Balanced Treatment Groups Research Articles

Assessment of the E-value in the presence of bias amplification: a simulation study

BackgroundThe E-value, a measure that has received recent attention in the comparative effectiveness literature, reports the minimum strength of association between an unmeasured confounder and the treatment and outcome that would explain away the estimated treatment effect. This study contributes to the literature on the applications and interpretations of E-values by examining how the E-value is impacted by data with varying levels of association of unobserved covariates with the treatment and outcome measure when covariate adjustment is applied. We calculate the E-value after using regression and propensity score methods (PSMs) to adjust for differences in observed covariates. Propensity score methods are a common observational research method used to balance observed covariates between treatment groups. In practice, researchers may assume propensity score methods that balance treatment groups across observed characteristics will extend to balance of unobserved characteristics. However, that assumption is not testable and has been shown to not hold in realistic data settings. We assess the E-value when covariate adjustment affects the imbalance in unobserved covariates.MethodsOur study uses Monte Carlo simulations to evaluate the impact of unobserved confounders on the treatment effect estimates and to evaluate the performance of the E-Value sensitivity test with the application of regression and propensity score methods under varying levels of unobserved confounding. Specifically, we compare observed and unobserved confounder balance, odds ratios of treatment vs. control, and E-Value sensitivity test statistics from generalized linear model (GLM) regression models, inverse-probability weighted models, and propensity score matching models, over correlations of increasing strength between observed and unobserved confounders.ResultsWe confirm previous findings that propensity score methods – matching or weighting – may increase the imbalance in unobserved confounders. The magnitude of the effect depends on the strength of correlation between the confounder, treatment, and outcomes. We find that E-values calculated after applying propensity score methods tend to be larger when unobserved confounders result in more biased treatment effect estimates.ConclusionsThe E-Value may misrepresent the size of the unobserved effect needed to change the magnitude of the association between treatment and outcome when propensity score methods are used. Thus, caution is warranted when interpreting the E-Value in the context of propensity score methods.

Consideration of stratification in confirmatory trials with time-to-event endpoint

Stratification in randomization and analysis are widely employed to balance treatment groups in clinical trials. However, the potential power loss due to under-stratification or over-stratification has not been thoroughly evaluated in the typical setting of confirmatory clinical trials. In cases where there are too many strata and some have small sample sizes or a small number of events, it is common practice to combine these small strata during analysis. However, there is a lack of guidance on how those small strata should be combined. This paper presents extensive simulation studies to evaluate the impact of under-stratification or over-stratification on the power of survival analysis and the estimate of hazard ratio using stratified log-rank test and Cox PH model, respectively. The difference in power between stratified and unstratified log-rank tests is also investigated under different scenarios. Our results suggest that failing to consider prognostic stratification factors with strong effects, and/or accounting for non-prognostic factors such as noise and predictive factors, may reduce the power of the stratified log-rank test. Additionally, methods of combining small strata are explored and compared.

Comparative effectiveness of tenofovir versus entecavir in patients with hepatitis B virus-related cirrhosis in Taiwan: a retrospective cohort study.

Background: Tenofovir and entecavir demonstrated substantial effectiveness in the reversion of fibrosis and reversed cirrhosis in patients with hepatitis B virus (HBV)-related cirrhosis. However, there has not been a definitive conclusion regarding the association between entecavir and tenofovir on the risk of cirrhosis-related complications. Therefore, this study aimed to investigate the comparative effectiveness between tenofovir and entecavir in HBV-related cirrhosis patients. Methods: This was a retrospective study using Taiwan's Health Insurance Research Database. We enrolled newly diagnosed HBV-related cirrhosis patients who initiated entecavir and tenofovir between 2011 and 2019. Treatment groups were determined by the initial HBV antiviral medication prescribed. The primary composite outcome was the development of hepatocellular carcinoma (HCC), death from any causes, and liver transplantation. The secondary outcomes included all the individual components of the primary outcome. The incidence rate was calculated for each outcome for both treatment groups using the Fine-Gray subdistribution hazard models. Propensity score adjustment was used to balance treatment groups. Results: A total of 7,316 propensity score-matched treatment-naïve patients and 3,524 propensity score-matched treatment-experienced patients were included. Within treatment-naïve patients, those receiving tenofovir showed significantly lower hazards of developing the composite outcome (HR, 0.79; p < 0.0001), hepatocellular carcinoma (HR, 0.86; p = 0.027), mortality (HR, 0.75; p < 0.0001), and liver transplantation (HR, 0.70; p = 0.0189) than those receiving entecavir. As for treatment-experienced patients, tenofovir was associated with a significantly lower risk of the composite outcome (HR, 0.82; p = 0.0033) and hepatocellular carcinoma (HR, 0.60; p < 0.0001), but it did not show a significantly different risk of all-cause mortality (HR, 0.93; p = 0.3374) or liver transplantation (HR, 1.17; p = 0.5112) compared to entecavir. Conclusion: Tenofovir presented a significantly lower incidence of cirrhosis-related complications than entecavir in patients with hepatitis B virus-related cirrhosis. However, no statistically significant difference in death and liver transplantation was seen in treatment-experienced patients.

Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD

BackgroundAbout 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile.MethodsIn this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization.The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders.Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument.ConclusionCurrently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety.Ethics and disseminationEthical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.Trial registrationClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.

Evaluating the Performance of High-Dimensional Propensity Scores Compared with Standard Propensity Scores for Comparing Antihypertensive Therapies in the CPRD GOLD Database.

Propensity score (PS) matching is widely used in medical record studies to create balanced treatment groups, but relies on prior knowledge of confounding factors. High-dimensional PS (hdPS) is a semi-automated algorithm that selects variables with the highest potential for confounding from medical databases. The objective of this study was to evaluate performance of hdPS and PS when used to compare antihypertensive therapies in the UK clinical practice research datalink (CPRD) GOLD database. Patients initiating antihypertensive treatment with either monotherapy or bitherapy were extracted from the CPRD GOLD database. Simulated datasets were generated using plasmode simulations with a marginal hazard ratio (HRm) of 1.29 for bitherapy versus monotherapy for reaching blood pressure control at 3months. Either 16 or 36 known covariates were forced into the PS and hdPS models, and 200 additional variables were automatically selected for hdPS. Sensitivity analyses were conducted to assess the impact of removing known confounders from the database on hdPS performance. With 36 known covariates, the estimated HRm (RMSE) was 1.31 (0.05) for hdPS and 1.30 (0.04) for PS matching; the crude HR was 0.68 (0.61). Using 16 known covariates, the estimated HRm (RMSE) was 1.23 (0.10) and 1.09 (0.20) for hdPS and PS, respectively. Performance of hdPS was not compromised when known confounders were removed from the database. With 49 investigator-selected covariates, the HR was 1.18 (95% CI 1.10; 1.26) for PS and 1.33 (95% CI 1.22; 1.46) for hdPS. Both methods yielded the same conclusion, suggesting superiority of bitherapy over monotherapy for time to blood pressure control. HdPS can identify proxies for missing confounders, thereby having an advantage over PS in case of unobserved covariates. Both PS and hdPS showed superiority of bitherapy over monotherapy for reaching blood pressure control.

Prognostic Value of Lymph Node Necrosis at Different N Stages in Patients with Nasopharyngeal Carcinoma.

Background: Lymph node necrosis (LNN), including retropharyngeal nodal necrosis and cervical nodal necrosis, which is related to radiotherapy/ chemotherapy resistance, is a common phenomenon in nasopharyngeal carcinoma (NPC). This study was to assess the prognostic value of LNN at different N stages in NPC patients. Materials and Methods: In total, 1,665 newly diagnosed NPC patients at stage TxN1-3M0 from two centers were enrolled. Univariate and multivariate models were constructed to assess the association between LNN and long-term survival outcomes. The propensity score matching method was performed to balance treatment groups for baseline characteristics. Results: Of the 1,665, 540 patients (540/1665, 32.4%) were diagnosed with LNN, of which 54.1% (292/540) patients were at stage N1, 31.3% (169/540) at stage N2, and 14.6% (79/540) at stage N3. Univariate and multivariate analyses indicated LNN as an independent predictor for progression‑free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) in stage N1-3 patients (all P<0.001). When patients were analyzed according to stage, similar findings were observed for N1 patients (all P<0.001); for N2 patients, LNN independently predicted PFS (P=0.003), OS (P=0.011), and DMFS (P=0.004), and for stage N3, LNN only independently predicted LRRFS (P=0.019). 123 pairs of patients who received induction chemotherapy plus concurrent chemoradiotherapy or only concurrent chemoradiotherapy were matched, adding induction chemotherapy improved 5-year OS, PFS and LRFFS, but the results were not statistically significant. Conclusions: In NPC patients, LNN could independently predict poor prognosis at all N1-3 stages and at each N stage (N1 to N3). The value of adding induction chemotherapy to concurrent chemoradiotherapy in patients with LNN still requires further prospective studies.

