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Background: This observational study compared effectiveness and safety of direct oral anticoagulants (DOACs; apixaban, rivaroxaban, dabigatran) or vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF) at high risk for gastrointestinal bleeding (GIB)., Methods: Anticoagulant-naïve adults with NVAF with ≥1 GIB risk factor, initiating anticoagulant treatment January 2016-December 2019, and covered by the French national health data system were eligible. Outcomes included major bleeding (MB) and stroke/systemic embolism (SE). Patient characteristics were balanced using propensity score matching., Results: A total of 314,184 patients were identified with 162,150 (51.5%) in the apixaban cohort, 88,427 (28.1%) in the rivaroxaban cohort, 16,465 (5.2%) in the dabigatran cohort, and 47,142 (15.0%) in the VKA cohort (mean age 79.0 years, standard deviation 10.5; 51.0% female). A total of 45,124 apixaban-VKAs, 38,737 rivaroxaban-VKAs, 16,415 dabigatran-VKAs, 88,414 apixaban-rivaroxaban, 16,464 apixaban-dabigatran, and 16,459 rivaroxaban-dabigatran pairs were retained after propensity score matching. Apixaban had lower risk of MB versus dabigatran (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.63-0.83) and rivaroxaban (HR, 0.63; 95% CI, 0.59-0.66). Apixaban had lower risk of GIB versus dabigatran (HR, 0.46; 95% CI, 0.37-0.56) and rivaroxaban (HR, 0.54; 95% CI, 0.49-0.59). Risk of GIB was similar with dabigatran versus rivaroxaban (HR, 1.05; 95% CI, 0.89-1.24). Apixaban had lower risk of stroke/SE versus rivaroxaban (HR, 0.90; 95% CI, 0.84-0.96), while risk was similar versus dabigatran (HR, 1.1; 95% CI, 0.9-1.3). All DOACs had lower risk of MB and stroke/SE versus VKAs (p<0.001 for all)., Conclusions: DOACs had improved safety and effectiveness from bleeding and stroke/SE, respectively, versus VKAs among patients with NVAF at high risk for GIB. Apixaban was associated with lower MB and GIB risk versus other DOACs. For stroke/SE, apixaban was associated with reduced risk versus rivaroxaban and similar risk versus dabigatran., Competing Interests: GYHL reported serving as a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos outside the submitted work. No fees are received personally. GYHL is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 899871. RB reported serving as a consultant for Alfasigma, Medtronic, Falk, Mayoli and Pfizer. ACM reported serving as a consultant and speaker for Abbott, Bayer, BMS/Pfizer, Boehringer Ingelheim, and received research grant from BMS/Pfizer. GP, GG, AK and NQ are employees of Certara, who were paid consultants to Pfizer and Bristol Myers Squibb in connection with the conduct of this study. FD, FS, JC, RS and RM are employees and shareholders of Pfizer. We confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Lip et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: While direct oral anticoagulants (DOACs) have improved oral anticoagulation management, inappropriate prescribing remains prevalent and leads to adverse drug events. Antithrombotic stewardship programs seek to enhance DOAC prescribing but require scalable and sustainable strategies., Objective: We present a pilot, prescriber-level randomized controlled trial to assess the effectiveness of electronic health record (EHR)-based medication alerts in a large health system., Methods: The pilot assessed prescriber responses to alerts for initial DOAC prescription errors (apixaban and rivaroxaban). A user-centered, multistage design process informed alert development, emphasizing clear indication, appropriate dosing based on renal function, and drug-drug interactions. Alerts appeared whenever a DOAC was being prescribed in a way that did not follow package label instructions. Clinician responses measured acceptability, accuracy, feasibility, and utilization of the alerts., Results: The study ran from August 1, 2022, through April 30, 2023. Only 1 prescriber requested trial exclusion, demonstrating acceptability. The error rate for false alerts due to incomplete data was 6.6% (16/243). Two scenarios with alert design and/or execution errors occurred but were quickly identified and resolved, underlining the importance of a responsive quality assurance process in EHR-based interventions. Trial feasibility issues related to alert-data capture were identified and resolved. Trial feasibility was also assessed with balanced randomization of prescribers and the inclusion of various alerts across both medications. Assessing utilization, 34.2% (83/243) of the encounters (with 134 prescribers) led to a prescription change., Conclusions: The pilot implementation study demonstrated the acceptability, accuracy, feasibility, and estimates of the utilization of EHR-based medication alerts for DOAC prescriptions and successfully established just-in-time randomization of prescribing clinicians. This pilot study sets the stage for large-scale, randomized implementation evaluations of EHR-based alerts to improve medication safety., Trial Registration: ClinicalTrials.gov NCT05351749; https://clinicaltrials.gov/study/NCT05351749., (©Shawna N Smith, Michael S M Lanham, F Jacob Seagull, Morris Fabbri, Michael P Dorsch, Kathleen Jennings, Geoffrey Barnes. Originally published in JMIR Formative Research (https://formative.jmir.org), 08.11.2024.)

Background: The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with BRAF V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival., Methods: We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival., Results: The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports., Conclusions: After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.)., (Copyright © 2024 Massachusetts Medical Society.)

Purpose: Long-acting cabotegravir/rilpivirine (LA-CAB/RPV) was approved for use in virally suppressed patients with human immunodeficiency virus (HIV) in January 2021. While this was a paradigm shift for many patients living with HIV, as LA-CAB/RPV was the first injectable complete regimen for the treatment of HIV, several patient populations, including those lacking virologic suppression, have not been able to easily access this advance in science and care., Summary: In this article, we provide an update on 2 patients from our previous report and describe one further patient who experienced treatment failure following initiation of LA-CAB/RPV. Additionally, we review reports published to date of the clinical outcomes of patients with viremia who have accessed LA-CAB/RPV in the setting of baseline resistance-associated mutations (RAMs) to either component and any resulting RAMs at virologic failure. On the basis of this evidence, we recommend that hybrid or all-injectable regimens be considered for patients who have struggled with adherence to oral antiretroviral therapy or have partial or full resistance to one component of LA-CAB/RPV., Conclusion: The case series reported here adds to literature supporting the notion that LA-CAB/RPV can be successfully used in patients who are viremic., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

HPTN 084 demonstrated the superiority of long-acting injectable cabotegravir (CAB-LA) compared with daily oral tenofovir disoproxil fumarate-emtricitabine (F/TDF) for HIV prevention in women. CAB-LA (600 mg) or placebo injections were administered 4 weeks after an initial dose (loading dose) and every 2 months (Q2M) thereafter; this is the approved regimen. Participants experienced both loading dose and Q2M delays during the trial. CAB concentrations were evaluated before a delay, at the visit associated with the delay, and the visit after a delayed injection was administered. During the blinded phase of the trial, 194 participants randomized to CAB-LA experienced at least one injection delay. Plasma CAB concentrations were maintained above the 4× protein adjusted 90% inhibitory concentration (4× PA-IC 90 ; protocol-specific threshold) for all loading dose and 98% of Q2M delays when injections were administered up to 6 weeks late. The feasibility of shifting to an every 3-month (Q3M) regimen in females was interrogated via simulation studies using a population pharmacokinetic model. Q3M injections in both CAB-naïve (with a loading dose) and previously CAB-exposed females were predicted to yield higher steady-state exposures than in males on the approved Q2M regimen. Although there is observed forgiveness following an isolated delayed CAB-LA injection and simulations suggest acceptable CAB-LA exposures in women with a 600 mg CAB-LA Q3M regimen, empirical efficacy of this regimen has not been established, and transitioning to this dosing schema is not recommended. Future pharmacokinetic bridging studies are aimed at evaluating higher dose CAB-LA formulations administered less frequently., Clinical Trials: This study is registered with ClinicalTrials.gov as NCT03164564., Competing Interests: K.H. and S.L.F. are employees and stockholders of GSK. A.R.R. is an employee of ViiV Healthcare and holds stock in GSK. J.F.R. is a paid employee of Gilead Sciences.

