Differences In Treatment Effects Research Articles

Sample size calculation for mixture cure model with restricted mean survival time as a primary endpoint.

It is not uncommon for a substantial proportion of patients to be cured (or survive long-term) in clinical trials with time-to-event endpoints, such as the endometrial cancer trial. When designing a clinical trial, a mixture cure model should be used to fully consider the cure fraction. Previously, mixture cure model sample size calculations were based on the proportional hazards assumption of latency distribution between groups, and the log-rank test was used for deriving sample size formulas. In real studies, the latency distributions of the two groups often do not satisfy the proportional hazards assumptions. This article has derived a sample size calculation formula for a mixture cure model with restricted mean survival time as the primary endpoint, and did simulation and example studies. The restricted mean survival time test is not subject to proportional hazards assumptions, and the difference in treatment effect obtained can be quantified as the number of years (or months) increased or decreased in survival time, making it very convenient for clinical patient-physician communication. The simulation results showed that the sample sizes estimated by the restricted mean survival time test for the mixture cure model were accurate regardless of whether the proportional hazards assumptions were satisfied and were smaller than the sample sizes estimated by the log-rank test in most cases for the scenarios in which the proportional hazards assumptions were violated.

Association of rheumatoid factor, anti-citrullinated protein antibodies and shared epitope with clinical response to initial treatment in patients with early rheumatoid arthritis: data from a randomised controlled trial

ObjectivesTo investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional...

Early Prostate-Specific Antigen Response by 6 Months Is Predictive of Treatment Effect in Metastatic Hormone Sensitive Prostate Cancer: An Exploratory Analysis of TITAN Trial.

Early PSA response has been found to be prognostic of outcomes in metastatic hormone sensitive prostate cancer. We performed a secondary analysis of the TITAN trial to determine if early PSA response was predictive of treatment efficacy in metastatic hormone sensitive prostate cancer patients. Early PSA response was defined as achieving a PSA level of ≤ 0.2 ng/mL by 6 months of random assignment. A Cox proportional hazard model was constructed in a landmark population with an interaction term between the treatment and early PSA response to determine differential treatment effect on overall survival (OS). We applied multivariable Cox proportional hazard regression model with time to early PSA response fitted with restricted cubic spline to determine the association of time to early PSA response with OS. Approximately 24% (124/524) of patients in the androgen deprivation therapy (ADT) alone group and 61% (321/524) in the apalutamide group had PSA response ≤ 0.2 ng/mL by 6 months. Longer time to early PSA response was associated with significantly superior OS in the apalutamide group. There was a significant difference in treatment effect from apalutamide on OS (P = .03 for interaction) among 6-month PSA responders (HR: 0.66; 95% CI: 0.44-1.00) vs nonresponders (HR: 1.14; 95% CI: 0.89-1.46). This difference in treatment effect was not statistically significant at 3 months (P = .17 for interaction). Among 6-month PSA responders, 3-year confounder-adjusted OS was 84% (80%-88%) for the apalutamide group and 74% (66%-82%) for the ADT alone group. Among nonresponders, 3-year adjusted OS for the 2 treatment arms were 58% (52%-65%) and 56% (51%-60%), respectively. Early PSA response by 6 months was a predictor of treatment efficacy from ADT plus apalutamide on OS. Longer time to early PSA response was associated with superior OS in the apalutamide arm.

Safety profile of proprotein convertase subtilisin/kexin type 9 inhibitors alirocumab and evolocumab: an updated meta-analysis and meta-regression

Background The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator. Methods Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration. Results We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, p = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, p = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, p < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, p < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, p = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p = 0.03; 12–24 weeks OR 2.12, 95% CI 1.20 to 3.73, p = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, p = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, p = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, p = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, p < 0.01). Conclusion Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.

