Effect of exogenous testosterone on cardiovascular, cerebrovascular, and thromboembolic adverse events: Results of three complementary research designs.

The cardiovascular risks of exogenous testosterone have been a subject of controversy. In this study, our objective was to examine the association between testosterone (versus glaucoma treatments as an active comparator, with no assumed effect) and the new onset of cardiovascular, cerebrovascular and thromboembolic adverse events, in a US commercial insurance database. Data was analyzed by three complementary designs: inverse propensity score weighting (IPSW), calendar time instrumental variable (IV) and instrumented difference-in-differences (iDiD).

Real-World Data and Real-World Evidence in Regulatory Decision Making: Report Summary From the Council for International Organizations of Medical Sciences (CIOMS) Working Group XIII.

Data from sources other than traditional randomized clinical trials are known as real-world data (RWD), and the evidence derived from the review and analysis of RWD is known as real-world evidence (RWE). RWD and RWE are used increasingly throughout the lifecycle of medicinal products to provide evidence about their effectiveness and safety. Recent regulatory guidance about RWE and approvals based on the use of RWE to demonstrate beneficial effects of products have created an urgency to develop generally accepted processes that promote trust in the evidence-generation process.

Characterizing Treatment Effect Heterogeneity Using Real-World Data.

Characterizing heterogeneity of treatment effects (HTE) is a fundamental goal of pharmacoepidemiology, addressing why medications work differently across patient populations. This paper reviews state-of-the-art methods for studying HTE using real-world data (RWD), which offer larger study sizes and more diverse patient populations compared to randomized clinical trials. The paper first defines HTE and discusses its measurement.

Effectiveness of Empagliflozin vs Dapagliflozin for Kidney Outcomes in Type 2 Diabetes.

Importance: No large randomized clinical trial has directly compared empagliflozin with dapagliflozin, leaving their comparative effectiveness regarding kidney outcomes unknown.

Objective: To compare kidney outcomes between initiation of empagliflozin vs dapagliflozin in adults with type 2 diabetes who were receiving antihyperglycemic treatment.

Design, Setting, And Participants: This target trial emulation used nationwide, population-based routinely collected Danish health care data to compare initiation of empagliflozin vs dapagliflozin in adults with type 2 diabetes who received antihyperglycemic treatment between June 1, 2014, and October 31, 2020.

Evaluation of Drug-Drug Interactions in Pharmacoepidemiologic Research.

Drug-drug interactions (DDIs) represent a significant concern for clinical care and public health, but the health consequences of many DDIs remain largely underexplored. This knowledge gap underscores the critical need for pharmacoepidemiologic research to evaluate real-world health outcomes of DDIs. In this review, we summarize the definitions commonly used in pharmacoepidemiologic DDI studies, discuss common sources of bias, and illustrate through examples how these biases can be mitigated.

Risk of Hypoglycemia Associated With Concomitant Use of Insulin Secretagogues and ACE Inhibitors in Adults With Type 2 Diabetes: A Systematic Review.

Insulin secretagogues and angiotensin-converting enzyme inhibitors (ACEIs) are commonly co-prescribed for patients with type 2 diabetes (T2D). Case reports suggesting that co-administration of insulin secretagogues with ACEIs is associated with an increased risk of serious hypoglycemia have led to warnings regarding a drug-drug interaction in widely used drug compendia. However, subsequent studies have had inconsistent results.

Defining key deprescribing measures from electronic health data: A multisite data harmonization project.

Background: Stopping or reducing risky or unneeded medications ("deprescribing") could improve older adults' health. Electronic health data can support observational and intervention studies of deprescribing, but there are no standardized measures for key variables, and healthcare systems have differing data types and availability. We developed definitions for chronic medication use and discontinuation based on electronic health data and applied them in a case study of benzodiazepines and Z-drugs in five diverse US healthcare systems.

Do relationships between ambient temperature and serious adverse health outcomes vary among users of different antidiabetes drugs? A retrospective cohort study of US Medicaid beneficiaries with type 2 diabetes.

Objective: Prior studies demonstrate that some untoward clinical outcomes vary by outdoor temperature. This is true of some endpoints common among persons with diabetes, a population vulnerable to climate change-associated health risks. Yet, prior work has been agnostic to the antidiabetes drugs taken by such persons.

Concomitant Use of Oral Anticoagulants With Oral Dipeptidyl Peptidase-4 Inhibitors and Serious Bleeding Events.

