A retrospective study of combination therapy with glucocorticoids and pirfenidone for PD-1 inhibitor-related immune pneumonitis.

Immune checkpoint inhibitor pneumonitis (ICIP) is thought to be a self-limiting disease; however, an effective treatment option does not currently exist. This study aimed to determine the clinical efficacy of combination therapy with glucocorticoids and pirfenidone for ICIP related to programmed cell death protein-1 (PD-1) inhibitors. We conducted a retrospective analysis of 45 patients with advanced non-small cell lung cancer who developed ICIP following PD-1 inhibitor and albumin-bound paclitaxel or carboplatin treatment at our hospital. The PD-1 inhibitor was discontinued, and glucocorticoids were used alone or in combination with pirfenidone to treat ICIP. The relevant clinical data of these patients were collected and analyzed. Compared with the glucocorticoid alone group, the glucocorticoid-pirfenidone group showed significant improvement in forced vital capacity (FVC), carbon monoxide diffusing capacity [%], peripheral capillary oxygen saturation, and 6-minute walk distance (P < .05). There were benefits with respect to the St. George's Respiratory Questionnaire score and the recurrence rate of ICIP, but there was no significant difference between the 2 groups (P > .05). Adding pirfenidone to glucocorticoid treatment was shown to be safe and may be more beneficial than glucocorticoids alone for improving pulmonary interstitial lesions, reversing ICIP, and preventing its recurrence.

Intracranial hemorrhage caused by dabrafenib and trametinib therapy for metastatic melanoma.

Although generally well tolerated compared with chemotherapy, molecular targeted therapy used in metastatic melanoma may be associated with life-threatening toxicity. We report the case of a patient with metastatic melanoma treated by dabrafenib plus trametinib who developed intracranial hemorrhage. Physicians should be aware of this rare but life-threatening adverse event of B-rapidly accelerated fibrosarcoma (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. However, they should be also careful about the bleeding origin, which can prove to be a new onset of melanoma metastasis or anticoagulation overdose, or even an uncontrolled arterial hypertension.

A 3.5-year clinical experience with perampanel for refractory epilepsy.

OBJECTIVE: This study aimed to evaluate the efficacy and tolerability of perampanel, which was used in a cohort of patients with refractory epilepsy for up to 3.5 years in a real-world setting in Saudi Arabia. PATIENTS AND METHODS: Data from the medical records of patients treated with perampanel between March 13th, 2017, and September 6th, 2020, at neurology clinics at King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh and Jeddah, Saudi Arabia, was collected. The Liverpool Adverse Events Profile (LAEP) scale was also used to measure the adverse effects of perampanel. RESULTS: Of the 75 included patients, 66.7% responded to perampanel at the last follow-up, including 22.7% seizure-free for at least the last six months, and 44% of patients responded with a ≥ 50% reduction in seizure frequency from baseline. The overall incidence of adverse effects that led to perampanel discontinuation was 13.3%; the most common adverse effect was aggressive behavior followed by sedation. Pre-existing psychiatric comorbidity was significantly associated with the incidence of psychiatric and behavioral adverse effects on perampanel (p = 0.0206). The mean score of LEAP was 40. The most frequently rated adverse effects in LEAP were "feelings of anger and aggression to others", "nervousness and/or agitation" and "sleepiness". The efficacy and tolerability of perampanel were dose-dependent. Dose 6 mg/day was the most frequently used dose that was taken by about one-third of patients at their last visit. CONCLUSIONS: Perampanel was effective as an adjunctive treatment for intractable seizures, with a responder rate of 66.7%. The long-term tolerability of perampanel was generally good. Aggressive behavior was the most common reason for perampanel discontinuation. Patients should be counseled and monitored for these adverse effects, particularly those with a history of previous psychiatric and behavioral problems.

The Effect of Levetiracetam Compared with Enzyme-Inducing Antiseizure Medications on Apixaban and Rivaroxaban Peak Plasma Concentrations.

