Point Estimate Of Treatment Effect Research Articles

Endovascular Thrombectomy Treatment Effect in Direct vs Transferred Patients With Large Ischemic Strokes

Patients with large ischemic core stroke have poor clinical outcomes and are frequently not considered for interfacility transfer for endovascular thrombectomy (EVT). To assess EVT treatment effects in transferred vs directly presenting patients and to evaluate the association between transfer times and neuroimaging changes with EVT clinical outcomes. This prespecified secondary analysis of the SELECT2 trial, which evaluated EVT vs medical management (MM) in patients with large ischemic stroke, evaluated adults aged 18 to 85 years with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) as well as an Alberta Stroke Program Early CT Score (ASPECTS) of 3 to 5, core of 50 mL or greater on imaging, or both. Patients were enrolled between October 2019 and September 2022 from 31 EVT-capable centers in the US, Canada, Europe, Australia, and New Zealand. Data were analyzed from August 2023 to January 2024. EVT vs MM. Functional outcome, defined as modified Rankin Scale (mRS) score at 90 days with blinded adjudication. A total of 958 patients were screened and 606 patients were excluded. Of 352 enrolled patients, 145 (41.2%) were female, and the median (IQR) age was 66.5 (58-75) years. A total of 211 patients (59.9%) were transfers, while 141 (40.1%) presented directly. The median (IQR) transfer time was 178 (136-230) minutes. The median (IQR) ASPECTS decreased from the referring hospital (5 [4-7]) to an EVT-capable center (4 [3-5]). Thrombectomy treatment effect was observed in both directly presenting patients (adjusted generalized odds ratio [OR], 2.01; 95% CI, 1.42-2.86) and transferred patients (adjusted generalized OR, 1.50; 95% CI, 1.11-2.03) without heterogeneity (P for interaction = .14). Treatment effect point estimates favored EVT among 82 transferred patients with a referral hospital ASPECTS of 5 or less (44 received EVT; adjusted generalized OR, 1.52; 95% CI, 0.89-2.58). ASPECTS loss was associated with numerically worse EVT outcomes (adjusted generalized OR per 1-ASPECTS point loss, 0.89; 95% CI, 0.77-1.02). EVT treatment effect estimates were lower in patients with transfer times of 3 hours or more (adjusted generalized OR, 1.15; 95% CI, 0.73-1.80). Both directly presenting and transferred patients with large ischemic stroke in the SELECT2 trial benefited from EVT, including those with low ASPECTS at referring hospitals. However, the association of EVT with better functional outcomes was numerically better in patients presenting directly to EVT-capable centers. Prolonged transfer times and evolution of ischemic change were associated with worse EVT outcomes. These findings emphasize the need for rapid identification of patients suitable for transfer and expedited transport. ClinicalTrials.gov Identifier: NCT03876457.

GRADUATE I AND II: Factors that may influence participant response to subcutaneous gantenerumab

AbstractBackgroundGRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two Phase III trials that investigated the efficacy and safety of gantenerumab, a subcutaneous fully human monoclonal antibody that binds aggregated forms of amyloid‐beta, in participants with early Alzheimer’s disease (AD). Although the studies did not meet their primary endpoints, participant characteristics that might influence response to gantenerumab were evaluated.MethodEligible participants with early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) were randomized 1:1 to receive gantenerumab or placebo. Gantenerumab‐treated participants were up‐titrated to 510 mg subcutaneous gantenerumab every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). Secondary endpoints of cognition (ADAS‐Cog13) and function (ADCS‐ADL, FAQ) were assessed. Pre‐specified and exploratory post‐hoc subgroup analyses on these endpoints were performed.ResultAcross endpoints, there were consistent trends towards larger point estimates of gantenerumab treatment effect compared with placebo at Week 116 in males (using CDR‐SB as representative example: GRADUATE I: 16% relative reduction (RR); GRADUATE II: 17% RR) vs females (GRADUATE I: 3% RR; GRADUATE II: –2% RR) and participants with MCI (GRADUATE I:15% RR; GRADUATE II:10% RR) vs mild AD (GRADUATE I: 4% RR; GRADUATE II: 2% RR). This pattern was not consistently seen when using CDR‐Global Score (0.5 vs >0.5) to define disease stage. Compliers, defined as participants who received ≥90% of the intended cumulative dose, had an increased point estimate of treatment effect (CDR‐SB: GRADUATE I: 17% RR; GRADUATE II: 18% RR) vs non‐compliers (CDR‐SB: GRADUATE I: –1% RR; GRADUATE II: –3% RR). In a pooled analysis, a larger point estimate of treatment effect vs placebo was observed in East‐Asian vs Non‐East‐Asian countries (CDR‐SB: RR 38% vs 5%). The East‐Asian population had lower baseline weight, greater treatment compliance, and accordingly higher plasma exposure, than the Non‐East‐Asian population, suggesting this observation is not driven by racial differences in treatment response.ConclusionSubgroup analyses in the GRADUATE studies provide insights into participant characteristics that may influence the degree of clinical response to gantenerumab treatment. Higher gantenerumab exposure may result in greater clinical efficacy.