Sequencing of Androgen Deprivation Therapy of Short Duration with Radiotherapy for Non-Metastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials

<h3>Purpose/Objective(s)</h3> Prior evidence from randomized controlled trials (RCTs) suggests that sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) impacts clinical outcomes, with a potential interplay with pelvic nodal RT (PNRT). Herein, we aim to further investigate this finding across 12 RCTs, and assess the interplay of ADT sequencing with PNRT in localized prostate cancer (LPCa). <h3>Materials/Methods</h3> The Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) consortium was accessed to obtain individual patient data (IPD) from 12 RCTs that included patients with LPCa who received neoadjuvant/concurrent (neo/conc) or concurrent/adjuvant (conc/adj) short-course ADT (4-6 months) with either prostate-only RT (PORT) or PNRT. Inverse probability of treatment weighting (IPTW) analyses were performed to balance treatment groups, with weights derived from propensity scores as a function of age, initial PSA, Gleason Score, T stage and mid-trial enrollment year. The primary endpoint was metastasis-free survival (MFS), as assessed by IPTW-adjusted Cox regression. IPTW-adjusted Fine and Gray competing risk models were developed to evaluate biochemical recurrence (BCR), distant metastasis (DM) and prostate cancer-specific mortality (PCSM). The regression models include ADT sequencing, PNRT and their interaction to account for effect modification. <h3>Results</h3> Overall, 7409 patients were included (6325 neo/conc, 1084 conc/adj) with a median follow-up of 10.2 years (10.3 neo/conc, 9.9 conc/adj). Conc/adj ADT was associated with improved MFS (10-year estimates: 66.3% vs. 60.6%, HR 0.70 [95% CI 0.59-0.83], p<0.0001), BCR (26.2% vs. 35.2%, sHR 0.43 [95% CI 0.34-0.56], p<0.0001), DM (11.5% vs. 9.0%, sHR 0.55 [95% CI 0.36-0.85], p=0.0073), and PCSM (4.6% vs. 6.2%, sHR 0.33 [95% CI 0.19-0.57], p<0.0001). A significant interaction between ADT sequencing and PNRT for all the above endpoints was observed (P-interaction <0.0001 for all). In patients receiving PORT, conc/adj ADT was associated with significantly improved BCR, DM, MFS and PCSM. In contrast, patients receiving PNRT neoadj/conc ADT was associated with significantly improved DM, MFS and PCSM. Comparing the 4 groups based on ADT sequencing and use of PNRT, after IPTW, conc/adj ADT with PORT (reference) had superior MFS compared to neo/conc + PORT (HR 1.59 [95% CI 1.33-1.91], p<0.0001), neo/conc + PNRT (HR 1.96 [95% CI 1.60-2.39], p<0.0001), or conc/adj +PNRT (HR 1.94 [95% CI 1.51-2.50], p<0.0001). <h3>Conclusion</h3> The sequencing of ADT with RT was significantly associated with clinical outcomes, with evidence of a significant interaction based on use of PNRT. PORT with conc/adj vs. neo/conc ADT had improved MFS, while PNRT with neo/conc vs. conc/adj ADT had improved MFS. Overall PORT with conc/adj ADT had superior outcomes. Given the non-randomized nature of the current pooled analysis, we await the results of NRG/RTOG 0924 to understand the role of PNRT in LPCa with neo/conc ADT sequencing.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

