Advancing the role of real-world evidence in comparative effectiveness research.

Aim: Comparative effectiveness research (CER) is essential for making informed decisions about drug access. It provides insights into the effectiveness and safety of new drugs compared with existing treatments, thereby guiding better healthcare decisions and ensuring that new therapies meet the real-world needs of patients and healthcare systems. Objective: To provide a tool that assists analysts and decision-makers in identifying the most suitable analytical approach for answering a CER question, given specific data availability contexts. Methods: A systematic literature review of the scientific literature was performed and existing regulatory and health technology assessment (HTA) guidance were evaluated to identify and compare recommendations and best practices. Based on this review a methods flowchart that synthesizes current practices and requirements was proposed. Results: The review did not find any papers that clearly identified the most appropriate analytical approach for answering CER questions under various conditions. Therefore, a methods flowchart was designed to inform analyst and decision makers choices starting from a well-defined scientific question. Conclusion: The proposed methods flowchart offers clear guidance on CER methodologies across a range of settings and research needs. It begins with a well-defined research question and considers multiple feasibility aspects related to CER. This tool aims to standardize methods, ensure rigorous and consistent research quality and promote a culture of evidence-based decision-making in healthcare.

Improving the Validity of Non-Interventional Comparative Effectiveness Research by Basing Study Design on a Specified Existing Randomised Controlled Trial.

This issue of AJE includes three articles (two reporting original analyses and one systematic review) in which non-interventional studies used an existing randomized controlled trial (RCT) as a reference standard to both inform non-interventional study design, and to benchmark results against. This commentary provides a brief background on the challenges of non-interventional comparative effectiveness research, before elaborating on (i) the potential benefits and challenges of basing non-interventional study design on a specified existing RCT, and (ii) the distinction between designing analysis based upon a specified existing RCT and studies based solely upon a hypothetical target trial. Finally, a number of recommendations for the conduct and reporting of non-interventional studies based upon existing RCTs are provided.

Five-year efficacy outcomes of ocrelizumab in relapsing multiple sclerosis: A propensity-matched comparison of the OPERA studies with other disease-modifying therapies in real-world lines of treatments.

Background: Clinical trials comparing the efficacy of ocrelizumab (OCR) with other disease-modifying therapies (DMTs) other than interferon (IFN) ß-1a in relapsing multiple sclerosis (RMS) are lacking. Objectives: To compare the treatment effect of OCR vs six DMTs' (IFN ß-1a, glatiramer acetate, fingolimod, dimethyl fumarate, teriflunomide, natalizumab) treatment pathways used in clinical practice by combining clinical trial and real-world data. Methods: Patient-level data from OPERA trials and open-label extension phase, and from the German NeuroTransData (NTD) MS registry, were used to build 1:1 propensity score-matched (PSM) cohorts controlling for seven baseline covariates, including brain imaging activity. Efficacy outcomes were time to first relapse and time to 24-week confirmed disability progression over 5.5 years of follow-up. Intention-to-treat analysis using all outcome data irrespective of treatment switch was applied. Results: The analyses included 611 OPERA patients and 7141 NTD patients. We built 12 paired-matched cohorts (six for each outcome, two for each DMT) to compare efficacy of OCR in OPERA with each DMT treatment pathway in NTD. Post-matching, baseline covariates and PS were well balanced (standardized mean difference <.2 for all cohorts). Over 5.5 years, patients treated with OCR showed a statistically significant reduction in the risk of relapse (hazard ratios [HRs] .30 to .54) and disability progression (HRs .51 to .67) compared with all index therapies and their treatment switching pathways in NTD. Treatment switch and/or discontinuation occurred frequently in NTD cohorts. Conclusion: OCR demonstrates superiority in controlling relapses and disability progression in RMS compared with real-world treatment pathways over a 5.5-year period. These analyses suggest that high-efficacy DMTs and high treatment persistence are critical to achieve greatest clinical benefit in RMS. Registration: OPERA I (NCT01247324), OPERA II (NCT01412333).

The Impact of Radical Prostatectomy Versus Radiation Therapy on Cancer-Specific Mortality for Nonmetastatic Prostate Cancer: Analysis of an Other-Cause Mortality Matched Cohort.