Introduction: Cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, an NNRTI, constitute the first long-acting (LA), injectable, two-drug ART regimen approved for the maintenance of virological suppression in persons living with HIV-1 (PLHIV). The aim of this study was to assess clinical effectiveness and tolerability of LA cabotegravir/rilpivirine in a real-world setting., Patients and Methods: We conducted a retrospective, single centre study, including all PLHIV receiving LA cabotegravir/rilpivirine as standard-of-care in our tertiary centre even if initiated in clinical trials., Results: Between 2014 and 2022, 126 PLHIV initiated LA cabotegravir/rilpivirine. All were ART-experienced, and 98.4% had a viral load (VL) of <50 copies/mL before LA cabotegravir/rilpivirine initiation. Median BMI at cabotegravir/rilpivirine initiation was 24 IQR (23-28). During a median follow-up of 9 months IQR (7-24), 27 patients discontinued cabotegravir/rilpivirine: 5 because of virological failure, 6 for adverse events, 11 for personal reasons unrelated to treatment tolerance and 5 for other reasons. Virological failure was not associated with a higher BMI, nor with weight gain during LA intramuscular (IM) cabotegravir/rilpivirine treatment, inadequate cabotegravir and rilpivirine concentrations, VL blips or the use of oral lead-in (OLI) or not. No drug resistance-associated mutation emerged. Adverse events leading to treatment interruption were injection-site pain (n = 3) and neuropsychological side effects (n = 3). A correlation between BMI and both cabotegravir and rilpivirine concentrations at 1 month post-initiation of LA-IM cabotegravir/rilpivirine was observed, with no impact of OLI., Conclusions: Data from this real-world cohort of PLHIV who received cabotegravir/rilpivirine LA injections suggest that this regimen is effective and well tolerated. Virological failures were not associated with the acquisition of resistance mutations., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Skin cancer, notably melanoma, poses a significant global health burden, with rising incidence and mortality rates. While therapeutic advancements have improved outcomes, metastatic melanoma remains challenging to treat. This study aims to systematically review systemic treatment options for advanced melanoma, focusing on efficacy and safety in the first-line setting. Through a comprehensive search and meta-analysis of randomized controlled trials conducted from 2013 to 2023, 11 studies encompassing 2816 participants were analyzed. Treatment options included BRAF inhibitors (vemurafenib, dabrafenib), MEK inhibitors (trametinib, cobimetinib), and immune checkpoint inhibitors (ipilimumab). Combined therapy with vemurafenib, cobimetinib, and ipilimumab demonstrated superior overall survival (OS) and progression-free survival (PFS) compared to monotherapy, with a significant odds ratio (OR) of 6.95 (95% CI: 4.25-9.64, p < 0.00001) for OS and 2.49 (95% CI: 1.42-3.56, p < 0.00001) for PFS. Additionally, dabrafenib and trametinib combination therapy showed improved outcomes with favorable tolerability, including a significant reduction in adverse event (AE) risk, with an OR of 2.20 (95% CI: 1.72-2.81). Furthermore, our analysis highlighted vemurafenib-associated dermatological toxicities, emphasizing the need for effective management strategies. The study underscores the evolving treatment landscape in melanoma management, with a potential shift towards immune checkpoint inhibitors in the adjuvant setting, particularly for BRAF-mutated disease. However, limitations in meta-analysis methodologies and the need for long-term investigations into treatment implications on survival and quality of life underscore the importance of continued research., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The direct factor Xa inhibitor apixaban is partially eliminated by the kidneys but is still prescribed at fixed doses without therapeutic drug monitoring across varying levels of renal function. If apixaban accumulates due to renal impairment, this may translate into safety concerns, e.g. the risk for bleeding. The purpose of this study was to measure apixaban trough concentrations in patients with different stages of renal function/renal impairment., Methods: Apixaban trough concentrations were measured using LC-MS/MS in patients with atrial fibrillation, having normal renal function (apixaban 5 mg BID, n=39), moderate renal impairment (apixaban 5 mg BID, n=40) and severe renal impairment (apixaban 2.5 mg BID, n=6). The median (min-max) relative eGFR values were 84.8 (71.7-111.4), 51.4 (31.3-67.2) and 23.0 (21.9-28.4) mL/min/1.73 m², in the three groups, respectively., Results: Patients with moderate renal impairment had significantly higher apixaban trough concentrations than patients with normal renal function. The median (min-max) trough concentrations were 59.8 ng/mL (15.5-170.9) for normal renal function, 128.9 ng/mL (41.4-295.4) for moderate renal impairment and 81.7 ng/mL (61.8-109.0) for severe renal impairment. The trough concentrations correlated significantly with renal function measured as relative/absolute eGFR creatinine/cystatin C., Conclusions: The standard dosing regimen of 5 mg apixaban BID renders exposure that is roughly twice as high in patients with moderately reduced renal function compared to patients with normal renal function. We suggest that patients with moderately reduced renal function ought to be monitored. Possibly, a dose reduction may be considered to achieve similar exposure as in patients with normal renal function., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: HIV infections are ongoing globally despite efficacious biomedical prevention options. We sought to determine whether an HIV prevention package providing choice of daily pills or long-acting injectable cabotegravir and opportunities to change prevention options could increase biomedical prevention coverage and reduce new HIV infections., Methods: This study was an extension of three randomised trials that used SEARCH dynamic choice HIV prevention to recruit adults (aged ≥15 years) at risk for HIV from antenatal, outpatient, and community settings in rural Uganda and Kenya. In this 48-week open-label extension, participants maintained their original (1:1) randomisation group; the option to choose cabotegravir long-acting injectable was added for intervention participants. Inclusion criteria for the extension were previous enrolment in a SEARCH dynamic choice HIV prevention trial, negative HIV rapid test, and residence in study region. The intervention provided person-centred choice of oral pre-exposure prophylaxis (PrEP) or post-exposure HIV prophylaxis (PEP) or cabotegravir long-acting injectable, with the option to switch according to participant preference. The control provided standard-of-care access to oral PrEP and PEP, but not cabotegravir long-acting injectable. Biomedical prevention coverage (proportion of follow-up covered by oral PrEP, PEP, or cabotegravir long-acting injectable; primary outcome) and HIV incidence (secondary outcome) were compared between groups using targeted minimum loss-based estimation. The trial (NCT05549726) is closed to recruitment., Findings: Of 1534 participants initially randomly assigned (from April 15, 2021 to Sept 29, 2022), 984 (487 in the intervention group and 497 in the standard-of-care group) reconsented to the extension (from Jan 2 to March 3, 2023). The mean proportion of follow-up covered by biomedical HIV prevention was 69·7% (95% CI 64·9-74·5) in the intervention group versus 13·3% (10·2-16·3) in the standard-of-care group, corresponding to an absolute difference of 56·4 percentage points (95% CI 50·8-62·1; p<0·0001). The intervention significantly improved coverage across prespecified subgroups (sex and age groups). During the study, 274 (56%) of 485 intervention participants used cabotegravir long-acting injectable, 255 (53%) used oral PrEP, and ten (2%) used PEP. Among cabotegravir long-acting injectable initiators, 118 (43%) of 274 were not previously using oral PrEP or PEP. There were seven incident HIV infections in 390 person-years of follow-up in the standard-of-care group and no infections in 400 person-years of follow-up in the intervention group (incidence rate difference per 100 person-years 1·8, 95% CI 0·4-3·2; p=0·014)., Interpretation: Offering people the choice of HIV biomedical prevention options including cabotegravir long-acting injectable in a flexible model can increase prevention coverage and reduce incident HIV infections. HIV programmes should support dynamic choice HIV prevention programmes that include effective oral and injectable long-acting products., Funding: National Institutes of Health., Competing Interests: Declaration of interests DVH reports funding from the US National Institutes of Health (NIH). MB is a salaried employee of the NIH, serving as Medical Officer for this study as part of her covered duties, which included assisting with protocol development and review, project oversight, and review of manuscripts. AR is a shareholder of GlaxoSmithKline. ViiV Healthcare provided CAB-LA for the study. All other authors declare no competing interests related to this work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib., Methods: This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics., Results: Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAF non-V600 -mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with KRAS-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in DUSP6 mRNA levels from baseline were 45.5% and 76.1% with naporafenib plus rineterkib or trametinib, respectively., Conclusions: Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect., Clinicaltrials: gov identifier: NCT02974725., Competing Interests: Declaration of competing interest David Planchard reports consulting, advisory role or lectures for AstraZeneca, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-fabre, Takeda, ArriVent, Mirati and Seagen; clinical trials research as principal investigator or co-investigator (institutional financial interests) for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Abbvie, Janssen, Pierre-fabre, Takeda, ArriVent, Mirati and Seagen; and travel, accommodation and expenses from AstraZeneca, Roche, Novartis and Pfizer. Jürgen Wolf reports grants from BMS, Janssen, Pharmaceutica, Novartis and Pfizer (payment to institution); and consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and/or travel, and participation on a data safety monitoring board or advisory board from Amgen,  AstraZeneca, Bayer, BluePrint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Pierre-Fabre, Roche, Seattle Genetics, Takeda and Turning Point. Benjamin Solomon reports fees for advisory boards from Pfizer, AstraZeneca, Janssen, Takeda, Bristol Myers Squibb, Meck, Roche-Genentech, Beigene and Amgen; payment or honoraria for lectures and presentations from AstraZeneca, Pfizer, Glaxo Smith Klein, Merck and Roche; and is a board director of Thoracic Oncology Group of Australasia, Cancer Council Victoria and International Association for the Study of Lung Cancer. Martin Sebastian reports grants or contracts to institution from AstraZeneca; consulting fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer lngelheim, Amgen, Takeda, Merck-Serono, Pfizer, Pierre-Fabre and DaiIchi- Sankyo; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer lngelheim, Amgen, Takeda, Merck, GSK, Daiichi and Pfizer; and support for attending meetings and/or travel from Pfizer, Merck and BMS. Martin Wermke reports research funding for institution from Roche; consulting fees from Bristol Myers Squibb, Novartis, Lilly, Boehringer Ingelheim, Immatics, Bayer and ImCheck Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Lilly, Boehringer Ingelheim, SNYLAB, Merck Serono, GWT, Amgen and Novartis; support for attending meetings and/or travel from Pfizer, Bristol Myers Squibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, Immatics and Merck Serono; and participation on a data safety monitoring board or advisory board for ISA Pharmaceuticals. Rebecca S. Heist reports grants to institution from Abbvie, Agios, Daichii Sankyo, Lilly, Novartis, Mythic, Mirati, Symphogen, Turning Point and Erasca; consulting fees from Novartis, EMD Serono, Daichii Sankyo, Abbvie, Regeneron, Sanofi, Lilly, Claim Therapeutics, AstraZeneca, Amgen and Gilead; and receiving medical writing services from Daichii Sankyo, Novartis, Lilly and Mirati. Jong-Mu Sun has no conflicts of interest to declare. Tae Min Kim reports consulting fees from AstraZeneca, Janssen, Regeneron, Samsung Bioepis, Takeda and Yuhan; participation on Advisory Board for AstraZeneca/Medimmune, Janssen and Regeneron; and other financial or non-financial interests received by the institution from ABBVIE, AstraZeneca, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, F. Hoffmann-La Roche Ltd/Genentech, Inc, Hanmi, Janssen, Novartis, Regeneron, Sanofi, Takeda and Yuhan. Noemi Reguart has received speaker’s honoraria or sponsorship to attend international scientific meetings from Bayer, MSD, BMS, Roche, Boehringer Ingelheim, Janssen, Pfizer, AbbVie, Novartis, Astrazeneca, Lilly, Takeda, Amgen and Merck; and research grants from Novartis, MSD and Pfizer (all for Institution). Miguel F. Sanmamed received research grants from Roche; consulting fees from Numab; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD; support for attending meetings and/or travel from Roche; and participation on advisory board for Numab. Enriqueta Felip reports consulting fees from Abbvie, Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point and Daiichi Sankyo; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda and Touch Oncology; and support for attending meetings and/or travel from AstraZeneca, Janssen and Roche. Pilar Garrido received personal fees for lectures, presentations, speakers bureaus or educational events from Janssen, MSD, Novartis, Medscape, Takeda, TouchTime and Medscape; support for attending meetings and/or travel from Astra Zeneca, Roche and Janssen; personal fees for advisory role from Abbvie, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda, and personal fees for steering committee from Novartis and IO Biotech IO102-Janssen. Armando Santoro received consultancy fees from Sanofi and Incyte; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Takeda, BMS, Roche, Abbvie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, ArQule, Lilly, Sandoz, Eisai, Novartis, Bayer, MSD and BeiGene; and participation on a data safety monitoring board or advisory board for BMS, Servier, Gilead, Pfizer, Eisai, Bayer and MSD. Douglas Bootle is a Novartis employee. Xuân-Mai Couillebault is a Novartis employee. Anil Gaur is a Novartis employee. Christina Mueller is a Novartis employee and Novartis stockholder. Teresa Poggio is a Novartis employee. Jie Yang is a Novartis employee and Novartis stockholder. Michele Moschetta is a previous Novartis employee, Novartis stockholder and has one patent issued relating to naporafenib. Christophe Dooms has no conflicts of interest to declare. All authors received medical writing support funded by Novartis Pharmaceuticals Corporation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Direct oral anticoagulants (DOACs) are widely used for treatment and secondary prophylaxis of venous thromboembolism (VTE) and represent the gold standard for VTE secondary prophylaxis, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit widespread DOACs usage there are few literature data regarding their efficacy and safety in major thrombophilia carriers and almost no data is available for low intensity apixaban and rivaroxaban as secondary VTE prophylaxis in such patients. The aim of our study is to evaluate and confront the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis, in major thrombophilia carriers vs patients at high risk of VTE recurrence for other reasons. We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5 mg BID or rivaroxaban 10 mg daily and that were screened for thrombophilia. The examined patients were 339. Baseline characteristics such as sex, age, obesity rate, smoking, number of previous VTEs and comorbidities (such as cardiovascular diseases, diabetes, mild CKD) were equally distributed in either group. The median low-dose DOACs administration time was 19.20 months (IQR 12.17-35.67). During low-dose DOACs treatment, 13 (3.8%) VTE recurrences were observed; 14 bleeding events were registered (4,1%), with no major bleeding (MB), 6 clinically relevant non major bleeding (CRNMB) (1.8%) and 8 minor bleeding (2.3%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between major thrombophilia carriers and non-major thrombophilia carriers. In multivariate analysis increased risk of VTE recurrence was found for patients with cardiovascular comorbidities (HR 4.00 - p = 0.034) and for patients with more than one previous VTE episode (HR 5.14 - p = 0.034). Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis for carriers of major thrombophilia with no increase in VTE recurrence and/or bleeding risk., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Apixaban is a widely used direct oral anticoagulant that is recommended over warfarin therapy for many clinical indications. In patients with atrial fibrillation, dose reductions are recommended for patients with advanced age (≥80 years), low weight (≤60 kg) or elevated serum creatinine (≥1.5 mg/dL), but there is no routine laboratory monitoring necessary for long term-use. Furthermore, apixaban dose reductions due to renal dysfunction are not recommended when treating acute venous thromboembolism. Apixaban-calibrated anti-Xa assays are readily available at some medical centres, and they may be of clinical utility in certain circumstances such as in patients with renal insufficiency, medication adherence assessment, periprocedural planning, extremes in body weight and advanced age. Here, we describe the case of an elderly patient with chronic kidney disease taking apixaban for acute pulmonary embolism. The patient had an unanticipated prolonged apixaban half-life, with detectable apixaban-calibrated anti-Xa levels for >10 days after the last administered dose, which delayed a necessary surgical intervention by >1 week. This case is an example of appropriately using apixaban-calibrated anti-Xa levels to guide therapeutic decision making in perioperative planning., (© 2024 British Pharmacological Society.)

