Discontinuation Of Therapy Research Articles

Effectiveness and safety of elexacaftor/tezacaftor/ivacaftor treatment in children aged 6-11 years with cystic fibrosis in a real-world setting.

Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF. This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV1, LCI2.5, body mass index(BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models. The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy. Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood.

Predictors of abemaciclib discontinuation in patients with breast cancer: a multicenter retrospective cohort study

ObjectiveThis study explored the predictors of abemaciclib discontinuation, a cyclin-dependent kinase 4 and 6 inhibitor, in patients with breast cancer.Material and MethodsBetween November 2018 and March 2023, 147 patients with breast cancer treated with abemaciclib at Osaka Medical and Pharmaceutical University Hospital and Kindai University Nara Hospital were included. The exclusion criteria were as follows: lack of blood testing within 2 weeks prior to starting abemaciclib therapy, transfer to another facility after the commencement of abemaciclib therapy, and discontinuation of abemaciclib therapy due to the diagnosis of another cancer. The duration from the initiation of abemaciclib to discontinuation for any reason and to temporary suspension or dose reduction due to adverse events were analyzed as outcome variables using multivariate Cox regression analysis.ResultsBaseline weight < 54 kg, bone metastases, and hemoglobin level ≤ 12.4 g/dL were independent predictors of abemaciclib discontinuation for any reason. The main adverse events leading to abemaciclib discontinuation were liver enzyme elevation and gastrointestinal symptoms. Additionally, focusing on the adverse event of abemaciclib, a baseline weight < 54 kg was an independent predictor of temporary suspension or dose reduction due to adverse events. The most common adverse events leading to temporary suspension or dose reduction were neutropenia and diarrhea.ConclusionPatients with lower body weight are more susceptible to the adverse events of abemaciclib, increasing their risk of treatment discontinuation. In such patients, strict monitoring of adverse events and consideration of more frequent medical visits are necessary from the start of abemaciclib therapy.

Outcomes of pregnancy in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors.

Young female patients with chronic myeloid leukemia (CML) often face challenges becoming pregnant due to the teratogenicity of tyrosine kinase inhibitors (TKIs). The authors conducted a nationwide survey of female patients with CML who experienced pregnancy between 2002 and 2020. Information for 70 pregnancies in 49 patients was obtained. There were three types of pregnancies: CML onset during pregnancy (n=9), unplanned pregnancy mostly during treatment with a TKI (n=25), and planned pregnancy during treatment-free remission (TFR) or treatment with interferon-alpha (IFN-α) (n=36). The median duration from CML diagnosis to pregnancy in patients with planned pregnancy was significantly longer than that in patients with unplanned pregnancy (10.6 years vs. 4.1 years, p<.001). In 48 pregnancies that resulted in childbirth, TFR and treatment with IFN-α were chosen in 26 and 17 pregnancies, respectively. Sustained major or deeper molecular response was observed in 18 of 26 pregnancies with TFR. The patients who fulfilled the requirements for TKI therapy discontinuation by European LeukemiaNet recommendations achieved a TFR rate of 77% in pregnancy. Treatment with IFN-α might be effective for patients who are in complete cytogenetic response or deeper response (response rate, 76%). Pregnancy by TFR or treatment with IFN-α could be a safe and feasible way for patients with CML. However, a substantial duration of treatment with a TKI before conception may be needed for planned pregnancy. Planning and evaluation for pregnancy should be considered at the time of CML onset for female patients with childbearing potential.

Evaluating the Risk of Traumatic Brain Injury in Adults Following a Fall With Concomitant Use of Anti-Coagulation: A Retrospective Cohort Study.

Introduction Falls and fractures are major health challenges for older adults in England. Despite the advantages of anticoagulants, their use in the elderly is often restricted due to concerns about fall-related injuries. However, there is a lack of clear data on the risk of discontinuing anticoagulation therapy solely due to fall risk. NICE guidelines (2021) advise that anticoagulation should not be withheld solely based on age or fall risk. This study aims to assess the incidence of significant brain injuries or intracranial haemorrhages in patients on anticoagulant therapy, also comparing the independent risk factors for traumatic brain injury. Objective This study aims to assess the incidence of TBI following falls in patients on anticoagulant therapy, comparing outcomes between those using DOACs and Vitamin K antagonists. Methods A retrospective cohort study was conducted at Queen Alexandra Hospital, University Hospitals Portsmouth NHS Trust, from November 2023 to May 2024. Data were collected from 3,468 CT head scans performed on patients with a history of falls, including 801 on anticoagulation therapy. Results Of the 801 patients on anticoagulation, 763 (95.2%) were aged 65 or older, with a mean age of 83.1 years. Acute hemorrhage was detected in 3.1% (25/801) of patients. Patients on Warfarin and Dabigatran had significantly higher TBI risk compared to those on Apixaban (6.7%, p=0.02; and 7.6%, p=0.01, respectively), while Edoxaban and Rivaroxaban showed no significant difference. Also, older age (≥65 years) and higher frailty scores (CFS 6 and 7) were associated with increased TBI risk (p<0.05). All patients with acute hemorrhage received conservative management, and two patients experienced mortality within six months. Discussion The study indicates that the risk of TBI following falls in anticoagulated patients is 3.1% relatively low, aligning with existing literature. This underscores the need for careful consideration before discontinuing anticoagulation therapy solely based on fall risk. Hence, discontinuation of anticoagulation should be a patient-specific decision that carefully considers the balance between the risk of traumatic brain injury (TBI) and the benefits of anticoagulation therapy. Factors such as age, frailty, and the type of anticoagulant should all be taken into account. Clinical judgment and selective CT imaging can help balance patient safety with healthcare costs. Conclusion The incidence of adverse outcomes following head injury in patients on anticoagulant therapy is 3.1% and relatively low. Careful decision-making regarding the discontinuation of anticoagulation therapy, informed by patient background and presentation and selective CT imaging, is essential to manage risks effectively and optimize healthcare resource utilization.

