Impact of the extended-release/long-acting opioid analgesics risk evaluation and mitigation strategy on prescribing practices.

OBJECTIVE: To assess the impact of extended-release (ER)/long-acting (LA) opioid prescriber training on prescribing behaviors. DESIGN: Retrospective cohort study. SETTING: Prescriber training was evaluated from June 1, 2013 through December 31, 2016. The full study period was 2 years longer, from June 1, 2012 through December 31, 2017, to include data for all prescribers' 1-year pretraining and post-training periods. PARTICIPANTS: 24,428 prescribers who wrote ER/LA opioid prescriptions for eligible patients, with a record of training from the partner continuing education provider between June 1, 2013 and December 31, 2016. INTERVENTION: ER/LA opioid prescriber training. MAIN OUTCOME MEASURES: Prescribing behaviors 1-year before (pretraining) and after (post-training) prescribers completed training, specifically the proportion of opioid-nontolerant patients receiving ER/LA opioids indicated for opioid-tolerant patients and for patients receiving ≥100 morphine equivalents dose daily, and the proportion of concomitant users of central nervous system depressant drugs. RESULTS: The differences in the proportion of opioid-nontolerant patients receiving ER/LA opioids indicated for opi-oid-tolerant patients and for patients receiving ≥100 morphine equivalents dose daily were -0.69 percent (95 percent confidence interval [CI]: -1.78 percent, 0.40 percent) and -0.23 percent (95 percent CI: -1.18 percent, 0.68 percent), respectively. The differences in the proportion of concomitant users of central nervous system depressant drugs were -0.94 percent (95 percent CI: -1.39 percent; -0.48 percent) for benzodiazepines, 0.06 percent (95 percent CI: -0.13 percent; 0.25 percent) for antipsychotics, -0.41 percent (95 percent CI: -0.69 percent; -0.13 percent) for hypnotics/sedatives, and 0.08 percent (95 percent CI: -0.40 percent; 0.57 percent) for muscle relaxants. CONCLUSIONS: While prescribers showed some changes in prescribing behavior after completing training, training was not associated with clinically relevant changes in prescribing behaviors.

Real-world treatment patterns and overall survival in BRAF-mutant melanoma patients treated with immunotherapy or targeted therapy.

Aim: To assess overall survival (OS) in patients with advanced BRAF-mutant melanoma by first-line (1L) targeted therapy (TT) or checkpoint inhibitor (CPI) use, second-line (2L) TT or CPI use, and treatment sequence. Patients & methods: Advanced BRAF-mutant melanoma patients treated with 1L CPI or TT were selected from a real-world, electronic health record-derived database. Results: CPI was associated with improved survival after adjustment for potential confounders (hazard ratio, 0.75 [95% CI, 0.66-0.87]). Median OS was similar between 2L therapies and among likely treatment sequences. Conclusion: This real-world study demonstrated a survival benefit with 1L CPI versus TT. Analyses of 2L and treatment sequences were unable to detect or rule out clinically relevant differences in OS.

Immune checkpoint inhibitors and targeted therapies are the preferred treatment options for patients with advanced BRAF-mutant melanoma, with more patients starting first-line treatment with checkpoint inhibitors in the real world. Our study suggests that starting treatment with checkpoint inhibitors instead of targeted therapies may improve survival; however, we were unable to determine the optimal sequence of treatments that patients should be given. The findings of this study highlight the need for further investigation into the optimal treatment sequence with checkpoint inhibitors and targeted therapies in advanced BRAF-mutant melanoma.

Impact of Immune Checkpoint Inhibitors on COVID-19 Severity in Patients with Cancer.

