Discontinuation Research Articles

Intestinal ultrasound accurately predicts future therapy failure in Crohn’s disease patients in a biologics-induced remission

Background Intestinal ultrasound (IUS) is used to assess disease activity, complications, and treatment follow-up in Crohn’s disease (CD). Less is known about the association of disease activity on IUS with the risk of future disease relapse during biologically sustained clinical remission in CD. Aim The study aimed to investigate the association between IUS activity parameters and subsequent therapy failure in asymptomatic biologically treated patients with CD. Methods A retrospective cohort study examined the association between IUS parameters and forthcoming therapy failure (drug discontinuation, dose escalation, corticosteroid use, hospitalization, or surgery) in CD patients on biological therapy in remission. Results A total of 57 patients with ileal (65%) or ileocolonic (35%) CD on biological therapy were included in the study. Therapy failure occurred in 50.8% [defined as need for dose escalation (31%), drug discontinuation (51.7%), steroid use (10.5%), and hospitalization (6.8%)] during a median follow-up of 5 (SD + 9.5) months after IUS. On univariate analysis, a bowel wall thickness (BWT) of 2.5 vs. 4 mm (P = 0.005), the existence of an enlarged lymph node (P = 0.02), and the loss of bowel wall stratification (P = 0.01) were correlated with therapy failure. On multivariable analysis, only BWT ≥ 4 mm was associated with the risk of future treatment failure (hazard ratio, 3.7; 95% confidence interval, 0.6–15; P = 0.02). Conclusion Our findings suggest that BWT ≥4 mm during clinical remission is associated with subsequent treatment failure in patients with CD treated with biologics. Our results support the use of IUS for monitoring CD during remission and may point to a novel threshold for predicting disease reactivation.

Enhancing healthcare outcomes and cost efficiency through patient support programs: a comprehensive analysis

Abstract Introduction Treatment retention is crucial for patients with chronic diseases, impacting both clinical outcomes and healthcare costs. Patient Support Programs (PSP), often sponsored by pharmaceutical companies as a wraparound support service for new and innovative medicines, have been shown to be a viable tool in supporting treatment retention and adherence1. Utilizing tools like Patient Activation Measure (PAM®) equips healthcare providers with a means to evaluate the impact of these PSPs on patients' activation and their potential to adhere to medication. The PAM is a behavioural concept focusing on a patient’s understanding of their role in their healthcare, and how competent they feel to fulfil that role. Crucially, there is substantial evidence indicating a strong association between higher PAM scores and improved clinical outcomes2. Aim This study objectives are to evaluate the effectiveness of PSP in reducing treatment drop-off; to investigate the impact of PSP on patient activation/PAM levels; and to analyse potential cost savings from patient activation through PSP participation. Methods The study population includes patients (n= 97795) diagnosed with chronic diseases receiving one of three services from a Clinical Homecare company: (1) Direct-to-patient medication delivery (DD); (2) DD plus self-administration training and (3) DD, self-administration training and PAM-based PSP. Patient “drop-off” from treatment was analysed across all three services and defined as discontinuation of medication due to unwillingness to engage, non-response to engagement attempts, or requests to put the service on hold. Additionally, change in PAM level/activation for patients who completed baseline and follow-up PAM surveys between October 2020 and March 2024 (n=1880) was considered. Finally, expected cost saving was examined, both as a result of the observed change in activation for PSP patients as well as in a hypothetical scenario where patients in DD and self-administration training are redirected to PSP. Ethical approval was not required because the study does not involve any patient interaction/intervention whatsoever. It was a retrospective data analytical study, using existing and fully anonymised patient data from routine clinical care. Results Fewer patients drop off from treatment when they are on the PSP (1.1%) compared to those that are on self-administration training (2.1%) or DD (2.8%). Participation in PSP also positively impacted PAM scores across all therapies, with average improvements ranging from 1 to 8.1 points per patient. Patients in the lower two activation levels (typically at the greatest risk of non-adherence) experienced the most substantial gains (ranging from 8.4 to 17.4 points) emphasizing the significance of intervention. These improvements in PAM scores by PSP translated to substantial cost savings for the health system, amounting to £1,028,669. Finally, where the same treatment drop-off rate and PAM performance ratio are applied to a hypothetical scenario involving the redirection of patients from DD and self-administration training to PSP, there is a further potential cost savings of £4,298,277. Conclusion Participation in PSP improves patient activation and the potential to adhere to prescribed medication, while producing significant financial benefits. Further research is needed to understand how these benefits may vary across different therapy areas and within primary, secondary, and homecare settings.