The initial high-dose versus maintenance-dose anticoagulation therapy with direct oral anticoagulants for cancer-associated venous thromboembolism: from the COMMAND VTE Registry-2

Abstract Background/Introduction Initial high-dose anticoagulation therapy with rivaroxaban and apixaban has been a standard treatment for venous thromboembolism (VTE), although there could be concerns of an increased risk of bleeding events especially among high bleeding-risk patients including those with active cancer. Purpose The present study aimed to evaluate the clinical outcome of initial high-dose anticoagulation therapy comparing to maintenance-dose anticoagulation therapy in patients with cancer-associated VTE using propensity score-matching analysis. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. Among 1507 patients with cancer-associated VTE, we evaluated 180-day clinical outcomes before discontinuation of anticoagulation therapy using a 1:1 propensity score-matching model with 21 risk-adjusting variables Results After the propensity score-matching, we enrolled 324 patients with initial high-dose anticoagulation therapy and 324 patients with initial maintenance dose anticoagulation therapy. Of patients with initial high-dose anticoagulation therapy, rivaroxaban and apixaban were administered in 198 and 126 patients, respectively. Of those with initial maintenance-dose anticoagulation therapy, rivaroxaban, apixaban, and edoxaban were administered in 34, 46 and 244 patients, respectively. The median durations of initial high-dose anticoagulation therapy were 18 [IQR: 15-21] days for rivaroxaban and 7 [IQR: 7-7] days for apixaban. In the current study population, the mean age was 67±12 years, 346 were women, and the mean body weight was 58±12 kg. There was no significant difference in the distribution of gastrointestinal cancer such as stomach and colorectal cancer between the 2 groups (4.6% vs. 4.9%, P=1.0, 8.3% vs. 11.4%, P=0.22). The cumulative 180-day incidence of discontinuation of anticoagulation was not significantly different between the 2 groups (27.8% vs. 30.5%, P=0.50). There were no significant differences in the cumulative 180-day incidences of recurrent VTE (3.1% vs. 1.0%, P=0.08), nor major bleeding (8.1% vs. 7.0%, P=0.66), nor all-cause death (25.1% vs. 21.6%, P=0.33) between the 2 groups. There were also no significant differences in the cumulative 180-day incidences of all clinically relevant bleeding (14.9% vs. 13.3%, P=0.72), gastrointestinal bleeding (8.4% vs. 5.4%, P=0.15), nor major gastrointestinal bleeding (5.4% vs. 2.7%, P=0.10). Conclusions There was no signal of an increased risk of recurrent VTE in the initial maintenance-dose anticoagulation therapy. Considering a numerically slightly higher incidence of gastrointestinal bleeding in the initial high-dose anticoagulation therapy for cancer-associated VTE, the initial maintenance-dose anticoagulation therapy could be a potential treatment option for selected patients including patients at a high risk of gastrointestinal bleeding.Study flow chartResults

The association between steroid use and recurrent venous thromboembolism: from the COMMAND VTE Registry-2

Abstract Background It is well known that use of oral steroids is a risk factor for development of venous thromboembolism (VTE). However, the impact of use of oral steroids on VTE recurrence has not been fully evaluated in the era of direct oral anticoagulants (DOAC), which has been a clinically relevant issue in the decision-making of anticoagulation strategies for patients who need oral steroids after VTE diagnosis. Purpose We aimed to investigate long-term clinical outcomes in VTE patients treated with oral steroids after VTE diagnosis in the DOAC era. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. The current study population were divided into 2 groups according to the use of oral steroids after VTE diagnosis; the steroid group and the non-steroid group. We compared clinical characteristics, management strategies, and outcomes including recurrent VTE, major bleeding and all-cause death, between the 2 groups. Results Patients with steroids and those without accounted for 693 (13%) and 4,504 (87%), respectively. Patients with steroids more often had chronic kidney disease (29% vs. 18%, P&amp;lt;0.001), autoimmune disease (50% vs. 5.4%, P&amp;lt;0.001), thrombocytopenia (7.7% vs 4.9%, P=0.002), and anemia (64.4% vs 54.1%, P&amp;lt;0.001), whereas there was no significant difference in the mean age (68.5 vs. 67.6 years old, P=0.16), the prevalence of women (62% vs 58%, P=0.06), active cancer (30% vs. 29%, P=0.42), and history of VTE (8.4% vs 6.8%, P=0.12) between the 2 groups. The cumulative 5-year incidence of discontinuation of anticoagulation therapy were not significantly different between the 2 groups (61.5% vs. 58.5%, log-rank P=0.16). The cumulative 5-year incidences of recurrent VTE nor major bleeding were not significantly different between the 2 groups (10.4% vs. 9.4%, log-rank P=0.55; 16.9% vs. 13.3%, log-rank P=0.16, respectively). Even after adjusting confounders, the risks of recurrent VTE nor major bleeding were not significantly different (adjusted hazard ratio = 0.97, 95% confidence interval = 0.65-1.45, P = 0.89; adjusted hazard ratio = 1.12, 95% confidence interval = 0.84-1.50, P = 0.44). The cumulative 5-year incidences of all-cause death was significantly different between the 2 groups (44.2% vs. 30.2%, log-rank P&amp;lt;0.001). Even after adjusting confounders, the risk of all-cause death remained significantly different (adjusted hazard ratio = 1.82, 95% confidence interval = 1.56-2.12, P&amp;lt;0.001). Conclusions Use of oral steroids after VTE diagnosis was not significantly associated with an increased risk of VTE recurrence in the DOAC Era, which might suggest that there could be no major concerns on an increased risk of recurrent VTE with oral steroids after VTE diagnosis under appropriate anticoagulation therapy.