Does The Lengthening Frequency Affect The Outcome of Distraction Osteogenesis? Comparing Two Times a Day with Four Times a Day Lengthening Protocol

Objective: Distraction osteogenesis (DO) is a well-known technique. The traditional method utilized the lengthening frequency of four times a day (QID). Many mechanical factors may affect the DO outcome. However, the effect of distraction frequency has not been proven clinically. Therefore, we aim to investigate whether the BID and QID lengthening frequency affect the healing index and complications of the DO. Materials and Methods: We retrospectively reviewed patients who had undergone DO from 2010 – 2021. The patient was divided into BID and QID groups. Demographics, lengthening outcomes, and complications between the two groups were compared. We used the inverse probability of treatment weighting (IPTW) to determine the effect of treatment. Results: The median healing index (HI) of the patients whose lengthening was done QID is 41.36 (IQR 32.72 - 67.68) days/cm, and BID is 49.12 (IQR 35.28 - 62.54) days/cm, which did not differ significantly. The Odds ratio of achieving HI &lt; 45 days/cm for patients receiving QID lengthening compare to BID is 1.12 (95% CI 0.31-3.99, p = 0.862 ). The IPTW did not show a difference in average treatment effects between QID and BID lengthening. The rates of minor and major complications were not significantly different between the two groups (26.1% in QID group and 32.1% in BID group). Conclusion: The frequency of QID and BID lengthening results in comparable HI and complications for patients who undergo DO. However, prospective research is needed to evaluate the effect of frequency differences in a clinical setting.

#2801 Which patients may benefit most from hemodiafiltration compared with hemodialysis: prediction of the individualized treatment effect

Abstract Background and Aims Haemodiafiltration (HDF) with an appropriate dosing reduces death from any cause based on an individual participant data meta-analysis and aggregated data meta-analyses of available randomized trials. No differences in treatment effect are reported for specific patient populations when defined on a single characteristic in subgroup analyses. Yet, it is unclear to what extent individual patients, characterized by a combination of clinical characteristics, may benefit from HDF. This study aimed to develop and internally validate a treatment effect prediction model to determine which individual patients would benefit most from well dosed HDF, compared with haemodialysis (HD), in terms of survival. Method Individual participant data from five randomized controlled trials (CONTRAST, ESHOL, Turkish HDF study, French HDF study, CONVINCE) comparing HDF with HD on all-cause mortality were used to derive a Royston-Parmar model for exploring the prediction of absolute treatment effect of HDF based on pre-specified patient and disease characteristics, notably age, sex, body mass index, diabetes mellitus, history of cardiovascular disease, creatinine levels, and c-reactive protein levels. Internal validation of the model was performed using internal-external cross validation. Results Among 4153 participants, with a median follow-up of 30 months (Q1-Q3: 24-36), death from any cause occurred in 558 patients (27.2%). The median predicted survival benefit of HDF compared with HD was 6.9 (Q1–Q3: 5.6–9.0) months, with a range of 2 to 42 months. Patients who were predicted to benefit most from HDF were younger, less likely to have diabetes or a cardiovascular history and had higher serum creatinine levels. Internal-external cross validation showed adequate discrimination and calibration. Conclusion All-cause mortality is reduced by HDF compared with HD in ESKD patients. Yet, the absolute survival benefit seems to considerably differ between individual patients. Our results suggest that the effects of HDF on absolute survival can be predicted accurately using a combination of readily available patient and disease characteristics. This prediction model approach exemplifies the potential of prediction algorithms in supporting clinical decision-making for the choice of treatment options. Validation and potential updates to the presented algorithm are necessary, along with a preferable randomized evaluation of its clinical impact before widespread implementation.

#1418 Phase II dose-selection, randomised, controlled trial of ASi BI 690517 with and without EMPA in CKD: subgroup analysis by T2D status