Ultrasound-guided popliteal sciatic nerve block for surgical anesthesia in wound care patients with ongoing anticoagulant/antiaggregant therapy: A single-center, prospective study.

Ultrasound-guided peripheral nerve blocks may be a good alternative in patients under antithrombotic drugs. We evaluated the efficacy of ultrasound-guided popliteal sciatic nerve block in patients undergoing lower extremity wound debridement of whom antithrombotic drugs could not be stopped. We focused on hemorrhagic complications related to sciatic nerve block. Wound care patients followed by Cardiovascular Surgery Department scheduled for lower extremity wound surgery were included in this prospective observational study. Data was collected between March 2021 and September 2022. All patient were under antithrombotic therapy and discontinuation of anticoagulant drugs were not possible. Single-insertion and multiple-injection sciatic nerve block at popliteal region was applied to all patients under ultrasound guidance. Primary outcome was the rate of hemorrhage. Secondary outcomes were block onset times, block success and postoperative analgesia times. Data of 105 patients was evaluated, 87 were male and 18 were female. Mean patient age was 61.92 ± 10.06, mean patient body mass index was 25.68 ± 6.33. All patients were under 1 or more antithrombotic drugs. Only one minor hematoma was detected by postoperative ultrasonography control in 1 patient. Hemorrhage complication rate was 1 of 105 (% 0.95, 95% CI, 0.00024-0.051). Overall block success rate was 99.05%. Mean block onset time was 16.27 ± 5.69 minutes. Mean postoperative analgesia time was 19.5 ± 11.22 hours. Sciatic nerve block under ultrasound guidance using in-plane technique was safe and provided sufficient surgical anesthesia and postoperative analgesia for lower extremity wound debridement surgery in patients on antithrombotic drugs.

Real-world clinical results of CGRP monoclonal antibody treatment for medication overuse headache of migraine without abrupt drug discontinuation and no hospitalization

Real-world clinical results of CGRP monoclonal antibody treatment for medication overuse headache of migraine without abrupt drug discontinuation and no hospitalization

From the INVICTUS Trial to Current Considerations: It’s Not Time to Retire Vitamin K Inhibitors Yet!

Atrial fibrillation (AF) is a common arrhythmia in clinical practice, and oral anticoagulation is the cornerstone of stroke prevention in AF. Direct oral anticoagulants (DOAC) significantly reduce the incidence of intracerebral hemorrhage with preserved efficacy for preventing stroke compared to vitamin K antagonists (VKA). However, the pivotal randomized controlled trials (RCTs) of DOAC excluded patients with valvular heart disease, especially mitral stenosis, which remains an exclusion criterion for DOAC use. The INVICTUS study was a large multicenter global RCT aimed at evaluating the role of DOAC compared to VKA in stroke prevention among patients with rheumatic valvular AF. In this study, rivaroxaban failed to prove superiority over VKA in preventing the composite primary efficacy endpoints of stroke, systemic embolism, myocardial infarction, and death. Unfortunately, the bleeding rates were not lower with rivaroxaban either. The death and drug discontinuation rates were higher in the DOAC arm. Close to the heels of the dismal results of INVICTUS, an apixaban trial in prosthetic heart valves, PROACT-Xa, was also prematurely terminated due to futility. Hence, for AF complicating moderate-to-severe mitral stenosis or prosthetic valve VKA remains the standard of care. However, DOAC can be used in patients with surgical bioprosthetic valve implantation, TAVR, and other native valve diseases with AF, except for moderate-to-severe mitral stenosis. Factor XI inhibitors represent a breakthrough in anticoagulation as they aim to dissociate thrombosis from hemostasis, thereby indicating a potential to cut down bleeding further. Multiple agents (monoclonal antibodies—e.g., osocimab, anti-sense oligonucleotides—e.g., fesomersen, and small molecule inhibitors—e.g., milvexian) have garnered positive data from phase II studies, and many have entered the phase III studies in AF/Venous thromboembolism. Future studies on conventional DOAC and new-generation DOAC will shed further light on whether DOAC can dethrone VKA in valvular heart disease.