INTRODUCTION: Studies comparing radical prostatectomy (RP) to radiation therapy (RT) have consistently shown that patients undergoing RT have a higher risk of other-cause mortality (OCM) compared to RP, signifying poor health status of the former patients. We aimed to evaluate the impact of RP versus RT on cancer-specific mortality (CSM) over a cohort with equivalent OCM risk. PATIENTS AND METHODS: The SEER database was queried to identify patients with nonmetastatic PCa between 2004 and 2009. Patients were matched based on their calculated 10-year OCM risk and further stratified for D'Amico Risk Score and Gleason Grade. A Cox-regression model was used to calculate the 10-year OCM risk. Propensity-score based on the calculated OCM risk were used to match RP and RT patients. Cumulative incidence curves and Competing-risk regression analyses were used to examine the impact of treatment on CSM in the matched cohort. RESULTS: We identified 55,106 PCa patients treated with RP and 36,674 treated with RT. After match, 6,506 patients were equally distributed for RT versus RP, with no difference in OCM rates (P = .2). The 10-year CSM rates were 8.8% versus 0.6% (P = .01) for RT versus RP in patients with unfavorable-intermediate-risk (Gleason Score 4 + 3) and 7.9% versus 3.9% (P = .003) for high-risk disease. There was no difference in CSM among RT and RP patients for favorable-intermediate-risk (Gleason Score 3 + 4) and low-risk disease. CONCLUSIONS: In a matched cohort of PCa patients with comparable OCM between the 2 arms, RP yielded a more favorable CSM rate compared to RT only for unfavorable-intermediate- and high-risk groups.

A Patient-Prioritized Research Agenda for Clinical Trials in Kidney Stone Disease.

PURPOSE: To ensure that research on kidney stones provides meaningful impact for the kidney stone community, patients and caregivers should be engaged as stakeholders in clinical trial design, starting at study inception. This project aimed to elicit, refine, and prioritize research ideas from kidney stone stakeholders to develop a patient-centered research agenda for clinical trials. MATERIALS AND METHODS: The Kidney Stone Engagement Core, a group of patients, caregivers, advocates, clinicians, and researchers, executed an iterative process of surveys and focus groups to elicit and refine research themes, which were then translated into research questions. A separate group of patients, caregivers, and clinicians prioritized these questions through parallel modified Delphi and crowd-sourced digital platforms. A research agenda was developed by the Kidney Stone Engagement Core based on the highest rated questions during a hybrid virtual/in-person capstone session. RESULTS: A total of 70 individuals (57 patients and caregivers, 13 researchers and clinicians) participated in the elicitation, 20 individuals (15 patients and caregivers, 5 researchers and clinicians) participated in refinement, and an additional 80 individuals (81 patients and caregivers, 9 researchers and clinicians) participated in prioritization. Key novel themes emerged from elicitation and refinement: ureteral stents, genetic evaluation, shared surgical decision-making, key subgroups, cumulative disease burden, genetic evaluation, and psychosocial support. Stakeholders generated 6 proposed trials from these themes focused on surveillance, surgical intervention, and medical prevention. CONCLUSIONS: Patients and caregivers valued comparative effectiveness kidney stone research that focused on individualized care, shared decision-making, and improvement of patient-reported experiences. This process provided actionable recommendations for future patient-centered clinical trials within kidney stone disease.

Frequency and outcomes of treatment dose escalation with biologics in moderate-to-severe psoriasis: a Swedish register study.

BACKGROUND: The advent of biosimilars may increase the frequency of dose escalation with biologics in psoriasis. OBJECTIVE: To explore the frequency and outcomes of dose escalation with adalimumab etanercept, and ustekinumab. METHODS: Data were extracted from DermaReg-Pso, a psoriasis register in Stockholm, Sweden. The main exposure was treatment, and the main outcome was dose escalation. We describe outcomes with dose escalation by estimating drug survival and changes in the Psoriasis Area and Severity Index (PASI). RESULTS: 554 patients had 946 treatment episodes with adalimumab, etanercept, or ustekinumab. The cumulative incidence of dose escalation was 4.1 per 100 treatment years. The Hazard Ratios (HRs) for dose escalation with ustekinumab vs adalimumab and ustekinumab vs etanercept were 1.93 (95% CI: 1.25-2.98), and 2.20 (95% CI: 1.42-3.41), respectively. After dose escalation, the HRs for treatment discontinuation with adalimumab and etanercept compared with ustekinumab were 3.10 (95% CI: 1.56-6.18) and 7.15 (95% CI: 3.96-12.94), respectively. PASI was higher after compared to before dose escalation for etanercept (p = 0.036), but not for adalimumab (p = 0.832) or ustekinumab (p = 0.300). CONCLUSIONS: Dose escalation was comparatively more frequent with ustekinumab than with adalimumab or etanercept; however, treatment discontinuation after dose escalation was more common with adalimumab and etanercept than ustekinumab.