PB1878: CROSS-TRIAL ANALYSIS OF FIXED-DURATION IBRUTINIB (I) PLUS VENETOCLAX (V) VS FLUDARABINE (F), CYCLOPHOSPHAMIDE (C), AND RITUXIMAB (R) AS FIRST-LINE TREATMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Background: While continuous single-agent I or I-based therapies are superior to FCR, FCR remains an efficacious fixed-duration regimen for fit patients (pts) with previously untreated CLL. CAPTIVATE (PCYC-1142; NCT02910583) is a multicenter phase 2 study of first-line treatment with the all-oral, once-daily, chemotherapy-free regimen of I+V in fit pts with CLL. Primary analysis of the CAPTIVATE Fixed Duration (FD) cohort demonstrated deep, durable responses with fixed-duration I+V (Ghia et al, ASCO 2021). Aims: We performed a cross-trial analysis to evaluate outcomes with fixed-duration I+V relative to FCR using data from the FD cohort of the CAPTIVATE study and the FCR arm of the recent E1912 study (NCT02048813; Shanafelt et al. NEJM 2019;381:432-43). Methods: This cross-trial analysis included pts with previously untreated CLL or SLL aged ≤70 y who were treated with I+V in the FD cohort of CAPTIVATE or with FCR in E1912. As pts with del(17p) were not enrolled in E1912, pts with del(17p) from CAPTIVATE were excluded from the analysis. In CAPTIVATE, pts received three 28-d cycles of I, followed by 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). In E1912, pts received six 28-d cycles of FCR (F 25 mg/m2 on days 1-3; C 250 mg/m2 on days 1-3; R 50 mg/m2 on day 1 and 325 mg/m2 on day 2 in cycle 1, then 500 mg/m2 on day 1 in cycles 2-6). PFS and OS were estimated by Kaplan-Meier method. Adjusted treatment effects for PFS, OS, and ORR were estimated by inverse probability of treatment weighting (IPTW) using propensity score (PS) which balanced treatment groups for the following baseline prognostic factors: age, sex, ECOG performance status ≥1, CLL/SLL diagnosis, time from diagnosis, advanced Rai stage, absolute lymphocyte count, beta-2 microglobulin >3.5 mg/L, and high-risk genomic features (TP53 mutated, del[11q], unmutated IGHV). AEs were evaluated using overall incidence and exposure-adjusted incidence rates (EAIRs). Results: Analysis included 136 pts without del(17p) treated with fixed-duration I+V in the CAPTIVATE FD cohort and 175 pts treated with FCR in E1912; baseline characteristics were generally well-balanced across groups, with notable differences in the proportions of pts aged ≥65 y and with baseline thrombocytopenia (Table). Median follow-up was 38.7 mo with I+V and 33.7 mo with FCR. After IPTW, PFS was improved with I+V relative to FCR (hazard ratio [HR] 0.42; 95% CI 0.25-0.71; log-rank P=0.0018; 36-mo PFS rate: 89% vs 70%), as was OS (HR 0.19; 95% CI 0.05-0.77; log-rank P=0.0084; 36-mo OS rate: 98% vs 90%). Results were generally similar in unadjusted analyses (Table). Adjusted ORRs were 96% for I+V and 85% for FCR (difference 11.2%; 95% CI 5.1–17.3; Chi-square P=0.0011). Median duration of treatment was 13.8 mo for I+V and 4.7 mo for FCR. Treatment was discontinued due to AEs in 5% and 21% of pts, respectively. Overall, grade ≥3 AEs occurred in 62% of pts with I+V and 90% with FCR. Grade ≥3 AEs in ≥5% of pts with I+V were neutropenia (36%), and with FCR were lymphopenia (67%), neutropenia (45%), leukopenia (41%), lymphocytosis (31%), anemia (18%), thrombocytopenia (18%), febrile neutropenia (16%), hypertension (6%), hyperglycemia (6%), and maculopapular rash (5%). EAIRs for grade ≥3 AEs and AEs of clinical interest of any grade were lower with I+V than with FCR (Table). Image:Summary/Conclusion: Results of this cross-trial analysis suggest superior PFS with fixed-duration I+V relative to FCR in first-line CLL. The safety profile with I+V appeared favorable relative to the safety profile of FCR, with lower AE rates and fewer discontinuations due to AEs.