BACKGROUND: Amid continued uncertainty about the management of cancer patients during the pandemic, this study sought to obtain real-world data on the use of immune checkpoint inhibitors (ICIs) before COVID-19 diagnosis and its association with severity and survival outcomes in cancer patients who contracted COVID-19. METHODS: Cancer patients diagnosed with COVID-19 were identified from a large electronic health record database; those treated with ICIs before COVID-19+ diagnosis were matched in a 1:2 ratio to those not treated with ICIs, using a 2-step matching procedure. A descriptive analysis examined the difference in COVID-19 mortality (30-day and overall) and severity outcomes between the 2 cohorts, and overall survival was compared. RESULTS: Among 17 545 adults ≥18 years with cancer who tested positive for COVID-19 between February 20, 2020, and January 28, 2021, in the US, 228 ICI-treated patients were matched to 456 non-ICI-treated patients, comprising the 2 study cohorts. Clinical characteristics differed significantly between the 2 cohorts before matching, with metastatic disease, lung cancer, a history of smoking, and the presence of pulmonary comorbidities being more common in the ICI-treated cohort; after matching, the 2 cohorts were similar. There were no significant differences between the ICI-treated and non-ICI-treated cohorts for 30-day mortality (12.7% vs. 14.9%, P = .235), overall mortality (22.4% vs. 22.4%, P = 1.000), hospitalization (38.6% vs. 39.0%, P = .912), or emergency department visits (16.7% vs. 14.7%, P = .500). Overall survival was similar between the 2 cohorts. CONCLUSION: This analysis adds to the clinical evidence base that use of ICIs before SARS-CoV-2 infection does not affect COVID-19 severity or survival outcomes, supporting the continued use of ICIs in cancer patients during the pandemic.

Factors associated with COVID-19 viral and antibody test positivity and assessment of test concordance: a retrospective cohort study using electronic health records from the USA.

OBJECTIVES: To identify factors associated with COVID-19 test positivity and assess viral and antibody test concordance. DESIGN: Observational retrospective cohort study. SETTING: Optum de-identified electronic health records including over 700 hospitals and 7000 clinics in the USA. PARTICIPANTS: There were 891 754 patients who had a COVID-19 test identified in their electronic health record between 20 February 2020 and 10 July 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: Per cent of viral and antibody tests positive for COVID-19 ('positivity rate'); adjusted ORs for factors associated with COVID-19 viral and antibody test positivity; and per cent concordance between positive viral and subsequent antibody test results. RESULTS: Overall positivity rate was 9% (70 472 of 771 278) and 12% (11 094 of 91 741) for viral and antibody tests, respectively. Positivity rate was inversely associated with the number of individuals tested and decreased over time across regions and race/ethnicities. Antibody test concordance among patients with an initial positive viral test was 91% (71%-95% depending on time between tests). Among tests separated by at least 2 weeks, discordant results occurred in 7% of patients and 9% of immunocompromised patients. Factors associated with increased odds of viral and antibody positivity in multivariable models included: male sex, Hispanic or non-Hispanic black or Asian race/ethnicity, uninsured or Medicaid insurance and Northeast residence. We identified a negative dose effect between the number of comorbidities and viral and antibody test positivity. Paediatric patients had reduced odds (OR=0.60, 95% CI 0.57 to 0.64) of a positive viral test but increased odds (OR=1.90, 95% CI 1.62 to 2.23) of a positive antibody test compared with those aged 18-34 years old. CONCLUSIONS: This study identified sociodemographic and clinical factors associated with COVID-19 test positivity and provided real-world evidence demonstrating high antibody test concordance among viral-positive patients.

Frequency of Early Refills for Opioids in the United States.

OBJECTIVE: Refilling an opioid prescription early is an important risk factor of prescription opioid abuse and misuse; we aimed to understand the scope of this behavior. This study was conducted to quantify the prevalence and distribution of early refills among patients prescribed opioids. METHODS: We conducted a retrospective cohort study utilizing dispensed prescription records. Patients filling one or more prescription opioids were identified and followed for one year. Early refills were defined as having a second prescription filled ≥15% early relative to the days' supply of the previous prescription for the same opioid (according to the National Drug Code [NDC]). The distribution of the number of early refills and patient characteristics were assessed. RESULTS: A total of 60.6 million patients met the study criteria; 28.8% had two or more opioid prescriptions for the same opioid during follow-up. Less than 3% of all patients receiving an opioid had an early refill. Approximately 10% of those with two or more opioid prescriptions for the same drug had an early refill. For patients with multiple fills (N = 1.5 million with extended-release long-acting [ER/LA] opioids; N = 17.1 million with immediate-release short-acting [IR/SA] opioids), early refills were more common among patients with an ER/LA opioid (18.5%) compared with an IR/SA opioid (8.7%). Three-quarters of patients with an early refill had only one (70.9% and 78.4% for ER/LA and IR/SA, respectively). CONCLUSION: Refilling an opioid prescription with the same opioid early is an infrequent behavior within all opioid users, but more common in ER/LA users. Patients who refilled early tended to do so just once.

