Relative Treatment Effects Research Articles

Effects of maxillofacial prosthetic treatment on oral health-related quality of life and masticatory ability of patients with head and neck tumors.

Using multivariate analysis, this study investigated the effectiveness of maxillofacial prosthetic treatment in relation to oral health-related quality of life (OHR-QoL), masticatory ability (food intake status score and gum-jelly test score) and related factors in patients who had undergone surgery for head and neck tumors. The study cohort comprised 112 patients who underwent surgical resection and prosthetic treatment among 224 patients with head and neck tumors seen at the Maxillofacial Prosthetics Clinic of Tohoku University Hospital in a 2-year period. Correlations between OHR-QoL, food intake status score, and gum-jelly test score (criterion variables), and age, sex, maxillary defect, tongue/soft tissue defect, reconstructive surgery, and chemoradiotherapy (explanatory variables) were investigated, and the data were examined statistically. Maxillary defect, tongue and soft palate tissue defect, and chemoradiotherapy were identified as factors that hindered the effectiveness of maxillofacial prosthetic treatment for improvement of the OHR-QoL, food intake status score, and gum-jelly test score. On the other hand, reconstructive surgery was a factor that facilitated the improvement of OHR-QoL and masticatory ability with maxillofacial prosthetic treatment. The factors identified to be related to the success or failure of maxillofacial prosthetic treatment suggest the importance of combining prosthetic intervention with surgical reconstruction.

Relative effects of melatonin and hydrogen sulfide treatments in mitigating salt damage in wheat.

Soil salinity poses a significant threat to agricultural productivity, impacting the growth and yield of wheat (Triticum aestivum L.) plants. This study investigates the potential of melatonin (MT; 100 µM) and hydrogen sulfide (H2S; 200 µM sodium hydrosulfide, NaHS) to confer the tolerance of wheat plants to 100 mM NaCl. Salinity stress induced the outburst of reactive oxygen species (ROS) resulting in damage to the chloroplast structure, growth, photosynthesis, and yield. Application of either MT or NaHS augmented the activity of antioxidant enzymes, superoxide dismutase, ascorbate peroxidase, glutathione reductase, and reduced glutathione (GSH) levels, upregulated the expression of Na+ transport genes (SOS1, SOS2, SOS3, NHX1), resulting in mitigation of salinity stress. Thus, improved stomatal behavior, gas-exchange parameters, and maintenance of chloroplast structure resulted in enhanced activity of the Calvin cycle enzymes and overall enhancement of growth, photosynthetic, and yield performance of plants under salinity stress. The use of DL-propargylglycine (PAG, an inhibitor of hydrogen sulfide biosynthesis) and p-chlorophenyl alanine (p-CPA, an inhibitor of melatonin biosynthesis) to plants under salt stress showed the comparative necessity of MT and H2S in mitigation of salinity stress. In the presence of PAG, more pronounced detrimental effects were observed than in the presence of p-CPA, emphasizing that MT was involved in mitigating salinity through various potential pathways, one of which was through H2S.

Digital Cloning of the Dead: Exploring the Optimal Default Rule

Abstract We conducted a survey experiment in the U.S. to analyze how the consent or dissent of a deceased individual influences the social acceptability of digital resurrection. The results showed a substantial relative treatment effect of consent versus dissent, with a 2-point difference in acceptability on a 5-point scale. When the deceased had consented, 58 % of respondents viewed digital resurrection as socially acceptable, whereas this number was only 3 % when the deceased had dissented. These findings suggest that relevant legal regulations should respect the decision of the deceased. Our study then explored the optimal default rule using observational research: 59 % of respondents were against the idea of their own digital resurrection. An opt-in rule seems socially desirable, where the default is the prohibition of digital resurrection, and exceptions allow it only with consent from the deceased.

Translating trial results into interpretable risk estimates: Systematic analysis of cardiorenal outcome trials of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors

Background and aimsIn a randomised controlled trial (RCT), the between-arm difference in the average probability of an event per unit of time (i.e., yearly incidence risk difference, YIRD) is an easy-to-interpret treatment effect metric. We aimed to quantify the YIRD in cardiorenal RCTs of GLP-1RAs or SGLT-2is. Methods and resultsWe digitally searched for RCTs published up to March 1st, 2023, including subjects with type 2 diabetes randomised to GLP-1RAs or SGLT-2is and investigating cardiorenal outcomes or death. We extracted information from Kaplan-Meier (KM) plots to obtain time-to-event individual data and estimate within-arm yearly incidence risk and YIRD. Data from 19 RCTs (28 kM plots) were analysed: comparing treatment to placebo, in GLP-1RA RCTs the YIRD ranged from 0.2 % (95 % CI: −0.7 %, 1.1 %) to −1.9 % (−3.1, −0.7), for primary outcome; and from −0.2 % (−0.5, 0.2) to −0.4 % (−0.7 %, −0.0 %), for mortality. With the exception of SOLOIST-WHF (YIRD 11.9 % for primary outcome), corresponding estimates in SGLT-2is RCTs were: from −0.1 % (−0.4, 0.1) to −5.0 % (−7.7, −2.6), for primary outcome; and from −0.1 % (−0.2, 0.1) to −1.9 % (−4.4 %, 0.6 %), for mortality. ConclusionThe YIRD metric complements other relative treatment effect estimates and helps quantify the absolute benefit of GLP-1RAs and SGLT-2is.