External Control Arms in Idiopathic Pulmonary Fibrosis Using Clinical Trial and Real World Data Sources.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, though the direct comparability of ECs to concurrent controls is unknown. To develop IPF ECs by fit for purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry [PFF-PR]), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the BMS-986020 phase 2 RCT. After data curation, the rate of change in forced vital capacity (FVC) from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed effects models with inverse probability weights. At 26 weeks, the rate of change in FVC was -32.71 mL (BMS-986020) versus -130.09 mL (BMS-placebo; difference, 97.4 mL, 95% CI, 24.6, 170.2), replicating the original BMS-986020 RCT. RCT-ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Both PFF-PR-ECs and EHR-ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment effect point estimates outside of the 95% CI of the original BMS-986020 RCT. IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, while ECs from real-world data sources, including registry or EHR data, do not. RCT-ECs may serve as a potentially useful supplement to future IPF RCTs.

Conservative or liberal oxygen therapy for mechanically ventilated adults with acute brain pathologies: A post-hoc subgroup analysis.

To compare the effect of conservative vs. liberal oxygen therapy in mechanically ventilated adults in the intensive care unit (ICU) with non-hypoxic ischemic encephalopathy (HIE) acute brain pathologies. Post-hoc analysis of data from 217 patients with non-HIE acute brain pathologies included in the ICU Randomized Trial Comparing Two Approaches to OXygen therapy (ICU-ROX). Patients allocated to conservative oxygen spent less time with oxygen saturation ≥ 97% (50.5 [interquartile range (IQR), 18.5-119] vs. 82 h [IQR, 38-164], absolute difference, -31.5 h; 95%CI, -59.6 to -3.4). At 180 days, 38 of 110 conservative oxygen patients (34.5%) and 28 of 104 liberal oxygen patients (26.9%) had died (absolute difference, 7.6 percentage points; 95%CI, -4.7 to 19.9 percentage points; P = 0.23; interaction P = 0.02 for non-HIE acute brain pathologies vs. HIE; interaction P = 0.53 for non-HIE acute brain pathologies vs. non-neurological conditions). In this post-hoc analysis, patients admitted to the ICU with non-HIE acute brain pathologies treated with conservative oxygen therapy did not have significantly lower mortality than those treated with liberal oxygen. A trial with adequate statistical power is needed to determine whether our day 180 mortality point estimate of treatment effect favoring liberal oxygen therapy indicates a true effect.

POSB426 Long-Term Time-Varying Survival Treatment Effect in the Presence of Scheduled Switch from Placebo to Active Treatment

To evaluate the treatment effect of tafamidis on overall survival (OS) using data from the long-term extension (LTE) of ATTR-ACT, accounting for treatment switching by placebo patients in the LTE. During ATTR-ACT, a 30-month trial, patients with transthyretin amyloid cardiomyopathy receiving tafamidis had improved survival versus placebo (hazard ratio: 0.70 [95% CI 0.51, 0.96]). The hazards were divergent during the trial; therefore, this point estimate of treatment effect may underestimate survival benefit.