BACKGROUND AND OBJECTIVE: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM. METHODS: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups. RESULTS: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC Cmax below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC Cmax below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19-2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban Cmax between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban Cmax in a multivariate linear regression. CONCLUSIONS: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban Cmax and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban Cmax. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes.

Comparative effectiveness of factor Xa non-vitamin K antagonist oral anticoagulants versus phenprocoumon in patients with non-valvular atrial fibrillation.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) have largely supplanted vitamin K antagonists (VKAs) for oral anticoagulation in non-valvular atrial fibrillation (NVAF). However, data on the real-world effectiveness of NOACs vs. phenprocoumon, a VKA widely used in Germany, are limited. The RELOADED study aimed to compare effectiveness of factor Xa NOACs and phenprocoumon in NVAF in clinical practice. METHODS: Patients who started on a factor Xa NOAC or phenprocoumon for NVAF during the study period were enrolled from the Institute for Applied Healthcare Research Berlin. Patients were followed from first prescription until the end of exposure or available data. Primary outcomes were analyzed by Cox proportional hazard regression models and included ischemic stroke and systemic embolism for effectiveness, and intracranial hemorrhage (ICH) for safety. Subgroups of interest were patients with diabetes and patients with renal impairment. RESULTS: The total study population was 64,920; 36.3% of patients initiated phenprocoumon, 34.4% initiated rivaroxaban, 25.0% apixaban, and 4.4% edoxaban. Treatment with phenprocoumon is associated with a similar risk of ischemic stroke/systemic embolism as treatment with rivaroxaban or apixaban; while rivaroxaban (adjusted hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.43-0.75) and apixaban (adjusted HR 0.43, 95% CI 0.31-0.6) were associated with a lower risk of ICH compared to phenprocoumon in NVAF patients. The use of rivaroxaban and apixaban was associated with a lower risk of developing kidney failure in patients with diabetes or renal impairment in comparison to those treated with phenprocoumon. CONCLUSION: The factor Xa NOACs rivaroxaban and apixaban demonstrated similar effectiveness and lower rates of ICH compared with phenprocoumon in this study.

Relationship of Warfarin and Apixaban with Vascular Function in Patients with Atrial Fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is associated with endothelial damage/dysfunction. Herein, we tested the hypothesis that brachial artery flow-mediated dilation (FMD) is superior in AF patients taking apixaban compared to warfarin. METHODS: AF patients on apixaban (n = 46; 67 [7] years; mean [standard deviation]; 15 women) and warfarin (n = 27; 73 [9] years (p < 0.01); 11 women) were recruited. Duplex Doppler ultrasound imaging was undertaken during baseline (2 min), cuff inflation (5 min), and following cuff deflation (3 min). FMD was defined as peak increase in brachial artery diameter following cuff deflation and analysed as percentage change in diameter, as a ratio of FMD, shear rate area under the curve (SRAUC; FMD-to-SRAUC), and using SRAUC as a covariate (FMDSR). RESULTS: Baseline artery diameter (4.96 [1.14] vs. 4.89 [0.88] mm), peak diameter (5.12 [1.17] vs. 5.14 [0.93] mm), and FMDSR (3.89 [3.62] vs. 4.80 [3.60] %) were not different between warfarin and apixaban (p > 0.05; analysis of covariance with age, CHA2DS2-VASc, years since AF diagnosis, number of diabetics, alcohol drinkers, and units of alcohol consumed per week as covariates). Stepwise multiple regression identified independent association of fibrillation, hypertension, and increased age with FMD. CONCLUSION: AF patients on warfarin and apixaban exhibit similar endothelium-dependent vasodilation. Increased blood pressure negatively impacts vasodilator capacity in AF patients.

Clot time ratio (CTR) and treatment outcomes in Apixaban-treated atrial fibrillation patients.