Abstract Background and Aims High aldosterone levels accelerate chronic kidney disease (CKD) progression. BI 690517 is a highly selective aldosterone synthase inhibitor (ASi) in clinical development for CKD treatment. ASi may reduce deleterious haemodynamic, inflammatory, and fibrotic actions of aldosterone. Coadministration of BI 690517 with a sodium-glucose cotransporter-2 inhibitor may also mitigate the risk of hyperkalaemia. This multinational, randomised, dose-finding, Phase II trial (NCT05182840) investigated the efficacy and safety of BI 690517, given either alone or in combination with empagliflozin (EMPA), in people who had CKD with or without type 2 diabetes (T2D) [1, 2]. Here, we present an analysis by T2D status (pooled for background randomizedon to EMPA or placebo [PBOEMPA]). Method Adults with CKD receiving a maximally tolerated dose of a renin-angiotensin system inhibitor were randomized (R1) 1:1 to an 8-week run-in to receive background EMPA 10 mg or PBOEMPA, then randomized again (R2) 1:1:1:1 to receive BI 690517 (3 mg, 10 mg, or 20 mg) or PBOASI for 14 weeks. The primary endpoint was the change from R2 baseline in urine albumin:creatinine ratio (UACR) in the first morning void of urine at Week 14. A secondary endpoint was UACR response (≥30% reduction from R2 baseline in UACR at Week 14). Changes in systolic blood pressure (SBP) and estimated glomerular filtration rate (eGFR) from R2 baseline to Week 14 were also assessed, as were safety outcomes. Results Of 586 people randomized at R2, 414 (70.6%) were reported to have T2D and 172 (29.4%) did not have T2D. Baseline demographics and clinical characteristics were mostly similar between these two groups [1]; however, those with T2D had higher mean BMI (30.6 vs 28.3 kg/m2), SBP (135.3 vs 130.2 mmHg) and eGFR (53.0 vs 49.4 mL/min/1.73 m2), and higher median UACR (444.7 vs 409.2 mg/g) than those without T2D. BI 690517 consistently reduced UACR versus PBOASI in people with and without T2D (p = 0.38, indicating no difference in treatment effect between these groups), with the largest reductions observed in the 10 mg and 20 mg dose groups; however, for the 3 mg dose group, UACR reduction was only observed in people with T2D (Figure). UACR response rates (≥30% reduction) were achieved in more than half of people with and without T2D in the BI 690517 10 mg and 20 mg dose groups, with the highest response rates in those also receiving EMPA (10 mg dose group: with T2D, 74.3%; without T2D, 64.0%). Decreases in SBP and small decreases in eGFR were also observed in people with and without T2D in response to BI 690517 10 mg and 20 mg, and were consistent with the observed changes in the overall population; however, for the 3 mg dose group, eGFR reduction was only observed in people with T2D. Adverse events leading to discontinuation in BI 690517 10 mg and 20 mg dose groups were more common among people with T2D than those without T2D who were receiving the same dose of BI 690517. Conclusion In people who had CKD, with or without T2D, BI 690517 dose-dependently reduced UACR, with high rates of UACR response suggestive of additive beneficial effects when given with EMPA.

#2119 Long-term efficacy of tolvaptan therapy in patients with ADPKD

Abstract Background and Aims Currently, the only available therapy to ameliorate disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) is tolvaptan, a vasopressin V2 receptor antagonist. Real-life data on tolvaptan treatment effect is sparce, with several limitations including restricted follow-up, relatively small patient groups, no control groups, or only data reported on kidney function without total kidney volume. We studied, therefore, the long-term effect of tolvaptan on kidney function as well as kidney growth in a relatively large number of real-life ADPKD patients and controls. Moreover, we investigated the effect of salt and protein intake on long-term treatment efficacy. Method Data from two national ADPKD cohorts were pooled. Kidney function (creatinine-based eGFR) was measured at least yearly and total kidney volume (TKV, measured by MRI or CT) at least 3-yearly. Salt and protein intake were measured by 24 h urine excretion. To investigate the long-term effects of tolvaptan we assessed change in eGFR and TKV before as well as after start of tolvaptan using linear mixed effects models. For this purpose, we excluded the acute treatment effect from start to 6 months after initiation of tolvaptan. As a control group, we included all patients who were not treated with tolvaptan, assessing change in eGFR and TKV before and after the theoretical start of treatment (based on the average time of tolvaptan initiation observed in the tolvaptan-treated group) as well as a matched control group. Subgroup analyses of salt and protein intake were based on the median urinary excretion of sodium or urea. Results 697 patients (47 ± 12 years, 59.1% female) were included, of which 104 patients used tolvaptan. Mean duration of tolvaptan use was 6.0 ± 4.5 years (range: 0.8 to 15.6). Tolvaptan use reduced yearly eGFR decline by 17.4% (−4.43 to −3.66 mL/min/1.73 m2/year, p = 0.03, number of measurements: n = 817), whereas in the non-tolvaptan control group after the theoretical start of treatment, eGFR decline increased by 13.3% (−1.95 to −2.21 mL/min/1.73 m2/year, p = 0.2, n = 2804). Long-term TKV growth did not change after start of tolvaptan treatment (4.90 to 5.53%/year, p = 0.5, n = 316). Similar results were obtained in the matched control group. A more substantial treatment effect of tolvaptan on eGFR slope was noted in patients with high compared to low salt intake (assessed as ≥ versus &amp;lt; median urinary sodium excretion of 146 mmol/24 h (difference 1.62 (0.22 to 3.02) mL/min/1.73 m2/year, p = 0.02). Subgroup analysis according to median protein intake did not show a significant difference in tolvaptan treatment effect. Conclusion In this study, with real-life patient data, long-term follow-up, and a control group, we found that tolvaptan attenuated long-term kidney function decline but, notably, did not influence kidney growth. Higher daily salt intake was associated with a more substantial tolvaptan treatment effect, perhaps due to higher vasopressin levels before treatment, and consequently more vasopressin antagonism by tolvaptan.