Half of implantable cardioverter-defibrillator patients remain at risk of painful shocks in the last moments of life

Abstract Background Patients with implantable cardioverter-defibrillators (ICDs) are at risk of receiving painful shocks near the end of life due to ongoing tachytherapy. Position papers of various international societies emphasize the need for advance care planning and timely deactivation of tachytherapy. This study aims to assess the real world practice of deactivating ICD tachytherapy prior to death over a consecutive 18-year period and strives to identify areas for improvement. Methods Medical records were reviewed of all patients who were carriers of an ICD or CRT-D and under follow-up at our university medical center. Those who deceased between 2006 and 2023 were identified from the municipal civil registry and their follow-up data were extracted from electronic patient records. The cause of death and status of ICD therapy at the time of death was analysed. Results During the study period, 1724 patients with an ICD expired (mean age 73 ± 10 years; 265 (15%) females; 1396 (81%) primary prevention; median time from initial ICD implantation 7.5 [interquartile range: 4 to 12] years. Baseline characteristics of patients who had tachytherapy deactivated prior to death did not differ significantly from those who did not. Overall, 769 (43%) devices were deactivated before death. The proportion of patients with deactivated tachytherapy prior to death gradually increased over time, surpassing to just &amp;gt;50% in the past decade (p&amp;lt;0.001), Figure 1. Causes of death differed between the two groups (p=0.022), Figure 2. The majority of patients with deactivated tachytherapy prior to death died due to: heart failure (38%); non-cardiac causes (23%) e.g. myocardial infarction or valvular disease; malignancy (23%) and other non-cardiac causes such as infectious diseases, stroke and trauma (31%). However, substantial proportions of patients dying from causes that could potentially be identified as an end-of-life phase, remained at risk of shocks in the last moments of life due to active tachytherapy (30% heart failure, 11% malignancy, 25% other non-cardiac causes). Conclusions The rate of patient with deactivated ICD tachytherapy before death doubled within the initial 4 years of the study period and more or less stabilized thereafter, thus leaving nearly half of ICD patients susceptible to painful shocks in their final moments of life. This underlines the necessity of timely advance care planning, including discussions regarding discontinuation of ICD therapy during the end-of-life phase.

Persistence and Adherence to GLP-1 RA treatment in Type 2 Diabetes Mellitus: a Nationwide registry study

Abstract Background The use of glucagon-like peptide-1 receptor agonsists (GLP-1 RA) continues to rise and is increasingly important in the treatment of type-2 diabetes mellitus (T2DM). Though the use of GLP-1 RA continues to increase, persistence and adherence to therapy remains suboptimal. Purpose We aimed to assess the level of adherence and persistence to GLP-1 RA using real-world data and to investigate sociodemographic and clinical factors associated with discontinuation of GLP-1 RA therapy. Methods In this retrospective cohort study, all first-time users of GLP-1 RA with T2DM ≥18 years from 2007-2020 were identified using the Danish registries (Figure 1A-1B). All participants had 18 months of follow-up. Medication possession ratio (MPR) was calculated by summing days of medication supply from all dispensed prescription made during the study period divided by number of days in study period. MPR ≥0.80 was used to define adherence. Discontinuation was defined as &amp;gt;90 days between the last day of prescription coverage and the first day of a new dispensed prescription. Adherence to GLP-1 RA therapy and the risk of discontinuing therapy was estimated at 6- and 12-months of follow-up. Multivariable logistic regression was used to identify sociodemographic and clinical factors associated with discontinuing GLP-1 RA therapy. Results In total, 44,343 first-time users of GLP-1 RA with T2DM were identified (mean age: 58.6 years, 42.7% female, 21.3% had cardiovascular disease, median duration of T2DM was 6.8 years, median HbA1c was 65 mmol/mol). The absolute risk of discontinuing GLP-1 RA at 6 and 12 months was 14.2% (95%CI: 13.9-14.6) and 21.4% (95%CI: 21.1-21.8), respectively (Figure 2A). Of the 9,520 (21.5%) who discontinued therapy during the 12-month follow-up, 1,947 (20.5%) occurred within the first 31 days of treatment. At 6 months, 58.5% were adherent to GLP-1 RA therapy with a median MPR of 0.84 [IQR: 0.70-0.95]. At 12 months, 61.1% were adherent to therapy with a median MPR of 0.85 [IQR: 0.71, 0.94]. In the multivariable model, low (&amp;lt;40 years) and high age (&amp;gt;75 years), lower household income, educational level, longer diabetes duration, and higher comorbidity burden were associated with a higher risk of discontinuing GLP-1 RA whereas baseline HbA1c was not (Figure 2B-2E). Conclusion Approximately one in five patients discontinued therapy within 12 months and a little over 60% were adherent. Sociodemographic factors, including household income, age, and comorbidity burden were associated with risk of discontinuing GLP-1 RA therapy. Given the changing landscape of who should be treated with GLP-1 RA, the cardio-renal benefits reported in recent trials, and the ongoing trials in the field, future research into adherence and persistence to GLP-1 RA and possible interventions to improve these, are needed.