Evaluation of renal function: choosing the right equation

The article presents examples of the difference in estimated GFR (eGFR) results obtained using different CKD-EPI creatinine equations (2009) and (2021). In these examples, the results were not reclassified to a higher level of renal function, but the eGFR obtained remained within the same CKD stage despite the different equations. However, it should be borne in mind that a significant reclassification to higher eGFR categories may have undesirable consequences, such as changes in the composition of the CKD population and for initiation of renoprotection measures, dosing and discontinuation of certain medications, timely referral to a nephrologist and RRT planning.The article presents validated eGFR estimating equations according to the KDIGO 2024 Guidelines for the Evaluation and Management of CKD (CKD-EPI creatinine equation (2009), CKD-EPI creatinine equation (2021), CKD-EPI creatinine-cystatin C equation (2021), EKFC equation et al.), as well as eGFR calculators available on the National Kidney Foundation (NKF) website.

Experience with expanded use of oritavancin in a tertiary hospital: indications, tolerability and outcomes.

Oritavancin is a lipoglycopeptide antibacterial agent used to treat infections caused by Gram-positive organisms. It is FDA-approved for the treatment of acute bacterial skin and soft tissue infections (ABSSIs) but is increasingly being used off-label to treat invasive bacterial infections such as osteomyelitis, prosthetic joint infection and infective endocarditis. This study describes the clinical outcomes and adverse reactions related to oritavancin. This was a retrospective study conducted over a 5 year period at a tertiary care medical centre. Ninety-five adult patients were included in this study and were followed for 1 year after the last dose of oritavancin. The most common indication for oritavancin at our institution was osteomyelitis, followed by ABSSI. Other indications were vertebral infection, hardware-associated infection, bacteraemia and infective endocarditis. Fourteen percent (13/95) of patients developed an adverse reaction to oritavancin during the study period. Cure with no recurrence up to 1 year after the last dose of oritavancin was achieved in 74% (53/71) of patients, and the treatment failure rate was 19% (14/71 patients). Oritavancin is an effective agent that can be used to treat invasive Gram-positive bacterial infections other than ABSSI. Adverse events requiring drug discontinuation were common.

Discontinuation of Alzheimer Disease Medications in Patients Receiving Home Care Medicine.

There is no consensus on how long antidementia medications should be administered to patients with Alzheimer disease (AD). To clarify this issue, we investigated the discontinuation of antidementia medications in Japanese home care settings, including community-dwelling and institutionalized patients. Using medical records from April 2017 to March 2022 at 3 clinics in Tokyo and Chiba prefectures, we selected patients with AD who started receiving home care medicine. Forty-nine patients discontinued antidementia medications during the observation period, there was no apparent deterioration in cognitive function or new occurrence of behavioral and psychological symptoms of dementia caused by the discontinuation of medications. More aggressive discontinuation of AD medications probably is recommended for patients with activities of daily living dysfunction, such as those receiving home care medicine.

