an MSU was associated with a better score on the UW-mRS at discharge (adjusted mean difference, 0.03; 95% CI, 0.01-0.05) and a higher likelihood of independent ambulation at discharge (53.3% [468 of 878 patients] vs 48.3% [5868 of 12 148 patients]; adjusted risk ratio [aRR], 1.08; 95% CI, 1.03-1.13). There was no statistically significant difference in sICH (5.2% [57 of 1094] vs 4.2% [545 of 13 014]; aRR, 1.30; 95% CI, 0.94-1.75]) or in-hospital mortality (5.7% [70 of 1237] vs 6.2% [1121 of 18 196]; aRR, 1.03; 95% CI, 0.78-1.27) between the 2 groups. Among patients with acute ischemic stroke potentially eligible for intravenous thrombolysis, prehospital management in an MSU compared with standard EMS management was associated with a significantly lower level of global disability at hospital discharge. These findings support policy efforts to expand access to prehospital MSU management.

Systematic review and indirect treatment comparisons of ritlecitinib against baricitinib in alopecia areata.

Ritlecitinib and baricitinib are recently approved systemic treatments for severe alopecia areata (AA). Both demonstrated superiority over placebo in hair regrowth measured by the Severity of Alopecia Tool (SALT), but they have not been directly compared in randomized controlled trials (RCTs). We conducted a systematic review of RCTs evaluating treatments in AA and estimated the efficacy and safety of ritlecitinib and baricitinib at Week 24 using Bayesian network meta-analysis. To adjust and explore effect modifiers, population-adjusted indirect comparison was performed via multilevel network meta-regression (ML-NMR) using ritlecitinib individual patient data (IPD). Co-primary endpoints were SALT ≤20 and SALT ≤10 at Week 24. Unanchored population adjusted ITCs were also computed to evaluate SALT ≤10 and SALT ≤20 endpoints at Week 48/52. Four RCTs (ALLEGRO 2a [NCT02974868], ALLEGRO 2b/3 [NCT03732807], BRAVE-AA1 [NCT03570749] and BRAVE-AA2 [NCT03899259]) were included. No evidence of a difference between ritlecitinib 50 mg and baricitinib 4 mg on SALT ≤10 (odds ratio, OR: 0.96, 95% credible interval, CrI: 0.18-7.21) and SALT ≤20 (OR: 2.16, 95% CrI: 0.48-16.46) at Week 24 was found. ML-NMR using ALLEGRO IPD adjusted for sex, SALT score at baseline, duration of current episode and disease duration found evidence of effect modification, although relative efficacy between ritlecitinib 50 mg and baricitinib 4 mg remained unchanged. Unanchored population-adjusted ITC at Week 48/52 was consistent with previous results. We found similar efficacy between ritlecitinib 50 mg and baricitinib 4 mg. These ITCs was informed by only four RCTs, uncertainty was considerable, and there was evidence of effect modification, highlighting the need for further quality research in AA.

An aspirin-free strategy for percutaneous coronary intervention in patients with diabetes: a pre-specified subgroup analysis of the STOPDAPT-3 trial.

Safety of aspirin-free strategy immediately after percutaneous coronary intervention (PCI) for cardiovascular events in patients with diabetes was unknown. We conducted the prespecified subgroup analysis on diabetes in the STOPDAPT-3 trial, which randomly compared prasugrel (3.75mg/day) monotherapy (2984 patients) to dual antiplatelet therapy (DAPT) with prasugrel and aspirin (2982 patients) in patients with acute coronary syndrome or high bleeding risk. The co-primary endpoints were major bleeding events (Bleeding Academic Research Consortium 3 or 5) and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) at 1 month. Of 5966 study patients, there were 2715 patients (45.5%) with diabetes. Patients with diabetes more often had chronic coronary syndrome, heart failure or cardiogenic shock, and comorbidities than those without. Patients with diabetes compared to those without had higher incidences of major bleeding and cardiovascular events. Regardless of diabetes, the effect of no-aspirin relative to DAPT was not different for the co-primary bleeding (diabetes: 5.05% versus 5.47%; HR, 0.92; 95%CI, 0.66-1.28 and non-diabetes: 3.99% versus 4.07%; HR, 0.98; 95%CI, 0.69-1.38; P for interaction=0.81) and cardiovascular (diabetes: 5.54% versus 5.15%; HR, 1.08; 95%CI, 0.78-1.49 and non-diabetes: 2.95% versus 2.47%; HR, 1.20; 95%CI, 0.79-1.82; P for interaction=0.70) endpoints. The incidences of subacute definite or probable stent thrombosis and any coronary revascularization were higher in the no-aspirin group than in the DAPT group regardless of diabetes. The effects of an aspirin-free prasugrel monotherapy (3.75mg/day) relative to DAPT for major bleeding and cardiovascular events were not different regardless of diabetes. Clinical trial registration: ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent-3 [STOPDAPT-3]; NCT04609111.