Prevalence of pyruvate kinase deficiency: A systematic literature review.

OBJECTIVES: Pyruvate kinase deficiency (PK deficiency) is a rare disorder caused by compound heterozygosity or homozygosity for > 300 mutations in the PKLR gene. To understand PK deficiency prevalence, we conducted a systematic literature review. METHODS: We queried Embase and Medline for peer-reviewed references reporting PK deficiency prevalence/incidence, PKLR mutant allele frequency (MAF) among the general population, or crude results from which these metrics could be derived. RESULTS: Of 1390 references screened, 1296 were excluded after title/abstract review; 60 were excluded after full-text review. Four of the remaining 34 studies were considered high-quality for estimating PK deficiency prevalence. Two high-quality studies identified cases from source populations of known sizes, producing estimates of diagnosed PK deficiency prevalence of 3.2 and 8.5 per million. Another high-quality study derived an estimate of diagnosed PK deficiency prevalence of 6.5 per million by screening jaundiced newborns. The final high-quality study estimated total diagnosed and undiagnosed PK deficiency prevalence to be 51 per million through extrapolation from observed MAFs. CONCLUSIONS: We conclude that prevalence of clinically diagnosed PK deficiency is likely between 3.2 and 8.5 per million in Western populations, while the prevalence of diagnosed and undiagnosed PK deficiency could possibly be as high as 51 per million.

Identification of incident pancreatic cancer in Ontario administrative health data: A validation study.

PURPOSE: To validate three approaches for identifying incident cases of pancreatic cancer in Ontario administrative claims data. METHODS: We created a cohort using Ontario (Canada) administrative health data from 2002 to 2012 and identified cases of pancreatic cancer with three approaches, using the Ontario Cancer Registry (OCR) as the reference standard. In the any diagnosis approach, cases were defined by primary or secondary diagnostic codes for pancreatic cancer in outpatient or inpatient records. In the any inpatient diagnosis approach, cases were defined using only diagnoses in hospital discharge abstracts. In the algorithm approach, cases were identified by an algorithm that combined the first two approaches. Comparing each approach to the OCR, we calculated the expected value and 95% confidence interval (CI) of the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We also compared the event dates using each approach with those recorded in the OCR. RESULTS: Among a total of 12 060 837 patients in Ontario administrative health data sources, 13 999 incident pancreatic cancer cases were identified in the OCR. Sensitivity ranged from 72.5% (algorithm) to 97.5% (any diagnosis), and PPV ranged from 38.4% (any diagnosis) to 78.9% (any inpatient diagnosis). Specificity and NPV were ~100% for all approaches. The median absolute difference in cancer event date ranged 0 to 15 days. The any inpatient diagnosis method had the highest PPV (78.9%; 95% CI: 78.2-79.5%) and moderate sensitivity (86.6%; 95% CI: 86.0-87.2%). CONCLUSION: Inpatient diagnoses of pancreatic cancer in Ontario administrative heath data are suitable for pancreatic cancer case identification.

A population-based analysis of antidiabetic medications in four Canadian provinces: Secular trends and prescribing patterns.

PURPOSE: To use the Canadian Network for Observational Drug Effect Studies (CNODES) to describe drug utilization of antidiabetic medications in four Canadian provinces. METHODS: With the use of data from CNODES, we constructed cohorts of patients with type 2 diabetes in four Canadian provinces (Manitoba, Ontario, Quebec, and Saskatchewan) who received their first-ever prescription for a noninsulin antidiabetic medication during the study period, defined as the earliest date of data availability in each province (range: 1993-1998) to the latest date of the data extraction in each province (range: 2013-2014). Prescriptions rates were calculated for all prescriptions by class and described over time. RESULTS: Across provinces, we identified 650 830 patients who initiated antidiabetic medications during the study period. In most provinces, the overall prescription rate of antidiabetic medications increased during the last two decades. Metformin particularly increased in popularity, surpassing sulfonylureas in all provinces as the most widely prescribed antidiabetic medication by the early 2000s. Thiazolidinediones grew in popularity from the onset of their availability until 2006 to 2007, at which point they rapidly declined. Dipeptidyl peptidase-4 inhibitors saw substantial growth in several provinces following their addition to provincial formularies in 2008 to 2012, while glucagon-like peptide-1 agonists experienced modest growth. Insulin prescription rates remained constant or steadily increased over the last two decades. CONCLUSIONS: CNODES can be used for cross-jurisdictional drug utilization studies. In Canada, trends in antidiabetic medication prescriptions followed changing guidelines reflecting up-to-date knowledge of drug effectiveness and safety.