Design and Statistical Methods for Handling Covariates Imbalance in Randomized Controlled Clinical Trials: Dilemmas Resolved

Introduction In practice, between groups baseline imbalance following randomization not only opens effect estimate to bias in controlled trials, it also has certain ethical consequences. Both design and statistical approaches to ensure balanced treatment groups in prognostic factors are not without their drawbacks. This article identified potential limitations associated with design and statistical approaches for handling covariate imbalance in randomized controlled clinical trials (RCTs) and proffered solutions to them. Methods A careful review of literatures coupled with a robust appraisal of statistical models of methods involved in a way that compared their strength and weaknesses in trial environments, was adopted. Results Stratification breaks down in small sample size trials and may not accommodate more than two stratification factors in practice. On the other hand, minimization that balances for multiple prognostic factors even in small trials is not a pure random procedure and in addition, could present with complexities in computations. Overall, either minimization or stratification factors should be included in the model for statistical adjustment. Statistically, estimate of effect by change score analysis (CSA) is susceptible to direction and magnitude of imbalance. Only analysis of covariance (ANCOVA) yields unbiased effect estimate in all trial scenarios including situations with baseline imbalance in known and unknown prognostic covariates. Conclusion Design methods for balancing covariates between groups are not without their limitations. Both direction and size of baseline imbalance also have profound consequence on effect estimate by CSA. Only ANCOVA yields unbiased treatment effect and is recommended at all trial scenarios, whether or not between groups covariate imbalance matters.

A Quasi-Experimental Study of Intensive Alternative Family Treatment to Prevent Entry of Youth to Psychiatric Residential Treatment

Intensive Alternative Family Treatment (IAFT®) is an enhanced therapeutic foster care program that serves children and youth at risk for entry into a more restrictive level of care. The purpose of this study was to examine the effectiveness of IAFT in reducing first entry into psychiatric residential treatment compared to usual care. We linked IAFT program data to Medicaid claims data in order to develop a quasi-experimental study design to compare outcomes for two groups (N = 1655): (a) youth referred to IAFT who received services and (b) youth referred to IAFT who did not receive IAFT services (i.e., usual care). Propensity score analysis was used to balance treatment and comparison groups on pre-referral indicators. Cox regression analysis was used to examine group differences. Findings supported a significant reduction in risk for entry to psychiatric residential treatment favoring IAFT (hazard ratio 0.72; 95% CI 0.55, 0.93). Results of this study support IAFT’s efficacy as an intensive therapeutic foster care model for delivering mental health services and viability as an alternative to residential care.

Effect of a newly developed pastille on the salivary flow rate in subjects with dry mouth symptoms: a randomized, controlled, monocentric clinical study

BackgroundXerostomia is associated with several diseases and is a side effect of certain drugs, resulting from reduced saliva secretion. Often, aged and sometimes younger people suffer from (idiopathic) xerostomia. Chewing gum and sucking pastilles may relieve symptoms of xerostomia by increasing the salivary flow rate due to the mechanical effect of sucking and gustatory stimulation. Swallowing problems and the urge to cough or experiencing a tickling sensation in the throat might be alleviated through a reduction in dry mouth symptoms. We investigated whether a pastille containing four polysaccharides increased the salivary flow rate and relieved the symptoms of dry mouth.MethodsParticipating subjects with xerostomia were randomized into two equally balanced treatment groups. Subjects received the pastille on Day 1 and a control product (Parafilm®) on Day 3, or vice versa. Unstimulated saliva was collected every 2.5 min for 0–10 min. Stimulated saliva was collected after subjects sucked the pastille or the control product. The salivary flow rate was determined gravimetrically, and, in parallel, the feeling of dry mouth was assessed using a visual analog scale. Saliva surface tension was measured in pooled saliva samples (0–5 min of sampling). Additionally, in stimulated saliva from six subjects who sucked the pastille, the presence of the main ingredient—gum arabic—was examined by Raman spectroscopy.ResultsChewing the pastille significantly increased the mean salivary flow rate by 8.03 g/10 min compared to the mean changes after chewing the control product (+ 3.71 g/10 min; p < 0.0001). The mean score of dry mouth was significantly alleviated by the pastille (− 19.9 ± 17.9 mm) compared to the control product (− 3.3 ± 18.1 mm). No difference between the two products was seen regarding the saliva surface tension. Gum arabic was present in the saliva of all investigated subjects for up to 10 min after sucking the pastille.ConclusionsThe pastille was well tolerated and effective in increasing the salivary flow rate and reducing mouth dryness after sucking. These results were in line with the detection of the main ingredient, gum arabic, in saliva for up to 10 min after sucking the pastille.Trial registration German Register Clinical Trials (Deutsches Register Klinische Studien, DRKS) DRKS-ID: DRKS00017393, Registered 29 May 2019, https://www.drks.de/drks_web/navigate.do?navigationId=trial. HTML&TRIAL_ID = DRKS00017393.