Music Therapy in Infancy and Neurodevelopmental Outcomes in Preterm Children

Preterm children are at risk for neurodevelopment impairments. To evaluate the effect of a music therapy (MT) intervention (parent-led, infant-directed singing) for premature children during the neonatal intensive care unit (NICU) stay and/or after hospital discharge on language development at 24 months' corrected age (CA). This predefined secondary analysis followed participants in the LongSTEP (Longitudinal Study of Music Therapy's Effectiveness for Premature Infants and Their Caregivers) randomized clinical trial, which was conducted from August 2018 to April 2022 in 8 NICUs across 5 countries (Argentina, Colombia, Israel, Norway, and Poland) and included clinic follow-up visits and extended interventions after hospital discharge. Participants were children born preterm (<35 weeks' gestation) and their parents. Participants were randomized at enrollment to MT with standard care (SC) or SC alone; they were randomized to MT or SC again at discharge. The MT was parent-led, infant-directed singing tailored to infant responses and supported by a music therapist and was provided 3 times weekly in the NICU and/or in 7 sessions across 6 months after discharge. The SC consisted of early intervention methods of medical, nursing, and social services, without MT. Primary outcome was language development, as measured by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) language composite score, with the remaining BSID-III composite and subscale scores as the secondary outcomes. Group differences in treatment effects were assessed using linear mixed-effects models using all available data. Of 206 participants (103 female infants [50%]; mean [SD] GA, 30.5 [2.7] weeks), 51 were randomized to MT and 53 to SC at enrollment; at discharge, 52 were randomized to MT and 50 to SC. A total of 112 (54%) were retained at the 24 months' CA follow-up. Most participants (79 [70%] to 93 [83%]) had BSID-III scores in the normal range (≥85). Mean differences for the language composite score were -2.36 (95% CI, -12.60 to 7.88; P = .65) for the MT at NICU with postdischarge SC group, 2.65 (95% CI, -7.94 to 13.23; P = .62) for the SC at NICU and postdischarge MT group, and -3.77 (95% CI, -13.97 to 6.43; P = .47) for the MT group at both NICU and postdischarge. There were no significant effects for cognitive or motor development. This secondary analysis did not confirm an effect of parent-led, infant-directed singing on neurodevelopment in preterm children at 24 months' CA; wide CIs suggest, however, that potential effects cannot be excluded. Future research should determine the MT approaches, implementation time, and duration that are effective in targeting children at risk for neurodevelopmental impairments and introducing broader measurements for changes in brain development. ClinicalTrials.gov Identifier: NCT03564184.

Sociodemographic and patient reported outcomes by racial and ethnicity status among participants in a randomized controlled trial for methamphetamine use disorder

BackgroundThere has been a significant increase in methamphetamine use and methamphetamine use disorder (Meth UD) in the United States, with evolving racial and ethnic differences. ObjectivesThis secondary analysis explored racial and ethnic differences in baseline sociodemographic and clinical characteristics as well as treatment effects on a measure of substance use recovery, depression symptoms, and methamphetamine craving among participants in a pharmacotherapy trial for Meth UD. MethodsThe ADAPT-2 trial (ClinicalTrials.gov number, NCT03078075; N=403; 69% male) was a multisite, 12-week randomized, double-blind, trial that employed a two-stage sequential parallel design to evaluate the efficacy of combination naltrexone (NTX) and oral bupropion (BUP) vs. placebo for Meth UD. Treatment effect was calculated as the weighted mean change in outcomes in the NTX-BUP minus placebo group across the two stages of treatment. ResultsOf the 403 participants in the ADAPT-2 trial, the majority (65%) reported non-Hispanic White, while 14%, 11% and 10% reported Hispanic, non-Hispanic Black, and non-Hispanic other racial and ethnic categories respectively. At baseline non-Hispanic Black participants reported less severe indicators of methamphetamine use than non-Hispanic White. Treatment effects for recovery, depression symptoms and methamphetamine cravings did not significantly differ by race and ethnicity. ConclusionsAlthough we found racial and ethnic differences at baseline, our findings did not show racial and ethnic differences in treatment effects of NTX-BUP on recovery, depression symptoms and methamphetamine cravings. However, our findings also highlight the need to expand representation of racial and ethnic minority groups in future trials.