Matching-adjusted indirect comparison of talquetamab vs selinexor-dexamethasone and vs belantamab mafodotin in patients with relapsed/refractory multiple myeloma.

OBJECTIVE: Talquetamab is the first GPRC5D-targeting bispecific antibody approved for the treatment of triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). This matching-adjusted indirect comparison (MAIC) study was conducted to compare the effectiveness of talquetamab vs selinexor-dexamethasone (sel-dex) and vs belantamab mafodotin (belamaf) in patients with TCE RRMM. METHODS: An unanchored MAIC was performed using individual patient-level data from patients treated with subcutaneous talquetamab 0.4 mg/kg weekly (QW) and 0.8 mg/kg every other week (Q2W) from MonumenTAL-1 (NCT03399799/NCT04636552) and published summary data for sel-dex from STORM (NCT02336815) and belamaf from DREAMM-2 (NCT0325678). Patients from MonumenTAL-1 who met key eligibility criteria for STORM and DREAMM-2 were included. Outcomes of interest were overall response rate (ORR), complete response or better (≥CR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: After adjustment for cross-trial differences, patients treated with both dosing schedules of talquetamab showed significantly better ORR, ≥CR, and DOR vs sel-dex and significantly higher ORR and ≥ CR vs belamaf; DOR was relatively similar to belamaf. PFS was significantly improved with talquetamab Q2W and numerically in favor of talquetamab QW vs sel-dex and significantly improved with both dosing schedules of talquetamab vs belamaf. OS was significantly improved with both dosing schedules of talquetamab vs sel-dex and was numerically in favor of both dosing schedules of talquetamab vs belamaf. CONCLUSION: These analyses show superior effectiveness of both talquetamab dosing schedules vs sel-dex and vs belamaf for most outcomes and highlight talquetamab as an effective treatment option for patients with TCE RRMM.

Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. OBJECTIVES: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. METHODS: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. RESULTS: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). CONCLUSIONS: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.

A matching-adjusted indirect comparison of centanafadine versus lisdexamfetamine, methylphenidate and atomoxetine in adults with attention-deficit/hyperactivity disorder: long-term safety and efficacy.

Aim: To compare long-term safety and efficacy outcomes of centanafadine versus lisdexamfetamine dimesylate (lisdexamfetamine), methylphenidate hydrochloride (methylphenidate) and atomoxetine hydrochloride (atomoxetine), respectively, in adults with attention-deficit/hyperactivity disorder (ADHD) using matching-adjusted indirect comparisons (MAICs). Patients & methods: Patient-level data from a centanafadine trial (NCT03605849) and published aggregate data from a lisdexamfetamine trial (NCT00337285), a methylphenidate trial (NCT00326300) and an atomoxetine trial (NCT00190736) were used. Patient characteristics were matched in each comparison using propensity score weighting. Study outcomes were assessed up to 52 weeks and included safety (rates of adverse events [AEs]) and efficacy (mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale [AISRS] or ADHD Rating Scale [ADHD-RS] score). Results: In all comparisons of matched populations, risks of AEs were statistically significantly lower with centanafadine or non-different between centanafadine and comparator; the largest differences in AE rates included upper respiratory tract infection (risk difference in percentage points: 18.75), insomnia (12.47) and dry mouth (12.33) versus lisdexamfetamine; decreased appetite (20.25), headache (18.53) and insomnia (12.65) versus methylphenidate; and nausea (26.18), dry mouth (25.07) and fatigue (13.95) versus atomoxetine (all p < 0.05). Centanafadine had a smaller reduction in the AISRS/ADHD-RS score versus lisdexamfetamine (6.15-point difference; p < 0.05) and no statistically significant difference in the change in AISRS score versus methylphenidate (1.75-point difference; p = 0.13) and versus atomoxetine (1.60-point difference; p = 0.21). Conclusion: At up to 52 weeks, centanafadine showed significantly lower incidence of several AEs than lisdexamfetamine, methylphenidate and atomoxetine; efficacy was lower than lisdexamfetamine and non-different from methylphenidate and atomoxetine.