Safety, tolerability, and basic pharmacokinetic parameters of AUX-001, a once-daily extended release nicorandil in healthy volunteers under fasting and fed conditions

Abstract Introduction Chronic-stable angina pectoris (CSAP) is one of the most common cardiovascular conditions in the developed world with a rising prevalence in both Europe and North America. Mounting evidence from chronic angina outcomes studies, including COURAGE, BARI, ORBITA and recently ISCHEMIA, has reemphasized optimized medical therapy (OMT) as first-line treatment for most chronic-stable angina pectoris (CSAP) patients over coronary revascularization. Yet, there has been a lack of development of new antianginal medications since 2006. To lessen polypharmacy and enable better long-term compliance in CSAP patients, AUX-001, a once-daily (QD), extended-release (ER) nicorandil is in clinical development for treating CSAP as an innovative, novel version of the immediate-release (IR) antianginal. Objective To test the safety, tolerability, and basic pharmacokinetic (PK) parameters of AUX-001 QD in fasting and fed conditions in healthy volunteers during this first-in-human phase 1a study. Methods 16 healthy adult volunteers were enrolled. Vital signs (HR, BP, respiratory rate) and any adverse events were collected during screening, pre-dose, 1, 2, 6, 12, 24-h, and 48-h post-dose and at end-of-study for the two respective periods (fasting and fed). Results Evaluable information was available on 16 patients for fasting and 15 for fed conditions with one patient excluded due to protocol violation. No patient discontinued due to safety or tolerability. No severe AEs were recorded. AEs observed during period 1 included headaches (n=12), asymptomatic hypotension (n=3), palpitation (n=1) and nasal congestion (n=1). In period 2, leading AEs were headaches (n=11), neck pain (n=1) and decreased hemoglobin (n=1). Most AEs were mild and transitory and did not trigger medical intervention or discontinuation. AUX-001 pharmacokinetics exhibited a reduced Cmax, a right-hand shift in Tmax, and an extension of T1/2 beyond 9 hours compared to the historical data of the commercially available IR nicorandil. AUX-001 had a small, temporary effect on heart rate and systolic and diastolic blood pressure but within the normal compensatory haemodynamic steady-state stability. The peak effect with the current AUX-001 prototype was at 6 hours, independent of the food effect. Conclusion AUX-001 was safe and well tolerated. Initial vasodilator-induced headaches were manageable by using simple OTC NSAIDs and led to no dropouts. No patients discontinued due to AEs or tolerability issues. There were no lasting significant haemodynamic effects of AUX-001 beyond 24hours. PK parameters of AUX-001 are characteristic of an ER formulation. Observed pharmacokinetics indicates that the achieved T1/2 is substantially longer than with IR nicorandil (~1hour vs >9h) and shows promise for a potential once daily treatment of exercise induced chronic angina.AUX-001 Study Data ESC Abstract 2024

Recombinant Erwinia asparaginase (JZP458) in ALL/LBL: complete follow-up of the Children’s Oncology Group AALL1931 study

AbstractThe Children’s Oncology Group study AALL1931 investigated the efficacy and safety of recombinant Erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma and hypersensitivity reactions/silent inactivation to Escherichia coli–derived asparaginases. Each pegylated E coli asparaginase dose remaining in a patient’s treatment plan was replaced by intramuscular (IM) or IV JZP458 (6 doses) administered Monday/Wednesday/Friday (MWF). Three IM cohorts (1a [25 mg/m2 MWF], n = 33; 1b [37.5 mg/m2 MWF], n = 83; 1c [25/25/50 mg/m2 MWF], n = 51) and 1 IV cohort (25/25/50 mg/m2 MWF, n = 62) were evaluated. The proportion of patients maintaining nadir serum asparaginase activity (NSAA) levels of ≥0.1 IU/mL at the last 72 (primary end point) and 48 hours during course 1 was 90% (95% confidence interval [CI], 81-98) and 96% (95% CI, 90-100) in IM cohort 1c, respectively, and 40% (95% CI, 26-54) and 90% (95% CI, 82-98) in the IV cohort. Population pharmacokinetic modeling results were comparable with observed data, predicting the vast majority of patients would maintain therapeutic NSAA levels when JZP458 is administered IM or IV 25 mg/m2 every 48 hours, or IM 25/25/50 mg/m2 MWF, or with mixed administration of IM and IV (IV/IV/IM 25/25/50 mg/m2 MWF). Drug discontinuation occurred in 23% and 56% of patients in the IM and IV cohorts, respectively; 13% and 33% because of treatment-related adverse events (mainly allergic reactions and pancreatitis). JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules based on a combination of observed and modeled data with a safety profile consistent with other asparaginases. This trial was registered at www.ClinicalTrials.gov as #NCT04145531.

