Clarifying the causal contrast: An empirical example applying the prevalent new user study design.

PURPOSE: The prevalent new user design extends the active comparator new user design to include patients switching to a treatment of interest from a comparator. We examined the impact of adding "switchers" to incident new users on the estimated hazard ratio (HR) of hospitalized heart failure. METHODS: Using MarketScan claims data (2000-2014), we estimated HRs of hospitalized heart failure between patients initiating GLP-1 receptor agonists (GLP-1 RA) and sulfonylureas (SU). We considered three estimands: (1) the effect of incident new use; (2) the effect of switching; and (3) the effect of incident new use or switching, combining the two population. We used time-conditional propensity scores (TCPS) and time-stratified standardized morbidity ratio (SMR) weighting to adjust for confounding. RESULTS: We identified 76 179 GLP-1 RA new users, of which 12% were direct switchers (within 30 days) from SU. Among incident new users, GLP-1 RA was protective against heart failure (adjHRSMR = 0.74 [0.69, 0.80]). Among switchers, GLP-1 RA was not protective (adjHRSMR = 0.99 [0.83, 1.18]). Results in the combined population were largely driven by the incident new users, with GLP-1 RA having a protective effect (adjHRSMR = 0.77 [0.72, 0.83]). Results using TCPS were consistent with those estimated using SMR weighting. CONCLUSIONS: When analyses were conducted only among incident new users, GLP-1 RA had a protective effect. However, among switchers from SU to GLP-1 RA, the effect estimates substantially shifted toward the null. Combining patients with varying treatment histories can result in poor confounding control and camouflage important heterogeneity.

Data quality considerations for evaluating COVID-19 treatments using real world data: learnings from the National COVID Cohort Collaborative (N3C).

BACKGROUND: Multi-institution electronic health records (EHR) are a rich source of real world data (RWD) for generating real world evidence (RWE) regarding the utilization, benefits and harms of medical interventions. They provide access to clinical data from large pooled patient populations in addition to laboratory measurements unavailable in insurance claims-based data. However, secondary use of these data for research requires specialized knowledge and careful evaluation of data quality and completeness. We discuss data quality assessments undertaken during the conduct of prep-to-research, focusing on the investigation of treatment safety and effectiveness. METHODS: Using the National COVID Cohort Collaborative (N3C) enclave, we defined a patient population using criteria typical in non-interventional inpatient drug effectiveness studies. We present the challenges encountered when constructing this dataset, beginning with an examination of data quality across data partners. We then discuss the methods and best practices used to operationalize several important study elements: exposure to treatment, baseline health comorbidities, and key outcomes of interest. RESULTS: We share our experiences and lessons learned when working with heterogeneous EHR data from over 65 healthcare institutions and 4 common data models. We discuss six key areas of data variability and quality. (1) The specific EHR data elements captured from a site can vary depending on source data model and practice. (2) Data missingness remains a significant issue. (3) Drug exposures can be recorded at different levels and may not contain route of administration or dosage information. (4) Reconstruction of continuous drug exposure intervals may not always be possible. (5) EHR discontinuity is a major concern for capturing history of prior treatment and comorbidities. Lastly, (6) access to EHR data alone limits the potential outcomes which can be used in studies. CONCLUSIONS: The creation of large scale centralized multi-site EHR databases such as N3C enables a wide range of research aimed at better understanding treatments and health impacts of many conditions including COVID-19. As with all observational research, it is important that research teams engage with appropriate domain experts to understand the data in order to define research questions that are both clinically important and feasible to address using these real world data.

CYP2D6 Substrate Dispensing Among Patients Dispensed Mirabegron: An Administrative Claims Analysis.