Background: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk., Methods: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years., Conclusion: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter., Trial Registration: ClinicalTrials.gov NCT05757869., Competing Interests: Disclosures SSJ reports consulting fees from Bristol Myers Squibb, ARTIS Ventures, and Broadview Ventures outside of the submitted work. KWM’s financial disclosures can be reviewed at http://med.stanford.edu/profiles/kenneth-mahaffey. KSP is a member of The Thrombosis Research Institute which has received institutional research grant support from Anthos Therapeutics and Bayer Pharmaceuticals. She has received honoraria from Element Science and Artivion, Inc. WS has received honoraria (>10K USD) from Daiichi Sankyo, Nippon Boehringer Ingelheim, and Pfizer Japan, and research grants (>50K USD) from Daiichi Sankyo and Nippon Boehringer Ingelheim. CTR reports Research Grants through Institution from: Athos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis. Honoraria for scientific ad boards and consulting from: Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen and Pfizer. He is a member of The TIMI Study Group which has received institutional research grant support through Brigham and Women's Hospital from: Abbott, Abiomed, Inc, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc, Janssen Research & Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, Saghmos Therapeutics, Inc, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc, Zora Biosciences. PRK reports consultancy from Anthos, J&J, BMS and Bayer. GS has received research grants from Amarin, AstraZeneca, and Sanofi; has participated in clinical trials, consulting, or speaking for Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Idorsia, Janssen, Novartis, Novo Nordisk, PhaseBio, Pfizer, and Sanofi; is a Senior Associate Editor at Circulation; and serves as the CMO for Bioquantis. RM reports institutional research payments from: Abbott, Affluent Medical, Alleviant Medical, Amgen, AstraZeneca, BAIM, Beth Israel Deaconess Medical Center, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CERC, Chiesi, Concept Medical, Daiichi Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Pi-Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi; consultant to Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, Esperion Science/Innovative Biopharma, Gaffney Events, Educational Trust, Global Clinical Trial Partners, Ltd., IQVIA, Medscape/WebMD Global, NovoNordisk, PeerView Institute for Medical Education, TERUMO Europe N.V., Radcliffe and honoararia from AMA and ACC. SCJ has received research support from Jansen, BMS, and AstraZeneca. GJH reports personal honoraria outside the submitted work from the American Heart Association (Associate Editor, Circulation), Bristol Myers Squibb (Steering Committee, AXIOMATIC-SSP trial of milvexian [factor XIa inhibitor] for secondary stroke prevention) and Janssen (Co-chair, Executive Committee, Librexia Stroke trial of milvexian for secondary stroke prevention). RAH has received research grants/contracts from NHLBI (ISCHEMIA), Duke/PCORI (ADAPTABLE), Janssen (Factor Xia inhibitor), CSL (HDL), Baim Institute, UColorado, Harvard (BWH), and Merck; has served as a consultant/advisor for NHLBI (COVID/CONNECTS), Atropos Health, Bitterroot Bio, Bristol Myers Squibb, Bridge Bio, Chiesi, CSL Behring, Edwards Lifesciences Corp, Element Science, Foresight, Merck, and WebMD; and serves on the Board of Directors for AHA and Cytokinetics. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has Received research support from Novo Nordisk and Roche Diagnostics; has Served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Hanmi, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as Co-founder and nonexecutive director of Us2.ai. The remaining authors report no relevant disclosures or competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Anti-fibrotics can reduce restrictive impairment in idiopathic pulmonary fibrosis (IPF). However, its effectiveness in non-IPF progressive fibrosing interstitial lung disease (non-IPF PF-ILD) remains uncertain., Objective: We assess the efficacy and safety of anti-fibrotics pirfenidone and nintedanib versus placebo among non-IPF PF-ILD adult patients., Methods: Meta-analysis was performed using PubMed, SCOPUS, and Cochrane databases to identify randomized controlled trials (RCTs). At respective centers, non-IPF PF-ILD was defined as clinical and radiological findings inconsistent with IPF and greater than 5 % forced vital capacity (FVC) decline, worsening radiological fibrosis or respiratory symptoms., Results: Among seven RCTs involving 1,816 non-IPF PF-ILD patients, anti-fibrotics significantly reduced decline in FVC from baseline in milliliters (MD -66.80milliliters; P < 0.01) and percent predicted (MD -1.80 %; P < 0.01) compared to placebo. However, severity of FVC decline was less than 10 % (P = 0.33) in both groups. No significant difference in the decline of 6MWD from baseline in meters (P = 0.19) while on anti-fibrotics, although those on pirfenidone had less decline in 6MWD (MD -25.12 m; P < 0.01) versus placebo. The rates of all-cause mortality (P = 0.34), all-cause hospitalization (P = 0.44), and hospitalization for respiratory etiology (P = 0.06) were comparable in both groups. Adverse events of nausea/vomiting (54.2 % vs. 20.3 %; P < 0.01), diarrhea (65.2 % vs. 27.6 %; P = 0.02), anorexia/weight loss (23.0 % vs. 7.7 %; P < 0.01), neurological disorders (20.8 % vs. 12.6 %; P < 0.01), and events requiring therapy discontinuation were higher (18.4 % vs. 9.9 %; P < 0.01) in the anti-fibrotic group. Other adverse events of skin (P = 0.18) and respiratory disorders (P = 0.20) were equal., Conclusion: The advent of anti-fibrotics offers alternative treatment to reduce lung function decline., Competing Interests: Declaration of competing interest We declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective Seasonal influenza affects healthcare demand. However, the efficacy of anti-influenza drugs, particularly among young patients at a low risk of complications, has rarely been evaluated. Therefore, we evaluated the efficacy of anti-influenza drugs against seasonal influenza in healthy young and middle-aged adults. Methods A systematic review and network meta-analysis were conducted. The Cochrane Central Register of Controlled Trials and Medical Literature Analysis and Retrieval System Online were searched for original articles reporting double-blind, randomized controlled trials published up to the end of July 2023. Clinical trials that tested the efficacy of anti-influenza drugs in young and middle-aged patients with seasonal influenza were also included. The primary outcome was time to fever alleviation. The efficacy and adverse effects of these treatments were estimated using a Bayesian hierarchical random-effects model and a Markov chain Monte Carlo simulation. Results In total, 24 articles with 34 treatments and 8,949 individuals were included. Oseltamivir (300 mg/day for 5 days) showed the largest reduction in time to fever alleviation by -19.1 [95% confidence interval (CI): -29.4, -10.7] h compared with a placebo. Baloxavir marboxil (40 mg/day) reduced the time to symptom alleviation by -28.2 (95% CI: -42.7, -13.7) h, and peramivir (300 mg/day) administered by intravenous infusion for 1 day reduced the time to resumption of usual activities by -43.5 (95% CI: -72.8, -14.2) h. Conclusion Several pharmaceutical treatments were able to reduce the recovery time for fever and symptom alleviation and resumption of usual activities in young and middle-aged adults with seasonal influenza without increasing the risk of complications.