Real-world experience with mavacamten in obstructive hypertrophic cardiomyopathy: observations from a tertiary care center

Abstract Background In symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients, mavacamten is commercially approved to help improve left ventricular (LV) outflow tract (LVOT) gradients, symptoms, and reduce eligibility for septal reduction therapy (SRT) under the risk evaluation and mitigation strategy (REMS) program. We sought to prospectively report the initial real-world clinical experience with the use of commercially available mavacamten in a multi-hospital tertiary healthcare system. Methods We studied the first 150 consecutive oHCM patients (mean age 65 years, 53% women, 83% on betablockers and 61% in New York Heart Association [NYHA] class III) who were initiated on 5 mg of mavacamten with dose titrations using symptom assessment and echocardiographic measurements of LVOT gradient and LV ejection fraction (LVEF) measurements. We measured changes in NYHA class, LVEF, LVOT gradients (resting and Valsalva) at baseline, 4, 8 and 12 weeks. Results At 261±143 days (range of 31-571 days), 69 (46%) patients had ≥1 NYHA class, 27 (18%) additional patients had ≥2 NYHA class improvement and 40 (27%) reported a no change in symptoms. The mean LVOT gradient at rest decreased from 41±33 mmHg at baseline to 16±17 mmHg at 4 weeks, 16±16 mmHg at 8 weeks and 15±16 mmHg at 12 weeks. The mean drop in resting LVOT gradient from baseline to last follow-up was 26±3 mmHg (p&amp;lt;0.0001). The mean Valsalva LVOT gradient decreased from 72±43 mmHg at baseline to 29±31 mmHg at 4 weeks, 29±28 mmHg at 8 weeks and 30±29 mmHg at 12 weeks (p&amp;lt;0.001). The mean reduction in post Valsalva LVOT gradient from baseline to last follow-up was 43±4 mmHg (p&amp;lt;0.0001). At baseline, 100% patients had Valsalva LVOT gradients ≥ 30 mm Hg and 142 (95%) had ≥ 50 mm Hg. After initiation of mavacamten therapy, Valsalva LVOT gradient ≥ 30 mm Hg was observed in 44/150 (29%) at 4 weeks, 40/141 (28%) at 8 weeks and 41/136 (30%) at 12 weeks. In 40 patients who reported no symptomatic improvement, the mean Valsalva LVOT gradient decreased from 73±39 mmHg at baseline to 34± 27 mmHg at 4 weeks, 35±28 mmHg at 8 weeks and 30±24 mmHg at 12 weeks (P&amp;lt;0.001). The mean LVEF at baseline was 66±6% and changed to 64±5% at 4 weeks, 63±5% at 8 weeks and 62±7% at 12 weeks (p&amp;lt;0.0001). No patient underwent SRT, developed LVEF ≤30% or developed heart failure requiring admission. Three (2%) patients needed temporary interruption of mavacamten due to LVEF&amp;lt;50. During follow up, dose reduction or discontinuation of background HCM therapy (betablockers, calcium channel blockers and disopyramide) occurred in 33 (22%) patients. The breakdown of various drug doses of mavacamten, at last follow-up, is as follows: 2.5 mg (n=29, 19%), 5 mg (n=80, 53%), 10 mg (n=37, 25%) and 15 mg (n=3, 2%). Conclusions In a real-world study in symptomatic oHCM patients at a multi-hospital tertiary care referral center, we demonstrate the efficacy and safety of prescribing mavacamten under the REMS program.

The upfront lipid-lowering combination therapy of statins and ezetimibe vs statin monotherapy in the reduction of cardiovascular outcomes. A meta-analysis.

Abstract Background Despite some data in last few years, there is still some inconsistency concerning the effectiveness and safety of the upfront intensive lipid lowering combination therapy (LLT; of moderate to high intensity statin therapy and ezetimibe) in comparison to high intensity statin therapy and recommended by some guidelines stepwise therapy approach. Purpose We sought to evaluate the efficacy of combination LLT compared with statin monotherapy for cardiovascular outcomes, LDL-C reduction, and associated adverse events. Methods A systematic literature search was conducted using PubMed, Embase, and ClinicalTrial.gov to identify relevant articles published from inception until 29th December 2023. The outcomes were assessed using pooled odds ratio (OR) for categorical data and mean difference (MD) for continuous data, with corresponding 95% confidence intervals (95% CI). Results A total of 11 studies (8 randomized controlled trials and 3 cohort studies) with 106,358 were involved in the analysis. The mean age of the patients in the combination LLT and statin monotherapy group was 65.3 and 65.7 years, respectively. Pooled analysis shows that combination LLT significantly reduces the LDL-C level from the baseline (MD, -12.13 mg/dl [0.31 mmol/l] (95%CI: -18.26 to -5.99 mg/dl), p&amp;lt;0.001), all-cause mortality (ACM) (OR, 0.75, 95%CI: 0.62 to 0.92, p=0.01), cardiovascular mortality (CVM) (OR 0.75, 95%CI: 0.66 to 0.84, p&amp;lt;0.001), major adverse cardiovascular events (MACE) (OR, 0.72 95%CI: 0.63 to 0.82, p&amp;lt;0.001), non-significant reduction in the incidence of stroke (OR 0.82, 95%CI: 0.66 to 1.01, p=0.06) when compared with statin monotherapy alone. Similarly, the therapy discontinuation rate was comparable between combination LLT and statin monotherapy groups (OR, 0.87 (95%CI: 0.53 to 1.40), p=0.56). The risk of adverse events related to the gastrointestinal tract (OR, 1.12 (95%CI: 0.93 to 1.36), p=0.23) and musculoskeletal system (OR, 0.88 (95%CI: 0.52 to 1.50), p=0.65) was comparable between both the groups of patients. Conclusion Combination LLT was associated with an overall greater reduction in LDL-C, a lower risk of ACM, MACE, and CVM compared to statin monotherapy alone.Forest Plot of desired outcomes.Central illustration with key findings.