Multiple imputation for systematically missing confounders within a distributed data drug safety network: A simulation study and real-world example.

PURPOSE: In distributed data networks, some data sites may be systematically missing important confounders that are captured by other sites in the network (eg, body mass index [BMI]). Multiple imputation may help repair bias in these scenarios. However, multiple imputation has not been described for distributed data networks where data access restrictions prevent centralized analysis. METHODS: We conducted a simulation study and a real-world analysis using the UK's Clinical Practice Research Datalink to evaluate multiple imputation for confounders that are systematically missing from a subset of data sites in mock distributed data networks. The simulation study addressed univariate missing data, while the real-world analysis addressed multivariate missing data. Both studies were designed as retrospective cohort studies of the effect of current statin use on the risk of myocardial infarction among patients with newly treated type 2 diabetes. RESULTS: In our simulation study, multiple imputation repaired bias from missing BMI in all scenarios, with a median bias reduction of 118% in the default scenario. In our real-world study, the multiply imputed analysis (hazard ratio [HR]: 0.86; 95% confidence interval [CI], 0.69-1.08) was closer to the analysis that considered the true confounder values (HR: 0.85; 95% CI, 0.66-1.10) than the analysis that ignored them (HR: 0.93; 95% CI, 0.73-1.20). CONCLUSIONS: Multiple imputation adapted to distributed data settings is a feasible method to reduce bias from unmeasured but measurable confounders when at least one database contains the variables of interest. Further research is needed to evaluate its validity in real distributed data networks.

Extreme restriction design as a method for reducing confounding by indication in pharmacoepidemiologic research.

PURPOSE: Confounding by indication is a concern in observational pharmacoepidemiologic studies, including those that use active comparator, new user (ACNU) designs. Here, we present a method of restriction to an indication, which we call "extreme restriction," to reduce confounding in such studies. METHODS: As a case study, we evaluated the effect of proton pump inhibitors (PPIs) on hospitalization for community-acquired pneumonia (HCAP). PPI use has been associated with increased HCAP risk, but this association likely results from confounding by indication due to gastroesophageal reflux disease (GERD). Using the UK's Clinical Practice Research Datalink, we compared the risk of HCAP within 180 days between PPI users and histamine-2 receptor antagonist (H2RA) users in an ACNU cohort using Cox proportional hazard models with a time-fixed exposure definition adjusted for high-dimensional propensity score deciles. We then performed the same analysis on an "extremely-restricted" cohort of incident nonsteroidal anti-inflammatory drug (NSAID) users, some of whom received PPIs for prophylaxis. Because PPIs were given as prophylaxis in this population, confounding due to GERD should be limited. We compared effect estimates between ACNU and restricted cohorts to evaluate confounding in both analyses. RESULTS: In the ACNU cohort, PPIs were associated with an increased risk of HCAP (hazard ratio [HR]: 1.25; 95% confidence interval [CI]: 1.05, 1.47), but this association was not present in the restricted cohort (HR: 1.06; 95% CI: 0.75, 1.49). CONCLUSIONS: Restriction to a single indication for treatment may reduce confounding by indication in studies conducted in distributed data networks and other large databases.

Carotid Stenting Versus Endarterectomy for Asymptomatic Carotid Artery Stenosis: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: There is no consensus on the comparative efficacy and safety of carotid artery stenting (CAS) versus carotid endarterectomy (CEA) in patients with asymptomatic carotid artery stenosis. To evaluate CAS versus CEA in asymptomatic patients, we conducted a systematic review and meta-analysis of randomized controlled trials. METHODS: We systematically searched EMBASE, PubMed, MEDLINE, and the Cochrane Library for randomized controlled trials comparing CAS to CEA in asymptomatic patients using a pre-specified protocol. Two independent reviewers identified randomized controlled trials meeting our inclusion/exclusion criteria, extracted relevant data, and assessed quality using the Cochrane risk of bias tool. Random effects models with inverse-variance weighting were used to estimate pooled risk ratios (RRs) comparing the incidences of periprocedural and long-term outcomes between CAS and CEA. RESULTS: We identified 11 reports of 5 randomized controlled trials for inclusion (n=3019) asymptomatic patients. The pooled incidences of any periprocedural stroke (RR, 1.84; 95% confidence interval [CI], 0.99-3.40), periprocedural nondisabling stroke (RR, 1.95; 95% CI, 0.98-3.89), and any periprocedural stroke or death (RR, 1.72; 95% CI, 0.95-3.11) trended toward an increased risk after CAS. We could not rule out clinically significant differences between treatments for long-term stroke (RR, 1.24; 95% CI, 0.76-2.03) and the composite outcome of periprocedural stroke, death or myocardial infarction, or long-term ipsilateral stroke (RR, 0.92; 95% CI, 0.70-1.21). CONCLUSIONS: Although uncertainty surrounds the long-term outcomes of CAS versus CEA, the potential for increased risks of periprocedural stroke and periprocedural stroke or death with CAS suggests that CEA is the preferred option for the management of asymptomatic carotid stenosis.