There are clinical situations where information about the anticoagulant effects of Apixaban could be useful. Specialised methods for measuring Apixaban concentrations are not available at all medical laboratories while methods for measuring the functional effects of Apixaban, using clot time ratio (CTR), can be performed in most medical laboratories around the clock using well-established measurement procedures. The aim of this study was to investigate CTR in trough and peak samples during Apixaban treatment of atrial fibrillation and to correlate the findings to bleeds and thrombotic events. Three trough- and three peak samples from 61 patients (31 on Apixaban 5 mg twice daily and 30 on Apixaban 2.5 mg twice daily) were analysed with MRX PT DOAC. Patients were followed for 30 + /-15 months, and bleeds and thrombotic events were documented. The effect of Apixaban could be measured with MRX PT DOAC and there was a statistically significant difference between CTR in trough samples compared to peak samples (p < 0.001). A total of 21 patients suffered bleeds during follow-up; two patients suffered major bleeds, and 19 suffered minor bleeds. Patients with major bleeds had both mean peak- and mean trough CTR above the respective first to third quartile (Q1-Q3) range. Four patients suffered thromboembolic events. Generally, the peak CTRs were below or in the lower end of the peak Q1-Q3 for these patients. The new test MRX PT DOAC can be used to measure the effect of Apixaban during the treatment of atrial fibrillation. High mean peak- and mean trough CTR were seen in 2 patients with major bleeds, and low peak CTR was seen in 4 patients with thromboembolic events.

Real-world experience of direct oral anticoagulant use in a single pediatric center.

BACKGROUND: Pediatric venous thromboembolism has increased by 130%-200%, specifically in hospitalized children, and direct oral anticoagulants (DOACs) offer several therapeutic advantages. METHODS: This study aims to evaluate the real-world epidemiological and outcome data from a retrospective review of pediatric patients treated with DOACs from January 1, 2013 to December 31, 2022. In this single-center, IRB-approved study, 65 patients were identified and analyzed using SPSS statistical software, and a descriptive statistical analysis was conducted. RESULTS: Of the 65 patients, 37% were on apixaban, 61.5% were on rivaroxaban, and 1.5% were on dabigatran. Per the 2023 ISTH outcome definitions, one (2%) patient had a major bleeding episode, six (9%) had clinically relevant non-major bleeding, three (5%) patients had patient-important heavy menstrual bleeding (HMB), and one (1.5%) patient had minor bleeding. Seven (19%) of 37 postmenarchal patients had evidence of HMB. Six (9.2%) patients had recurrent venous thromboembolism while on a DOAC (one was on apixaban, and five were on rivaroxaban) and were transitioned to other forms of anticoagulation. CONCLUSION: Thus, bleeding rates after DOAC therapy are comparable to previous DOAC trials, as well as other anticoagulants in pediatrics. HMB is an important outcome measure and should continue to be investigated. This study reports a higher rate of recurrent thrombosis (9.2%) compared to other trials. However, this observation may be attributed to patients who had ongoing risk factors, as well as a longer duration of study follow-up. Additional multicentered outcome studies evaluating DOAC use in children are needed to determine long-term recurrence and HMB risks.

Dolutegravir-induced hand-foot skin reaction in a seropositive male: A rare presentation.

Hand-foot skin reaction (HFSR) is a specific but uncommon cutaneous side effect mainly following chemotherapeutic drugs such as multitargeted kinase inhibitors. HFSR is reversible and non-life-threatening. HFSR, also known as palmoplantar erythrodysesthesia, presents with various degrees of erythema, edema, hyperkeratosis, blister, and sometimes with a fine white scale. Dolutegravir, a first next-generation integrase inhibitor, is used with other antiretroviral therapy (ART) to treat mainly HIV infections. HFSR is diagnosed depending on the suggestive association of drug intake and characteristic palmoplantar eruption. ART can cause several cutaneous adverse drug reactions though no case report of dolutegravir-induced HFSR has been reported till date in literature. Here, we present a case of HFSR in a seropositive male on ART.

The safety and efficacy of dabrafenib and trametinib in patients with glioma: A systematic review and meta-analysis.