Federated Causal Inference in Heterogeneous Observational Data

Analyzing observational data from multiple sources can be useful for increasing statistical power to detect a treatment effect; however, practical constraints such as privacy considerations may restrict individual-level information sharing across data sets. This paper develops federated methods that only utilize summary-level information from multiple heterogeneous data sets. Our federated methods provide doubly-robust point estimates of treatment effects as well as variance estimates. We derive the asymptotic distributions of our federated estimators, which are shown to be asymptotically equivalent to the corresponding estimators from the combined individual-level data. We show that to achieve these properties, federated methods should be adjusted based on conditions such as whether models are correctly specified and stable across heterogeneous data sets.

Integrating expert opinions with clinical trial data to analyse low-powered subgroup analyses: a Bayesian analysis of the VeRDiCT trial

BackgroundTypically, subgroup analyses in clinical trials are conducted by comparing the intervention effect in each subgroup by means of an interaction test. However, trials are rarely, if ever, adequately powered for interaction tests, so clinically important interactions may go undetected. We discuss the application of Bayesian methods by using expert opinions alongside the trial data. We applied this methodology to the VeRDiCT trial investigating the effect of preoperative volume replacement therapy (VRT) versus no VRT (usual care) in diabetic patients undergoing cardiac surgery. Two subgroup effects were of clinical interest, a) preoperative renal failure and b) preoperative type of antidiabetic medication.MethodsClinical experts were identified within the VeRDiCT trial centre in the UK. A questionnaire was designed to elicit opinions on the impact of VRT on the primary outcome of time from surgery until medically fit for hospital discharge, in the different subgroups. Prior beliefs of the subgroup effect of VRT were elicited face-to-face using two unconditional and one conditional questions per subgroup analysis. The robustness of results to the ‘community of priors’ was assessed. The community of priors was built using the expert priors for the mean average treatment effect, the interaction effect or both in a Bayesian Cox proportional hazards model implemented in the STAN software in R.ResultsExpert opinions were obtained from 7 clinicians (6 cardiac surgeons and 1 cardiac anaesthetist). Participating experts believed VRT could reduce the length of recovery compared to usual care and the greatest benefit was expected in the subgroups with the more severe comorbidity. The Bayesian posterior estimates were more precise compared to the frequentist maximum likelihood estimate and were shifted toward the overall mean treatment effect.ConclusionsIn the VeRDiCT trial, the Bayesian analysis did not provide evidence of a difference in treatment effect across subgroups. However, this approach increased the precision of the estimated subgroup effects and produced more stable treatment effect point estimates than the frequentist approach. Trial methodologists are encouraged to prospectively consider Bayesian subgroup analyses when low-powered interaction tests are planned.Trial registrationISRCTN, ISRCTN02159606. Registered 29th October 2008.

Profits from participation in high value agriculture: Evidence of heterogeneous benefits in contract farming schemes in Southern India

This paper assesses the variable impact of participation in high value agriculture through contract farming arrangements in southern India. Using survey data for 474 farmers in four commodity sectors, gherkins, papaya marigold and broiler, an endogenous switching model is used to estimate net profits from participation. Findings suggest that average treatments effect vary widely across contract commodities. Papaya and broiler contracting offer clear net gains for participants whereas marigold contracting leaves participants worse off. For gherkins, while contracting holds net gains for participating farmers overall, this is true of contracts with some firms but not others. The standard deviations of point estimates of treatment effects are quite large indicating variability in profit gains even within the same commodity sectors. Thus, notwithstanding the sign of average treatment effects, contract farming arrangements have diverse impacts on income for individual farmers and these could have implications for sustained participation of farmers in high value agriculture.

Concordance of effects of medical interventions on hospital admission and readmission rates with effects on mortality.