The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors.

In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization.

The oxidative potential of PM2.5 exposures from indoor and outdoor sources in rural China.

BACKGROUND: Airborne particulate matter (PM) is a widespread environmental exposure and leading health risk factor. The health effects of PM may be mediated by its oxidative potential; however, the combustion and non-combustion sources and components of PM responsible for its oxidative potential are poorly understood, particularly in low- and middle-income rural settings where coal and biomass burning for cooking and heating contribute to PM exposure. METHODS: We measured 24-h personal exposures to fine particulate matter (PM2.5) of 20 rural women in northern (Inner Mongolia) and southern (Sichuan) Chinese provinces who used solid fuels (i.e., coal, biomass). PM2.5 exposures were characterized for mass, black carbon, water-soluble organic carbon, major water-soluble ions, and 47 elements. The oxidative potential of PM2.5 exposures was measured using acellular (dithiothreitol-based) and cellular (macrophage-based) assays. We performed factor and correlation analyses using the chemical components of PM2.5 to identify sources of exposure to PM2.5 and their chemical markers. Associations between oxidative potential and chemical markers for major sources of PM2.5 exposure were assessed using linear regression models. RESULTS: Women's geometric mean PM2.5 exposures were 249µgm(-3) (range: 53.9-767) and 83.9µgm(-3) (range: 73.1-95.5) in Inner Mongolia and Sichuan, respectively. Dust, biomass combustion, and coal combustion were identified as the major sources of exposure to PM2.5. Markers for dust (iron, aluminum) were significantly associated with intrinsic oxidative potential [e.g., one interquartile range increase in iron (ppm) was associated with an 85.5% (95% CI: 21.5, 149) increase in cellular oxidative potential (µgZymosanmg(-1))], whereas markers for coal (arsenic, non-sulfate sulfur) and biomass (black carbon, cadmium) combustion were not associated with oxidative potential. CONCLUSIONS: Dust was largely responsible for the intrinsic oxidative potential of PM2.5 exposures of rural Chinese women, whereas biomass and coal combustion were not significantly associated with intrinsic oxidative potential.

Seasonal and Diurnal Air Pollution from Residential Cooking and Space Heating in the Eastern Tibetan Plateau.

Residential combustion of solid fuel is a major source of air pollution. In regions where space heating and cooking occur at the same time and using the same stoves and fuels, evaluating air-pollution patterns for household-energy-use scenarios with and without heating is essential to energy intervention design and estimation of its population health impacts as well as the development of residential emission inventories and air-quality models. We measured continuous and 48 h integrated indoor PM2.5 concentrations over 221 and 203 household-days and outdoor PM2.5 concentrations on a subset of those days (in summer and winter, respectively) in 204 households in the eastern Tibetan Plateau that burned biomass in traditional stoves and open fires. Using continuous indoor PM2.5 concentrations, we estimated mean daily hours of combustion activity, which increased from 5.4 h per day (95% CI: 5.0, 5.8) in summer to 8.9 h per day (95% CI: 8.1, 9.7) in winter, and effective air-exchange rates, which decreased from 18 ± 9 h(-1) in summer to 15 ± 7 h(-1) in winter. Indoor geometric-mean 48 h PM2.5 concentrations were over two times higher in winter (252 µg/m(3); 95% CI: 215, 295) than in summer (101 µg/m(3); 95%: 91, 112), whereas outdoor PM2.5 levels had little seasonal variability.