BACKGROUND: Overactive bladder (OAB) is characterized by the presence of bothersome urinary symptoms. Pharmacologic treatment options for OAB include anticholinergics and ß3-adrenergic agonists. Use of ß3-adrenergic agonists may result in similar treatment efficacy with a decreased side effect profile compared with anticholinergics because high anticholinergic burden is associated with cardiovascular and neurologic side effects. However, the ß3-adrenergic agonist mirabegron, one of two approved drugs within this class, is a moderate cytochrome P450 (CYP) 2D6 inhibitor, and coadministration of drugs that are CYP2D6 substrates with mirabegron may lead to adverse drug effects. OBJECTIVE: The aim of this study was to quantify how often CYP2D6 substrates were dispensed in patients receiving mirabegron among adults of any age and among those ≥ 65 years of age. METHODS: In this retrospective descriptive analysis, a deidentified administrative claims database in the United States, IQVIA PharMetrics® Plus, was used to identify dispensing claims for CYP2D6 substrates and mirabegron from November 2012 to September 2019. Prevalence of CYP2D6 substrate dispensing was assessed in patients dispensed mirabegron among all adults ≥ 18 years old and additionally among a cohort of those ≥ 65 years old. Patient baseline profiles at the time of mirabegron and CYP2D6 substrate codispensing and at the time of mirabegron dispensing were compared. CYP2D6 substrates were categorized as those with the potential for increased risk of QT prolongation, with anticholinergic properties, with narrow therapeutic index (NTI), contraindicated or having a black box warning when used with CYP2D6 inhibitors, or used for depression or other psychiatric disease. Dispensing data and patient profiles were summarized descriptively. RESULTS: Overall, 68.5% of adults ≥ 18 years old dispensed mirabegron had overlapping dispensings for one or more CYP2D6 substrate; 60.6% and 53.6% had overlapping dispensings for CYP2D6 substrates with anticholinergic properties or risk of QT prolongation, respectively. CYP2D6 substrates with NTI, contraindicated with CYP2D6 inhibitors, or for psychiatric use were codispensed in 17.7%, 16.6%, and 38.0% of adult mirabegron users, respectively. Mirabegron users receiving one or more concurrent CYP2D6 substrate were more likely to be older, have more comorbidities and baseline polypharmacy, and have increased healthcare resource utilization compared with those without concurrent CYP2D6 substrates. Commonly codispensed CYP2D6 substrates included hydrocodone, oxycodone, tramadol, metoprolol, and tamsulosin. Findings were similar for patients in the older cohort (≥ 65 years old), with 72.1% receiving overlapping CYP2D6 substrates. CONCLUSIONS: Codispensing of CYP2D6 substrates, especially those with anticholinergic properties or risk of QT prolongation, was common among adults and older adults receiving mirabegron. Results highlight the need for improved awareness of CYP2D6 substrate prescribing among patients receiving pharmacologic treatment for OAB that inhibits the CYP2D6 pathway.

Considerations for observational study design: Comparing the evidence of opioid use between electronic health records and insurance claims.

PURPOSE: Pharmacoepidemiology studies often use insurance claims and/or electronic health records (EHR) to capture information about medication exposure. The choice between these data sources has important implications. METHODS: We linked EHR from a large academic health system (2015-2017) to Medicare insurance claims for patients undergoing surgery. Drug utilization was characterized based on medication order dates in the EHR, and prescription fill dates in Medicare claims. We compared opioid use documented in EHR orders to prescription claims in four time periods: 1) Baseline (182 days before surgery); 2) Perioperative period; 3) Discharge date; 4) Follow-up (90 days after surgery). RESULTS: We identified 11 128 patients undergoing surgery. During baseline, 34.4% (EHR) versus 44.1% (claims) had evidence of opioid use, and 56.9% of all baseline use was reflected only in one data source. During the perioperative period, 78.8% (EHR) versus 47.6% (claims) had evidence of use. On the day of discharge, 59.6% (EHR) versus 45.5% (claims) had evidence of use, and 51.8% of all discharge use was reflected only in one data source. During follow-up, 4.3% (EHR) versus 10.4% (claims) were identified with prolonged opioid use following surgery with 81.4% of all prolonged use reflected only in one data source. CONCLUSIONS: When characterizing opioid exposure, we found substantial discrepancies between EHR medication orders and prescription claims data. In all time periods assessed, most patients' use was reflected only in the EHR, or only in the claims, not both. The potential for misclassification of drug utilization must be evaluated carefully, and choice of data source may have large impacts on key study design elements.

Impacts of Initial Prescription Length and Prescribing Limits on Risk of Prolonged Postsurgical Opioid Use.