Long-Term Effects of Empagliflozin in Patients with Chronic Kidney Disease.

In the EMPA-KIDNEY trial, empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, had positive cardiorenal effects in patients with chronic kidney disease who were at risk for disease progression. Post-trial follow-up was designed to assess how the effects of empagliflozin would evolve after the discontinuation of the trial drug. In the active trial, patients with chronic kidney disease were randomly assigned to receive either empagliflozin (10 mg once daily) or matching placebo and were followed for a median of 2 years. All the patients had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area or an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Subsequently, surviving patients who consented were observed for 2 additional years. No trial empagliflozin or placebo was administered during the post-trial period, but local practitioners could prescribe open-label SGLT2 inhibitors, including open-label empagliflozin. The primary composite outcome was kidney disease progression or cardiovascular death as assessed from the start of the active-trial period to the end of the post-trial period. Of the 6609 patients who had undergone randomization in the active trial, 4891 (74%) were enrolled in the post-trial period. During this period, the use of open-label SGLT2 inhibitors was similar in the two groups (43% in the empagliflozin group and 40% in the placebo group). During the combined active- and post-trial periods, a primary-outcome event occurred in 865 of 3304 patients (26.2%) in the empagliflozin group and in 1001 of 3305 patients (30.3%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.72 to 0.87). During the post-trial period only, the hazard ratio for a primary-outcome event was 0.87 (95% CI, 0.76 to 0.99). During the combined periods, the risk of kidney disease progression was 23.5% in the empagliflozin group and 27.1% in the placebo group; the risk of the composite of death or end-stage kidney disease was 16.9% and 19.6%, respectively; and the risk of cardiovascular death was 3.8% and 4.9%, respectively. There was no effect of empagliflozin on death from noncardiovascular causes (5.3% in both groups). In a broad range of patients with chronic kidney disease at risk for progression, empagliflozin continued to have additional cardiorenal benefits for up to 12 months after it was discontinued. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EuDRACT number, 2017-002971-24.).

One-Year and Five-Year Outcomes in Medication Overuse Headache: A Real-World Study.

Medication overuse headache (MOH) is one of the global health-related problems that imposes significant morbidity. Effective management requires the abrupt cessation of the overused medications, transition therapy in the initial days, and initiation of preventive treatment. The objective of this study is to provide one-year and five-year follow-ups of study participants diagnosed with chronic migraine and MOH. The study will examine the efficacy of withdrawal therapy, the use of conventional preventive medication, and the use of anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies. We conducted a single-center, prospective, and descriptive study at a tertiary center in Brazil. The population was included by convenience sampling of consecutive subjects diagnosed with chronic migraine and MOH. Demographics and clinical data at baseline and one-year and five-year follow-ups were collected in the clinical records. Among 142 subjects, 116 were females and 26 were males, with a mean age of 42.1±14.3. They were followed for five years. The diagnosis was performed at the mean age of 24.9±14.7 years after the headache onset, and the time with headache ≥15 days per month was 6.3±7.6 years. On baseline, the average number of headache days per month (HDM) was 25.2±5.9. There was a reduction in HDM. At one-year and five-year follow-ups, a ≥75% reduction in HDM was observed, respectively, in 51.4% and 70.4% of the sample. The five-year follow-up of chronic migraine and MOH treated with the discontinuation of excessive medication, the use of preventative pharmacological agents, and the optional inclusion of anti-CGRP pathway monoclonal antibody led to a significant decrease in the initial occurrence of HDM.

