Propensity score methodology for confounding control in health care utilization databases

Propensity score (PS) methodology is a common approach to control for confounding in nonexperimental studies of treatment effects using health care utilization databases. This methodology offers researchers many advantages compared with conventional multivariate models: it directly focuses on the determinants of treatment choice, facilitating the understanding of the clinical decision-making process by the researcher; it allows for graphical comparisons of the distribution of propensity scores and truncation of subjects without overlapping PS indicating a lack of equipoise; it allows transparent assessment of the confounder balance achieved by the PS at baseline; and it offers a straightforward approach to reduce the dimensionality of sometimes large arrays of potential confounders in utilization databases, directly addressing the “curse of dimensionality” in the context of rare events. This article provides an overview of the use of propensity score methodology for pharmacoepidemiologic research with large health care utilization databases, covering recent discussions on covariate selection, the role of automated techniques for addressing unmeasurable confounding via proxies, strategies to maximize clinical equipoise at baseline, and the potential of machine-learning algorithms for optimized propensity score estimation. The appendix discusses the available software packages for PS methodology. Propensity scores are a frequently used and versatile tool for transparent and comprehensive adjustment of confounding in pharmacoepidemiology with large health care databases

Comparative safety of anesthetic type for hip fracture surgery in adults: retrospective cohort study

Objective: To evaluate the effect of anesthesia type on the risk of in-hospital mortality among adults undergoing hip fracture surgery in the United States. Design: Retrospective cohort study. Setting: Premier research database, United States. Participants: 73 284 adults undergoing hip fracture surgery on hospital day 2 or greater between 2007 and 2011. Of those, 61 554 (84.0%) received general anesthesia, 6939 (9.5%) regional anesthesia, and 4791 (6.5%) combined general and regional anesthesia. Main outcome measure In-hospital all cause mortality. Results: In-hospital deaths occurred in 1362 (2.2%) patients receiving general anesthesia, 144 (2.1%) receiving regional anesthesia, and 115 (2.4%) receiving combined anesthesia. In the multivariable adjusted analysis, when compared with general anesthesia the mortality risk did not differ significantly between regional anesthesia (risk ratio 0.93, 95% confidence interval 0.78 to 1.11) or combined anesthesia (1.00, 0.82 to 1.22). A mixed effects analysis accounting for differences between hospitals produced similar results: compared with general anesthesia the risk from regional anesthesia was 0.91 (0.75 to 1.10) and from combined anesthesia was 0.98 (0.79 to 1.21). Findings were also consistent in subgroup analyses. Conclusions: In this large nationwide sample of hospital admissions, mortality risk did not differ significantly by anesthesia type among patients undergoing hip fracture surgery. Our results suggest that if the previously posited beneficial effect of regional anesthesia on short term mortality exists, it is likely to be more modest than previously reported

Risk of Ischemic Cerebrovascular and Coronary Events in Adult Users of Anticonvulsant Medications in Routine Care Settings

Background: Older‐generation anticonvulsants that highly induce cytochrome P450 enzyme system activity produce metabolic abnormalities that may increase cardiovascular risk. The objective of this study was to evaluate the risk of ischemic cerebrovascular and coronary events in adult new users of anticonvulsants that highly induce cytochrome P450 activity compared with other anticonvulsant agents, as observed in a routine care setting. Methods and Results: This was a cohort study of patients 40 to 64 years old from the HealthCore Integrated Research Database who had initiated an anticonvulsant medication between 2001 and 2006 and had no recorded major coronary or cerebrovascular condition in the 6 months before treatment initiation. Propensity score (PS) matching was used to evaluate ischemic cerebrovascular and coronary risk among anticonvulsant new users. High‐dimensional propensity score (hdPS)–matched analyses were used to confirm adjusted findings. The study identified 913 events in 166 031 unmatched new treatment episodes with anticonvulsant drugs. In a PS‐matched population of 22 864 treatment episodes, the rate ratio (RR) for ischemic coronary or cerebrovascular events associated with highly inducing agents versus other agents was 1.22 (95% CI, 0.90‐1.65). The RR moved to 0.99 (95% CI, 0.73‐1.33) with adjustment for hdPS matching (RR, 1.47; 95% CI, 0.95‐2.28 for cerebrovascular events; RR, 0.70; 95% CI, 0.47‐1.05 for coronary events). Conclusions: In this exploratory analysis, there was no evidence of a consistent and statistically significant effect of initiating anticonvulsants that highly induce cytochrome P450 activity on ischemic coronary or cerebrovascular outcomes compared with other agents, given routine care utilization patterns

Comparative Cardiovascular Risk of Abatacept and Tumor Necrosis Factor Inhibitors in Patients With Rheumatoid Arthritis With and Without Diabetes Mellitus: A Multidatabase Cohort Study