Objectives: Direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, commonly used direct oral anticoagulant (DOAC), are widely used to prevent and treat stroke and venous thromboembolic events in patients with atrial fibrillation (AF). This study aimed to assess and compare reports of adverse events associated with rivaroxaban, apixaban, and edoxaban, including hemorrhagic and non-hemorrhagic events., Methods: Reporting odds ratio (ROR), proportional reporting ratio (PRR), Medications and Health Care Products Regulatory Agency (MHRA), and the information component (IC) were used to perform a risk assessment of adverse event reports in the FDA Adverse Event Reporting System (FAERS) database for the years 2018-2022., Results: Combined with disproportionality analysis in different backgrounds, the salient risks of the three-factor Xa inhibitors varied. Rivaroxaban had the most significant risk of hemorrhage, apixaban had a higher incidence and risk of death, cardiac and cerebral adverse events, and edoxaban showed a more prominent risk in the kidneys and urinary system., Conclusion: Hemorrhage is a common risk with factor Xa inhibitors, with rivaroxaban being the most significant. Apixaban and edoxaban also showed significant association with non-hemorrhagic adverse events, and increased attention to non-hemorrhagic adverse events is needed in clinical use.

Previously, we reported the efficacy and safety of tazemetostat in Japanese patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) harboring the EZH2 mutation in a multicenter, open-label, phase II study. Here, we present a follow-up analysis of tazemetostat at a long-term median follow-up of 35.0 months. Twenty patients were enrolled: 17 in the FL cohort and three in the DLBCL cohort. In the FL cohort, the objective response rate was 70.6%, consistent with the primary analysis, and the median progression-free survival (PFS) was not reached. The 24-month and 36-month PFS rates were 72.1% (95% confidence interval [CI] 41.5%-88.6%) and 64.1% (95% CI 33.7%-83.4%), respectively. The median duration of treatment was 30.2 months. After the primary analysis at a median follow-up of 12.9 months, grade 1-2 urinary tract infection, peripheral motor neuropathy, and hypogammaglobulinemia newly emerged, but the incidence of adverse events (AEs) did not increase notably during this follow-up period. No unexpected grade ≥ 3 treatment-related AEs were reported. Long-term oral monotherapy with tazemetostat showed favorable efficacy and safety profiles, indicating that it may be a useful third-line or later treatment option for patients with relapsed/refractory FL harboring the EZH2 mutation. Trial registration: ClinicalTrials.gov: NCT03456726., (© 2024. The Author(s).)

The pediatric clinical development programs of the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and dabigatran have recently been completed, with apixaban close to the finish line. One common pharmacokinetic (PK) characteristic of these four DOACs is that renal excretion contributes 27% or more in their elimination, resulting in age-dependent drug clearance in both pediatric and adult subjects. Several lessons have been learned from adult exposure matching and pediatric dose selection for DOACs. The main goal of this tutorial is to provide an informed perspective on pediatric dose selection for renally excreted drugs, using these four DOACs as case examples. This tutorial is organized into seven steps: (1) consideration of age-related differences in disease and response to treatment; (2) consideration of age-related differences in drug absorption, distribution, metabolism, and excretion; (3) selection of the reference adult population and exposure for pediatric exposure matching; (4) prediction of pediatric clearance and pediatric dose selection based on data from young adults; (5) conduct and design of efficient pediatric PK and pharmacodynamic (PD) studies that inform dose selection; (6) assessment of exposure matching and dose adjustment using population PK simulation; (7) evaluation of the need for dose adjustment in pediatric sub-populations., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

An 87-year-old woman receiving aspirin and apixaban with a history of large artery atherosclerotic stroke, and pulmonary embolism presented to the hospital for aphasia and right hemiplegia. A head CT scan showed 18-ml hematoma in the left thalamus. Low-dose Andexanet alfa was administered 84 minutes after the onset of stroke, and 10 hours and 24 minutes after the last dose of apixaban. Three hours later after admission, she had flaccid hemiplegia and became comatose. CT and CT angiography revealed occlusion of left internal carotid artery (ICA) and no evidence of hematoma expansion. Although repetitive mechanical thrombectomy resulted in recanalization (modified TICI 2b), carotid ultrasound revealed the occlusion of left ICA on next day. On day 7, she died of brain herniation following extensive cerebral infarction. It has been reported that some patients did experience thrombotic events after administration of Andexanet alfa. Our case illustrates that even large vessel occlusion might occur after intravenous injection of Andexanet alfa. Thus, careful follow-up, including cerebrovascular imaging, is required immediately after administration of Andexanet alfa.

Direct oral anticoagulants (DOACs) have been used clinically in patients with chronic thromboembolic pulmonary hypertension (CTEPH) for secondary prevention after acute venous thromboembolism, although the data are limited. We evaluated the effects of DOACs-especially factor Xa (FXa) inhibitors-by measuring anti-factor Xa activity (AXA). Fifty consecutive CTEPH patients treated with rivaroxaban, apixaban, or edoxaban were enrolled. Heparin-calibrated AXA was measured at peak and trough. The median peak heparin-calibrated AXA across all 50 patients was 1.90 IU/mL and was comparable among the three FXa inhibitors. At trough, heparin-calibrated AXA was significantly higher in apixaban-treated patients (median 0.70 IU/mL) than in those given rivaroxaban (median 0.11 IU/mL) or edoxaban (median 0.11 IU/mL, p < 0.001). Peak heparin-calibrated AXA was significantly lower with reduced-dosage FXa inhibitor (edoxaban 30 mg/day) than with the reference dosage (edoxaban 60 mg/day, apixaban 10 mg/day, or rivaroxaban 15 mg/day, p = 0.01). The heparin-calibrated AXA of both rivaroxaban and apixaban was strongly significantly correlated with the plasma concentration of each drug. The cumulative rate of major and clinically relevant non-major bleeding was significantly higher in patients with peak heparin-calibrated AXA ≥ 2.09 IU/mL. Heparin-calibrated AXA could provide useful information for treating CTEPH patients with FXa inhibitors., (© 2024. The Author(s).)

Background: Although long-acting, injectable cabotegravir (CAB-LA) pre-exposure prophylaxis (PrEP) has proven efficacious for HIV prevention in clinical trials, research is needed to guide effective implementation in real-world settings. Formative work with community members and health care providers (HCPs) is important to provide insight into the needs and contexts of specific populations and reveal potential barriers and facilitators for implementation projects., Objective: We aimed to describe the results from formative work to develop an implementation package for CAB-LA PrEP within the ImPrEP CAB Brasil study., Methods: ImPrEP CAB Brasil is an implementation study of same-day delivery of CAB-LA PrEP for young sexual and gender minority (SGM) groups (aged 18-30 years) in 6 existing oral PrEP public health clinics. We conducted formative research to prepare for the implementation of ImPrEP CAB Brasil through community mobilization, process mapping with HCPs with experience in CAB-LA, and focus group discussions (FGDs) with young SGM groups (n=92) and HCPs (n=20) to identify initial perceptions of facilitators and barriers for CAB-LA PrEP implementation, refine the mobile health (mHealth) educational tool, and evaluate the acceptability of using a text message appointment reminder intervention through WhatsApp. FGDs were recorded, transcribed, systematically coded, and analyzed with thematic categorization by trained researchers using a qualitative data analysis program ATLAS.ti (version 7)., Results: A community mobilization team comprising 34 SGM community leaders collaborated in creating a prototype for an mHealth educational tool and contributed to the planning of peer education activities. We created 3 process maps for each site to describe the initial visit, follow-up visits, and laboratory flow. The main challenge identified for same-day CAB-LA PrEP delivery was the extended duration of clinic visits due to the numerous laboratory tests and HIV counseling steps required. Proposed solutions included having point-of-care HIV rapid tests instead of laboratory tests and additional counseling staff. Barriers for CAB-LA PrEP implementation identified through FGDs were the training of HCPs, support for adherence to injection appointments, and stigma or discrimination against SGM groups and persons using PrEP. The mHealth educational tool and WhatsApp reminders were highly acceptable by SGM groups and HCPs, indicating their potential to support PrEP choice and adherence. Content analysis on the cultural appropriateness of the language and overall clarity of the material contributed to the refinement of the mHealth tool., Conclusions: Structured formative work with SGM persons and HCPs generated important refinements to context-specific materials and plans to launch ImPrEP CAB Brasil in public health clinics. Ongoing implementation monitoring will use the process maps to identify additional barriers and potential solutions to same-day delivery of CAB-LA PrEP. Summative evaluations are needed to measure the effectiveness of the mHealth educational tool to support PrEP choice and the use of WhatsApp appointment reminders., (©M Cristina Pimenta, Thiago Silva Torres, Brenda Hoagland, Mirian Cohen, Claudio Gruber Mann, Cristina M Jalil, Eduardo Carvalheira, Lucilene Freitas, Nilo Fernandes, Debora Castanheira, Marcos Benedetti, Julio Moreira, Keila Simpson, Roberta Trefiglio, Gabrielle O’Malley, Valdilea G Veloso, Beatriz Grinsztejn. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 24.10.2024.)

Background: Various oral anticoagulants have been used for stroke prevention in older patients with atrial fibrillation (AF). However, the optimal anticoagulants for stroke prevention has not yet been developed. We performed a systematic review and network meta-analysis to determine the optimal instructions., Methods: We searched for randomized controlled trials (RCTs) from PubMed, Embase, and the Cochrane Library without restriction for publication date or language at January 2024. Any RCTs that compared the effectiveness of a direct oral anticoagulant and a vitamin K antagonist (VKA) for stroke prevention in older patients with AF were included in this network meta-analysis. The Bayesian network meta-analysis used a random effects model and surface under the cumulative ranking curve analysis to rank results. All analyses were done using R software with gemtc package, with statistical significance set at P < .05., Results: We included 7 RCTs (79,003 patients) comparing 8 different instructions including Apixaban 5 mg, Dabigatran 110 mg, Dabigatran 150 mg, Edoxaban 30 mg, Edoxaban 60 mg, Rivaroxaban 15 mg, Rivaroxaban 20 mg, and VKA. Apixaban 5 mg, Dabigatran 110 mg, and Dabigatran 150 mg was more effective than the VKA for reducing stroke or systemic embolism risks, and the difference was statistically significant (P < .05). Apixaban 5 mg, Dabigatran 110 mg, Dabigatran 150 mg, Edoxaban 30 mg, and Edoxaban 60 mg was associated with a reduction of the intracranial hemorrhage rate than the VKA (P < .05). The surface under the cumulative ranking curve shows that Dabigatran 110 mg ranked first for reducing stroke or systemic embolism risks. Edoxaban 60 mg ranked first for major bleeding. Dabigatran 110 mg ranked first for intracranial hemorrhage. Apixaban 5 mg ranked first for all bleeding events., Conclusions: Direct oral anticoagulants were found to have lower rates of thromboembolic events compared to VKAs in older patients with AF. Apixaban 5 mg, Dabigatran 110 mg, Dabigatran 150 mg, Edoxaban 30 mg, and Edoxaban 60 mg were also associated with a reduction of intracranial hemorrhage than VKA., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE., Patients and Methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ- CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires., Results: 44 patients enrolled and 42 started trametinib. TAZ- CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094-19.0], median PFS was 10.4 months (95%CI, 7.1-NA), and 2-year OS rate was 33.3%(95%CI, 19.1-58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib., Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552., (©2024 American Association for Cancer Research.)