Downstream Effects of Market Changes on Inhalers: Impacts on Individuals With Chronic Lung Disease.

COPD and asthma are two of the most common chronic lung diseases, affecting over 545 million people globally and 34 million in the United States. Annual health care costs related to chronic lung disease are estimated at €380 billion in the European Union, and $24-$50 billion in the United States averaging to $4,000 in out-of-pocket costs per person in the U.S. A full-text literature search was conducted for English publications between January 1, 2005-March 18, 2024. It returned over 5,000 publications that were further narrowed using key search words, resulting in 172 peer-reviewed articles. Using their experience and subject expertise, the authors further narrowed the peer-reviewed articles to 55 that were in their opinion relevant. Also, 38 recently published industry reports and news articles specific to downstream effects of inhaler market changes and the future impact were included. The literature suggests that individuals with chronic lung disease face increased challenges with access to inhaled medication due to rising medication costs, discontinuation of branded medications, introduction of generic medications not covered by insurance, exclusionary preferred drug list tactics that force health care providers into non-medical switching of medication or devices, and ongoing medication shortages. Providers experience ongoing hurdles in prescribing appropriate inhaled medications for individuals with chronic lung disease, including increased time and costs spent on administrative tasks due to inhaler denials, a loss of patient trust, and limits on their ability to prescribe appropriate inhaled medication for individuals with chronic lung disease.

Assessing causality in deprescribing studies: A focus on adverse drug events and adverse drug withdrawal events.

Generating real-world evidence about the effect of medication discontinuation or dose reduction on outcomes, such as reduction of adverse drug effects (ADE; intended benefit) and occurrence of adverse drug withdrawal events (ADWE; unintended harm), is crucial to informing deprescribing decisions. Determining the causal effects of deprescribing is difficult for many reasons, including lack of randomization in real-world study designs and other design and measurement issues that pose threats to internal validity. The inherent challenge is how to identify the effects, both intended benefits and unintended harms, of a new medication stoppage or reduction when implemented in patients with many potential clinical and social risks that may influence the likelihood of deprescribing as well as outcomes. We discuss methodological issues of estimating the effect of medication discontinuation or reduction on risk of ADEs and ADWEs considering: (1) sampling study populations of sufficient size with the potential to demonstrate clinically meaningful and quantifiable outcomes, (2) accurate and appropriately timed measurement of covariates, outcomes, and discontinuation, and (3) statistical approaches to managing confounding and other biases inherent in long-term medication use by individuals with multiple morbidities. Designing rigorous deprescribing studies that address internal validity threats will support evidence generation by improving the ability to assess benefits and harms when the exposure of interest is the absence of a medication. Iterative learnings about data quality, variable definition, variable measurement, and exposure-outcome associations will inform strategies to improve the causal inferences possible in real-world deprescribing studies.

Rilzabrutinib-induced transition from <i>pemphigus vulgaris</i> to <i>pemphigus foliaceous</i>: case report and review of the literature

The discovery of the role of Bruton’s Tyrosine Kinase (BTK) in inflammation and autoimmunity has recently led to the development of BTK inhibitors for the treatment of autoimmune diseases, including pemphigus vulgaris. We herein present the case of a patient affected by pemphigus vulgaris, refractory to conventional immunosuppressive therapies and to multiple courses of rituximab, who was treated with rilzabrutinib and achieved disease control, but whose immunological profile switched from pemphigus vulgaris to pemphigus foliaceus after drug discontinuation. Furthermore, we review the literature in order to better characterize the phenotypic transitions from pemphigus vulgaris to pemphigus foliaceus reported so far. The factors underlying this transition are largely unknown, although it has been postulated that immunosuppressive therapies may be more effective against anti-desmoglein 3 antibodies compared to anti-desmoglein 1. However, further studies are needed to better define the effect of rilzabrutinib (and immunosuppressive therapies in general) on anti-desmoglein 1 and anti-desmoglein 3 antibodies.