BACKGROUND: Dabrafenib and trametinib represent targeted therapy options under investigation for treatment of gliomas harboring BRAF V600 mutations. We systematically reviewed the literature and conducted meta-analyses to assess the efficacy and safety of these agents. METHODS: PubMed, Embase, and Scopus were searched from inception to September 2023 for studies examining dabrafenib and/or trametinib for gliomas. Outcomes included response rates (ORR, CR, PR), progression rates (PD), 6- and 12-month PFS, adverse events, and dosing modifications. Meta-analyses were conducted using random effect models. RESULTS: Nine studies met the inclusion criteria. Meta-analysis demonstrated overall response rates (ORR) of 50% (95% confidence interval (CI): 35-65%) for low-grade gliomas (LGG) and 40% (95% CI: 29-51%) for high-grade gliomas (HGG). Pooled ORR was 45% (95% CI: 36-54%) for both glioma grades. The complete response rate was 13% (95% CI: 05-27%) for HGG and 5% (95% CI: 1-10%) for both LGG and HGG. Six-month progression-free survival (PFS) rates reached 87% in LGG and 67% in HGG and a pooled 6-month PFS 78% (95% CI: 58-98%), declining at 12 months to 67% and 44%, respectively, with a pooled 12-month PFS 56% (95% CI: 34-79%). Grade 1-4 adverse events occurred in 100% of LGG and 63% of HGG patients. CONCLUSIONS: Dabrafenib and trametinib demonstrate promising anti-tumor efficacy in gliomas, particularly low-grade tumors, achieving durable disease stabilization in many patients. However, toxicity significantly limited tolerability. Additional research should further examine efficacy and refine safe administration protocols across glioma subtypes.

Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial.

Importance: Atrial cardiopathy is associated with stroke in the absence of clinically apparent atrial fibrillation. It is unknown whether anticoagulation, which has proven benefit in atrial fibrillation, prevents stroke in patients with atrial cardiopathy and no atrial fibrillation. Objective: To compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy. Design, Setting, and Participants: Multicenter, double-blind, phase 3 randomized clinical trial of 1015 participants with cryptogenic stroke and evidence of atrial cardiopathy, defined as P-wave terminal force greater than 5000 µV × ms in electrocardiogram lead V1, serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m2 or greater on echocardiogram. Participants had no evidence of atrial fibrillation at the time of randomization. Enrollment and follow-up occurred from February 1, 2018, through February 28, 2023, at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium. Interventions: Apixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508). Main Outcomes and Measures: The primary efficacy outcome in a time-to-event analysis was recurrent stroke. All participants, including those diagnosed with atrial fibrillation after randomization, were analyzed according to the groups to which they were randomized. The primary safety outcomes were symptomatic intracranial hemorrhage and other major hemorrhage. Results: With 1015 of the target 1100 participants enrolled and mean follow-up of 1.8 years, the trial was stopped for futility after a planned interim analysis. The mean (SD) age of participants was 68.0 (11.0) years, 54.3% were female, and 87.5% completed the full duration of follow-up. Recurrent stroke occurred in 40 patients in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (hazard ratio, 1.00 [95% CI, 0.64-1.55]). Symptomatic intracranial hemorrhage occurred in 0 patients taking apixaban and 7 patients taking aspirin (annualized rate, 1.1%). Other major hemorrhages occurred in 5 patients taking apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (hazard ratio, 1.02 [95% CI, 0.29-3.52]). Conclusions and Relevance: In patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.

Bleeding Outcomes in Patients Treated With Asundexian in Phase II Trials.