Management of children with heterozygous familial hypercholesterolemia worldwide: a meta-analysis

Abstract Background HeFH is one of the most frequent monogenic disorders in the world, leading to premature ASCVD. Purpose The aim of this meta-analysis was to evaluate the efficacy and safety of lipid lowering therapy (LLT) and achievement of LDL-C goal in heFH children. Methods The main endpoint was efficacy of goal achievement for LDL-C and other lipid parameters: total cholesterol [TC], triglycerides [TG], high density lipoprotein cholesterol [HDL-C], apolipoprotein B [apo B] and lipoprotein(a) [Lp(a)]), and the LLT safety (adverse events [AEs], including endocrine function, and growth indices). The secondary endpoint was an effect of LLT on attainment of LDL-C goal treatment (&amp;lt;3.5 mmol/L/130 mg/dL). Results A total of 41 studies with 4667 pediatric patients at mean age 12.08±2.4 years were included. At median follow-up of 18.8 months, the group on LLT had significantly higher mean reductions of TC, LDL-C, TG, and increased HDL-C compared to control (-1.75 [-67,7 mg/dl], -1.84 [-71.2 mg/dl], -0.11 [-9.74 mg/dl], 0.08 mmol/L [3.1 mg/dl], respectively, p&amp;lt;0.001 for all). In the subgroup analysis according to different types of LLT we observed a significantly higher mean reduction of LDL-C by statin combined with ezetimibe treatment, followed by PCSK9 inhibitors, statins in monotherapy, and monotherapy with ezetimibe (-2.48 [-95.9 mg/dl], -2.16 [-83.5 mg/dl], -2.03 [-78.5 mg/dl], and -1.50 mmol/L [-58 mg/dl], respectively, test for overall effect: p&amp;lt;0.001). The pooled LDL-C was reduced by 33.44% (-2.14 mmol/L [-82.8 mg/dl], p&amp;lt;0.001) and failed to reach the goal treatment (&amp;lt;3.5 mmol/L) by 12.6% (95%CI, 12.4 – 12.9%). 38.7% of children achieved the LDL-C goal, 23.9% fell short by up to 10%, 10.7% experienced moderate failure (were over the LDL-C target between &amp;gt;10-20%), and 26.7% failed by more than 20% to reach the LDL-C target. When comparing different regions, only Sweden and Greece achieved the LDL-C goal &amp;lt;3.5 mmol/L in the follow-up, followed by the Netherlands, Norway, Poland, USA, UK, France, Spain, Belgium, and Austria (with the following additional required LDL-C reduction to be on the goal: 2.2%, 3.4%, 3.5%, 8.9%, 10.2%, 11.2%, 11.2%, 15%, 19.4%, respectively). For other investigated countries over 20% mean LDL-C reduction was required. All parameters related to endocrine function and demographic indices were unaffected by LLT therapy (p&amp;gt;0.05). The adverse events were not reported significantly higher when compared to the control and the prevalence of therapy discontinuation was only 0.8%. Conclusions Despite the efficacy of LLT in children with HeFH and the low occurrence of discontinuation-related adverse events, achieving LDL-C treatment goals was relatively rare, with large differences between the investigated countries. These results underscore the importance of considering early combination therapy of statins and ezetimibe, and PCSK9 inhibitors (if available) to attain LDL-C goals effectively.Lipoproteins reduction with LLT.Goal achievement and therapy safety.

Real-World Experience Of The Association of HLADQA1*05 Allele with Loss of Response to Anti-TNF Inhibitors

Abstract Goals and Background Anti–tumor necrosis factor (anti-TNF) biologics have revolutionized the treatment of inflammatory bowel disease (IBD). Previously, studies have shown an association between the HLADQA1*05 allele and the development of antibodies and was predictive of loss of response. We sought to investigate the rate of the HLADQA1*05 allele in patients with IBD at a New England center and its association with antibody development and discontinuation of anti-TNF therapy. Study A single center retrospective cohort study with patients on anti-TNF inhibitor therapy being followed at our IBD clinic who had testing performed for the HLADQA1*05 allele were identified and separated into two different groups: HLADQA1*05 positive (HLA-carriers) or HLADQA1*05 negative (HLA non-carriers). Persistence of remaining on anti-TNF therapy, measurement of drug/antibody levels, and need for dose escalation was collected and stratified amongst the two groups. Results The prevalence of the HLADQA1*05 allele among all IBD patients followed was 53%. We identified 67 IBD patients being treated with anti-TNF medications, 46 (69%) patients with Crohn’s disease and 21 (31%) with ulcerative colitis. Most of the HLA carriers (85%) and HLA non-carriers (92%) remained on anti-TNF therapy at the end of the study period. 36 (84%) patients had therapeutic drug monitoring performed during maintenance therapy. Three patients in the HLA carrier group had meaningful anti-drug antibody levels necessitating cessation of therapy compared to one patient in the HLA non-carrier group (p = 0.61). Only 3 (13%) of HLA carriers and 4 (21%) of HLA non-carriers were on combination therapy with an immunomodulator. 65% of HLA carriers required dose escalation compared to 50% of HLA non-carriers (p= 0.70). Conclusion The prevalence of the HLADQA1*05 allele was 53% in our New England IBD patient population, similar to what has previously been reported in European studies. The majority of patients remained on anti-TNF therapy at the end of the study period despite carrier status. While there was a trend toward increased need for dose escalation among HLA carriers, this was not statistically significant. Future studies are needed to determine if the presence of the HLADQA1*05 allele leads to the antibody development against anti-TNF inhibitors and treatment failure in patients with IBD.