Background: We examined the cardiovascular risk of abatacept compared with tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis with and without diabetes mellitus (DM). Methods and Results: We conducted a cohort study of patients with rheumatoid arthritis who newly started abatacept or TNF inhibitors using claims data from Medicare and MarketScan. The primary outcome was a composite cardiovascular end point of myocardial infarction (MI), stroke/transient ischemic attack, and coronary revascularization. To account for >60 baseline characteristics, abatacept initiators were 1:1 propensity score (PS) matched to TNF initiators in each database. Cox proportional hazards models estimated hazard ratio (HR) and 95% confidence interval (CI) in the PS‐matched cohort per database. A fixed‐effects meta‐analysis pooled database‐specific HRs. We included a total of 13 039 PS‐matched pairs of abatacept and TNF inhibitor initiators (6103 pairs in Medicare and 6936 pairs in MarketScan). A total of 34.7% in Medicare and 19.8% in MarketScan had baseline DM. The HR (95% CI) for the primary outcome associated with abatacept use versus TNF inhibitor was 0.81 (0.66–0.99) in Medicare and 0.95 (0.74–1.23) in MarketScan, with a pooled HR of 0.86 (95% CI, 0.73–1.01; P=0.3 for heterogeneity). The risk of the primary outcome was lower in abatacept initiators versus TNF inhibitors in the DM subgroup, with a pooled HR of 0.74 (95% CI, 0.57–0.96; P=0.7 for heterogeneity), but not in the non‐DM subgroup, with a pooled HR of 0.94 (95% CI, 0.77–1.14; P=0.4 for heterogeneity). Conclusions: In this large population‐based cohort of patients with rheumatoid arthritis, abatacept use appeared to be associated with a modestly reduced cardiovascular risk when compared with TNF inhibitor use, particularly in patients with DM

How Well Can We Assess the Validity of Non-Randomised Studies of Medications? A Systematic Review of Assessment Tools

Objective To determine whether assessment tools for non-randomised studies (NRS) address critical elements that influence the validity of NRS findings for comparative safety and effectiveness of medications. Design Systematic review and Delphi survey. Data sources We searched PubMed, Embase, Google, bibliographies of reviews and websites of influential organisations from inception to November 2019. In parallel, we conducted a Delphi survey among the International Society for Pharmacoepidemiology Comparative Effectiveness Research Special Interest Group to identify key methodological challenges for NRS of medications. We created a framework consisting of the reported methodological challenges to evaluate the selected NRS tools. Study selection Checklists or scales assessing NRS. Data extraction Two reviewers extracted general information and content data related to the prespecified framework. Results Of 44 tools reviewed, 48% (n=21) assess multiple NRS designs, while other tools specifically addressed case–control (n=12, 27%) or cohort studies (n=11, 25%) only. Response rate to the Delphi survey was 73% (35 out of 48 content experts), and a consensus was reached in only two rounds. Most tools evaluated methods for selecting study participants (n=43, 98%), although only one addressed selection bias due to depletion of susceptibles (2%). Many tools addressed the measurement of exposure and outcome (n=40, 91%), and measurement and control for confounders (n=40, 91%). Most tools have at least one item/question on design-specific sources of bias (n=40, 91%), but only a few investigate reverse causation (n=8, 18%), detection bias (n=4, 9%), time-related bias (n=3, 7%), lack of new-user design (n=2, 5%) or active comparator design (n=0). Few tools address the appropriateness of statistical analyses (n=15, 34%), methods for assessing internal (n=15, 34%) or external validity (n=11, 25%) and statistical uncertainty in the findings (n=21, 48%). None of the reviewed tools investigated all the methodological domains and subdomains. Conclusions The acknowledgement of major design-specific sources of bias (eg, lack of new-user design, lack of active comparator design, time-related bias, depletion of susceptibles, reverse causation) and statistical assessment of internal and external validity is currently not sufficiently addressed in most of the existing tools. These critical elements should be integrated to systematically investigate the validity of NRS on comparative safety and effectiveness of medications

Framework for the Synthesis of Non-Randomised Studies and Randomised Controlled Trials: A Guidance on Conducting a Systematic Review and Meta-Analysis for Healthcare Decision Making