BACKGROUND: Phase II trials of asundexian were underpowered to detect important differences in bleeding. OBJECTIVES: The goal of this study was to obtain best estimates of effects of asundexian vs active control/placebo on major and clinically relevant nonmajor (CRNM) and all bleeding, describe most common sites of bleeding, and explore association between asundexian exposure and bleeding. METHODS: We performed a pooled analysis of 3 phase II trials of asundexian in patients with atrial fibrillation (AF), recent acute myocardial infarction (AMI), or stroke. Bleeding was defined according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. RESULTS: In patients with AF (n = 755), both asundexian 20 mg and 50 mg once daily vs apixaban had fewer major/CRNM events (3 of 249; incidence rate [IR] per 100 patient-years 5.47 vs 1 of 254 [IR: not calculable] vs 6 of 250 [IR: 11.10]) and all bleeding (12 of 249 [IR: 22.26] vs 10 of 254 [IR: 18.21] vs 26 of 250 [IR: 50.56]). In patients with recent AMI or stroke (n = 3,409), asundexian 10 mg, 20 mg, and 50 mg once daily compared with placebo had similar rates of major/CRNM events (44 of 840 [IR: 7.55] vs 42 of 843 [IR: 7.04] vs 56 of 845 [IR: 9.63] vs 41 of 851 [IR: 6.99]) and all bleeding (107 of 840 [IR: 19.57] vs 123 of 843 [IR: 22.45] vs 130 of 845 [IR: 24.19] vs 129 of 851 [IR: 23.84]). Most common sites of major/CRNM bleeding with asundexian were gastrointestinal, respiratory, urogenital, and skin. There was no significant association between asundexian exposure and major/CRNM bleeding. CONCLUSIONS: Analyses of phase II trials involving >500 bleeds highlight the potential for improved safety of asundexian compared with apixaban and similar safety compared with placebo. Further evidence on the efficacy of asundexian awaits the results of ongoing phase III trials.

The impact of chelation compliance in health outcome and health related quality of life in thalassaemia patients: a systematic review.

Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2-92.2% for deferiprone and 90-100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence.

Does amiodarone impact on apixaban levels? The effect of amiodarone on apixaban level among Thai patients with non-valvular Atrial Fibrillation.

BACKGROUND: Apixaban and amiodarone are drugs used for non-valvular atrial fibrillation (NVAF) in routine practice. The evidence about apixaban plasma levels in patients who receive apixaban with amiodarone, including bleeding outcomes, has been limited. This study aimed to compare the apixaban plasma levels and bleeding outcomes between apixaban monotherapy and apixaban with amiodarone groups. METHODS: This study was a prospective, observational, and single-center research which was conducted from January 2021 to January 2022 in NVAF patients who received apixaban at a tertiary care hospital located in the center of Bangkok, Thailand. RESULTS: Thirty-three patients were measured for their median (5th-95th percentile) apixaban plasma levels. The trough of apixaban plasma level (Ctrough) were 108.49 [78.10-171.52] and 162.05 [87.94-292.88] µg/L in the apixaban monotherapy and apixaban with amiodarone groups, respectively (p = 0.028). Additionally, the peaks of apixaban plasma level (Cpeak) were 175.36 [122.94-332.34] and 191 [116.88-488.21] µg/L in the apixaban monotherapy and apixaban with amiodarone groups, respectively (p = 0.375). There was bleeding that occurred in 7 patients (21.21%); 5 patients in the apixaban monotherapy group and 2 patients in the apixaban with amiodarone group, respectively. CONCLUSIONS: Amiodarone may increase the peaks and troughs of apixaban plasma levels. The co-administration of apixaban with amiodarone is generally well tolerated. However, the careful observation of bleeding symptoms in individual cases is necessary to ensure safety.

Long-term efficacy and safety of perampanel as an add-on therapy in patients with epilepsy.