BACKGROUND: In response to concerns about opioid addiction following surgery, many states have implemented laws capping the days supplied for initial postoperative prescriptions. However, few studies have examined changes in the risk of prolonged opioid use associated with the initial amount prescribed. OBJECTIVE: The objective of this study was to estimate the risk of prolonged opioid use associated with the length of initial opioid prescribed and the potential impact of prescribing limits. RESEARCH DESIGN: Using Medicare insurance claims (2007-2017), we identified opioid-naive adults undergoing surgery. Using G-computation methods with logistic regression models, we estimated the risk of prolonged opioid use (≥1 opioid prescription dispensed in 3 consecutive 30-d windows following surgery) associated with the varying initial number of days supplied. We then estimate the potential reduction in cases of prolonged opioid use associated with varying prescribing limits. RESULTS: We identified 1,060,596 opioid-naive surgical patients. Among the 70.0% who received an opioid for postoperative pain, 1.9% had prolonged opioid use. The risk of prolonged use increased from 0.7% (1 d supply) to 4.4% (15+ d). We estimated that a prescribing limit of 4 days would be associated with a risk reduction of 4.84 (3.59, 6.09)/1000 patients and would be associated with 2255 cases of prolonged use potentially avoided. The commonly used day supply limit of 7 would be associated with a smaller reduction in risk [absolute risk difference=2.04 (-0.17, 4.25)/1000]. CONCLUSIONS: The risk of prolonged opioid use following surgery increased monotonically with increasing prescription duration. Common prescribing maximums based on days supplied may impact many patients but are associated with relatively low numbers of reduced cases of prolonged use. Any prescribing limits need to be weighed against the need for adequate pain management.

Association of Preoperative Depression and Anxiety With Long-term Opioid Use After Hysterectomy for Benign Indications.

OBJECTIVE: To assess whether preoperative depression or anxiety is associated with increased risk of long-term, postoperative opioid use after hysterectomy among women who are opioid-naïve. METHODS: We conducted an observational cohort study of 289,233 opioid-naïve adult women (18 years or older) undergoing hysterectomy for benign indications from 2010 to 2017 using IBM MarketScan databases. Opioid use and refills in the 180 days after surgery and preoperative depression and anxiety were assessed. Secondary outcomes included 30-day incidence of emergency department visits, readmission, and 180-day incidence of opioid complications. The association of depression and anxiety were compared using inverse-probability of treatment weighted log-binomial and proportional Cox regression. RESULTS: Twenty-one percent of women had preoperative depression or anxiety, and 82% of the entire cohort had a perioperative opioid fill (16% before surgery, 66% after surgery). Although perioperative opioid fills were relatively similar across the two groups (risk ratio [RR] 1.07, 95% CI 1.06-1.07), women with depression or anxiety were significantly more likely to have a postoperative opioid fill at every studied time period (RRs 1.44-1.50). Differences were greater when restricted to persistent use (RRs 1.49-2.61). Although opioid complications were rare, women with depression were substantially more likely to be diagnosed with opioid dependence (hazard ratio [HR] 5.54, 95% CI 4.12-7.44), and opioid use disorder (HR 4.20, 95% CI 1.97-8.96). CONCLUSION: Perioperative opioid fills are common after hysterectomy. Women with preoperative anxiety and depression are more likely to experience persistent use and opioid-related complications.

Day-of-Surgery Gabapentinoids and Prolonged Opioid Use: A Retrospective Cohort Study of Medicare Patients Using Electronic Health Records.

BACKGROUND: While preoperative gabapentinoids are commonly used in surgical multimodal analgesia protocols, little is known regarding the effects this therapy has on prolonged postsurgical opioid use. In this observational study, we used data from a large integrated health care system to estimate the association between preoperative day-of-surgery gabapentinoids and the risk of prolonged postsurgical opioid use. METHODS: We identified adults age ≥65 years undergoing major therapeutic surgical procedures from a large integrated health care system from 2016 to 2019. Exposure to preoperative gabapentinoids on the day of surgery was measured using inpatient medication administration records, and the outcome of prolonged opioid use was measured using outpatient medication orders. We used stabilized inverse probability of treatment-weighted log-binomial regression to estimate risk ratios and 95% confidence intervals (CIs) of prolonged opioid use, comparing patients who received preoperative gabapentinoids to those who did not and adjusting for relevant clinical factors. The main analysis was conducted in the overall surgical population, and a secondary analysis was conducted among procedures where at least 30% of all patients received a preoperative gabapentinoid. RESULTS: Overall, 13,958 surgical patients met inclusion criteria, of whom 21.0% received preoperative gabapentinoids. The observed 90-day risk of prolonged opioid use following surgery was 0.91% (95% CI, 0.77-1.08). Preoperative gabapentinoid administration was not associated with a reduced risk of prolonged opioid use in the main analysis conducted in a broad surgical population (adjusted risk ratio [adjRR], 1.19 [95% CI, 0.67-2.12]) or in the secondary analysis conducted in patients undergoing colorectal resection, hip arthroplasty, knee arthroplasty, or hysterectomy (adjRR, 1.01 [95% CI, 0.30-3.33]). CONCLUSIONS: In a large integrated health system, we did not find evidence that preoperative gabapentinoids were associated with reduced risk of prolonged opioid use in patients undergoing a broad range of surgeries.