In a prior screening study, saxagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i), was found to have an increased rate of serious bleeding when used concomitantly with several oral anticoagulants (OACs). We aimed to confirm or refute the associations between concomitant use of individual OACs and DPP-4is and serious bleeding in a large US database, using self-controlled case series (SCCS) and case-crossover (CCO) designs. The study population was eligible Medicare beneficiaries co-exposed to a DPP-4i (precipitant) and either an OAC (object drug) or lisinopril (negative control object drug) in 2016-2020.

Comparative Cardiovascular Effectiveness of Empagliflozin Versus Dapagliflozin in Adults With Treated Type 2 Diabetes: A Target Trial Emulation.

Background: Empagliflozin and dapagliflozin have proven cardiovascular benefits in people with type 2 diabetes at high cardiovascular risk, but their comparative effectiveness is unknown.

Methods: This study used nationwide, population-based Danish health registries to emulate a hypothetical target trial comparing empagliflozin versus dapagliflozin initiation, in addition to standard care, among people with treated type 2 diabetes from 2014 through 2020. The outcome was a composite of myocardial infarction, ischemic stroke, heart failure (HF), or cardiovascular death (major adverse cardiovascular event).

Antibiotic use among extremely low birth-weight infants from 2009 to 2021: a retrospective observational study.

Objective: To assess trends in antibiotic use across a large cohort of extremely low birth-weight (<1000 g; ELBW) infants admitted to academic and community neonatal intensive care units (NICUs) across the USA over a 13-year period.

Design: Repeated cross-sectional cohort study.

Setting: Premier Health Database, a comprehensive administrative database of inpatient encounters from academic and community hospitals across the US.

Severe Acute Liver Injury After Hepatotoxic Medication Initiation in Real-World Data.

Importance: Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure.

Objective: To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports.

Thinking Three-Dimensionally: A Self- and Externally-Controlled Approach to Screening for Drug-Drug-Drug Interactions Among High-Risk Populations.

The global rise in polypharmacy has increased both the necessity and complexity of drug-drug interaction (DDI) assessments, given the growing potential for interactions involving more than two drugs. Leveraging large-scale healthcare claims data, we piloted a semi-automated, high-throughput case-crossover-based approach for drug-drug-drug interaction (3DI) screening. Cases were direct-acting oral anticoagulant (DOAC) users with either a major bleeding event during ongoing dispensings for potentially interacting, enzyme-inhibiting antihypertensive drugs (AHDs) (Study 1), or a thromboembolic event during ongoing dispensings for potentially interacting, enzyme-inducing antiseizure medications (ASMs) (Study 2).

Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants.

Concurrent use of skeletal muscle relaxants (SMRs) and opioids has been linked to an increased risk of injury. However, it remains unclear whether the injury risks differ by specific SMR when combined with opioids. We conducted nine retrospective cohort studies within a US Medicaid population.

Comparative safety of antimuscarinics versus mirabegron for overactive bladder in Parkinson disease.

Background: Overactive bladder (OAB) is a common non-motor symptom of Parkinson disease (PD), often treated with antimuscarinics or beta-3 agonists. There is lack of evidence to guide OAB management in PD.

Objectives: To assess the comparative safety of antimuscarinics versus beta-3 agonists for OAB treatment in PD.

Combining Super Learner with high-dimensional propensity score to improve confounding adjustment: A real-world application in chronic lymphocytic leukemia.

Purpose: High-dimensional propensity score (hdPS) is a semiautomated method that leverages a vast number of covariates available in healthcare databases to improve confounding adjustment. A novel combined Super Learner (SL)-hdPS approach was proposed to assist with selecting the number of covariates for propensity score inclusion, and was found in plasmode simulation studies to improve bias reduction and precision compared to hdPS alone. However, the approach has not been examined in the applied setting.

Off-brand: A 6-year study of medication brand and generic name usage in a multifacility academic healthcare system.

Background: Usage of medication brand names in electronic health records may introduce conflicts of interest, perpetuate false perceptions of brand superiority, alter prescribing practices, and cause confusion leading to errors.

Objective: We sought to identify the frequency of brand name medication usage in clinical documentation, as well as factors associated with increased usage.

Designs, Settings, And Participants: We conducted a retrospective analysis of all clinical documentation written at our healthcare system (a multifacility academic urban healthcare system) between 2015 and 2020.