Cancer-associated thrombosis (CAT) remains a challenging aspect of managing patients with cancer. This review discusses evidence regarding anticoagulants in the treatment of CAT, with particular emphasis on direct oral anticoagulants (DOAC). Apixaban, rivaroxaban and edoxaban have proven attractive alternatives to low-molecular weight heparins, and interactions with medical cancer treatment does not pose a major challenge. The majority of guidelines have endorsed the use of DOAC, and we highlight points to consider when choosing the optimal anticoagulant for the individual patient., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: Inconsistent study results and contradictory recommendations from health authorities regarding the use of apixaban in patients on hemodialysis have generated considerable uncertainty among clinicians, making investigations of appropriate dosing an unmet need., Methods: We analyzed pre-dialysis apixaban drug levels from a tertiary care dialysis unit, comparing 2.5 mg once versus twice daily dosing. We applied mixed-effects models including dialysis modality, adjusted standard Kt/V, ultrafiltration, and dialyzer characteristics. We included an exploratory analysis of bleeding events and compared the drug levels of our dialysis patients to those from non-CKD reference populations taking the standard dose of 5 mg twice daily., Results: We analyzed 143 drug levels from 24 patients. Mean (SD) age at first drug level measurement was 64.7 (15.9) years (50 % female), median (IQR) follow-up was 12.5 (5.5 - 21) months. For the apixaban 2.5 mg once and twice daily groups, median (IQR) drug levels were 54.4 (< 40 - 72.1) and 71.3 (48.8 - 104.1) ng/mL respectively (P < 0.001). Levels were below the detection limit in 30 % (with 2.5 mg once daily) and 14 % (with 2.5 mg twice daily) respectively. Only dosing group (twice versus once daily) was independently associated with higher drug levels (P = 0.002). Follow-up did not suggest accumulation. The 95 th percentile of drug levels did not exceed those of non-CKD populations taking 5 mg twice daily. Median (IQR) drug levels before a bleeding (8 episodes) were higher than those without a subsequent bleeding: 111.6 (83.1 - 129.3) versus 54.8 (< 40 - 77.1) ng/mL (P < 0.001). Concomitant antiplatelet therapy was used in 86% of those with bleeding events versus 6% without bleeding events (P < 0.001)., Conclusions: Drug monitoring may be a contributory tool to increase patient safety. Despite non-existing target ranges, drug levels on both edges of the spectrum (e.g. below detectability or beyond the 95 th percentiles of reference populations) may improve decision-making in highly individualized risk-benefit analyses., (© 2024. The Author(s).)

Purpose: Patients with BRAF V600 / NRAS Q61 wild-type melanoma who progress after immune checkpoint inhibitors (ICIs) have a poor prognosis. MEK inhibition has shown activity in this patient population but is associated with treatment-limiting skin toxicity. Combining a BRAF inhibitor with a MEK inhibitor is associated with less skin toxicity., Methods: This phase II trial investigated trametinib (2 mg once daily) in patients with advanced BRAF V600 / NRAS Q61 wild-type, ICI-refractory melanoma. In case of treatment-limiting skin toxicity, low-dose dabrafenib (50 mg twice daily) was added to trametinib. After a trial amendment, both drugs were combined up-front. The confirmed objective response rate (cORR) served as the primary end point., Results: Twenty-four patients were included (50% male; median age 57 years; 92% Eastern Cooperative Oncology Group Performance Status 0-2; 75% stage IV-M1c/stage IV-M1d; median number of prior therapies: two [range, 1-5]). Three patients were enrolled before and 21 patients after the amendment, respectively. Seven confirmed and one unconfirmed partial responses (PRs) were observed (cORR, 29.2%). The median duration of response was 16.6 weeks (95% CI, 5.5 to 27.7). Stable disease (SD) was the best response in an additional five patients. Among the responding patients, genetic alterations causing mitogen-activated protein kinase (MAPK) pathway activation were documented in six patients. The disease control rate in patients with MAPK pathway-activating alterations was 64.3% (five confirmed PR, one unconfirmed PR, and three SD). The median progression-free survival was 13.3 weeks (95% CI, 3.5 to 23.1), and the median overall survival was 54.3 weeks (95% CI, 37.9 to 70.6). Adding low-dose dabrafenib to trametinib effectively mitigated or prevented treatment-limiting trametinib-related skin toxicity., Conclusion: The combination of trametinib plus low-dose dabrafenib demonstrated encouraging efficacy and effective mitigation of skin toxicity in patients with advanced, ICI-pretreated BRAF V600 / NRAS Q61 wild-type melanoma patients. MAPK pathway-activating alterations hold promise as a predictive biomarker.

Background: Preclinical models of pancreatic cancer (PDAC) suggest a synergistic role for combined MEK and autophagy signaling inhibition, as well as MEK and CDK4/6 pathway targeting. Several case reports implicate clinical activity of the combination of either trametinib and hydroxychloroquine (HCQ) in patients with KRAS-mutant PDAC or trametinib with CDK4/6 inhibitors in patients with KRAS and CDKN2A/B alterations. However, prospective data from clinical trials is lacking. Here, we aim to provide clinical evidence regarding the use of these experimental regimens in the setting of dedicated precision oncology programs., Methods: In this retrospective case series, PDAC patients who received either trametinib/HCQ (THCQ) or trametinib/palbociclib (TP) were retrospectively identified across 11 participating cancer centers in Germany., Results: Overall, 34 patients were identified. 19 patients received THCQ, and 15 received TP, respectively. In patients treated with THCQ, the median duration of treatment was 46 days, median progression-free survival (PFS) was 52 days and median overall survival (OS) was 68 days. In the THCQ subgroup, all patients evaluable for response (13/19) had progressive disease (PD) within 100 days. In the TP subgroup, the median duration of treatment was 60 days, median PFS was 56 days and median OS was 195 days. In the TP subgroup, 9/15 patients were evaluable for response, of which 1/9 showed a partial response (PR) while 8/9 had PD. One patient achieved a clinical benefit despite progression under TP., Conclusion: THCQ and TP are not effective in patients with advanced PDAC harboring KRAS mutations or alterations in MAPK/CDKN2A/B., (© 2024. The Author(s).)

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease, and developing an effective treatment remains a challenge. The limited therapeutic options are primarily delivered by the oral route, among which pirfenidone (PFD) improves pulmonary dysfunction and patient quality of life. However, its high dose and severe side effects (dyspepsia and systemic photosensitivity) limit its clinical value. Intratracheal aerosolization is an excellent alternative method for treating lung diseases because it increases the concentration of the drug needed to reach the focal site. Tetrahedral framework nucleic acid (tFNA) is a drug delivery system with exceptional delivery capabilities. Therefore, we synthesized a PFD-tFNA (Pt) complex using tFNA as the delivery vehicle and achieved quantitative nebulized drug delivery to the lungs via micronebulizer for lung fibrosis treatment. In vivo , Pt exhibited excellent immunomodulatory capacity and antioxidant effects. Furthermore, Pt reduced mortality, gradually restored body weight and improved lung tissue structure. Similarly, Pt also exhibited superior fibrosis inhibition in an in vitro fibrosis model, as shown by the suppression of excessive fibroblast activation and epithelial-mesenchymal transition (EMT) in epithelial cells exposed to TGF-β1. Conclusively, Pt, a complex with tFNA as a transport system, could enrich the therapeutic regimen for IPF via intratracheal aerosolization inhalation.

Background: Immunosuppressants, biologic agents, antifibrotic drugs, and other drugs can be used to treat autoimmune disease-associated interstitial lung disease (ILD), but the preferred treatment is uncertain. We aimed to evaluate the efficacy and safety of multiple drugs in the treatment of autoimmune disease-associated ILD., Methods: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched for relevant randomized controlled trials (RCTs) from inception to July 2023. Primary outcomes were percentage of predicted forced vital capacity (FVC% predicted) and discontinuations for adverse events (AEs). We estimated summary mean differences (MDs) and odds ratios (ORs) using network meta-analysis with fixed effects., Results: The analysis is based on 15 RCTs involving 1832 patients. In terms of FVC% predicted, mycophenolate mofetil (MMF) (MD 1.27, 95 % credible interval [CrI] 0.08 to 2.43), cyclophosphamide (1.89, 0.10 to 3.68), rituximab (9.29, 2.79 to 15.80), tocilizumab (6.30, 3.27 to 9.34), nintedanib (1.71, 0.54 to 2.88), pirfenidone (2.03, 0.65 to 3.40) and nintedanib+MMF (2.43, 0.95 to 3.89) were more effective than placebo. Analysis based on a small sample size showed that riociguat also had good therapeutic potential when compared with placebo. By contrast, bosentan and pomalidomide showed no significant difference compared with placebo. Regarding discontinuations for AEs, nintedanib (OR 2.09, 95 %CrI 1.20 to 3.73) and pirfenidone (3.46, 1.31 to 10.56) were associated with higher dropout rates than placebo, and the combination therapy of nintedanib+MMF did not increase the risk of AEs compared with nintedanib monotherapy., Conclusions: MMF, cyclophosphamide, rituximab, tocilizumab, nintedanib and pirfenidone are effective in the treatment of autoimmune disease-associated ILD. The efficacy of riociguat and the superiority of combination therapy need to be demonstrated in more RCTs. The tolerance of nintedanib and pirfenidone is a concern, but most of their AEs are mild and controllable., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Bleeding after endoscopic submucosal dissection (ESD) for gastric tumors in patients taking antithrombotic drugs, in particular direct oral anticoagulants (DOACs), remains unresolved; therefore, we evaluated the risk factors for post-ESD bleeding and drug differences in patients taking DOACs., Methods: We included 278 patients taking antithrombotic drugs who underwent gastric ESD between January 2017 and March 2022. Antithrombotic drugs were withdrawn following the 2017 guidelines (Appendix on anticoagulants including DOACs). To further clarify differences in antithrombotic agents' effects, the peri-cancerous mucosa in the resected specimen was pathologically evaluated according to the Updated Sydney System. Multivariate analysis was performed to assess the risk of post-ESD bleeding., Results: The incidence of post-ESD bleeding in patients taking DOACs was 19.6% (10/51). Among patients taking antithrombotic drugs, DOACs were identified as a possible factor involved in post-ESD bleeding (odds ratio [OR] 4.92). Among patients taking DOACs, possible factors included resection length diameter ≥30 mm (OR 3.72), presence of neutrophil infiltration (OR 2.71), lesions occurring in the lower third of stomach (OR 2.34), and preoperative antiplatelet use (OR 2.22). Post-ESD bleeding by DOAC type was 25.0% of patients (4/16) receiving apixaban, in 20.0% (3/15) receiving edoxaban, in 21.4% (3/14) receiving rivaroxaban, and in none of those receiving dabigatran., Conclusions: The administration of DOACs was shown to be a possible factor involved in post-ESD bleeding, and risk factors for patients taking DOACs included neutrophil infiltration. The pharmacological differences in the effects of DOACs contributing to bleeding in gastric ulcers suggest comparatively less bleeding with dabigatran after ESD., (© 2024 Japan Gastroenterological Endoscopy Society.)