Clinical Presentations and Treatment Outcomes of Mycoplasma genitalium Infections at a Large New York City Health Care System.

Mycoplasma genitalium (MG) is an emerging sexually transmitted infection. Treatment of MG is complicated by increasing resistance to primary treatment regimens, including macrolides and fluoroquinolones. Understanding the various clinical presentations and relative effectiveness of treatments for MG is crucial to optimizing care. Patients with a positive MG nucleic acid amplification test between July 1, 2019, and June 30, 2021, at a large health system in New York City were included in a retrospective cohort. Demographics, clinical presentations, coinfections, treatment, and follow-up microbiologic tests were obtained from the electronic medical record. Associations with microbiologic cure were evaluated in bivariate and multivariable logistic regression models. Five hundred two unique patients had a positive MG nucleic acid amplification test result during the study period. Male individuals presented predominantly with urethritis (117 of 187 [63%]) and female individuals with vaginal symptoms (142 of 315 [45%]). Among patients with follow-up testing who received a single antibiotic at the time of treatment, 43% (90 of 210) had persistent infection and 57% (120 of 210) had microbiologic cure. Eighty-two percent of patients treated with moxifloxacin had microbiologic cure compared with 41% of patients receiving azithromycin regimens ( P < 0.001). In multivariable analysis, treatment with moxifloxacin was associated with 4 times the odds of microbiologic cure relative to low-dose azithromycin (adjusted odds ratio [aOR], 4.18; 95% confidence interval, 1.73-10.13; P < 0.01). Clinical presentations of MG vary, with urethritis or vaginal symptoms in most cases. Among patients who received a single antibiotic, only treatment with moxifloxacin was significantly associated with microbiologic cure relative to low-dose azithromycin.

Effects of tissue heterogeneity and comparisons of collapsed cone and Monte Carlo fast neutron patient dosimetry using the University of Washington clinical neutron therapy system (CNTS)

Fast neutron therapy is a high linear energy transfer (LET) radiation treatment modality offering advantages over low LET radiations. Multileaf collimator technology reduces normal-tissue dose (toxicity) and makes neutron therapy more comparable to MV x-ray treatments. Published clinical-trial and other experiences with fast neutron therapy are reported. Early comparative studies failed to consider differences in target-dose spatial conformality between x-ray and neutron treatments, which is especially important for organs-at-risk close to tumor targets. Treatments planning systems (TPS) for high-energy neutrons lag behind TPS tools for MV x-rays, creating challenges for comparative studies of clinical outcomes. A previously published Monte Carlo model of the University of Washington (UW) Clinical Neutron Therapy System (CNTS) is refined and integrated with the RayStation TPS as an external dose planning/verification tool. The collapsed cone (CC) dose calculations in the TPS are based on measured dose profiles and output factors in water, with the absolute dose determined using a tissue-equivalent ionization chamber. For comparison, independent (external) Monte Carlo simulation computes dose on a voxel-by-voxel basis using an atlas that maps Hounsfield Unit (HU) numbers to elemental composition and density. Although the CC algorithm in the TPS accurately computes neutron dose to water compared to Monte Carlo calculations, calculated dose to water differs from bone or tissue depending largely on hydrogen content. Therefore, the elemental composition of tissue and bone, rather than the material or electron density, affects fast neutron dose. While the CC algorithm suffices for reproducible patient dosimetry in fast neutron therapy, adopting methods that consider tissue heterogeneity would enhance patient-specific neutron dose accuracy relative to national standards for other types of ionizing radiation. Corrections for tissue composition have a significant impact on absolute dose and the relative biological effectiveness (RBE) of neutron treatments compared to other radiation types (MV x-rays, protons, and carbon ions).