Sex differences in treatment effect in neuroprotectant trials for acute ischemic stroke: A systematic review

BackgroundPre-clinical data suggest sex differences in mechanisms of cerebral ischemic injury. This might result in differential outcomes of putative neuroprotectants by sex, though little systematic data is available to assess this. MethodsWe performed a systematic review of multicenter randomized controlled trials published from January 1980–June 2022 enrolling >100 subjects and testing neuroprotectants in acute ischemic stroke (AIS). For each trial, reported treatment effect by sex was extracted. When published results by sex were not available, we contacted individual authors to attempt to retrieve these data. ResultsWe identified 59 publications reporting 64 trials that met inclusion criteria. Of these, data on treatment effect by sex were published for 14/64 trials. Unpublished data for an additional 5 trials were obtained from trial investigators (19/64, or 29.7%). Two trials (one testing uric acid and one dexborneol) reported treatment benefit in women but not men. Pooled analysis of six trials of tirilazad reported worse treatment outcomes in women and no effect in men. No clear difference was apparent in the other trials. ConclusionsMost trials did not report treatment effect by sex. Of those that did, there was little evidence of systematic sex differences in treatment response.

Regional Differences in Outcomes with Ablation Versus Drug Therapy for Atrial Fibrillation: Results from the CABANA Trial

The finding of unexpected variations in treatment benefits by geographic region in international clinical trials raises complex questions about the interpretation and generalizability of trial findings. We observed such geographical variations in outcome and in the effectiveness of atrial fibrillation (AF) ablation versus drug therapy in the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial. This paper describes these differences and investigates potential causes. The examination of treatment effects by geographic region was a prespecified analysis. CABANA enrolled patients from 10 countries, with 1,285 patients at 85 North American (NA) sites and 919 at 41 non-NA sites. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Death and first atrial fibrillation recurrence were secondary endpoints. At least 1 primary endpoint event occurred in 157 patients (12.2%) from NA and 33 (3.6%) from non-NA sites over a median 54.9 and 40.5 months of follow-up, respectively (NA/non-NA adjusted hazard ratio (HR) 2.18, 95% confidence interval (CI) 1.48-3.21, P < .001). In NA patients, 78 events occurred in the ablation and 79 in the drug arm, (HR 0.91, 95% CI 0.66, 1.24) while 11 and 22 events occurred in non-NA patients (HR 0.51, 95% CI 0.25,1.05, interaction P = .154). Death occurred in 53 ablation and 51 drug therapy patients in the NA group (HR 0.96, 95% CI 0.65,1.42) and in 5 ablation and 16 drug therapy patients in the non-NA group (HR 0.32, 95% CI 0.12,0.86, interaction P = .044). Adjusting for baseline regional differences or prognostic risk variables did not account for the regional differences in treatment effects. Atrial fibrillation recurrence was reduced by ablation in both regions (NA: HR 0.54, 95% CI 0.46, 0.63; non-NA: HR 0.44, 95% CI 0.30, 0.64, interaction P = .322). In CABANA, primary outcome events occurred significantly more often in the NA group but assignment to ablation significantly reduced all-cause mortality in the non-NA group only. These differences were not explained by regional variations in procedure effectiveness, safety, or patient characteristics. ClinicalTrials.gov Identifier: NCT0091150; https://clinicaltrials.gov/study/NCT00911508.