It remains unclear whether non-vitamin K antagonist oral anticoagulants (NOACs) are more effective and safer than warfarin in low-weight patients with atrial fibrillation (AF). Here, we retrospectively compared the effectiveness and safety of NOACs with those of warfarin in low-weight patients with AF. We extracted the July 2011-September 2022 data of patients with AF treated with a NOAC (dabigatran, rivaroxaban, apixaban, or edoxaban) or warfarin at a tertiary hospital. The patients were divided into low-weight (body weight ≤ 60 kg) and non-low-weight (body weight = 60-100 kg) groups. The primary outcomes were hospitalization for ischemic stroke (IS) or systemic embolism (SE) and major bleeding, whereas the secondary outcomes were any ischemic and bleeding events. We used the inverse probability of treatment weighting to balance the baseline characteristics between the groups. In total, 5,044 patients (mean age = 73.7 years, mean CHA2DS2-VASc score = 3.0, mean HAS-BLED score = 2.3) were enrolled and divided into low-weight and non-low-weight groups-containing 1,666 (1,406 NOAC users, 260 warfarin users) and 3,378 (2,978 NOAC users, 400 warfarin users) patients, respectively. NOACs were associated with a lower risk of any bleeding event in the low-weight group (adjusted hazard ratio = 0.61, 95% confidence interval = 0.51-0.73). The between-group differences in the risks of IS/SE, any ischemic event, major bleeding, and any bleeding event were nonsignificant. Thus, the use of NOACs (specifically dabigatran or edoxaban) is associated with a lower risk of any bleeding event than warfarin use in low-weight patients with AF., (© 2024. The Author(s).)

Aims: Trans/transfeminine women are disproportionally affected by HIV. Concerns regarding negative drug-drug interactions (DDIs) between ART drugs and gender-affirming hormone therapy (GAHT), specifically feminizing hormone therapy (FHT), may contribute to the lower ART uptake by trans women with HIV compared with their cis counterparts. The aim of this study is to investigate the bidirectional pharmacokinetic effects of components of FHT regimens (oral oestradiol and androgen-suppressing medications) with the ART regimen (bictegravir/emtricitabine/tenofovir alafenamide [B/F/TAF)]., Methods: We present a protocol for a three-armed, parallel-group, longitudinal (6-month), DDI study. Group 1 includes 15 3trans women with HIV taking FHT and ART; group 2 includes 15 premenopausal cis women with HIV taking ART; group 3 includes 15 trans women without HIV taking FHT. Women with HIV must be on or switch to B/F/TAF at baseline and be virally suppressed for ≥3 months. Trans women must be taking a stable regimen of ≥2 mg daily oral oestradiol and an anti-androgen (pharmaceutical, and/or surgical, and/or medical) for ≥3 months. Plasma ART drug concentrations will be sampled at Month 2 and compared between groups 1 and 2. Serum oestradiol concentrations will be sampled at baseline and Month 2 visits and compared between groups 1 and 3. The primary outcomes are B/F/TAF pharmacokinetic parameters (C min , C max and AUC) and oestradiol concentrations (C min , C 4h, C max and AUC) at month 2., Discussion: This study is of global importance as it provides critical information regarding safe coadministration of B/F/TAF and FHT, both of which are life-saving therapies for trans women with HIV., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives: This study aimed to describe and evaluate the transition from a specialty service-based prospective order approval system to a computerized clinical decision support (CCDS) tool for apixaban dosing at a community teaching hospital. The primary objective was to assess the impact of the transition on the appropriateness of apixaban prescribing., Methods: A CCDS tool for apixaban dosing was developed and implemented using interprofessional collaboration. A retrospective chart review was conducted for apixaban orders placed before (preimplementation) and after (postimplementation) the CCDS transition. The primary outcome was the percent change in inappropriate apixaban orders, with secondary outcomes exploring percent change of apixaban orders with inappropriate dosing in different patient groups and indications per package insert., Results: Fifty orders were assessed in both arms, with 8% of orders preimplementation and 10% postimplementation deemed inappropriate. After accounting for questionable orders, overall appropriateness of prescribing was 88% preimplementation and 84% postimplementation ( P = 0.7). Challenges with implementation of CCDS included working with available information technology resources and facilitating acceptance of a new ordering process., Conclusions: The implementation of a CCDS tool for apixaban dosing at a community teaching hospital demonstrated comparable rates of appropriateness to the previous specialty service-based approval process. While the transition streamlined resources and improved efficiency, ongoing efforts are needed to address specific dosing challenges. Future research should explore the sustainability and generalizability of CCDS tools in diverse healthcare settings., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The differences in the safety and efficacy of anticoagulation between different types of new oral anticoagulants(NOACs) and low molecular weight heparin(LMWH) are still controversial. The main purposes of this study were to analyze safety and efficacy of NOACs versus LMWH for thromboprophylaxis, and perform subgroup analyses stratified by individual NOACs and different populations after total hip arthroplasty (THA) or total knee arthroplasty (TKA). Literature search was performed in PubMed, EMBASE, Cochrane Library, CNKI and Wanfang databases until June 31, 2022. This systematic review and meta-analysis included 46 randomized controlled trials (RCT) with 39, 924 patients. We evaluated the safety and efficacy of thromboprophylaxis between LMWH and NOACs. NOACs were more effective in reducing deep vein thrombosis (DVT) (RR0.59; 95%CI 0.49-0.71) and adverse events (RR: 0.96; 95%CI: 0.93-0.99) than LMWH. The subgroup analyses for different anticoagulants revealed that rivaroxaban (RR:0.49; 95%CI:0.36-0.66), apixaban (RR: 0.54; 95%CI: 0.36-0.81) and edoxaban (RR:0.49; 95%CI: 0.32-0.75) have the lower risk of DVT than LMWH. Apixaban (RR:0.89; 95%CI: 0.80-1.00) had superior prevention of bleeding to LMWH. Edoxaban exhibited a lower risk of VTE (RR: 0.46; 95%CI: 0.33-0.65), advantage events (RR: 0.87; 95%CI: 0.82-0.93), and drug-related adverse events (DRAEs) (RR: 0.64; 95%CI: 0.53-0.76) than LMWH. East Asian population was superior to western population for preventing DVT, advantage events, and DRAE using NOACs. In conclusion, NOACs are more effective than LMWH at preventing DVT and adverse events after arthroplasty. Apixaban has lower bleeding than LMWH, and East Asian populations may benefit more than western population from NOACs., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Background: It is uncertain whether prothrombin complex concentrate (PCC) improves hemostasis in patients on treatment with oral factor Xa-inhibitors (XaI) who require emergency surgery., Objectives: To evaluate whether, in patients with therapeutic levels of oral XaI, preoperative PCC prevents excessive bleeding during and after emergency surgery and is not associated with thrombotic complications., Methods: We conducted a prospective cohort study wherein a fixed 2000 IU dose of 4-factor PCC was given to patients taking oral XaI with plasma XaI levels of at least 75 ng/mL before the emergency surgery with an expected blood loss of at least 50 mL. Patients were followed for 30 days. The primary efficacy outcome was the incidence of normal or mildly abnormal surgical hemostasis, as assessed by the surgeon; primary safety outcome was the incidence of thromboembolic events within 7 days., Results: We included 20 patients, of which 50% were female, on apixaban (75%) or rivaroxaban (25%) with median XaI level of 128 ng/mL (range, 77-497 ng/mL). The median duration of surgery was 2 hours 42 minutes (range, 15 minutes to 8 hours 17 minutes). Normal or mildly abnormal hemostasis was observed in 16 patients (80%); 2 patients had moderately abnormal and 2 had severely abnormal hemostasis, 1 each of those was considered due to local or technical factors. There were 4 deaths (20%) secondary to underlying disease and 1 incidental pulmonary embolism in a patient with cancer., Conclusion: A fixed dose of PCC appears to control hemostasis in patients with therapeutic plasma levels of apixaban or rivaroxaban requiring emergency surgery., Competing Interests: Declaration of competing interests S.S. served on data safety monitoring boards for Alexion, Bayer, Boehringer-Ingelheim, Regeneron, and Sanofi; served on a steering committee for Octapharma; served on event adjudication for Daiichi Sankyo and Takeda. V.B. received honorarium from Bayer. F.G.’s institution received research funding from Novo Nordisk, Roche, Takeda, Bayer, Pfizer, BioMarin, and CSL. R.I. received honoraria for advisory boards for Aspen, LeoPharma, Sanofi, and Inari. P.L.G. is named on a patent, “Novel methods to measure protease inhibitors.” N.C., A.I., S.M., and J.I.W. have no relevant conflicts., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To examine the efficacy and safety of perampanel (PER) in patients with post-stroke epilepsy (PSE), brain tumor-related epilepsy (BTRE), and post-traumatic epilepsy (PTE) using Japanese real-world data., Methods: The prospective post-marketing observational study included patients with focal seizures with or without focal to bilateral tonic-clonic seizures who received PER combination therapy. The observation period was 24 or 52 weeks after the initial PER administration. The safety and efficacy analysis included 3716 and 3272 patients, respectively. This post hoc analysis examined responder rate (50% reduction in seizure frequency), seizure-free rate (proportion of patients who achieved seizure-free), and safety in patients included in the post-marketing study who had PSE, BTRE, and PTE in the 4 weeks prior to the last observation., Results: Overall, 402, 272, and 186 patients were included in the PSE, BTRE, and PTE subpopulations, and 2867 controls in the "Other" population (etiologies other than PSE, BTRE, or PTE). Mean modal dose (the most frequently administered dose) values at 52 weeks were 3.38, 3.36, 3.64, and 4.04 mg/day for PSE, BTRE, PTE, and "Other," respectively; PER retention rates were 56.2%, 54.0%, 52.6%, and 59.7%, respectively. Responder rates (% [95% confidence interval]) were 82% (76.3%-86.5%), 78% (70.8%-83.7%), 67% (56.8%-75.6%), and 50% (47.9%-52.7%) for PSE, BTRE, PTE, and "Other," respectively, and seizure-free rates were 71% (64.5%-76.5%), 62% (54.1%-69.0%), 50% (40.6%-60.4%), and 28% (25.8%-30.1%), respectively. Adverse drug reactions tended to occur less frequently in the PSE (14.7%), BTRE (16.5%), and PTE (16.7%) subpopulations than in the "Other" population (26.3%)., Significance: In real-world clinical conditions, efficacy and tolerability for PER combination therapy were observed at low PER doses for the PSE, BTRE, and PTE subpopulations., Plain Language Summary: To find out how well the medication perampanel works and whether it is safe for people who have epilepsy after having had a stroke, brain tumor, or head injury, we used information from real-life medical situations in Japan. We looked at the data of about 3700 Japanese patients with epilepsy who were treated with perampanel. We found that perampanel was used at lower doses and better at controlling seizures, and had fewer side effects for patients with epilepsy caused by these etiologies than the control group., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Competing Interests: CO has received research grants to their institution from Gilead Sciences, Viiv Healthcare, MSD, Janssen Pharmaceuticals, and Astra Zeneca, and has received honoraria and travel scholarships from Gilead Sciences, ViiV Healthcare, MSD, Janssen Pharmaceuticals, and Bavarian Nordic. KR has received speaker and consultations fees from ViiV Healthcare and is an investigator on drug trials sponsored by Gilead Sciences and MSD.