The impact of standard postoperative opioid prescribing guidelines on racial differences in opioid prescribing: A retrospective review.

BACKGROUND: Racial disparities in opioid prescribing are widely documented, though few studies assess racial differences in the postoperative setting specifically. We hypothesized standard opioid prescribing schedules reduce total opioids prescribed postoperatively and mitigate racial variation in postoperative opioid prescribing. METHODS: This is a retrospective review of adult general surgery cases at a large, public academic institution. Standard opioid prescribing schedules were implemented across general surgery services for common procedures in late 2018 at various timepoints. Interrupted time series analysis was used to compare mean biweekly discharge morphine milligram equivalents prescribed in the preintervention (Jan-Jun 2018) versus postintervention (Jan-Jun 2019) periods for Black and White patients. Linear regression was used to compare mean difference in discharge morphine milligram equivalents among White and Black patients in each study period, while controlling for demographics, chronic opioid use, and procedure/service. RESULTS: A total of 2,961 cases were analyzed: 1,441 preintervention and 1,520 postintervention. Procedural frequencies, proportion of Black patients (17% Black), and chronic opioid exposure (7% chronic users) were similar across time periods. Interrupted time series analysis showed significantly lower mean level of morphine milligram equivalents prescribed postintervention compared with the predicted nonintervention trend for both Black and White patients. Adjusted analysis showed on average in 2018 Black patients received significantly higher morphine milligram equivalents than White patients (+19 morphine milligram equivalents, 95% confidence interval 0.5-36.5). There was no significant difference in 2019 (-8 morphine milligram equivalents, 95% confidence interval -20.5 to 4.6). CONCLUSION: Standard opioid prescribing schedules were associated with the elimination of racial differences in postoperative opioid prescribing after common general surgery procedures, while also reducing total opioids prescribed. We hypothesize standard opioid prescribing schedules may mitigate the effect of implicit bias in prescribing.

Postsurgical Opioid Prescriptions and Risk of Long-term Use: An Observational Cohort Study Across the United States.

OBJECTIVE: The aim of this study was to evaluate differences in risk of long-term opioid therapy after surgery among an opioid-naive population using varying cutoffs based on days supplied (DS), total morphine milligram equivalents (MME) dispensed, and quantity of pills (QTY) dispensed. BACKGROUND: In response to the US opioid crisis, opioid prescription (Rx) limits have been implemented on a state-by-state basis beginning in 2016. However, there is limited evidence informing appropriate prescribing limits, and the effect of these policies on long-term opioid therapy. METHODS: Using the MarketScan claims databases, we identified all opioid-naive patients undergoing outpatient surgery between July 1, 2006 and June 30, 2015. We identified the initial postsurgical opioid prescribed, examining the DS, total MME, and QTY dispensed. We used Poisson to estimate adjusted risk differences and risk ratios of long-term opioid use comparing those receiving larger versus smaller volume of opioids. RESULTS: We identified 5,148,485 opioid-naive surgical patients. Overall, 55.5% received an opioid for postoperative pain, with median days supply = 5 and median total MME = 240. The proportion of patients receiving prescriptions above 7 DS increased from 11% in 2006 to 19% in 2015. Among those receiving postoperative opioids, 8% had long-term opioid use, and risk of long-term use was 1.16 times [95% confidence interval (CI), 1.10-1.25] higher among those receiving >7 days compared with those receiving ≤7 days. Those receiving >400 total MME (15% of patients) were at 1.17 times (95% CI, 1.10-1.25) the risk of long-term use compared with those receiving ≤400 MME. CONCLUSIONS: Between 2005 and 2015, the amounts of opioids prescribed for postoperative pain increased dramatically, and receipt of larger volume of opioids was associated with increased risk of long-term opioid therapy.

Oral contraceptive use and anterior cruciate ligament injury: comparison of active comparator new user cohort and case-control study designs.