ANALYSIS FOR MULTIPLE RESPONSES IN A COMPLETELY RANDOMIZED EXPERIMENTAL DESIGN

Multiple responses are often generated in agricultural and forestry research. For example, the moisture content, fatty acids, carbohydrates, size, diameter, length, shape and hardness, among other characteristics are measured to cottonseed. Of course, multiple responses are observed in many other areas of research. Multivariate analysis of variance (MANOVA) can be useful for multiple response analysis when differences in treatment effects are to be determined. However, the performance of current post hoc tests in this context is not satisfactory due to the limitations of the available methods, or because they are difficult to use for non-statistician researchers. Furthermore, this methodology requires the assumptions of multivariate normality and homogeneity of variance and covariance matrices, assumptions that are difficult to verify if the sample size is small. This research proposes an alternative analysis to test the hypothesis of equality of effects between treatments and post hoc tests in the case of multiple responses. An asymptotic result is demonstrated for the random variable generated in the proposal for the case of uncorrelated normal variables and the case for correlated normal random variables is left open. A simulation study shows that the performance of the proposal with small samples is satisfactory in terms of power and that it has advantages compared to MANOVA. Furthermore, the methodological approach allows for post hoc testing in the case of multiple responses in the completely randomized experimental design.

Efficacy of ravulizumab in patients with generalized myasthenia gravis by time from diagnosis: A post hoc subgroup analysis of the CHAMPION MG study.

The CHAMPION MG study demonstrated that ravulizumab significantly improved Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores versus placebo in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ gMG). This post hoc analysis aimed to assess these outcomes by time from MG diagnosis. Changes from baseline to week 26 in MG-ADL and QMG total scores were analyzed by time from MG diagnosis to study entry (≤2 vs. >2 years). Within each subgroup, least-squares (LS) mean changes for ravulizumab and placebo were compared using mixed models for repeated measures. In ravulizumab-treated patients, differences in LS mean (standard error of the mean) changes from baseline to week 26 were not statistically significant in the ≤2-years subgroup versus the >2-years subgroup for MG-ADL (-4.3 [0.70] vs. -2.9 [0.37]; p = .0511) or QMG (-4.3 [0.94] vs. -2.5 [0.50]; p = .0822) scores. No clear trends were observed in the placebo group. LS mean changes from baseline were significantly greater for ravulizumab versus placebo in both the ≤2 and >2 years from diagnosis subgroups for MG-ADL and QMG scores (all p < .05). The difference in treatment effect between the ≤2-years and >2-years subgroups was not statistically significant. No clinically meaningful between-subgroup differences in treatment-emergent adverse events were observed in ravulizumab-treated patients. Ravulizumab treatment improved clinical outcomes for patients with AChR+ gMG regardless of time from diagnosis. A numerical trend was observed favoring greater treatment effect with earlier versus later treatment after diagnosis. Further studies are required for confirmation.

A Comparison of the Impact of Pharmacological Treatments on Cardioversion, Rate Control, and Mortality in Data-Driven Atrial Fibrillation Phenotypes in Critical Care.

Critical care physicians are commonly faced with patients exhibiting atrial fibrillation (AF), a cardiac arrhythmia with multifaceted origins. Recent investigations shed light on the heterogeneity among AF patients by uncovering unique AF phenotypes, characterized by differing treatment strategies and clinical outcomes. In this retrospective study encompassing 9401 AF patients in an intensive care cohort, we sought to identify differences in average treatment effects (ATEs) across different patient groups. We extract data from the MIMIC-III database, use hierarchical agglomerative clustering to identify patients' phenotypes, and assign them to treatment groups based on their initial drug administration during AF episodes. The treatment options examined included beta blockers (BBs), potassium channel blockers (PCBs), calcium channel blockers (CCBs), and magnesium sulfate (MgS). Utilizing multiple imputation and inverse probability of treatment weighting, we estimate ATEs related to rhythm control, rate control, and mortality, approximated as hourly and daily rates (%/h, %/d). Our analysis unveiled four distinctive AF phenotypes: (1) postoperative hypertensive, (2) non-cardiovascular mutlimorbid, (3) cardiovascular multimorbid, and (4) valvulopathy atrial dilation. PCBs showed the highest cardioversion rates across phenotypes, ranging from 11.6%/h (9.35-13.3) to 7.69%/h (5.80-9.22). While CCBs demonstrated the highest effectiveness in controlling ventricular rates within the overall patient cohort, PCBs and MgS outperformed them in specific phenotypes. PCBs exhibited the most favorable mortality outcomes overall, except for the non-cardiovascular multimorbid cluster, where BBs displayed a lower mortality rate of 1.33%/d [1.04-1.93] compared to PCBs' 1.68%/d [1.10-2.24]. The results of this study underscore the significant diversity in ATEs among individuals with AF and suggest that phenotype-based classification could be a valuable tool for physicians, providing personalized insights to inform clinical decision making.