Background and Objective: Multiple randomized controlled studies have shown that pirfenidone and nintedanib are effective and safe for treating idiopathic pulmonary fibrosis. This study aimed to evaluate their efficacy, safety, and tolerability in a real-world setting., Methods: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for real-world studies published up to March 3, 2023, on pirfenidone and nintedanib for idiopathic pulmonary fibrosis., Results: A total of 74 studies with 23,119 participants were included. After 12 months of treatment, the change from baseline in percent predicted FVC (%FVC) was - 0.75% for pirfenidone and - 1.43% for nintedanib. The change from baseline in percent predicted DLCO (%DCLO) was - 2.32% for pirfenidone and - 3.95% for nintedanib. The incidence of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was 12.5% for pirfenidone and 14.4% for nintedanib. The IPF-related mortality rates of pirfenidone and nintedanib were 13.4% and 7.2%, respectively. The all-cause mortality was 20.1% for pirfenidone and 16.6% for nintedanib. In the pirfenidone group, 16.6% of patients discontinued treatment because of adverse events, and in the nintedanib group, 16.2% of patients discontinued treatment because of adverse events. The incidence of adverse events was 56.4% and 69.7% for pirfenidone and nintedanib, respectively., Conclusion: The results of this study indicate that pirfenidone and nintedanib are both effective in slowing down the decline of lung function in IPF patients in real-world settings. The incidence of adverse events with pirfenidone is lower than that with nintedanib, but both are below the clinical trial data, and no new major adverse events have been observed. The discontinuation rates due to adverse reactions of the two drugs are consistent with clinical trial data, indicating good tolerability. However, the mortality rates and AE-IPF incidence rates of these two drugs in real-world settings are higher than those in previous clinical trials, with pirfenidone patients showing a higher mortality rate. Further large-sample studies are needed to investigate the risks of these drugs in these aspects. Additionally, we recommend that future real-world studies pay more attention to patients' subjective symptoms and conduct stratified analyses of the efficacy and safety of pirfenidone and nintedanib based on factors such as patients' baseline lung function, comorbidities, and age, in order to provide more personalized medication advice for IPF patients in clinical practice., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Optimal antithrombotic therapy after percutaneous left atrial appendage occlusion (LAAO) is not well established as no randomized evaluation has been performed to date., Objective: To compare the efficacy and safety of low-dose direct oral anticoagulation (low-dose DOAC) vs dual antiplatelet therapy (DAPT) for 3 months after LAAO., Design, Setting, and Participants: The ADALA (Low-Dose Direct Oral Anticoagulation vs Dual Antiplatelet Therapy After Left Atrial Appendage Occlusion) study was an investigator-initiated, multicenter, prospective, open-label, randomized clinical trial enrolling participants from June 12, 2019, to August 28, 2022 from 3 European sites. Patients who underwent successful LAAO were randomly assigned 1:1 to low-dose DOAC vs DAPT for 3 months after LAAO. The study was prematurely terminated when only 60% of the estimated sample size had been included due to lower recruitment rate than anticipated due to the COVID-19 pandemic., Interventions: The low-dose DOAC group received apixaban, 2.5 mg every 12 hours, and the DAPT group received aspirin, 100 mg per day, plus clopidogrel, 75 mg per day, for the first 3 months after LAAO., Main Outcomes and Measures: The primary end point was a composite of safety (major bleeding) and efficacy (thromboembolic events including stroke, systemic embolism, and device-related thrombosis [DRT]) within the first 3 months after successful LAAO. Secondary end points included individual components of the primary outcome and all-bleeding events., Results: A total of 90 patients (mean [SD] age, 76.6 [8.1] years; 60 male [66.7%]; mean [SD] CHADS-VASc score, 4.0 [1.5]) were included in the analysis (44 and 46 patients in the low-dose DOAC and DAPT groups, respectively). A total of 53 patients (58.8%) presented with previous major bleeding events (60 gastrointestinal [66.7%] and 16 intracranial [17.8%]). At 3 months, low-dose DOAC was associated with a reduction of the primary end point compared with DAPT (2 [4.5%] vs 10 [21.7%]; hazard ratio, 0.19; 95% CI, 0.04-0.88; P = .02). Patients in the low-dose DOAC group exhibited a lower rate of DRT (0% vs 6 [8.7%]; P = .04) and tended to have a lower incidence of major bleeding events (2 [4.6%] vs 6 [13.0%]; P = .17), with no differences in thromboembolic events such as stroke and systemic embolism between groups (none in the overall population)., Conclusions and Relevance: This was a small, randomized clinical trial comparing different antithrombotic strategies after LAAO. Results show that use of low-dose DOAC for 3 months after LAAO was associated with a better balance between efficacy and safety compared with DAPT. However, the results of the study should be interpreted with caution due to the limited sample size and will need to be confirmed in future larger randomized trials., Trial Registration: ClinicalTrials.gov Identifier: NCT05632445.

Purpose: BRAF mutations are detected in 30%-80% of papillary thyroid cancer (PTC) cases. DaBRAFenib and trametinib showed promising antitumor activity in patients with BRAFV600E-mutated metastatic melanoma and non-small cell lung cancer. This study aimed to evaluate the efficacy and safety of daBRAFenib and trametinib in patients with metastatic BRAFV600E-mutated thyroid cancer., Materials and Methods: This was a retrospective study to evaluate the efficacy of daBRAFenib and trametinib in patients with metastatic BRAFV600E-mutated PTC. The patients received daBRAFenib 150 mg twice daily and trametinib 2 mg once daily at the Samsung Medical Center. This study evaluated the progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) overall survival (OS), and safety of daBRAFenib and trametinib., Results: Between December 2019 and January 2022, 27 PTC patients including eight patients with poorly differentiated or anaplastic transformation, received daBRAFenib and trametinib. The median age was 73.0 years, and the median follow-up period was 19.8 months. The majority (81.5%) had undergone thyroidectomy, while 8 patients had received prior systemic treatments. ORR was 73.1%, with 19 partial responses, and DCR was 92.3%. Median PFS was 21.7 months, and median OS was 21.7 months. Treatment-related adverse events included generalized weakness (29.6%), fever (25.9%), and gastrointestinal problems (22.2%). Dose reduction due to adverse events was required in 81.5% of the patients., Conclusion: DaBRAFenib and trametinib demonstrated a high ORR with promising PFS; however, most patients with BRAFV600E-mutated metastatic PTC required a dose reduction.