P75: Using music to reduce depressive symptoms among nursing home residents: Preliminary results of a Bayesian Network Meta-Analysis of Randomized Controlled Trials

Objective:Reviews show that music interventions may be effective in reducing depressive symptoms among nursing home residents. Since interventions use various ways to include music, results on the effectiveness on depressive symptoms are often inconsistent. A previous review found that receptive music interventions (e.g., music listening) are more effective than active music interventions to reduce depressive symptoms among nursing home residents. Other research suggest that active music interventions (e.g., playing instruments, dancing) are more effective. Moreover, therapists seem to prefer using active music interventions. Because of its low costs, the previously found effectiveness and low side effects, it is important to gain more insight into components specific to the intervention that may contribute to its effectiveness in reducing depressive symptoms. This insight may help to fine-tune interventions and develop treatment protocols.Method:A Bayesian Network Meta-analysis was conducted to calculate the relative effectiveness of interventions including music. In addition, different network-meta-regression analyses were conducted to explorer components that may contribute to the effectiveness of the included studies.Results:Our search strategy resulted in N=22 eligible Randomized Controlled Trials (RCT), that included music in the reported interventions. Compared to Care as Usual, a multidisciplinary approach including music was the most effective (MD=-0.92, 95% CrI -2.8 to 0.97), followed by music interventions focused on sensory stimulation (MD=-0.43, 95% CrI -1.1 to 0.19), music interventions with reminiscence (MD=-0.38, 95% CrI -1.2 to 0.45) and cognitive interventions with music (MD=-0.31, 95% CrI -2.0 to 1.40). Level of depression (ƅ=-0.88, CrI 95% [-1.81 to 0.06]), and being physical dependent (ƅ=-0.29, CrI 95% [-1.20 to 0.61]), moderated the effectiveness of interventions, although this was not significant. We did not found any difference between active and receptive music interventions.Conclusion:In the constructed network, interventions that included music, were not more effective in reducing depressive symptoms among nursing home residents when compared to the care as usual group. However, some subgroups seem to benefit more from music than others. To gain more insight in the effectiveness of music in reducing depressive symptoms, more research is needed, targeting those specific target groups.

Applying Trial-Derived Treatment Effects to Real-World Populations: Generalizing Cost-Effectiveness Estimates When Modeling Complex Hazards

ObjectivesGeneralizability of trial-based cost-effectiveness estimates to real-world target populations is important for decision making. In the context of independent aggregate time-to-event baseline and relative effects data, complex hazards can make modeling of data for use in economic evaluation challenging. Our article provides an overview of methods that can be used to apply trial-derived relative treatment effects to external real-world baselines when faced with complex hazards and follows with a motivating example. MethodsApproaches for applying trial-derived relative effects to real-world baselines are presented in the context of complex hazards. Appropriate methods are applied in a cost-effectiveness analysis using data from a previously published study assessing the real-world cost-effectiveness of a treatment for carcinoma of the head and neck as a motivating example. ResultsLack of common hazards between the trial and target real-world population, a complex baseline hazard function, and nonproportional relative effects made the use of flexible models necessary to adequately estimate survival. Assuming common distributions between trial and real-world reference survival substantially affected survival and cost-effectiveness estimates. Modeling time-dependent vs proportional relative effects affected estimates to a lesser extent, dependent on assumptions used in cost-effectiveness modeling. ConclusionsAppropriately capturing reference treatment survival when attempting to generalize trial-derived relative treatment effects to real-world target populations can have important impacts on cost-effectiveness estimates. A balance between model complexity and adequacy for decision making should be considered where multiple data sources with complex hazards are being evaluated.

Outcomes of direct-acting antivirals in patients with HCV decompensated cirrhosis: a systematic review and meta-analysis

BackgroundDirect-acting antivirals (DAA) are effective for chronic hepatitis C virus (HCV) treatment. However, their impact on overall survival (OS), hepatocellular carcinoma (HCC) occurrence, HCC-free survival, and liver function in patients with HCV decompensated cirrhosis remains uncertain. This study aimed to evaluate the effects of DAA treatment on this population.MethodsStudies were identified by searching the MEDLINE, SCOPUS, and CENTRAL databases. OS and HCC-free survival probabilities and time data were extracted from Kaplan-Meier curves. A one-stage meta-analysis using parametric Weibull regression was conducted to estimate the relative treatment effects of DAA vs. no DAA. The primary outcome was the OS rate. The secondary outcomes were HCC-free survival, HCC occurrence rate, and improvement in the Model for End-stage Liver Disease (MELD) score.ResultsEight cohorts comprising 3,430 participants (2,603 in the DAA group and 1,999 in the no-DAA group) were included. The OS probabilities at 12 and 24 months were 95 and 90% for the DAA group, respectively, compared with 89 and 80% in the no-DAA group, respectively. Hazard ratio (HR) was 0.48 (95% confidence interval (CI): 0.39, 0.60; p &amp;lt; 0.001). The HCC-free survival probabilities at 12 and 24 months were 96 and 90%, respectively, in the former, and 94 and 85%, respectively, in the latter. The HR of HCC occurrence was 0.72 (95% CI: 0.52, 1.00; p = 0.05), which suggests that DAA treatment in decompensated cirrhosis may lead to a 28% lower risk of HCC occurrence. The mean MELD score difference was −7.75 (95% CI: −14.52, −0.98; p = 0.02).ConclusionImprovement in OS and MELD score is a long-term benefit of DAA treatment in patients with HCV decompensated cirrhosis, with a marginal effect of the treatment on HCC development.