Exploring the causal effects of bicycling for transportation on mental health

Few studies have investigated how transportation-related bicycling might contribute to better mental health. We investigated the effects of utilitarian bicycling frequency on psychological distress and life satisfaction, and explored the possible causal mechanisms, using large and state-wide representative survey data from Victoria, Australia. Propensity score methods were applied to balance treatment and control groups, effectively reducing the selection bias that potentially confounds the causal effects. This study finds that occasional bicycling was not significantly associated with mental health, while regular bicycling was negatively associated with psychological distress and positively associated with life satisfaction. This study also finds that physical activity levels, physical health conditions, and neighborhood physical environment do not fully mediate the effects of utilitarian bicycling on mental wellbeing. These findings support the policies of promoting transportation bicycling to improve population mental health, and highlight the potential role of regular bicycling in combating psychological distress and improving life satisfaction.

PNS176 Is the Door for Rwe in Benefit Assessment in German HTA NOW OPEN?

GSAV, the German law for more safety in drug supply, stipulates that routine clinical practice data may be included in the benefit (re-)assessment of drugs and since 2019 the G-BA may ask for their collection to supplement submitted data. The concepts for generation of routine practice data and their use for the benefit assessment have recently been published by IQWiG. The objective of this study was to critically assess these. We analysed published evidence and engaged in discussions with internal and external experts in the fields of German assessment methodology, RWE and statistics, focusing on the proposed criteria for routine practice data generation and their potential use for conducting treatment comparisons as part of German benefit assessment, comparing to other markets. In A19-43, IQWiG rules out using EMR and claims data for the benefit assessment, due to limited data availability and inconsistent quality. Disease registries are described as the only suitable tool for data collection for benefit assessment. For non-randomised studies, propensity score methods are described as the main acceptable approach to balance treatment groups. In contrast, other HTA bodies (e.g. NICE) allow for more methodological flexibility when generating treatment effect estimates (e.g. multivariate regression analyses). IQWiG concludes that even following the stringent criteria for establishing a registry and guidelines for confounder adjustment, only evidence of ‘low-qualitative certainty’ can be generated. Therefore, our expert panel recommends exploring the use of EMR or claims data, which may fulfil the outlined quality requirements in some cases, in combination with registries. By not making use of the available routine practice data, IQWiG overlooks a data source widely accepted by other HTA bodies. However, the door for RWE in German HTA has now been opened. Other analyses based on propensity score methods, e.g. matched adjusted comparisons may become acceptable in the future.

Perioperative Nonsteroidal Anti-inflammatory Drugs (NSAID) Administration and Acute Kidney Injury (AKI) in Major Gastrointestinal Surgery: A Prospective, Multicenter, Propensity Matched Cohort Study.