Loss to follow-up of patients after antiviral treatment as an additional barrier to HCV elimination

BackgroundEliminating hepatitis C virus (HCV) infections is a goal set by the World Health Organization. This has become possible with the introduction of highly effective and safe direct-acting antivirals (DAA) but limitations remain due to undiagnosed HCV infections and loss of patients from the cascade of care at various stages, including those lost to follow-up (LTFU) before the assessment of the effectiveness of the therapy. The aim of our study was to determine the extent of this loss and to establish the characteristics of patients experiencing it.MethodsPatients with chronic HCV infection from the Polish retrospective multicenter EpiTer-2 database who were treated with DAA therapies between 2015 and 2023 were included in the study.ResultsIn the study population of 18,968 patients, 106 had died by the end of the 12-week post-treatment follow-up period, and 509 patients did not report for evaluation of therapy effectiveness while alive and were considered LTFU. Among patients with available assessment of sustained virological response (SVR), the effectiveness of therapy was 97.5%. A significantly higher percentage of men (p<0.0001) and a lower median age (p=0.0001) were documented in LTFU compared to the group with available SVR assessment. In LTFU patients, comorbidities such as alcohol (p<0.0001) and drug addiction (p=0.0005), depression (p=0.0449) or other mental disorders (p<0.0001), and co-infection with human immunodeficiency virus (HIV) (p<0.0001) were significantly more common as compared to those with SVR assessment. They were also significantly more often infected with genotype (GT) 3, less likely to be treatment-experienced and more likely to discontinue DAA therapy.ConclusionsIn a real-world population of nearly 19,000 HCV-infected patients, we documented a 2.7% loss to follow-up rate. Independent predictors of this phenomenon were male gender, GT3 infection, HIV co-infection, alcohol addiction, mental illnesses, lack of prior antiviral treatment and discontinuation of DAA therapy.

56 Iron deficiency is common in extreme preterm infants despite prophylactic iron supplementation

Abstract Background Iron deficiency (ID) in childhood is linked to adverse neurodevelopmental outcomes in the long-term. Extremely premature infants (EPI; born &amp;lt; 28 weeks gestation) are more susceptible to ID due to a multitude of factors including lower iron reserves at birth, rapid growth, immature erythropoiesis, and multiple phlebotomy tests during hospital stay. Therefore, professional societies advise prophylactic iron therapy for these infants from 2-6 weeks age until 6-12 months. However, there is paucity of data on the iron status in EPI receiving this prophylactic iron supplementation. Objectives To investigate the prevalence and risk factors associated with ID in EPI. Design/Methods A retrospective cohort study analyzed a Provincial database of EPIs born between 2005-2018. Infants with congenital malformations, chromosomal anomalies and blood disorders were excluded. All included infants received prophylactic iron supplementation from 2-4 weeks of chronological age that was recommended to continue at discharge until 9-12 months corrected age (CA). At 4-6 months CA, these infants underwent blood testing. ID was defined as serum ferritin &amp;lt; 20mcg/L at 4 months CA or SF &amp;lt; 12mcg/L at 6 months CA. Through a univariate analysis using single-variable logistic regression, factors linked to ID were identified. Those with a p-value &amp;lt; 0.20 progressed to a multivariable model, retaining variables with a p-value &amp;lt; 0.05. Results Of 146 infants, 45.9% had ID. ID group had lower mean ferritin (16.4 µg/L vs 50.0 µg/L, p &amp;lt; .001) and reticulocyte hemoglobin equivalent (28.4pg vs 31.6pg, p &amp;lt; .001) compared to the non-ID group. ID prevalence reduced from 59.7% in 2005-2011 to 40.3% in 2012-2018 cohort. Exclusive or partial breastfeeding at 4-6 months CA was protective against ID (Odds: 0.2, p = 0.003). Iron therapy at 4-6 months CA was not protective in the final model. Notably, 27.4% stopped iron therapy before 4-6 months CA, and exclusive formula-fed infants had notably lower iron intake than breastfed infants (66.1% vs 99.1%, p = 0.006). Conclusion Nearly half of the EPI exhibited ID at 4-6 months CA despite prophylactic iron supplementation. About a quarter discontinued therapy before reaching this age. Breastfeeding at this age was protective against ID. This high prevalence of ID in EPI underscores the need of future studies to discern strategies to mitigate ID in this vulnerable population.

Rapid reduction in fracture risk after the discontinuation of long-term oral glucocorticoid therapy: a retrospective cohort study using a nationwide health insurance claims database in Japan.

We investigated changes in fracture risk following discontinuation of long-term oral glucocorticoids (GCs) using Japan's nationwide health insurance claims database (NDBJ). We identified patients aged ≥ 50 years who initiated GC therapy in 2012-2019. Those receiving ≥ 5mg (prednisolone or equivalent, PSL)/day for ≥ 72days in the initial 90days of GC therapy were classified as the GC-exposure group, and those receiving < 5mg PSL/day for < 30days were classified as the reference group. Patients discontinuing GC after 90days of GC therapy were classified as the GC-discontinuation group; all others were classified as the GC-continuation group. We tracked the incidence rates of hip and clinical vertebral fractures for up to 990days, and assessed fracture risk after GC discontinuation by hazard ratios (HR) adjusted by inverse probability weighting using propensity scores for GC discontinuation. There was a total of 52,179 GC-discontinuation, 91,969 GC-continuation, and 43,138 reference group women, and 57,560, 93,736, and 33,696 men in the corresponding groups, respectively. According to adjusted HRs, incidence rates of fractures were significantly lower in the GC-discontinuation group than in the GC-continuation group in the initial 90days after GC discontinuation and remained significant for 360days, except for hip fracture in men. HRs for hip fractures remained significantly higher in the GC-discontinuation group compared to the reference group for 720days post-discontinuation. Fracture risk declines rapidly in the first year after GC discontinuation, but vigilance is necessary as the increased risk persists for two years post-discontinuation.