Zanubrutinib vs FCR in Fit Treatment-Naive Patients with Chronic Lymphocytic Leukemia: A Matching-Adjusted Indirect Comparison

Background: Fludarabine, cyclophosphamide, and rituximab (FCR) is the standard first-line therapy for fit (physically active, with no major health problems and normal renal function) treatment-naive patients with chronic lymphocytic leukemia (CLL) (Eichhorst et al. Ann Oncol. 2015). Due to the safety profile of FCR, including severe hematotoxicity, and severe infections, treatments with improved efficacy and safety are of interest (Hallek et al. Lancet. 2010; Fischer et al. Blood. 2016). Zanubrutinib, a highly specific and potent small-molecule inhibitor of Bruton tyrosine kinase, has been approved for treatment-naive patients with CLL. However, the comparative efficacy of zanubrutinib vs FCR in patients with CLL has not been investigated. Objective: The objective of this study was to determine the relative treatment effects of zanubrutinib vs FCR in fit treatment-naive patients with CLL. Methods: The CLL10 trial (NCT00769522; Eichhorst et al. Lancet Oncol. 2016) investigated FCR and bendamustine + rituximab (BR), while the SEQUOIA trial compared zanubrutinib to BR (NCT03336333; Tam et al. Lancet Oncol. 2022). Zanubrutinib and FCR were compared by means of an anchored matching-adjusted indirect comparison (MAIC) in which the BR arm of each trial served as a common comparator. Propensity score matching was conducted using patient-level data from SEQUOIA to adjust for differences between trial populations, per National Institute for Health and Care Excellence MAIC methods (Philippo et al. NICE DSU Technical Support Document 18. 2016). Progression-free survival (PFS), as assessed by the independent review committee, was then compared based on the matched patient populations. The selection of matching variables was based on literature review and consultation with clinical experts. As the indirect treatment comparison was anchored on the common comparator arm (BR), patient characteristics that are solely prognostic did not need to be incorporated. The core model included immunoglobulin heavy chain gene mutation, cytogenetic mutations (11q deletion), β2-microglobulin, Binet stage, and age. Geographic region, sex, creatinine clearance, Cumulative Illness Rating Scale (CIRS) score, Eastern Cooperative Oncology Group performance status (ECOG PS), and previous infections were tested in sensitivity analyses. Results: PFS was favorable with zanubrutinib vs FCR, and statistically significant differences were observed in the base case model (hazard ratio [HR], 0.41; 95% CI, 0.20-0.81; p-value=0.01). Sensitivity analyses showed significantly improved PFS with zanubrutinib when adding geographic region (HR, 0.43; 95% CI, 0.21-0.90; p-value=0.03), sex (HR, 0.44; 95% CI, 0.22-0.89; p-value=0.02), ECOG PS (HR, 0.30; 95% CI, 0.14-0.64; p-value&amp;lt;0.01), and previous infections (HR, 0.45; 95% CI, 0.22-0.93; p-value=0.03) to the base case set of matching variables. A sensitivity analysis incorporating CIRS (HR, 0.45; 95% CI, 0.16-1.24; p-value=0.12) showed only numerically favorable PFS with zanubrutinib, owing in part to the low effective sample size (ESS) in the expanded model. Similar results were obtained when creatinine clearance was added to the base case matching set of variables (HR, 0.52; 95% CI, 0.24-1.13; p-value=0.10). Conditional on the number of matching variables, ESS ranged from 174.1 in the core model to 64.05 in the analysis that included the CIRS score. Conclusion:Our findings suggest that zanubrutinib offers clinically meaningful benefits in PFS over FCR in fit treatment-naive patients with CLL. MAICs rely on reporting of relevant patient characteristics in published studies. In the current study, ZAP-70 methylation and TP53 mutation, which were considered treatment effect modifiers, were not reported in CLL10 and were not accounted for in the propensity model.

Estimating and visualising the trade-off between benefits and harms on multiple clinical outcomes in network meta-analysis

BackgroundThe relative treatment effects estimated from network meta-analysis can be employed to rank treatments from the most preferable to the least preferable option. These treatment hierarchies are typically based on ranking metrics calculated from a single outcome. Some approaches have been proposed in the literature to account for multiple outcomes and individual preferences, such as the coverage area inside a spie chart, that, however, does not account for a trade-off between efficacy and safety outcomes.We present the net-benefit standardised area within a spie chart, SAWIS to explore the changes in treatment performance with different trade-offs between benefits and harms, according to a particular set of preferences.MethodsWe combine the standardised areas within spie charts for efficacy and safety/acceptability outcomes with a value λ specifying the trade-off between benefits and harms. We derive absolute probabilities and convert outcomes on a scale between 0 and 1 for inclusion in the spie chart.ResultsWe illustrate how the treatments in three published network meta-analyses perform as the trade-off λ varies. The decrease of the SAWIS quantity appears more pronounced for some drugs, e.g. haloperidol. Changes in treatment performance seem more frequent when SUCRA is employed as outcome measures in the spie charts.ConclusionsSAWIS should not be interpreted as a ranking metric but it is a simple approach that could help identify which treatment is preferable when multiple outcomes are of interest and trading-off between benefits and harms is important.