Introduction: Long-acting injectable cabotegravir + rilpivirine (CAB + RPV LAI) was approved for use in virally suppressed adults in the England and Wales national health service in November 2021. We describe a service evaluation of delivery processes and outcomes in 12 clinics., Methods: Centres populated a database using information from local policies and clinical records. Services were asked to describe approval processes, clinic pathways, and adherence to national guidelines. Additional data were collected on reasons for regimen choice, treatment discontinuations, and management of viraemia., Results: In total, 518 adults from 12 clinics were approved for CAB + RPV LAI between February 2022 and December 2023. Of the 518 people approved for CAB + RPV LAI, 423 received at least one injection. Median duration on CAB + RPV was 7.5 months (interquartile range 3.7-11.3). In total, 97% of injections were administered within the ±7-day window. Virological failure occurred in 0.7%, and 6% discontinued CAB + RPV., Conclusion: In this large UK-based cohort, robust approval processes and clinic protocols facilitated on-time injections and low rates of both discontinuation and virological failure., (© 2024 The Author(s). HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Introduction: The monitoring of unfractionated heparin (UFH) by anti-factor Xa activity (AXA) is commonly used to ensure effective anticoagulation and prevent bleeding risk. However, in patients previously treated with an anti-Xa direct oral anticoagulant (DOAC) switching to UFH therapy, there is a risk of interference that may lead to inappropriate anticoagulation. The first objective of this study was to validate DOAC-Remove to remove DOAC for measuring UFH specific AXA. The second objective was to assess the length of DOAC interference on UFH monitoring and to identify potential predictive factors., Materials and Methods: This monocentric retrospective study included all patients admitted from April 2019 to April 2021 previously treated with anti-Xa DOAC, and for whom an interference on UFH monitoring was suspected. Interference was defined as a difference in the AXA measured before and after using DOAC-Remove >2.8-fold standard deviation of the method., Results: Removal with DOAC-Remove was specific of DOAC (apixaban n = 42, rivaroxaban n = 41, UFH n = 20) and sufficient to avoid interference on UFH AXA measurement. The exact interference length was 6.0 days [IQR 3.0-11.0] for apixaban (n = 26) and 4.5 days [IQR 2.0-5.8] for rivaroxaban (n = 20). Among the 89 patients sorted based on an interference length ≤ or >3 days, 74 (83.1%) presented an interference greater than 3 days. Correlations were observed with age for apixaban and creatinine for rivaroxaban., Conclusions: Our results suggest that DOAC-Remove could be of high interest in patients receiving UFH previously treated with an anti-Xa DOAC even if DOAC was stopped for more than 3 days., (© 2024 John Wiley & Sons Ltd.)

Purpose: To investigate the safety and efficacy of direct oral anticoagulants (DOACs) in the treatment of the acute phase of heparin-induced thrombocytopenia (HIT)., Summary: A systematic review of the literature was conducted on PubMed, MEDLINE, Embase, and Web of Science Core Collection through July 2023. Search terms included "heparin-induced thrombocytopenia AND direct-oral-anticoagulants" in addition to a list of oral anticoagulants. Adult patients who used direct oral anticoagulants as the initial treatment for the acute phase of HIT were included. A total of 1,188 articles were initially identified, with 770 articles reviewed following removal of duplicates. Following the application of inclusion and exclusion criteria, 12 articles were ultimately included. Rivaroxaban was the most-utilized DOAC (28 patients), followed by apixaban (7 patients) and dabigatran (1 patient). All patients with thrombocytopenia demonstrated successful platelet recovery, with two patients presenting with normal platelet counts. One patient developed a deep venous thrombosis with no other new or recurrent thromboses. There were no reported clinically significant adverse events in any patient. Obstacles and deterrents to the use of the standards of care in the acute phase of HIT exist. Argatroban and bivalirudin require intravenous infusion and require close aPTT monitoring and dose adjustment. Fondaparinux requires injection and is contraindicated with body weight <50kg. DOACs would offer the novel ability for an oral treatment in the treatment of the acute phase HIT and allow for minimal monitoring and consistent dosing strategies. Therefore, DOACs are an intriguing choice for the treatment of the acute phase of HIT., Conclusion: Data from 12 publications and across 36 patients suggests that the use of DOACs in the acute phase of HIT may be a safe and efficacious treatment option with favorable ease of monitoring and management., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Patients with thrombotic antiphospholipid syndrome (APS) are at high risk for recurrent thrombosis, and indefinite anticoagulation is recommended. Patients with APS merit indefinite anticoagulation, and vitamin K antagonists (VKAs) have historically been the standard treatment. Direct oral anticoagulants (DOACs) present an appealing alternative to VKAs. Due to their pharmacokinetic and pharmacodynamic characteristics, DOACs offer advantages over VKAs, namely the lack of need for laboratory monitoring, the usage of a fixed dosage, and the absence of significant interaction with dietary components and drugs. The efficacy and safety of DOACs in patients with APS have been studied in four phase II/III clinical trials (three with rivaroxaban and one with apixaban). These studies showed DOACs' inferiority compared to VKAs in preventing recurrent thrombosis. Recurrence was significantly greater in patients with arterial thrombotic events and a triple positivity for antiphospholipid antibodies. No differences were observed in the incidence of venous thromboembolism between both groups. Major bleeding was similar in patients treated with DOACs or VKAs. Several observational studies have reported similar results. This review aims to analyse the existing evidence on the efficacy and safety of DOACs for secondary prevention in patients with APS.

Background/aims: Early studies on direct oral anticoagulants (DOACs) reported a higher risk of gastrointestinal bleeding (GIB) compared with warfarin; however, recent studies have reported a reduced risk. Therefore, this study was designed to evaluate the risk of GIB in users of DOAC and warfarin., Methods: Using a common data model, we investigated the comparative risk of GIB in subjects from eight hospitals who were newly prescribed DOACs or warfarin. We excluded subjects who had a prior history of GIB or had been prescribed both medications. After propensity score matching, we analyzed 3,347 matched pairs of new DOAC and new warfarin users., Results: The risk of GIB in new DOAC users was comparable to that in new warfarin users (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.65 to 1.40; p=0.808). New DOAC users had a similar risk of GIB to new warfarin users among older patients >65 years (HR, 1.00; 95% CI, 0.69 to 1.52; p=0.997) and in older patients >75 years (HR, 1.21; 95% CI, 0.68 to 2.10; p=0.509). In addition, the risk of GIB was not significantly different between two groups according to sex. We also found that the risk of GIB in DOAC users was 26% lower in edoxaban or apixaban subgroups compared to rivaroxaban or dabigatran subgroups (HR, 0.74; 95% CI, 0.69 to 1.00; p=0.049)., Conclusions: In real-world practice, the risk of GIB in new DOAC users is comparable to that in new warfarin users. In DOAC users, the risk of GIB was lower in edoxaban or apixaban subgroups than rivaroxaban or dabigatran subgroups.

Background: The optimal antithrombotic regimen for patients with atrial fibrillation (AF) who had an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is not known., Objectives: The authors sought to determine which antithrombotic regimen best balances safety and efficacy., Methods: AUGUSTUS, a multicenter 2 × 2 factorial design randomized trial compared apixaban with vitamin K antagonist (VKA) and aspirin with placebo in patients with AF with recent ACS and/or PCI treated with a P2Y 12 inhibitor. We conducted a 4-way analysis comparing safety and efficacy outcomes in the 4 randomized groups. The primary outcome was a composite of all-cause death, major or clinically relevant nonmajor bleeding, or hospitalization for cardiovascular causes over 6-month follow-up. Secondary outcomes included individual components of the primary endpoint., Results: A total of 4,614 patients were enrolled. All patients were treated with a P2Y 12 inhibitor. The primary endpoint occurred in 21.9% of patients randomized to apixaban plus placebo, 27.3% randomized to apixaban plus aspirin, 28.0% randomized to VKA plus placebo, and 33.3% randomized to VKA plus aspirin. Rates of major or clinically relevant nonmajor bleeding and hospitalization for cardiovascular causes were lower with apixaban and placebo compared with the other 3 antithrombotic strategies. There was no difference between the 4 randomized groups with respect to all-cause death., Conclusions: In patients with AF and a recent ACS and/or PCI, an antithrombotic regimen that included a P2Y 12 inhibitor and apixaban without aspirin resulted in a lower incidence of the composite of death, bleeding, or cardiovascular hospitalization than regimens including VKA, aspirin, or both. (An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention; NCT02415400)., Competing Interests: Funding Support and Author Disclosures The AUGUSTUS study and this analysis were funded by Bristol Myers Squibb and Pfizer. Dr Berwanger has received research grants from AstraZeneca, Pfizer, Bayer, Amgen, Novartis, Servier, and Boehringer Ingelheim. Dr Fanaroff has received research grants from the American Heart Association and National Institutes of Health; and has received consulting fees from Abbott Laboratories. Dr Granger has received research grants from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Armetheon, AstraZeneca, U.S. Food and Drug Administration, GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic Inc, and Novartis; and has received consulting fees from Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Abbvie, Armetheon, AstraZeneca, Eli Lilly, Gilead, GlaxoSmithKline, Hoffmann-La Roche, The Medicines Company, National Institutes of Health, Novartis, Sirtex, Verseon, Apple, Medscape, LLC, Merck, Novo Nordisk, Roche Diagnostics, and Rho Pharmaceuticals. Dr Mehran has received institutional research grants from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol Myers Squibb/Sanofi, CSL Behring, Eli Lilly/Daiichi-Sankyo, Medtronic, Novartis, and OrbusNeich; has received consulting fees from Boston Scientific, Abbott Vascular, Medscape, Siemens Medical Solutions, Roivant Sciences Inc, and Sanofi; has consulted (no fees) for Regeneron Pharmaceuticals Inc; has received institutional consulting fees from Abbott Vascular, Spectranetics/Phillips/Volcano Corporation, Bristol Myers Squibb, Novartis, and Watermark Research; is an executive committee member for Janssen Pharmaceuticals and Bristol Myers Squibb; and has <1% equity in Claret Medical and Elixir Medical. Dr Aronson is an employee of Bristol Myers Squibb. Dr Windecker has received institutional research and educational grants from Abbott, Amgen, Bayer, Bristol Myers Squibb, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. Dr Goodman has received research grant support and/or speaker/consulting honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, Eli Lilly, Esperion, Fenix Group International, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, Janssen/Johnson and Johnson, Luitpold Pharmaceuticals, Matrizyme, Merck, Novartis, Novo Nordisk A/C, Pfizer, Regeneron, Sanofi, Servier, Tenax Therapeutics, Heart and Stroke Foundation of Ontario/University of Toronto, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Duke Clinical Research Institute, and PERFUSE. Dr Alexander has received research grants from Bristol Myers Squibb, Boehringer Ingelheim, AstraZeneca, CryoLife, CSL Behring, U.S. Food and Drug Administration, National Institutes of Health, Sanofi, and VoluMetrix; and has received consulting fees from Pfizer, Bristol Myers Squibb, AbbVie Pharmaceuticals, CSL Behring, Novo Nordisk, Portola Pharmaceuticals, Quantum Genomics, Teikoku Pharmaceuticals, VA Cooperative Studies, and Zafgen. Dr Lopes has received research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; has received funding for educational activities or lectures from Pfizer, Daiichi-Sankyo, and Novo Nordisk; and has received funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)