Separable effects for adherence.

Comparing different medications is complicated when adherence to these medications differs. We can overcome the adherence issue by assessing effectiveness under sustained use, as in usual causal 'per-protocol' estimands. However, when sustained use is challenging to satisfy in practice, the usefulness of these estimands can be limited. Here we propose a different class of estimands: separable effects for adherence. These estimands compare modified medications, holding fixed a component responsible for non-adherence. Under assumptions about treatment components' mechanisms of effect, a separable effects estimand can quantify the effectiveness of medication initiation strategies on an outcome of interest under the adherence mechanism of one of the medications. These assumptions are amenable to interrogation by subject-matter experts and can be evaluated using causal graphs. We describe an algorithm for constructing causal graphs for separable effects, illustrate how these graphs can be used to reason about assumptions required for identification, and provide semi-parametric weighted estimators.

A New Horizon for Understanding the Comparative Effectiveness for Cooling Prospectively Infants with Mild Encephalopathy.

The authors summarize the methodology for a new pragmatic comparative effectiveness research investigation, Cooling Prospectively Infants with Mild Encephalopathy (COOLPRIME), which uses sites' existing mild hypoxic-ischemic encephalopathy (HIE) treatment preference (hypothermia or normothermia) to assess hypothermia effectiveness and safety. COOLPRIME's primary aim is to determine the safety and effectiveness of hypothermia compared to normothermia in mild HIE. Engagement of Families and Community Affected by Hypoxic-Ischemic Encephalopathy strongly favored Effectiveness over Efficacy Trials leading to COOL PRIME design.

Up-front matching: an ongoing recruitment method for prospective observational studies that mimics randomization for selected baseline covariates.

In a prospective observational study (POS) designed to assess the average causal effect of a treatment (e.g. Drug A) compared to a comparator (e.g. Drug B) in the treatment population, enrolling all patients who are assigned to the treatments of interest for follow-up has a potentially large negative impact on the statistical efficiency and bias of the analysis of the outcomes and on the cost of the study. "Up-front matching" is an innovative enrollment method for selecting patients for long-term follow-up among those who have already been assigned to treatment or comparator which uses frequency matching and hence avoids the restrictions of individual matching that other methods have used. To achieve potential statistical and logistical efficiencies in the POS, in up-front matching, a target population is defined based on a retrospective database which then enables selecting populations of patients for follow-up that have desirable statistical properties. In particular, the resulting populations of patients who are enrolled look like the population of treatment patients were randomized to treatment or comparator for the baseline covariates that are used to select patients for follow-up. The method is illustrated in detail for a study designed to assess the effect of injectable antipsychotics versus oral antipsychotics.

Remdesivir is Associated with Reduced Mortality in Patients Hospitalized for COVID-19 Not Requiring Supplemental Oxygen.

Background: Remdesivir has demonstrated benefit in some hospitalized patients with coronavirus disease 2019 (COVID-19) on supplemental oxygen and in nonhospitalized patients breathing room air. The durability of this benefit across time periods with different circulating severe acute respiratory syndrome coronavirus 2 variants of concern (VOC) is unknown. This comparative effectiveness study in patients hospitalized for COVID-19 and not receiving supplemental oxygen at admission compared those starting remdesivir treatment in the first 2 days of admission with those receiving no remdesivir during their hospitalization across different VOC periods. Method: Using a large, multicenter US hospital database, in-hospital mortality rates were compared among patients hospitalized for COVID-19 but not requiring supplemental oxygen at admission between December 2020 and April 2022. Patients receiving remdesivir at hospital admission were matched 1:1 to those not receiving remdesivir during hospitalization, using propensity score matching. Cox proportional hazards models were used to assess 14- and 28-day in-hospital mortality rates or discharge to hospice. Results: Among the 121 336 eligible patients, 58 188 remdesivir-treated patients were matched to 17 574 unique patients not receiving remdesivir. Overall, 5.4% of remdesivir-treated and 7.3% in the non-remdesivir group died within 14 days, and 8.0% and 9.8%, respectively, died within 28 days. Remdesivir treatment was associated with a statistically significant reduction in the in-hospital mortality rate compared with non-remdesivir treatment (14-day and 28-day adjusted hazard ratios [95% confidence interval], 0.75 [0.68-0.83] and 0.83 [0.76-0.90], respectively). This significant mortality benefit endured across the different VOC periods. Conclusions: Remdesivir initiation in patients hospitalized for COVID-19 and not requiring supplemental oxygen at admission was associated with a significantly reduced in-hospital mortality rate. These findings highlight a potential survival benefit when clinicians initiated remdesivir on admission across the dominant variant eras of the evolving pandemic.