Effects of icosapent ethyl on residual cardiovascular risk according to predicted baseline risk: results from REDUCE-IT

Abstract Background Icosapent ethyl is recommended by the ESC CVD Prevention Guidelines as one of the intensified prevention strategies to be considered in patients with established CVD and a high residual risk.[1] Treatment effects of icosapent ethyl may vary between individual patients. This study aimed to determine the relative and absolute treatment effects of icosapent ethyl according to baseline CVD risk. Methods Participants from the REDUCE-IT trial with established CVD were included (n = 5,785).[2] Baseline 5-year risk of major adverse cardiovascular events (MACE), defined here as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke was estimated using the ESC guideline-recommended SMART2 risk score.[3] Modification of the relative treatment effect of icosapent ethyl by baseline risk was assessed using a Cox proportional hazards model including a treatment-by-risk interaction. Next, relative treatment effects were derived stratified by quartiles of baseline risk. The observed 5-year absolute risk reduction (ARR) with icosapent ethyl within each risk quartile was assessed based on Kaplan-Meier estimates of the cumulative incidence of MACE. Results During a median follow-up of 4.8 years (interquartile range 3.2-5.3), 361 MACE events occurred in the icosapent ethyl group vs 489 in the placebo group (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.63-0.82). Mean predicted vs observed 5-year risk of MACE was 9.1% vs 10.2% in the first quartile (range 3.6-11.4%), 13.8% vs 14.6% in the second quartile (range 11.5-16.0%), 19.2% vs 19.5% in the third quartile (range 16.1-23.4%), and 33.4% vs 32.2% in the fourth quartile (range 23.5-83.0%). Icosapent ethyl significantly reduced MACE in all risk quartiles, with an HR (95% CI) of 0.62 (0.43-0.88), 0.66 (0.48-0.92), 0.69 (0.53-0.90), and 0.78 (0.63-0.96) respectively (p for treatment-by-risk interaction = 0.06). The 5-year ARR (95% CI) with icosapent ethyl increased across risk quartiles, i.e. was 5.3% (1.8-8.7%), 5.6% (1.9-9.4%), 7.4% (3.0-11.8%), and 10.8% (5.3-16.2%) respectively (Figure). This translates to a number needed to treat (NNT; 95% CI) of 19 (11-54), 18 (11-52), 14 (8-34), and 9 (6-19). Conclusions Among CVD patients with elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE in individuals with a low, moderate, and high baseline risk. Absolute treatment benefits are largest for patients at the highest risk, as reflected by the twofold increase in ARR and decrease in NNT in the highest as compared to the lowest risk quartile.Icosapent ethyl effect in risk quartiles

Course of the effects of LDL-cholesterol reduction on cardiovascular risk over time: a meta-analysis of 59 trials

Abstract Background Therapies lowering low-density lipoprotein cholesterol (LDL-c) are widely used to reduce cardiovascular disease (CVD) risk in patients with or at high risk of CVD. Therapy is usually continued lifelong, but whether the effects of LDL-c reduction remain stable over time is uncertain. This study aimed to establish the course of the relative treatment effects of LDL-c reduction on cardiovascular risk over time, i.e. treatment duration and age. Methods Randomized controlled trials (RCTs) of LDL-c lowering therapies were identified through a search in MEDLINE and EMBASE (1966-January 2023). RCTs of guideline-recommended therapies (i.e. statins, ezetimibe, and proprotein convertase subtilisin–kexin type 9 inhibitors [PCSK9i]) were selected for the primary analyses, with RCTs of other therapies included in sensitivity analyses. Random-effects meta-analyses were performed to establish the average relative risk (RR) for major vascular events (cardiovascular death, myocardial infarction or other acute coronary syndrome, coronary revascularization, or stroke) per 1 mmol/L LDL-c reduction. Course of the effects over time was assessed using random-effects meta-regression analyses for the association between follow-up duration, age, and the RR for major vascular events per 1 mmol/L LDL-c reduction. Analyses were also stratified for primary and secondary prevention. Results A total of 59 trials (26 statin trials, 2 ezetimibe trials, 3 statin/ezetimibe combination trials, 7 PCSK9i trials, and 21 other trials) were selected, including 394,989 participants and 49,642 major vascular events. Mean follow-up was 3.9 years (range 0.9-9.7), and age was 63.8 years (range 48.0-77.0). The average RR for major vascular events per 1 mmol/L LDL-c reduction was 0.78 (95% confidence interval [CI] 0.75-0.81), with slightly larger risk reductions in primary (RR 0.74; 95% CI 0.68-0.81) as compared to secondary prevention (RR 0.80; 95% CI 0.77-0.83). Follow-up duration was not associated with the RR for major vascular events (p = 0.615), with the meta-regression line showing a stable RR over follow-up time (RR for change per year 0.994; 95% CI 0.971-1.017). The RR for major vascular events increased (i.e. risk reduction decreased) with age in primary prevention (RR for change per 5 years 1.094; 95% CI 1.028-1.165; p = 0.018), but remained largely unchanged in secondary prevention (RR for change per 5 years 0.986; 95% CI 0.943-1.031; p = 0.533). Consistent results were found for statin trials only, and all trials combined. Conclusions The relative treatment effects of LDL-c reduction are stable over time in secondary prevention, but may decrease with age in primary prevention.Meta-analysisMeta-regression analyses