This study aimed to determine the relationship between early postoperative nonsteroidal anti-inflammatory drug (NSAID) administration and postoperative acute kidney injury (AKI) and anastomotic leak. NSAIDs have analgesic, opioid-sparing, and anti-inflammatory effects. However, their postoperative use is limited by concerns around increased risk of AKI and anastomotic leak. A secondary analysis of a multicenter, prospective cohort study including patients undergoing elective or emergency major gastrointestinal surgery from September to December 2015 across 173 hospitals in the United Kingdom and ireland. Exposure to early postoperative NSAIDs was defined as NSAID administration on postoperative days 0 to 3. The primary outcome was the 7-day postoperative AKI rate. Propensity score matching was used to balance treatment groups and estimate treatment effects that are presented as odds ratios, alongside the corresponding 95% confidence interval (CI). Overall 19.8% (1039/5240) of patients received early NSAIDs. AKI rates were 10.6% in the early NSAID group and 14.9% in the no NSAID group. The anastomotic leak rate in patients who received an anastomosis was 4.8% in the NSAIDs group and 6.0% in the no NSAIDs group. Following propensity score matching, early use of NSAIDs was not significantly associated with AKI (adjusted odds ratio 0.80, 95% CI 0.63-1.00, P = 0.057). This finding was consistent in subgroup analyses by NSAID dosage and timing. In patients who had a gastrointestinal anastomosis, NSAIDs were not associated with anastomotic leak (adjusted odds ratio 0.85, 95% CI 0.58-1.21, P = 0.382). Administration of NSAIDs in the early postoperative period is safe in selected patients following major gastrointestinal surgery.

Evaluation of Medication Adherence and Rescue Medication Use in Non-Exacerbating Patients with COPD Receiving Umeclidinium/Vilanterol or Budesonide/Formoterol as Initial Maintenance Therapy.

BackgroundAdherence to inhaled maintenance therapy is critical to managing chronic obstructive pulmonary disease (COPD), while increasing rescue medication usage may indicate worsening symptoms. This study evaluated adherence and rescue medication use in patients with COPD without a history of exacerbation who initiated combination therapy with budesonide/formoterol (B/F) or umeclidinium/vilanterol (UMEC/VI).MethodsRetrospective observational study of commercially insured and Medicare Advantage with Part D enrollees who initiated UMEC/VI or B/F between January 1, 2014 and December 31, 2017 (earliest fill defined as index date). Eligibility criteria included age ≥40 years, 12 months continuous enrollment pre- and post-index, ≥1 pre-index COPD diagnosis, no pre-index asthma diagnosis, COPD-related exacerbations, or medication fills containing inhaled corticosteroids, long-acting β2-agonists, or long-acting muscarinic antagonists. Inverse probability of treatment weighting (IPTW) was used to balance treatment groups on potential confounders. Medication adherence (primary endpoint) was evaluated by the proportion of days covered (PDC). Rescue medication use (secondary endpoint) was standardized to canister equivalents (1 metered dose inhaler [200 puffs] or ~100 nebulized doses of short-acting β2-agonist- and/or short-acting muscarinic agonist-containing medication).ResultsAfter IPTW, covariates were balanced between cohorts (UMEC/VI: N=4082; B/F: N=9529). UMEC/VI initiators had a significantly greater mean PDC (UMEC/VI: 0.47 [0.33]; B/F: 0.38 [0.30]; P<0.001) and significantly higher rates of adherence (PDC≥0.80) than B/F initiators (UMEC/VI: n=1004 [25%], B/F: n=1391 [15%]; relative risk: 1.68, 95% CI: 1.57, 1.81; P<0.001). In the year following initiation, UMEC/VI initiators filled significantly fewer rescue medication canister equivalents than B/F initiators (predicted mean [95% CI]: 1.78 [1.69, 1.88] vs 2.15 [2.08, 2.23]; mean difference [95% CI]: −0.37 [−0.50, −0.24]; P<0.001), corresponding to 17% less (estimated) rescue medication use (incidence rate ratio [95% CI]: 0.83 [0.78, 0.88]).ConclusionAmong non-exacerbating patients with COPD initiating dual therapy, UMEC/VI demonstrated improved adherence and reduced rescue medication use compared with B/F.