Factors influencing the discontinuation of biologic therapies in patients with ulcerative colitis

BackgroundThe therapeutic landscape for ulcerative colitis (UC) has recently broadened to include anti-TNFα, anti-integrin, and anti-IL-12/23p40 antibody agents. These biological agents are tailored to individual patient profiles. However, some patients cease biological treatment. This study investigates factors influencing the discontinuation of biological treatment in UC patients.MethodsThis retrospective single-cohort study encompasses UC patients who commenced treatment with biological agents like infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab from April 2019 to March 2022. Patients were categorized into continuation and discontinuation groups based on their one-year treatment status. Baseline characteristics were compared between the groups.ResultsOf the 116 UC patients, 102 were included in the study. Among these, 74 (72.5%) continued and 28 (27.5%) discontinued biological therapy. Discontinuation rates for infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab were 33.3%, 25.0%, 50.0%, 30.2%, and 15.6%, respectively. The primary discontinuation reason was lack of efficacy (85.7%), followed by adverse events (7.1%), pregnancy (3.6%), and death (3.6%). The discontinuation group had a significantly lower rate of concomitant thiopurine compared to the continuation group (28.6% vs. 56.8%, p = 0.0132). Multivariable analysis revealed that concomitant thiopurine was independently associated with therapy continuation (p = 0.0075).ConclusionThe study indicates that concomitant thiopurine significantly correlates with the continuation of biological therapies in UC patients, underscoring the importance of concomitant thiopurine in sustaining biological therapy. Further studies are warranted to assess the efficacy of combination therapy.

Uterine fibroids with heavy menstrual bleeding stratified by race in a commercial and Medicaid database

BackgroundHistorically, the clinical characteristics and treatment pathways for patients with uterine fibroids and heavy menstrual bleeding have differed between White and Black women. ObjectiveTo provide a contemporary comparison of patient characteristics and treatment patterns among White and Black women with uterine fibroids and heavy menstrual bleeding in the United States. Study DesignThis retrospective cohort study included administrative claims data from 46,139 White and 17,297 Black women with uterine fibroids and heavy menstrual bleeding from the Optum Clinformatics database (January 2011–December 2020) and 7353 White and 16,776 Black women from the IBM MarketScan Multi-State Medicaid Insurance database (January 2010–December 2019). Patients were indexed at their initial uterine fibroid diagnosis claim and were required to have a claim for heavy menstrual bleeding and ≥12 months of continuous enrollment pre- and postindex. Patients were followed until the earliest of death, disenrollment, hysterectomy date, or end of study database. Outcomes were stratified by race and included patient demographics, clinical characteristics, pharmacologic treatment patterns, and surgeries/procedures. Pearson's Chi-square test for categorical variables and Student's t-test for continuous data were used to evaluate differences in baseline characteristics. Descriptive statistics were used to characterize treatment pathways for hormonal contraceptive use in women with ≥24 months of follow-up. Kaplan–Meier survival analysis was used to estimate time until hysterectomy, with log-rank testing to assess between-group differences. ResultsThe mean (standard deviation) duration of follow-up was 44.6 (27.9) and 41.0 (24.9) months in the commercial and Medicaid databases, respectively. Mean (standard deviation) age at uterine fibroid diagnosis was lower for Black than White women in both databases (commercial: 42.3 [6.5] vs 44.4 [6.3] years; P<.0001; Medicaid: 39.6 [7.1] years vs 40.2 [7.2] years; P<.0001). Anemia was more prevalent in Black vs White women in both databases (commercial: 5.9% [1028/17,297] vs 3.6% [1648/46,139]; P<.0001; Medicaid: 7.0% [1180/16,776] vs 4.5% [331/7353]; P<.0001). In the commercial database, approximately one-half of women had claims for ≥1 bulk symptom, with no significant differences between groups. In the Medicaid database, significantly more White than Black women had claims for bulk symptoms (77.0% [5665/7353] vs 68.4% [11,477/16,776]; P<.0001). Approximately 40% of all patients received hormonal drug therapies as initial treatment, most commonly hormonal contraceptives. However, discontinuation of hormonal contraceptive therapy was nearly universal, with one-half discontinuing within a median treatment duration of ∼5 months. Most women stopped treatment after 1 or 2 agents (commercial: White, 89.9% [9757/10,857]; Black, 90.0% [3594/3993]; Medicaid: White, 92.2% [1635/1773]; Black, 94.2% [4454/4726]). Hysterectomy was the most common procedure, and was more common among White vs Black women (commercial: 43.9% [20,235/46,139] vs 37.8% [6536/17,297]; Medicaid: 46.8% [3444/7353] vs 32.0% [5364/16,776]). ConclusionsBlack women with UF-HMB were diagnosed at a younger age than White women, and White women had higher hysterectomy rates than Black women, representing a shift from earlier researched treatment patterns. Patients with UF-HMB were also highly reliant on hormonal contraceptives, followed by nearly universal therapeutic discontinuation.