Recurrent Hospitalizations and Response to Vericiguat in Heart Failure and Reduced Ejection Fraction

BackgroundIn VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction. ObjectivesThis study explored the association between vericiguat and recurrent hospitalizations and subsequent mortality after HF hospitalization. MethodsThe treatment effect of vericiguat on the burden of HF hospitalizations was evaluated by assessing total HF hospitalization and cardiovascular death in the overall trial and based on baseline N-terminal pro–B-type natriuretic peptide levels with and without adjustment for VICTORIA model covariates (ie, baseline variables associated with the primary endpoint) assessed via the Andersen-Gill method. Associations between vericiguat and recurrent hospitalization and mortality adjusted for VICTORIA model covariates are reported. ResultsThere were 1,222 total HF hospitalizations and cardiovascular deaths among 2,526 patients in the vericiguat group and 1,336 total events among 2,524 patients in the placebo group (unadjusted HR: 0.89 [95% CI: 0.81-0.97] and adjusted HR: 0.92 [95% CI: 0.84-1.01]). In the subgroup with N-terminal pro–B-type natriuretic peptide levels ≤2,816 pg/mL (ie, Q1 and Q2; median or below), there was a suggestion of a benefit with vericiguat (adjusted HRs of 0.80 [95% CI: 0.64-1.01] and 0.77 [95% CI: 0.62-0.94], respectively) compared with those above this value (adjusted HRs of 1.12 [95% CI: 0.93-1.34] and 0.87 [95% CI: 0.74-1.04] for Q3 and Q4). There was no significant difference in treatment effect between patients with vs without an HF hospitalization. After HF hospitalization, the all-cause mortality rate (events per 100 patient-years) was 48.6 for vericiguat and 44.1 for placebo. ConclusionsAdditional investigation of the association between vericiguat and cardiovascular death and total HF hospitalizations by recurrent event analysis did not show a statistically significant reduction in events. Mortality was high after HF hospitalization, emphasizing the need for further therapies to reduce morbidity and mortality. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)

Bayesian meta-analysis for evaluating treatment effectiveness in biomarker subgroups using trials of mixed patient populations.

During drug development, evidence can emerge to suggest a treatment is more effective in a specific patient subgroup. Whilst early trials may be conducted in biomarker-mixed populations, later trials are more likely to enroll biomarker-positive patients alone, thus leading to trials of the same treatment investigated in different populations. When conducting a meta-analysis, a conservative approach would be to combine only trials conducted in the biomarker-positive subgroup. However, this discards potentially useful information on treatment effects in the biomarker-positive subgroup concealed within observed treatment effects in biomarker-mixed populations. We extend standard random-effects meta-analysis to combine treatment effects obtained from trials with different populations to estimate pooled treatment effects in a biomarker subgroup of interest. The model assumes a systematic difference in treatment effects between biomarker-positive and biomarker-negative subgroups, which is estimated from trials which report either or both treatment effects. The systematic difference and proportion of biomarker-negative patients in biomarker-mixed studies are used to interpolate treatment effects in the biomarker-positive subgroup from observed treatment effects in the biomarker-mixed population. The developed methods are applied to an illustrative example in metastatic colorectal cancer and evaluated in a simulation study. In the example, the developed method improved precision of the pooled treatment effect estimate compared with standard random-effects meta-analysis of trials investigating only biomarker-positive patients. The simulation study confirmed that when the systematic difference in treatment effects between biomarker subgroups is not very large, the developed method can improve precision of estimation of pooled treatment effects while maintaining low bias.

Frontloading Home Physical Therapy Visits for Patients With Heart Failure: A Multi-center Randomized Controlled Trial.