BACKGROUND: Perampanel (PER) is a newly developed amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist that has been globally approved for the treatment of both focal and generalized seizures. The efficacy and safety of PER have only been reported over short periods of treatment so far. This study aims to clarify the long-term efficacy and safety of PER as an add-on therapy. METHOD: This retrospective observational study investigated 176 epilepsy patients who received PER as add-on medical therapy in two Japanese epilepsy centers between June 2016 and July 2022. The adherence, seizure frequency, and plasma concentration of PER were evaluated at three time points: 6 months, 12 months, and 24 months or longer after the start of adjunctive PER treatment. RESULTS: 112 patients undergoing PER treatment were evaluated at 6 months, 86 were evaluated at 12 months, and 52 were evaluated at 24 months or longer. Overall, 42.9 % (48/112), 45.4 % (40/86), and 44.2 % (23/52) of the patients were seizure-free at 6, 12, and 24 months or longer, respectively. The rate of PER tolerance was 78.3 %, 69.9 %, and 54.7 % at 6, 12, and 24 months or longer, respectively. At the latest timepoint, the seizure-free group was taking a significantly lower dose of PER than the seizure-remnant group, and the number of anti-seizure medications (ASMs) was associated with seizure outcomes. In addition, the seizure-free rate was significantly higher in patients who received PER as a first add-on than in those who received it as a late add-on. No significant difference was found in the plasma concentration of PER between the seizure-free and seizure-remnant groups at 24 months or longer. Among the patients receiving PER at dose of 2 mg, however, the plasma concentrations were significantly higher in the seizure-free group than in the seizure-remnant group (282.7 ± 109.8 µg/ml vs 94.7 ± 54.9 µg/ml, p = 0.0024). CONCLUSION: This long-term retrospective observational study provides evidence of the efficacy and safety of PER over 2 years treatment period in Japan. Notably, patients who started on PER as the first add-on showed a better seizure outcome than those who received it as a late add-on over the long term. Measured plasma concentrations may provide valuable guidance for the management of patients. Higher plasma concentration at low dose PER may suggest the better seizure control.

The tolerability and efficacy of antifibrotic therapy in patients with idiopathic pulmonary fibrosis: Results from a real-world study.

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive and fatal lung disease lacking effective therapeutics. Treatment with pirfenidone or nintedanib is recommended for patients to delay the progression of their disease. Adverse reactions caused by anti-fibrosis drugs can sometimes interrupt treatment and even change the progression of the disease. OBJECTIVE: This study aimed to investigate the clinical use, adverse reactions, tolerability of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and the efficacy of antifibrotic therapy in a real world. METHODS: We recruited patients with idiopathic pulmonary fibrosis treated with pirfenidone or nintedanib at China-Japan Friendship Hospital from February 2017 to February 2022. We investigated the medication situation, adverse reactions, tolerability and survival of patients taking medications. RESULTS: A total of 303 patients with idiopathic pulmonary fibrosis were enrolled in the study. Treatment was divided between 205 patients receiving pirfenidone and 98 patients receiving nintedanib. Baseline data between the two groups were not significantly different. Patients treated with nintedanib had a higher overall discontinuation rate than those treated with pirfenidone (61.22 vs. 32.68 %, p < 0.001). Across all patient groups, the most common reason for discontinuing treatment was medication-related adverse effects. Compared to pirfenidone, nintedanib had a significantly higher discontinuation rate due to adverse events (48.98 % vs 27.80 %, p < 0.001). The most common side effect of both drugs was diarrhea. Pirfenidone was associated with a higher rate of extra-digestive adverse effects than nintedanib. Survival was not significantly different between the two drugs and using pirfenidone above 1200 mg/day did not confer significant survival benefits. The survival rate of patients who adhere to anti-fibrosis therapy for more than 6 months can be significantly improved (HR = 0.323, p = 0.0015). CONCLUSION: Gastrointestinal adverse effects were the most common adverse effects and the main reason of discontinuation of antifibrotic therapy, especially nintedanib. Consistent adherence to antifibrotic therapy may make the patients benefit from adjusting their antifibrotic medications, dosage, and active management of side effects.

A comprehensive comparison of the safety and efficacy of drugs in the treatment of idiopathic pulmonary fibrosis: a network meta-analysis based on randomized controlled trials.