Matching-Adjusted Indirect Comparison (MAIC) of Brexucabtagene Autoleucel (Brexu-cel) and Pirtobrutinib in Patients with Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor (cBTKi)

Introduction: Patients with MCL often require multiple lines of therapy and exhibit a generally unfavorable prognosis, particularly following failure of cBTKi therapy. Therapies such as chimeric antigen receptor (CAR) T-cell therapies and non-covalent BTKi therapies have shown promise in improving outcomes. Brexu-cel (formerly known as KTE-X19) is the only CAR T-cell therapy approved in the US for R/R MCL based on results from a phase 2 multicenter, single-arm trial (ZUMA-2; NCT02601313) in patients with R/R MCL who had 1-5 prior therapies, including a BTKi. Pirtobrutinib, a highly selective, non-covalent BTKi, was recently approved in the US for treatment of R/R MCL after at least two lines of systemic therapy including a BTKi, based on ongoing results from a multicenter phase 1/2 study (BRUIN; NCT03740529). In the absence of a direct head-to-head trial comparing brexu-cel and pirtobrutinib, we performed an unanchored MAIC to estimate the relative treatment effects of these therapies in the post-BTKi setting for R/R MCL. Methods: Individual patient-level data were available for ZUMA-2 (N=68; 35.8 months median follow-up as of July 24, 2021 data cut-off) whereas study-level data were available for BRUIN (N=90 in the BTKi pre-treated cohort; 23.5 months median follow-up as of July 29, 2022 data cut-off). Longer-term overall survival (OS) data for ZUMA-2 from the July 23, 2022 data cut-off (46.1 months median follow-up) were available and used. Logistic propensity score models were used to weight the brexu-cel infused population from ZUMA-2 to match the aggregate baseline characteristics of the BTKi pre-treated cohort in BRUIN. These baseline characteristics represented clinically relevant prognostic factors which were pre-specified based on input from clinical experts and data availability. The base-case model incorporated the top five most pertinent factors, which were reported in at least 50% of patients in both trials: blastoid morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplantation. A sensitivity analysis additionally incorporated TP53 mutation (missing in &amp;gt;50% of patients in ZUMA-2 and BRUIN) and Ki-67 proliferation index (missing in &amp;gt;50% of patients in BRUIN). Several prognostic factors (response to prior BTKi therapy, response to last therapy, and duration on prior BTKi therapy) could not be considered due to not being reported for BRUIN. The effective sample size was calculated as a measure of the degree of precision after weighting, reflecting the extent of overlap in the distribution of covariates between the trial populations. Relative treatment effects were expressed as odds ratios or hazard ratios with 95% confidence intervals. Outcomes included objective response (ORR), complete response (CR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: In the base-case MAIC, a significant difference in the odds of ORR and CR in favor of brexu-cel versus pirtobrutinib was observed (Table 1). Similarly, brexu-cel demonstrated a significant improvement in PFS (Table 2). OS and DOR point estimates were in favor of brexu-cel when compared to pirtobrutinib, although not statistically significant. These findings were consistent with unadjusted naïve analyses as well as the sensitivity analyses including adjustment for TP53 mutation and Ki-67 proliferation index. Conclusions: While acknowledging the inherent limitations of an unanchored indirect comparison, our findings suggest that brexu-cel offers clinically and statistically significant efficacy benefits in terms of ORR, CR, and PFS compared to pirtobrutinib in patients with R/R MCL after prior cBTKi therapy. Both treatments were not statistically different in terms of OS and DOR although the estimated hazard ratios indicated a favorable trend for brexu-cel; however, given the relatively shorter follow-up and the high degree of censoring in BRUIN, an updated analysis incorporating longer follow-up data with more events from BRUIN could provide more reliable results. Although efforts were made to ensure a robust approach to the selection of prognostic factors for inclusion in the model, the possibility of some residual confounding variables cannot be completely ruled out. Nevertheless, these results provide valuable insights that may help inform treatment decisions for this population.