Upadacitinib in Adolescents With Moderate to Severe Atopic Dermatitis

The Measure Up 1, Measure Up 2, and AD Up studies demonstrated the efficacy and adverse events of upadacitinib through 52 weeks in adults and adolescents with atopic dermatitis (AD); however, longer-term outcomes (longer than 1 year) in adolescents have not previously been available. To evaluate the efficacy and adverse events of upadacitinib in adolescent patients with moderate to severe AD through 76 weeks. The Measure Up 1, Measure Up 2, and AD Up trials are ongoing double-blind, placebo-controlled phase 3 randomized clinical trials including adolescents (aged 12 to 17 years) with moderate to severe AD. Data were collected from August 2018 to April 2022, and data were analyzed from June 2022 to September 2023. Adolescents were randomized 1:1:1 to receive once-daily oral upadacitinib, 15 mg; upadacitinib, 30 mg; or placebo, either alone (Measure Up 1 and Measure Up 2 trials) or with topical corticosteroids (AD Up). At week 16, placebo-treated patients were rerandomized to receive upadacitinib, 15 mg, or upadacitinib, 30 mg, daily. Coprimary end points assessing efficacy included achievement of 75% reduction or more in the Eczema Area and Severity Index Score (EASI-75) from baseline, Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of clear (0) or almost clear (1) with 2 grades or more of improvement, and Worst Pruritus Numerical Rating Scale (WP-NRS) improvement of 4 points or greater through week 76 for participants with a WP-NRS score of 4 points or higher at baseline. From all studies, 542 adolescents were included; of these, 284 (52.4%) were female. At week 76, among patients in the Measure Up 1, Measure Up 2, and AD Up trials, EASI-75 was achieved by 89.1%, 84.4%, and 87.8% of adolescents taking upadacitinib, 15 mg, respectively, and by 96.1%, 93.6%, and 82.7% of adolescents taking upadacitinib, 30 mg, indicating maintenance or improvement of EASI-75 across 76 weeks with upadacitinib. Efficacy measured by achievement of vIGA-AD score of 0 or 1 and WP-NRS improvement of 4 points or more from baseline was similarly maintained or improved through week 76 for adolescents taking upadacitinib, 15 mg or 30 mg. Long-term outcomes in Measure Up 1, Measure Up 2, and AD Up participants were consistent with the known adverse event profile of upadacitinib (herpetic infection: 4.0, 1.9, and 1.1 events per 100 patient-years, respectively; creatine kinase elevation: 11.6, 11.0, and 7.1 events per 100 patient-years); no new signals were observed with either dose. In this study assessing 3 randomized clinical trials, long-term treatment of adolescents with moderate to severe AD with upadacitinib demonstrated a favorable benefit-risk profile, with sustained efficacy responses through 76 weeks. Measure Up 1 trial: ClinicalTrials.gov Identifier: NCT03569293; Measure Up 2 trial: NCT03607422; AD Up trial: NCT03568318.

Long-term management of moderate-to-severe atopic dermatitis with lebrikizumab and concomitant topical corticosteroids: a 68-week, randomized, double-blind, placebo-controlled phase III trial in Japan (ADhere-J).

Moderate-to-severe atopic dermatitis (AD) impacts patients' quality of life (QOL). More treatment options are urgently needed to manage this chronic disease. Lebrikizumab is a monoclonal antibody that binds to IL-13, a key mediator in AD pathogenesis. In Japanese patients, lebrikizumab has been evaluated through week (W) 16 in the randomized, placebo-controlled, phase III ADhere-J study. To evaluate long-term efficacy and safety of lebrikizumab in combination with topical corticosteroids (TCS) in the ADhere-J study. Patients aged ≥12 years and weighing ≥40 kg with moderate-to-severe AD, and receiving either subcutaneous lebrikizumab 250 mg every 2 weeks (Q2W)/every 4 weeks (Q4W) or placebo during the 16-week induction period, were evaluated during the long-term maintenance period from W16 to W68. Responders achieved co-primary endpoints at W16: Investigator's Global Assessment score of 0 or 1 (IGA [0,1]) with ≥2-point improvement from baseline, and/or ≥75% improvement from baseline in Eczema Area and Severity Index (EASI 75). In this analysis, W16 responders received lebrikizumab 250 mg Q2W or Q4W combined with TCS during the maintenance period (maintenance primary population; MPP); W16 per-protocol nonresponders received lebrikizumab Q2W with TCS (maintenance escape population; MEP). Major endpoints included IGA (0,1) with ≥2-point improvement from baseline and EASI 75 through W68. Other outcomes included QOL, itch, and serum thymus and activation-regulated chemokine. At W68, 66-81% of 103 patients in the MPP and 32-38% of 168 patients in the MEP achieved IGA (0,1) with ≥2-point improvement from baseline. EASI 75 was maintained by 83-89% of patients in the MPP, while 71-80% of patients in the MEP achieved this outcome by W68. Across treatment arms, patients in the MPP tended to maintain improvements recorded at W16, while patients in the MEP steadily improved across the maintenance period. No new safety signals were reported, and most treatment-emergent adverse events were mild or moderate in severity in both populations. Safety outcomes were consistent with previous reports for lebrikizumab treatment in global studies. These results support the use of lebrikizumab in combination with TCS for moderate-to-severe AD in the Japanese population over the long term. ClinicalTrials.gov (NCT04760314).