Many clinical trials examine a composite outcome of admission to hospital and death, or infer a relationship between hospital admission and survival benefit. This assumes concordance of the outcomes "hospital admission" and "death." However, whether the effects of a treatment on hospital admissions and readmissions correlate to its effect on serious outcomes such as death is unknown. We aimed to assess the correlation and concordance of effects of medical interventions on admission rates and mortality. We searched the Cochrane Database of Systematic Reviews from its inception to January 2012 (issue 1, 2012) for systematic reviews of treatment comparisons that included meta-analyses for both admission and mortality outcomes. For each meta-analysis, we synthesized treatment effects on admissions and death, from respective randomized trials reporting those outcomes, using random-effects models. We then measured the concordance of directions of effect sizes and the correlation of summary estimates for the 2 outcomes. We identified 61 meta-analyses including 398 trials reporting mortality and 182 trials reporting admission rates; 125 trials reported both outcomes. In 27.9% of comparisons, the point estimates of treatment effects for the 2 outcomes were in opposite directions; in 8.2% of trials, the 95% confidence intervals did not overlap. We found no significant correlation between effect sizes for admission and death (Pearson r = 0.07, p = 0.6). Our results were similar when we limited our analysis to trials reporting both outcomes. In this metaepidemiological study, admission and mortality outcomes did not correlate, and discordances occurred in about one-third of the treatment comparisons included in our analyses. Both outcomes convey useful information and should be reported separately, but extrapolating the benefits of admission to survival is unreliable and should be avoided.

Bevacizumab (BEV) continued beyond first progression in patients (pts) with metastatic colorectal cancer (mCRC) previously treated with BEV + chemotherapy (CT): Biomarker findings from ML18147.

452 Background: In ML18147, BEV + standard CT was continued as 2nd-line treatment for pts with mCRC progressing after 1st-line BEV + CT. ML18147 met its primary and secondary endpoints and had a comprehensive biomarker programme, including exploratory analyses of immunohistochemistry (IHC) and single nucleotide polymorphisms (SNPs). Methods: Tumour samples were analysed by IHC for VEGFA, VEGFR1, VEGFR2 and neuropilin-1; H-scores were generated. Tumor angiogenesis was determined by stereological analysis of CD31-stained microvessels; 183 SNPs of 30 mainly angiogenesis-related genes were genotyped. We assessed consistency of treatment effect point estimates, i.e. hazard ratios (HRs) on the same side of 1. Analyses were not adjusted for multiple testing or powered to detect statistically significant treatment by biomarker interactions. Results: IHC data were available for 213 pts (26% of ITT population) and SNP data for 274 pts (33% of ITT). There was no significant evidence of biomarker expression levels or their cellular localisation correlating with BEV treatment effect. Point estimates for a CD31 derivative (i.e. vessel or tumour area) suggested a trend for being predictive for overall survival (OS; HR 1.39 and 0.70 for CD31 derivative <median and ≥median, respectively), similar to data from previous studies. Other previously reported correlations (progression-free survival [PFS] with VEGFA and NRP1 in NO16966; OS with NRP1 in AVAGAST) were not seen. SNP analyses confirmed previous correlations for OS (VEGFA, VEGFR2) and suggested additional biomarker candidates (PFS: VEGFA, VEGFR1, VEGFR2, EGLN3; OS: VEGFR2, EGLN1). Five EPAS1 (HIF2α) SNPs were associated with BEV treatment effect, thus confirming previous findings of HIF2α SNPs as a predictive biomarker for BEV treatment effects. Conclusions: Exploratory IHC and SNP analyses in ML18147 revealed potential biomarker candidates for BEV in pts with mCRC. SNP analyses of angiogenesis-relevant genes were consistent with previous findings for a subset of SNPs, consolidating their role as potential predictive biomarkers of BEV treatment across indications. Clinical trial information: NCT00700102.