Unpicking medication discontinuation and non-adherence in heart failure.

Unpicking medication discontinuation and non-adherence in heart failure.

Amyloid-Directed Antibodies: Past, Present, and Future.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in patient demographics over 65 years old causing debilitating cognitive impairment. Most commonly, AD is diagnosed clinically as "probable AD", and definitive diagnosis is confirmed through postmortem brain autopsies to detect extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau tangles. The exact mechanism causing AD is still unknown, but treatments for AD have been actively investigated. Currently, immunotherapies have shown substantial promise in reducing the pathologic and clinical signs of AD. This review aims to evaluate passive immunotherapies deemed to have promise for further development and use in the treatment of AD. Immunotherapies were selected via a narrative review of medications that have potential clinical effectiveness with a status of FDA accepted, FDA fast-track, FDA status pending, or emerging therapies poised to pursue FDA approval. This review has yielded two anti-Aβ monoclonal antibodies (mAb) that are currently fully FDA approved, one mAb granted FDA fast-track status, two therapies on hold, three discontinued medications, and three promising emerging therapies. We conclude that, in the near future, passive immunotherapies will be the preferred and evidence-based method of treatment for AD with the presence of brain Aβ deposits for both symptom management and potential slowing of disease progression. Specifically, lecanemab and donanemab will require further clinical studies to optimize patient selection based on safety profiles. Despite some key limitations, these two drugs are paving the way for disease-modifying treatments in patients displaying early signs of amyloid pathology.

Comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban in dogs.

Comparative pharmacokinetics and pharmacodynamics (PK/PD) of apixaban and rivaroxaban have not been studied in dogs and the propensity of these drugs to cause hypercoagulability after discontinuation is unknown. Compare the PK/PD of clinical dosing regimens of PO apixaban and rivaroxaban administered repeatedly to healthy dogs and assess the effect of abrupt drug discontinuation on coagulation. Six University-owned, purpose-bred, middle-aged, mixed-breed dogs (4 male, 2 female). Dogs were given apixaban or rivaroxaban PO at 0.5 mg/kg q12h for 7 days with a 14-day washout period between drugs. Plasma drug concentrations were quantitated, and anticoagulant effects were measured using clotting times, calibrated anti-Xa bioactivity assays, and measurements of thrombin generation. The potential for rebound hypercoagulability was assessed by measuring D-dimers, thrombin-antithrombin (TAT) complexes, and antithrombin activity after drug discontinuation. Plasma drug concentrations and anti-Xa bioactivities were closely correlated for both drugs, but drug concentrations varied considerably among dogs, despite consistent dose regimens. Thrombin generation variables were significantly correlated with the anti-Xa bioactivity of both drugs and no significant differences in the effects of apixaban and rivaroxaban on thrombin generation were observed. Drug discontinuation had no effect on D-dimer concentrations. The concentration of TAT complexes decreased after apixaban discontinuation and did not change after rivaroxaban discontinuation. Repeated PO administration of apixaban or rivaroxaban to healthy dogs produced comparable anticoagulant effects measured by inhibition of thrombin formation. Rebound hypercoagulability after drug discontinuation was not observed and weaning of these drugs in clinical patients might not be necessary.

Drug Survival of Dupilumab, Methotrexate, and Cyclosporine A in Children With Atopic Dermatitis