Semi-automated assessment of the risk of bias due to missing evidence in network meta-analysis: a guidance paper for the ROB-MEN web-application

Network meta-analysis compares multiple interventions and estimates the relative treatment effects between all interventions, combining both direct and indirect evidence. Recently, a framework was developed to assess the Risk Of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) which is part of the more comprehensive framework to evaluate the Confidence In the evidence for Network Meta-Analysis (CINeMA). To produce an overall risk of bias judgement for each network estimate, ROB-MEN: performs an assessment of the bias due to missing evidence in each possible pairwise comparison; combines the assessment with the contribution from the direct pairwise comparisons; considers the potential for small-study effects. To facilitate and semi-automate this process, ROB-MEN has been implemented in a user-friendly web-application (https://cinema.ispm.unibe.ch/rob-men). Here we provide a tutorial detailing the functionality and use of the application consisting of data upload, analysis configuration, output visualisation, and production of the tool’s output tables for recording the risk of bias assessment. We also illustrate an example application using the demo dataset available for download on the application’s homepage. The ROB-MEN web-application is open-source and freely available (https://github.com/esm-ispm-unibe-ch/rob-men).

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients.

Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

Second-Line Pharmaceutical Treatments for Patients with Type 2 Diabetes

Assessing the relative effectiveness and safety of additional treatments when metformin monotherapy is insufficient remains a limiting factor in improving treatment choices in type 2 diabetes. To determine whether data from electronic health records across the University of California Health system could be used to assess the comparative effectiveness and safety associated with 4 treatments in diabetes when added to metformin monotherapy. This multicenter, new user, multidimensional propensity score-matched retrospective cohort study with leave-one-medical-center-out (LOMCO) sensitivity analysis used principles of emulating target trial. Participants included patients with diabetes receiving metformin who were then additionally prescribed either a sulfonylurea, dipeptidyl peptidase-4 inhibitor (DPP4I), sodium-glucose cotransporter-2 inhibitor (SGLT2I), or glucagon-like peptide-1 receptor agonist (GLP1RA) for the first time and followed-up over a 5-year monitoring period. Data were analyzed between January 2022 and April 2023. Treatment with sulfonylurea, DPP4I, SGLT2I, or GLP1RA added to metformin monotherapy. The main effectiveness outcome was the ability of patients to maintain glycemic control, represented as time to metabolic failure (hemoglobin A1c [HbA1c] ≥7.0%). A secondary effectiveness outcome was assessed by monitoring time to new incidence of any of 28 adverse outcomes, including diabetes-related complications while treated with the assigned drug. Sensitivity analysis included LOMCO. This cohort study included 31 852 patients (16 635 [52.2%] male; mean [SD] age, 61.4 [12.6] years) who were new users of diabetes treatments added on to metformin monotherapy. Compared with sulfonylurea in random-effect meta-analysis, treatment with SGLT2I (summary hazard ratio [sHR], 0.75 [95% CI, 0.69-0.83]; I2 = 37.5%), DPP4I (sHR, 0.79 [95% CI, 0.75-0.84]; I2 = 0%), GLP1RA (sHR, 0.62 [95% CI, 0.57-0.68]; I2 = 23.6%) were effective in glycemic control; findings from LOMCO sensitivity analysis were similar. Treatment with SGLT2I showed no significant difference in effectiveness compared with GLP1RA (sHR, 1.26 [95% CI, 1.12-1.42]; I2 = 47.3%; no LOMCO) or DPP4I (sHR, 0.97 [95% CI, 0.90-1.04]; I2 = 0%). Patients treated with DPP4I and SGLT2I had fewer cardiovascular events compared with those treated with sulfonylurea (DPP4I: sHR, 0.84 [95% CI, 0.74-0.96]; I2 = 0%; SGLT2I: sHR, 0.78 [95% CI, 0.62-0.98]; I2 = 0%). Patients treated with a GLP1RA or SGLT2I were less likely to develop chronic kidney disease (GLP1RA: sHR, 0.75 [95% CI 0.6-0.94]; I2 = 0%; SGLT2I: sHR, 0.77 [95% CI, 0.61-0.97]; I2 = 0%), kidney failure (GLP1RA: sHR, 0.69 [95% CI, 0.56-0.86]; I2 = 9.1%; SGLT2I: sHR, 0.72 [95% CI, 0.59-0.88]; I2 = 0%), or hypertension (GLP1RA: sHR, 0.82 [95% CI, 0.68-0.97]; I2 = 0%; SGLT2I: sHR, 0.73 [95% CI, 0.58-0.92]; I2 = 38.5%) compared with those treated with a sulfonylurea. Patients treated with an SGLT2I, vs a DPP4I, GLP1RA, or sulfonylurea, were less likely to develop indicators of chronic hepatic dysfunction (sHR vs DPP4I, 0.68 [95% CI, 0.49-0.95]; I2 = 0%; sHR vs GLP1RA, 0.66 [95% CI, 0.48-0.91]; I2 = 0%; sHR vs sulfonylurea, 0.60 [95% CI, 0.44-0.81]; I2 = 0%), and those treated with a DPP4I were less likely to develop new incidence of hypoglycemia (sHR, 0.48 [95% CI, 0.36-0.65]; I2 = 22.7%) compared with those treated with a sulfonylurea. These findings highlight familiar medication patterns, including those mirroring randomized clinical trials, as well as providing new insights underscoring the value of robust clinical data analytics in swiftly generating evidence to help guide treatment choices in diabetes.