PRM45 Are Minimal Clinically Important Difference Measures (MCIDs) Relevant for Survival Outcomes? Introducing the MCID-CAC

Minimal Clinically Important Difference margins (MCIDs) are being applied by reimbursement agencies to assess the non-inferiority of new medications against comparator medications in the Asia Pacific Region. If a new medication is deemed non-inferior to an all ready reimbursed medication either via direct or indirect comparison methods the newer product is generally reimbursed at the same price as the comparator medication (ie. through cost-minimisation). The concept of an MCID margin for survival outcomes, however, is problematic and controversial. A superficial consideration of MCIDs for survival outcomes may lead to the conclusion that the MCID for survival is inappropriate and no difference in survival is acceptable. As such, the MCID for survival should be zero. In this case such an analysis would become a superiority analysis. If this approach to the assessment of such products were to prevail, new products with a high likelihood of affording patients a survival benefit compared to their comparator products may be rejected even on a cost-minimisation basis. Instead, where the point estimate of treatment effect favours the new treatment serious consideration should be given to reimbursing the new product at the same or higher price. Using indirect comparison methods and real world hazard ratio data this research introduces the concept of MCID-cumulative acceptability curves (MCID-CAC) as an aid to making pragmatic reimbursement decisions for new products that may extend patients lives.

Active vs Passive Recruitment to Quitline Studies: Public Health Implications

such as telephone recruitment and targeted mailings can achieve point estimates almost as high as passive recruitment has enormous implications for the public health impact of quitline-delivered cessation treatment. Quitlines represent a highly valuable resource for smokers interested in quitting and for health- care providers in need of effi cacious treatment referral options for smokers under their care. Although passive recruitment is effective in reaching smokers highly motivated to quit, it is associated with very low treatment enrollment rates. The fi nding that active recruitment can result in point estimates of treatment effects essentially equivalent to those of passive recruitment strongly supports the importance of efforts to expand reach. Active recruitment strategies such as nationally promoted “Ask — Advise — Refer” initiatives represent the currently recommended standard of care. “Ask-Advise-Refer” is an abbreviated version of the “5 As” (Ask — Advise — Assess — Assist — Arrange) and is intended to reduce time demands of health- care providers by referring smokers to evidence-based cessation programs such as

Mortality and Morbidity Reduction by Primary Percutaneous Coronary Intervention Is Independent of the Patient's Age

The aim of this study was to obtain a valid estimate of the clinical effects of primary percutaneous coronary intervention (PPCI) in relation to age. Treatment with PPCI is most beneficial in high-risk myocardial infarction patients. Paradoxically, elderly patients, who are at increased risk of adverse outcome, are often withheld PPCI. Individual patient data were obtained from 22 randomized trials (n = 6,763) evaluating the clinical effects of PPCI versus fibrinolysis (FL). Differences in 30-day death, repeat myocardial infarction, and stroke between patients randomized to FL and PPCI were determined in 5 age-strata: < or =50, >50 to 60, >60 to 70, >70 to 80, and >80 years. Treatment effects are reported as odds ratios (ORs) and 95% confidence intervals (CI). Multivariable logistic regression analyses, which included age x treatment interaction, were applied to examine evidence of heterogeneity in age-specific ORs. Thirty-day death increased with increasing age and ranged from 1.1% (FL) and 1.8% (PPCI) in patients < or =50 years to 26.4% and 18.3% in patients >80 years of age. The point estimate of treatment effect (overall adjusted OR: 0.65; 95% CI: 0.52 to 0.79) was compatible with a mortality reduction favoring PPCI in all age-strata (except in patients < or =50 years of age), and 95% CIs were largely overlapping. There was no evidence of heterogeneity in ORs between age categories. Similar results were observed for repeat myocardial infarction and stroke. In this analysis of randomized trials, the reduction in clinical end points by PPCI was not influenced by age. Hence, age per se should not be considered an exclusion criterion for the application of PPCI.

3. Bounding Disagreements about Treatment Effects: A Case Study of Sentencing and Recidivism

Empirical inference on treatment effects is a core objective of social science research. The conventional practice is to obtain point estimates of treatment effects using models that make strong and thereby controversial assumptions about treatment selection and outcomes. In this paper we obtain bounds under weak nonparametric assumptions and explore how the bounds vary with the assumptions imposed. This mode of analysis clarifies the source of common disagreements about the magnitudes and signs of treatment effects. We use a treatment question facing the juvenile justice system to showcase the value of the approach in empirical social science research. We compare the impacts on recidivism of the two main sentencing options available to judges: confinement in residential treatment facilities and diversion to nonresidential treatment.