Behavioral carry-over effect and power consideration in crossover trials.

A crossover trial is an efficient trial design when there is no carry-over effect. To reduce the impact of the biological carry-over effect, a washout period is often designed. However, the carry-over effect remains an outstanding concern when a washout period is unethical or cannot sufficiently diminish the impact of the carry-over effect. The latter can occur in comparative effectiveness research, where the carry-over effect is often non-biological but behavioral. In this paper, we investigate the crossover design under a potential outcomes framework with and without the carry-over effect. We find that when the carry-over effect exists and satisfies a sign condition, the basic estimator underestimates the treatment effect, which does not inflate the type I error of one-sided tests but negatively impacts the power. This leads to a power trade-off between the crossover design and the parallel-group design, and we derive the condition under which the crossover design does not lead to type I error inflation and is still more powerful than the parallel-group design. We also develop covariate adjustment methods for crossover trials. We evaluate the performance of cross-over design and covariate adjustment using data from the MTN-034/REACH study.

Comparative Effectiveness of Placental Allografts in the Treatment of Diabetic Lower Extremity Ulcers and Venous Leg Ulcers in U.S. Medicare Beneficiaries: A Retrospective Observational Cohort Study Using Real-World Evidence.

Objective: To compare the effectiveness of cellular tissue products (CTP) versus standard care in U.S. Medicare beneficiaries with diabetic lower extremity ulcers (DLEUs) or venous leg ulcers (VLUs). Approach: We performed a retrospective cohort study using real-world evidence from U.S. Medicare claims for DLEUs or VLUs between 2016 and 2020. There were three cohorts evaluated: viable cryopreserved placental membrane (vCPM) or viable lyopreserved placental membrane (vLPM); other CTP; and standard care. Claims were collapsed into episodes of care. Univariate and bivariate statistics were used to examine the frequency distribution of demographics and clinical variables. Multivariable zero-inflated binomial regressions were used to evaluate mortality and recurrence trends. Logistic regression compared three adverse outcomes (AOs): amputation; 1-year mortality; and wound recurrence. Results: There were 333,362 DLEU episodes among 261,101 beneficiaries, and 122,012 VLU episodes among 80,415 beneficiaries. DLEU treatment with vLPM was associated with reduced 1-year mortality (-26%), reduced recurrence (-91%), and reduced AOs (-71%). VLU treatment with vCPM or vLPM was associated with reduced 1-year mortality (-23%), reduced recurrence (-80%), and 66.77% reduction in AOs. These allografts were also associated with a 49% and 73% reduced risk of recurrence in DLEU and VLU, respectively, compared with other CTPs. Finally, vCPM or vLPM were associated with noninferior prevention of AOs related to amputation, mortality, and recurrence (95% CI: 0.69-1.14). Conclusions: DLEUs and VLUs treated with vCPM and vLPM allografts are associated with lowered 1-year mortality, wound recurrence, and AOs in DLEUs and VLUs compared with standard care. Decision makers weighing coverage of placental allografts should consider these added short- and long-term clinical benefits relative to costly management and high mortality of Medicare's most frequent wounds.

Using Claims Data to Predict Pre-Operative BMI Among Bariatric Surgery Patients: Development of the BMI Before Bariatric Surgery Scoring System (B3S3).