OBJECTIVE: Randomized controlled trials(RCTs) of multiple drugs for Idiopathic pulmonary fibrosis(IPF) have been reported and achieved a certain degree of efficacy, however, the difference in safety and efficacy of them for IPF is not yet well understood. The aim of this network meta-analysis is to assess their safety and efficacy in the treatment of IPF and differences in this safety and efficacy comprehensively. METHODS: The PubMed, EMbase, CENTRAL and MEDLINE were retrieved to find out the RCTs of drugs in the treatment of IPF. The retrieval date is from construction to November 10, 2022. Stata 14.0 and RevMan 5.3 was used for statistical analysis. REGISTRATION NUMBER: CRD42023385689. RESULTS: Twenty-four studies with a total of 6208 patients were finally included, including RCTs of 13 drugs. The results of safety showed that there' s no difference in the incidence of SAEs of 13 drugs treated with IPF compared to placebo (P>0.05), and it's also found that Warfarin had a higher all-cause mortality for IPF than placebo (OR = 5.63, 95% CI [1.54 to 20.55]). SUCRA' s scatterplot showed that Pirfenidone, Nintedanib, Sildenafil and Imatinib were lower than placebo, and Warfarin, Ambrisentan and N-acetylcysteine were higher than placebo. The results of effectiveness showed that Nintedanib (MD = -0.08, 95% CI [-0.12 to -0.04]) improved FVC (L)absolute change from baseline in patients better than placebo, and Nintedanib (OR=1.81, 95% CI [1.23 to 2.66]), Pirfenidone (OR=1.85, 95%CI [1.26 to 2.71]) and Pamrevlumab (OR=4.11, 95% CI [1.25 to 13.58]) improved the proportion of patients with a decline in FVC ≥10% predicted better than placebo. SUCRA' s scatterplot showed that Pamrevlumab, Pirfenidone and Nintedanib were lower than placebo, and Warfarin and Ambrisentan were higher than placebo. CONCLUSION: Compared with other drugs, Nintedanib and Pirfenidone can significantly slow the decline of lung function in patients with IPF, and the safety is higher. Therefore, they can be further promoted in clinical practice. Warfarin and Ambrisentan shouldn't be used clinically for IPF as the safety and efficacy of them are poor compared to other drugs and placebo. Pamrevlumab may become important drugs for the treatment of IPF in the future.

Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation.

BACKGROUND: Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit. METHODS: We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason). RESULTS: We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group. CONCLUSIONS: Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.).

Risk of ischemic stroke associated with direct oral anticoagulants discontinuation on patients with non-valvular atrial fibrillation.

INTRODUCTION: Although direct oral anticoagulants' (DOACs) prescriptions have experienced immense growth in the last decade, the proportion of discontinuers is still common yielding an increased risk of ischemic stroke (IS) onset. AIMS: We aimed to estimate the association between DOACs discontinuation and risk of IS among patients with non-valvular atrial fibrillation (NVAF). METHODS: We used data from a cohort of new DOACs users, followed patients from the first DOAC prescription date up to IS (index date) and conducted a nested case-control analysis using conditional logistic regression. Adjusted odds ratios, 95% confidence intervals were calculated for discontinuation of DOACs (current use compared with past use). The latter, subdivided among those stopping treatment 3 to 2 months and 6 and 3 months prior to index date. The effect of naïve current users against IS onset compared with non-naïve current users was also evaluated. RESULTS: DOACs discontinuation showed an OR of IS of 1.47 (95% CI: 1.02-2.12); estimates were 2.51 (95% CI: 1.84-3.42) for whom discontinued treatment within months 3 and 2 and 1.43 (95% CI: 0.96-2.13) for those between months 6 and 3 prior to index date. Analyzing DOACs individually, risk of IS associated with past users compared with current users: 1.98 (95% CI: 1.25-3.12) for apixaban, 1.38 (95% CI: 0.40-4.72) for edoxaban, 1.98 (95% CI: 1.24-2.65) for dabigatran and 1.87 (95% CI: 1.26-2.76) for rivaroxaban. Similar results were found when stratified by naïve and non-naïve users. CONCLUSIONS: DOACs' discontinuation is associated with higher risk of IS, especially in the second and third months following interruption.