Frontloading home care visits has been found to be effective in the nursing profession but has not been investigated in physical therapy (PT) practice. This study aimed to examine the impact of frontloading home PT visits on function in persons with heart failure (HF). This was a prospective multi-center randomized controlled trial with blinded raters. A total of 82 ambulatory patients with a primary diagnosis of HF discharged from an acute care facility to home care participated in the study. Subjects were randomly allocated to an experimental frontloaded group (FLG) or control group (CG) for 4 weeks. FLG visit frequencies were five sessions per week for 2 weeks, and three sessions per week for 2 weeks. The CG received two sessions per week for 4 weeks. Functional measures including the 2-minute step test (2MST), 2-minute walk test (2MWT), gait speed (GS), Timed Up and Go (TUG), and 30-second chair rise test (30-CRT) were collected at the onset of care, at the end of 2 weeks and 4 weeks. The groups were statistically similar at baseline for all measures. All subjects significantly improved scores in all functional measures over time, within-subject main effect (p < .01). Significant between-subject effects were noted for 30-CRT (p = .04). Interaction effects were noted for GS (p = .03) and TUG test (p = .02). This is the first study to report meaningful improvements in function in individuals with HF. Significant treatment effect differences between the FLG and CG were found for GS, TUG, and 30-CRT. Future studies should examine the use of a standardized intervention to validate the effectiveness of frontloading home visits on quality of life and readmission rates.

Frontloading Home Physical Therapy Visits for Patients With Heart Failure: A Multi-center Randomized Controlled Trial.

Frontloading home care visits has been found to be effective in the nursing profession but has not been investigated in physical therapy (PT) practice. This study aimed to examine the impact of frontloading home PT visits on function in persons with heart failure (HF). This was a prospective multi-center randomized controlled trial with blinded raters. A total of 82 ambulatory patients with a primary diagnosis of HF discharged from an acute care facility to home care participated in the study. Subjects were randomly allocated to an experimental frontloaded group (FLG) or control group (CG) for 4 weeks. FLG visit frequencies were five sessions per week for 2 weeks, and three sessions per week for 2 weeks. The CG received two sessions per week for 4 weeks. Functional measures including the 2-minute step test (2MST), 2-minute walk test (2MWT), gait speed (GS), Timed Up and Go (TUG), and 30-second chair rise test (30-CRT) were collected at the onset of care, at the end of 2 weeks and 4 weeks. The groups were statistically similar at baseline for all measures. All subjects significantly improved scores in all functional measures over time, within-subject main effect (p < .01). Significant between-subject effects were noted for 30-CRT (p = .04). Interaction effects were noted for GS (p = .03) and TUG test (p = .02). This is the first study to report meaningful improvements in function in individuals with HF. Significant treatment effect differences between the FLG and CG were found for GS, TUG, and 30-CRT. Future studies should examine the use of a standardized intervention to validate the effectiveness of frontloading home visits on quality of life and readmission rates.

Comparison of initial percutaneous balloon compression versus radiofrequency thermocoagulation followed by percutaneous balloon compression in the treatment of trigeminal neuralgia.

There are a variety of minimally invasive interventional treatments for trigeminal neuralgia, and the efficacy evaluation is different. The preferred treatment scheme is still controversial. This study aims to investigate the differences in treatment effects between patients with primary trigeminal neuralgia (PTN) treated with percutaneous balloon compression (PBC) for the first intervention and patients with pain recurrence after radiofrequency thermocoagulation (RT) who then received PBC for PTN, and to offer clinicians and patients more scientifically grounded and precise treatment alternatives. We retrospectively analyzed 103 patients with PTN admitted to the Department of Pain Management of the Second Affiliated Hospital of Guangxi Medical University from January 2020 to December 2021, including 49 patients who received PBC for the first time (PBC group) and 54 patients who received PBC for pain recurrence after RT (RT+PBC group). General information, preoperative pain score, intraoperative oval foramen morphology, oval foramen area, balloon volume, duration of compression, and postoperative pain scores and pain recurrence at each time point on day 1 (T1), day 7 (T2), day 14 (T3), 1 month (T4), 3 months (T5), and 1 year (T6) were collected and recorded for both groups. The differences in treatment effect, complications and recurrence between the 2 groups were compared, and the related influencing factors were analyzed. The differences of general information, preoperative pain scores, foramen ovale morphology, foramen ovale area, T1 to T3 pain scores between the 2 groups were not statistically different (all P>0.05). The balloon filling volume in the PBC group was smaller than that in the RT+PBC group, the pain scores at T4 to T6 and pain recurrence were better than those in the RT+PBC group (all P<0.05). Pain recurrence was positively correlated with pain scores of T2 to T6 (r=0.306, 0.482, 0.831, 0.876, 0.887, respectively; all P<0.01). The choice of PBC for the first intervention in PTN patients is superior to the choice of PBC after pain recurrence after RT treatment in terms of treatment outcome and pain recurrence.