Background: Lack of body mass index (BMI) measurements limits the utility of claims data for bariatric surgery research, but pre-operative BMI may be imputed due to existence of weight-related diagnosis codes and BMI-related reimbursement requirements. We used a machine learning pipeline to create a claims-based scoring system to predict pre-operative BMI, as documented in the electronic health record (EHR), among patients undergoing a new bariatric surgery. Methods: Using the Optum Labs Data Warehouse, containing linked de-identified claims and EHR data for commercial or Medicare Advantage enrollees, we identified adults undergoing a new bariatric surgery between January 2011 and June 2018 with a BMI measurement in linked EHR data ≤30 days before the index surgery (n=3226). We constructed predictors from claims data and applied a machine learning pipeline to create a scoring system for pre-operative BMI, the B3S3. We evaluated the B3S3 and a simple linear regression model (benchmark) in test patients whose index surgery occurred concurrent (2011-2017) or prospective (2018) to the training data. Results: The machine learning pipeline yielded a final scoring system that included weight-related diagnosis codes, age, and number of days hospitalized and distinct drugs dispensed in the past 6 months. In concurrent test data, the B3S3 had excellent performance (R2 0.862, 95% confidence interval [CI] 0.815-0.898) and calibration. The benchmark algorithm had good performance (R2 0.750, 95% CI 0.686-0.799) and calibration but both aspects were inferior to the B3S3. Findings in prospective test data were similar. Conclusion: The B3S3 is an accessible tool that researchers can use with claims data to obtain granular and accurate predicted values of pre-operative BMI, which may enhance confounding control and investigation of effect modification by baseline obesity levels in bariatric surgery studies utilizing claims data.

Pre-operative BMI is an important potential confounder in comparative effectiveness studies of bariatric surgeries.Claims data lack clinical measurements, but insurance reimbursement requirements for bariatric surgery often result in pre-operative BMI being coded in claims data.We used a machine learning pipeline to create a model, the B3S3, to predict pre-operative BMI, as documented in the EHR, among bariatric surgery patients based on the presence of certain weight-related diagnosis codes and other patient characteristics derived from claims data.Researchers can easily use the B3S3 with claims data to obtain granular and accurate predicted values of pre-operative BMI among bariatric surgery patients.

Assessing the performance of physician's prescribing preference as an instrumental variable in comparative effectiveness research with moderate and small sample sizes: a simulation study.

Aim: This simulation study is to assess the utility of physician's prescribing preference (PPP) as an instrumental variable for moderate and smaller sample sizes. Materials & methods: We designed a simulation study to imitate a comparative effectiveness research under different sample sizes. We compare the performance of instrumental variable (IV) and non-IV approaches using two-stage least squares (2SLS) and ordinary least squares (OLS) methods, respectively. Further, we test the performance of different forms of proxies for PPP as an IV. Results: The percent bias of 2SLS is around approximately 20%, while the percent bias of OLS is close to 60%. The sample size is not associated with the level of bias for the PPP IV approach. Conclusion: Irrespective of sample size, the PPP IV approach leads to less biased estimates of treatment effectiveness than OLS adjusting for known confounding only. Particularly for smaller sample sizes, we recommend constructing PPP from long prescribing histories to improve statistical power.

Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.

Percutaneous electrical nerve field stimulation for adolescents with irritable bowel syndrome: Cost-benefit and cost-minimization analysis.

Abdominal pain drives significant cost for adolescents with irritable bowel syndrome (IBS). We performed an economic analysis to estimate cost-savings for patients' families and healthcare insurance, and health outcomes, based on abdominal pain improvement with percutaneous electrical nerve field stimulation (PENFS) with IB-Stim® (Neuraxis). We constructed a Markov model with a 1-year time horizon comparing outcomes and costs with PENFS versus usual care without PENFS. Clinical outcomes were derived from a sham-controlled double-blind trial of PENFS for adolescents with IBS. Costs/work-productivity impact for parents were derived from appropriate observational cohorts. PENFS was associated with 18 added healthy days over 1 year of follow-up, increased annual parental wages of $5,802 due to fewer missed work days to care for the child, and $4744 in cost-savings to insurance. Percutaneous electrical field nerve stimulation for adolescents with IBS appears to yield significant cost-savings to patients' families and insurance.