Malakoplakia, a rare inflammatory condition presenting as a colon polyp

Abstract Introduction/Objective Malakoplakia is a rare histiocytic disease caused by defects in phagocytic or degradative functions of histiocytes in response to gram negative coliforms (E. coli or Proteus) that results in chronic inflammatory state, followed by intracellular deposition of iron and calcium (known as Michaelis-Gutmann bodies). It’s more common in immunocompromised patients and the mean age at diagnosis is fifth decade. It occurs in all organs, common in GU tract, particularly bladder, but also seen in gastrointestinal tract (most commonly colon, followed by stomach and duodenum), central nervous system and female genital tract. In gastrointestinal tract, it can present as a polyp with diffuse mucosal involvement, submucosal thickening, and even may cause mass. Methods/Case Report A 60 -year-old male smoker presented to our hospital with history of colon polyps; colonoscopy revealed a 6 mm sessile polyp at the hepatic flexure. A biopsy was performed which showed numerous epithelioid histiocytes with granular eosinophilic cytoplasm, abundant Michaelis-Gutmann bodies and increased lymphocytes. Immunohistochemical stains showed diffuse positivity for CD68; and PAS stain was positive for histiocytic cytoplasmic granules. Based on this data, the diagnosis of Malakoplakia was confirmed. Malakoplakia is treated with antibiotics that concentrate in macrophages (quinolones or trimethoprim-sulfamethoxazole), antibiotics directed against E. coli, surgery and possibly discontinuation of immunosuppressive drug therapy. Results (if a Case Study enter NA) Malakoplakia, in this case, was presented clinically as a sessile colon polyp and histologically showed numerous epithelioid histiocytes with granular eosinophilic cytoplasm, with Immunohistochemical stains (CD68; and PAS stain) the correct diagnosis was made. Other presentations of Malakoplakia include diffuse mucosal involvement, submucosal thickening, or mass. Histologically, it may rarely be mistaken as signet ring carcinoma. These variable presentations in GU tract or colon can be interpreted as malignancy with consequent unnecessary interventions. Hence, awareness of Malakoplakia with careful histopathologic examination and the use of immunohistochemical studies are advisable in that cases. Conclusion We would like to emphasize that Malakoplakia can be clinically and histologically misdiagnosed as a malignant condition; therefore histopathologic and immunohistochemical studies are needed to correctly diagnose this entity.

Treatment of anal fissures using the new TRPM8 receptor therapy - own experience.

&lt;b&gt;Introduction:&lt;/b&gt; Anal fissure, a longitudinal or oval crack in the anal anoderm above the dentate line, is one of the most common diseases of the anal area. The following article shows the effectiveness of anal fissure treatment based on our own experience, using new receptor therapy in the form of Procto-Zac Memethol Barrier Spray [(1R,2S,5R)-2-isopropyl-5-methylcyclohexanol, sodium hydrogen carbonate, 7-(dimethylamino) phenothiazin-3-ylidene]- dimethylazanium; chloride, 1,2-propanediol, purified water], preparation containing soluble fiber and oral probiotic.&lt;b&gt;Aim:&lt;/b&gt; The aim of the following article is to present our experience and observations in the conservative treatment of acute and chronic anal fissure using Procto-Zac Memethol Barrier Spray and preparations containing soluble fiber and oral probiotic.&lt;b&gt;Material and methods:&lt;/b&gt; The study included a group of 120 patients with anal fissure between 18 and 45 years of age. Each patient in the group received a therapy consisting of Procto-Zac Memethol Barrier Spray (8 sprays once a day, 2 packages) and preparation containing fiber and oral probiotic. A high-fiber, gluten-free and lactose-free diet was also recommended. A follow-up was carried out in our clinic after 4 and 8 weeks. If the symptoms do not disappear completely, also after 3 months from the start of treatment.&lt;b&gt;Results:&lt;/b&gt; Complete relief of symptoms was achieved in 62 patients after 4 weeks of treatment. After 8 weeks, complete relief of symptoms was achieved in another 49 people. In 6 people, after 3 months of treatment, the symptoms were partially relieved, but the anal fissure was not completely healed. Three people did not come for a follow-up visit. In 20 patients, skin burning around the anus was observed during the above therapy.The above symptoms did not require discontinuation of Procto-Zac Memethol Barrier Spray therapy and disappeared after completion of treatment. No other side effects of the preparations used were found.&lt;b&gt;Conclusions:&lt;/b&gt; According to our observations, the use of new TRPM8 receptor therapy MemeThol Barrier Spray, a preparation containing soluble fiber and oral probiotic, turned out to be an effective method of treating anal fissure. In the future, it is advisable to conduct further studies, including multicenter studies, to assess the full tolerability and effectiveness of the described therapy.

Comparison of Oral Procainamide and Mexiletine Treatment of Recurrent and Refractory Ventricular Tachyarrhythmias

Background: Antiarrhythmic therapy for recurrent ventricular arrhythmias (VAs) in patients having undergone catheter ablation and in whom amiodarone and/or beta-blockers were ineffective or contraindicated is a controversial issue. Purpose: The present study sought to compare the efficacy and tolerability of oral procainamide and mexiletine in patients with recurrent ventricular arrhythmias when the standard therapy strategy failed. Methods: All patients with an implantable cardioverter defibrillator (ICD) treated with oral procainamide or mexiletine for recurrent ventricular tachycardia (VT) or ventricular fibrillation (VF) in two cardiology divisions between January 2010 and January 2020 were enrolled. Patients were divided into group A (oral procainamide) and group B (mexiletine) and the two groups were compared to each other. The primary endpoint was the efficacy of therapy; the secondary endpoint was the discontinuation of therapy. All events that occurred during procainamide or mexiletine treatment were compared with a matched duration period before the initiation of the therapy. Antiarrhythmic therapy was considered effective when a ≥80% reduction of the sustained ventricular arrhythmias burden recorded by the ICD was achieved. Results: A total of 68 consecutive patients (61 males, 89.7%; mean age 74 ± 10 years) were included in this retrospective analysis. After a median follow-up of 19 months, 38 (56%) patients had a significant reduction in the VA burden. After multivariable adjustment, therapy with procainamide was independently associated with an almost 3-fold higher efficacy on VA suppression compared to mexiletine (HR 2.54, 95% CI 1.06–6.14, p = 0.03). Only three patients (9%) treated with procainamide presented severe side effects (dyspnea or hypotension) requiring discontinuation of therapy compared with six patients (18%) treated with mexiletine who interrupted therapy because of severe side effects (p = 0.47). Conclusions: Compared to mexiletine, oral procainamide had a higher efficacy for the treatment of recurrent and refractory VAs, and showed a good profile of tolerability.