Introduction: High-quality randomised controlled trials (RCTs) provide the most reliable evidence on the comparative efficacy of new medicines. However, non-randomised studies (NRS) are increasingly recognised as a source of insights into the real-world performance of novel therapeutic products, particularly when traditional RCTs are impractical or lack generalisability. This means there is a growing need for synthesising evidence from RCTs and NRS in healthcare decision making, particularly given recent developments such as innovative study designs, digital technologies and linked databases across countries. Crucially, however, no formal framework exists to guide the integration of these data types. Objectives and Methods: To address this gap, we used a mixed methods approach (review of existing guidance, methodological papers, Delphi survey) to develop guidance for researchers and healthcare decision-makers on when and how to best combine evidence from NRS and RCTs to improve transparency and build confidence in the resulting summary effect estimates. Results: Our framework comprises seven steps on guiding the integration and interpretation of evidence from NRS and RCTs and we offer recommendations on the most appropriate statistical approaches based on three main analytical scenarios in healthcare decision making (specifically, ‘high-bar evidence’ when RCTs are the preferred source of evidence, ‘medium,’ and ‘low’ when NRS is the main source of inference). Conclusion: Our framework augments existing guidance on assessing the quality of NRS and their compatibility with RCTs for evidence synthesis, while also highlighting potential challenges in implementing it. This manuscript received endorsement from the International Society for Pharmacoepidemiology

Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: population based cohort study

Objective: To provide absolute and relative risk estimates of neonatal abstinence syndrome (NAS) based on duration and timing of prescription opioid use during pregnancy in the presence or absence of additional NAS risk factors of history of opioid misuse or dependence, misuse of other substances, non-opioid psychotropic drug use, and smoking. Design: Observational cohort study. Setting: Medicaid data from 46 US states. Participants: Pregnant women filling at least one prescription for an opioid analgesic at any time during pregnancy for whom opioid exposure characteristics including duration of therapy: short term (<30 days) or long term (≥30 days); timing of use: early use (only in the first two trimesters) or late use (extending into the third trimester); and cumulative dose (in morphine equivalent milligrams) were assessed. Main outcome measure Diagnosis of NAS in liveborn infants. Results: 1705 cases of NAS were identified among 290 605 pregnant women filling opioid prescriptions, corresponding to an absolute risk of 5.9 per 1000 deliveries (95% confidence interval 5.6 to 6.2). Long term opioid use during pregnancy resulted in higher absolute risk of NAS per 1000 deliveries in the presence of additional risk factors of known opioid misuse (220.2 (200.8 to 241.0)), alcohol or other drug misuse (30.8 (26.1 to 36.0)), exposure to other psychotropic medications (13.1 (10.6 to 16.1)), and smoking (6.6 (4.3 to 9.6)) than in the absence of any of these risk factors (4.2 (3.3 to 5.4)). The corresponding risk estimates for short term use were 192.0 (175.8 to 209.3), 7.0 (6.0 to 8.2), 2.0 (1.5 to 2.6), 1.5 (1.0 to 2.0), and 0.7 (0.6 to 0.8) per 1000 deliveries, respectively. In propensity score matched analyses, long term prescription opioid use compared with short term use and late use compared with early use in pregnancy demonstrated greater risk of NAS (risk ratios 2.05 (95% confidence interval 1.81 to 2.33) and 1.24 (1.12 to 1.38), respectively). Conclusions: Use of prescription opioids during pregnancy is associated with a low absolute risk of NAS in the absence of additional risk factors. Long term use compared with short term use and late use compared with early use of prescription opioids are associated with increased NAS risk independent of additional risk factors

Work-related injuries in young workers: an Italian multicentric epidemiological survey.

Emergency departments records from 33 hospitals were reviewed to disclose work-related injuries occurred in teen-subjects living in 14 Italian cities. During January-June 2000, 317 work-related injuries were reported. Male subjects, 17 year old, working in the industrial field, resulted the most affected,probably due to the fact that among young workers this sex and age class is the most represented one. Cluster analysis identified two groups of work-related injuries: one includes mainly transportation injuries causing lower extremities or multiple body sites traumas. The other is more strictly related to specific working tasks and includes mostly traumas and cut wounds in hand/wrist and head, together with eye lesions. A more intensive supervision on the use of protective equipment, a more appropriate training in hazard recognition and safe work practices, including operation of vehicles in the work site, must be implemented to reduce work-related injuries

Empagliflozin cardiovascular and renal effectiveness and safety compared to dipeptidyl peptidase-4 inhibitors across 11 countries in Europe and Asia : Results from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study

Background: Continued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies. Methods: The EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014 -2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary end-points included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined.Findings: Among 83,946 matched patient pairs, (0.7 years overall mean follow-up time), initiation of empagli-flozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0.70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0.55; 0.48 to 0.63), stroke (0. 82; 0.71 to 0.96), and end-stage renal disease (0.43; 0.30 to 0.63) were lower and risk for myocardial infarc-tion, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1.97; 1.28 to 3.03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions.Interpretation: Results from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors.(c) 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Peer reviewe