Некоторые особенности исправительного воздействия в отношении больных осужденных

Taking into account the opinions of experts, the article analyzes various aspects of legal regulation and evaluation of the effectiveness of correctional treatment in relation to sick convicts. The conclusion is made about the need for comprehensive consideration of the state of health and other individual characteristics of sick convicts in the context of the use of various means of correction. The author suggests considering treatment as a means of correction, and also to establish in the penal enforcement legislation the possibility of suspending the execution of penalties for sick convicts in the form of placement in a penal isolation cell, a cell-type room, a single cell-type room and solitary confinement until their recovery or the end of inpatient treatment.

CausalCmprsk: An R package for nonparametric and Cox-based estimation of average treatment effects in competing risks data

Background and ObjectiveCompeting risks data arise in both observational and experimental clinical studies with time-to-event outcomes, when each patient might follow one of the multiple mutually exclusive competing paths. Ignoring competing risks in the analysis can result in biased conclusions. In addition, possible confounding bias of the treatment-outcome relationship has to be addressed, when estimating treatment effects from observational data. In order to provide tools for estimation of average treatment effects on time-to-event outcomes in the presence of competing risks, we developed the R package causalCmprsk. We illustrate the package functionality in the estimation of effects of a right heart catheterization procedure on discharge and in-hospital death from observational data. MethodsThe causalCmprsk package implements an inverse probability weighting estimation approach, aiming to emulate baseline randomization and alleviate possible treatment selection bias. The package allows for different types of weights, representing different target populations. causalCmprsk builds on existing methods from survival analysis and adapts them to the causal analysis in non-parametric and semi-parametric frameworks. ResultsThe causalCmprsk package has two main functions: fit.cox assumes a semiparametric structural Cox proportional hazards model for the counterfactual cause-specific hazards, while fit.nonpar does not impose any structural assumptions. In both frameworks, causalCmprsk implements estimators of (i) absolute risks for each treatment arm, e.g., cumulative hazards or cumulative incidence functions, and (ii) relative treatment effects, e.g., hazard ratios, or restricted mean time differences. The latter treatment effect measure translates the treatment effect from probability into more intuitive time domain and allows the user to quantify, for example, by how many days or months the treatment accelerates the recovery or postpones illness or death. ConclusionsThe causalCmprsk package provides a convenient and useful tool for causal analysis of competing risks data. It allows the user to distinguish between different causes of the end of follow-up and provides several time-varying measures of treatment effects. The package is accompanied by a vignette that contains more details, examples and code, making the package accessible even for non-expert users.

Conditional average treatment effect estimation with marginally constrained models

Abstract Treatment effect estimates are often available from randomized controlled trials as a single average treatment effect for a certain patient population. Estimates of the conditional average treatment effect (CATE) are more useful for individualized treatment decision-making, but randomized trials are often too small to estimate the CATE. Examples in medical literature make use of the relative treatment effect (e.g. an odds ratio) reported by randomized trials to estimate the CATE using large observational datasets. One approach to estimating these CATE models is by using the relative treatment effect as an offset, while estimating the covariate-specific untreated risk. We observe that the odds ratios reported in randomized controlled trials are not the odds ratios that are needed in offset models because trials often report the marginal odds ratio. We introduce a constraint or a regularizer to better use marginal odds ratios from randomized controlled trials and find that under the standard observational causal inference assumptions, this approach provides a consistent estimate of the CATE. Next, we show that the offset approach is not valid for CATE estimation in the presence of unobserved confounding. We study if the offset assumption and the marginal constraint lead to better approximations of the CATE relative to the alternative of using the average treatment effect estimate from the randomized trial. We empirically show that when the underlying CATE has sufficient variation, the constraint and offset approaches lead to closer approximations to the CATE.