YI02.03 Statistical Pitfalls in Clinical Trial Design

YI02.03 Statistical Pitfalls in Clinical Trial Design

Statistical Inference for Covariate-Adaptive Randomization Procedures

Covariate-adaptive randomization (CAR) procedures are frequently used in comparative studies to increase the covariate balance across treatment groups. However, because randomization inevitably uses the covariate information when forming balanced treatment groups, the validity of classical statistical methods after such randomization is often unclear. In this article, we derive the theoretical properties of statistical methods based on general CAR under the linear model framework. More importantly, we explicitly unveil the relationship between covariate-adaptive and inference properties by deriving the asymptotic representations of the corresponding estimators. We apply the proposed general theory to various randomization procedures such as complete randomization, rerandomization, pairwise sequential randomization, and Atkinson’s DA-biased coin design and compare their performance analytically. Based on the theoretical results, we then propose a new approach to obtain valid and more powerful tests. These results open a door to understand and analyze experiments based on CAR. Simulation studies provide further evidence of the advantages of the proposed framework and the theoretical results. Supplementary materials for this article are available online.

Five Steps to Successfully Implement and Evaluate Propensity Score Matching in Clinical Research Studies.

In clinical research, the gold standard level of evidence is the randomized controlled trial (RCT). The availability of nonrandomized retrospective data is growing; however, a primary concern of analyzing such data is comparability of the treatment groups with respect to confounding variables. Propensity score matching (PSM) aims to equate treatment groups with respect to measured baseline covariates to achieve a comparison with reduced selection bias. It is a valuable statistical methodology that mimics the RCT, and it may create an "apples to apples" comparison while reducing bias due to confounding. PSM can improve the quality of anesthesia research and broaden the range of research opportunities. PSM is not necessarily a magic bullet for poor-quality data, but rather may allow the researcher to achieve balanced treatment groups similar to a RCT when high-quality observational data are available. PSM may be more appealing than the common approach of including confounders in a regression model because it allows for a more intuitive analysis of a treatment effect between 2 comparable groups.We present 5 steps that anesthesiologists can use to successfully implement PSM in their research with an example from the 2015 Pediatric National Surgical Quality Improvement Program: a validated, annually updated surgery and anesthesia pediatric database. The first step of PSM is to identify its feasibility with regard to the data at hand and ensure availability of data on any potential confounders. The second step is to obtain the set of propensity scores from a logistic regression model with treatment group as the outcome and the balancing factors as predictors. The third step is to match patients in the 2 treatment groups with similar propensity scores, balancing all factors. The fourth step is to assess the success of the matching with balance diagnostics, graphically or analytically. The fifth step is to apply appropriate statistical methodology using the propensity-matched data to compare outcomes among treatment groups.PSM is becoming an increasingly more popular statistical methodology in medical research. It often allows for improved evaluation of a treatment effect that may otherwise be invalid due to a lack of balance between the 2 treatment groups with regard to confounding variables. PSM may increase the level of evidence of a study and in turn increases the strength and generalizability of its results. Our step-by-step approach provides a useful strategy for anesthesiologists to implement PSM in their future research.

Marketplace Coverage and Limited Access to Care Among Employed Beneficiaries? Evidence From Ohio.

This article examines the initial effect of Affordable Care Act (ACA) Health Insurance Marketplace (Exchange) insurance on access to care among employed beneficiaries in a highly populated US state. Does Exchange insurance lead to better/worse health care access for employed beneficiaries, compared with similar individuals covered through standard employer-sponsored insurance (ESI) coverage? This retrospective study uses data from the 2015 Ohio Medicaid Assessment Survey, a dual-frame and computer-assisted telephone survey administered by the Ohio Colleges of Medicine Graduate Resource Center, the Ohio Department of Medicaid, the Ohio Department of Health, and Ohio State University, in conjunction with RTI International. This study examines a sub-sample of employed adults (age 18-64) covered by either an Exchange plan or ESI, extracted from the full sample of n = 42 876. We use linear propensity score matching using Euclidean distance to balance treatment groups and logistic regression models to estimate the treatment effect of Exchange coverage on all outcome variables. McNemar tests, Rosenbaum sensitivity analysis, and Benjamini-Hochberg procedure adjustments are also conducted. Compared with ESI insurance, Exchange insurance has no significant effect on outcomes measuring either perceived access to care or, more specifically, perceived financial barriers to accessing care. Exchange plan viability remains a hot topic of debate across the United States, given the potential repeal of the individual mandate. We use risk-adjustment methods to demonstrate that Exchange plan beneficiaries do not experience worse access to care than ESI beneficiaries. That said, several key limitations are discussed.