Dupilumab, methotrexate (MTX), and cyclosporine A (CsA) are valuable treatment options for pediatric patients with refractory moderate to severe atopic dermatitis (AD). Yet, comparative data on these treatments in pediatric patients are scarce. To evaluate drug survival of dupilumab, MTX, and CsA, and identify associated predictors in a multicenter daily practice cohort study of pediatric patients with AD. This multicenter daily practice cohort study included patients with AD aged 2 to 17 years treated with dupilumab, MTX, and/or CsA in 5 tertiary centers in the Netherlands between 2013 and 2023. Data were extracted from the prospective BioDay and TREAT Netherlands registries and electronic medical records. Dupilumab, MTX, CsA. Drug survival was analyzed using Cox proportional hazard regression models. Univariable and multivariable Cox regression analyses were conducted to identify variables associated with drug discontinuation. A total of 502 treatment episodes in 362 unique patients were included, comprising 192 dupilumab episodes, 94 MTX episodes, and 216 CsA episodes. Overall, the mean (SD) age at treatment initiation was 12.9 (3.8) years, and 272 treatment episodes (54.2%) in female patients. The 1-year, 2-year, and 3-year overall drug survival rates, respectively, were 84.1%, 72.3%, and 62.0% for dupilumab; 60.7%, 39.3%, and 25.3% for MTX; and 43.9%, 21.5%, and 10.4% for CsA. Ineffectiveness was the most frequent reason for drug discontinuation, accounting for 178 episodes (35.5%), mostly in patients treated with CsA, followed by adverse effects in 94 patients (18.7%). Treatment with MTX and treatment with CsA were independently associated with a higher risk for drug discontinuation due to ineffectiveness (hazard ratio [HR], 4.45 [95% CI, 2.38-8.34] and HR, 10.88 [95% CI, 6.23-19.02], respectively) and adverse effects (HR, 4.39 [95% CI, 2.05-9.39] and HR, 3.83 [95% CI, 1.85-7.92], respectively) compared to treatment with dupilumab. Patients aged 12 to 17 years starting systemic treatment were independently associated with a higher risk for drug discontinuation due to ineffectiveness (HR, 1.55 [95% CI, 1.10-2.20]) and adverse effects (HR, 2.39 [95% CI, 1.33-4.30]). This multicenter daily practice cohort study demonstrated a superior 1-year, 2-year, and 3-year overall drug survival for dupilumab, followed by MTX, with the lowest rates observed for CsA in pediatric patients with AD. This study also identified characteristics associated with discontinuation. These results provide insight into drug survival resulting from the effectiveness, safety, and tolerability of these systemic treatments in pediatric patients with AD and contribute to the optimization of patient outcomes.

Pharmacotherapy for patients with calcium oxalate stones and abnormal urine chemistry: A systematic review and meta-analysis for the Japanese Clinical Practice Guidelines for the Management of Urinary Stones, Third Edition.

We performed a systematic review and meta-analysis to evaluate the benefits and harms of pharmacotherapies for patients with calcium oxalate stones and abnormal urine chemistry. This article is a modified and detailed version of the commentary on Clinical Question 10 described in the Japanese Clinical Practice Guidelines for the Management of Urinary Stones, Third Edition. PubMed and Ichushi Web were searched through August 2020 for articles on pharmacotherapies for calcium oxalate stones (thiazides, citrate preparations, uric acid production inhibitors, and magnesium preparations). Two reviewers independently selected randomized controlled trials reporting reduction of stone recurrence and adverse drug reactions as outcomes and performed data extraction and quality assessment. Meta-analyses with random effects models and rating of the strength of evidence were performed. Pharmacotherapies were shown to significantly reduce stone recurrence (risk ratio 0.47, 95% confidence interval 0.35-0.63). Meanwhile, the pharmacotherapies increased adverse drug reactions leading to study dropout (risk ratio 2.51, 95% confidence interval 1.09-5.75) and adverse drug reactions/adverse events (risk ratio 1.95, 95% confidence interval 1.07-3.56). The reported adverse drug reactions were, however, mainly minor and did not frequently require discontinuation of medication (2%-16%). The strengths of evidence for both outcomes were rated as moderate, because the risk of bias, indirectness, inconsistency, imprecision, and publication bias were all serious except for one item. The overall strength of evidence across outcomes was therefore determined to be moderate. These results support the conditional recommendation to initiate pharmacotherapies for patients with calcium oxalate stones and abnormal urine chemistry.