BACKGROUND: This study further investigates a protective association between oral contraceptive (OC) use and anterior cruciate ligament (ACL) injury noted in prior case-control studies. METHODS: Active comparator new user cohort analysis of women aged 13-45 years in the United States from the IBM MarketScan Commercial Claims and Encounters database who newly-initiated low-dose OCs (exposed) or underwent intrauterine device (IUD) insertion (comparison group) from 2000 to 2014. Women were followed for ACL injury starting 90 days after OC initiation or IUD insertion until OC or IUD discontinuation or end of continuous enrollment. Adjusted hazard ratios (adjHR) and 95% confidence intervals (CI) were estimated controlling for age. Secondary analysis replicated previously-published case-control studies assessing "ever" versus "never" OC use over 1- and 5-year periods among women who underwent ACL reconstruction compared to age-matched controls. RESULTS: In the cohort analysis, 2,370,286 women initiated OCs and 621,798 underwent IUD insertion. There were 3571 (0.15%) ACL injuries during an average 370.6 days of continuous OC use and 1620 (0.26%) during an average 590.5 days of IUD use. No difference in risk of ACL injury was observed between OC initiators and IUD users (adjHR = 0.95; 95%CI 0.89, 1.01). The case-control analysis replicated the slight protective association observed in prior studies over a 5-year period (OR = 0.90; 95%CI 0.85, 0.94). CONCLUSIONS: This cohort study suggests no association between OC use and ACL injury, while the case-control study suggested bias from uncontrolled confounding and selection factors may have influenced previous findings that suggested a protective association between OC use and ACL injury.

Perioperative opioid prescriptions associated with stress incontinence and pelvic organ prolapse surgery.

BACKGROUND: There is an opioid epidemic in the United States with a contributing factor of opioids being prescribed for postoperative pain after surgery. OBJECTIVE: Among women who underwent stress urinary incontinence and pelvic organ prolapse surgeries, our primary objective was to determine the proportion of women who filled perioperative opioid prescriptions and to compare factors associated with these opioid prescriptions. We also sought to assess the risk of prolonged opioid use through 1 year after stress urinary incontinence and pelvic organ prolapse surgeries. STUDY DESIGN: Using a population-based cohort of commercially insured individuals in the 2005-2015 IBM MarketScan databases, we identified opioid-naive women ≥18 years who underwent stress urinary incontinence and/or pelvic organ prolapse procedures based on Current Procedural Terminology codes. We defined the perioperative period as the window beginning 30 days before surgery extending until 7 days after surgery. Any filled opioid prescription in this window was considered a perioperative prescription. For our primary outcome, we reported the proportion of opioid-naive women who filled a perioperative opioid prescription and reported the median quantity dispensed in the perioperative period. We also assessed demographic and perioperative factors associated with perioperative opioid prescription fills. Previous studies have defined prolonged use as the proportion of women who fill an opioid prescription between 90 and 180 days after surgery. We report this estimate as well as continuous opioid use, defined as the proportion of women with ongoing monthly opioid prescriptions filled through 1 year after stress urinary incontinence and/or pelvic organ prolapse surgery. RESULTS: Among the 217,460 opioid-naive women who underwent urogynecologic surgery, 61,025 (28.1%) had pelvic organ prolapse and stress urinary incontinence surgeries, 85,575 (39.4%) had stress urinary incontinence surgery without pelvic organ prolapse surgery, and 70,860 (32.6%) had pelvic organ prolapse surgery without stress urinary incontinence surgery. Overall, 167,354 (77.0%) filled a perioperative opioid prescription, and the median quantity was 30 pills (interquartile range, 20-30). In a multivariate regression model, younger age, pelvic organ prolapse surgery with or without stress urinary incontinence surgery, abdominal route, hysterectomy, and mesh use remained significantly associated with opioid prescriptions filled. Among those with a filled perioperative opioid prescription, the risk of prolonged use defined as an opioid prescription filled between 90 and 180 days was 7.5% (95% confidence interval, 7.3-7.6). However, the risk of prolonged use defined as continuous use with at least 1 monthly opioid prescription filled after surgery was significantly lower: 1.2% (1.13-1.24), 0.32% (0.29-0.35), 0.06% (0.05-0.08), and 0.04% (0.02-0.05) at 60, 90, 180, and 360 days after surgery, respectively. CONCLUSION: Among privately insured, opioid-naive women undergoing stress urinary incontinence and/or pelvic organ prolapse surgery, 77% of women filled an opioid prescription with a median of 30 opioid pills prescribed. For prolonged use, 7.5% (95% confidence interval, 7.3-7.6) filled an opioid prescription within 90 to 180 days after surgery, but the rates of continuously filled opioid prescriptions were significantly lower at 0.06% (95% confidence interval, 0.05-0.08) at 180 days and 0.04% (95% confidence interval, 0.02-0.05) at 1 year after surgery.

Persistent Opioid Use After Hysterectomy in the United States, 2005-2015.

OBJECTIVE: To assess variables associated with opioid prescriptions filled perioperatively after hysterectomy and the risk of prolonged opioid use through 1 year after hysterectomy. METHODS: In this retrospective cohort study, we used the 2005-2015 IBM MarketScan databases to identify women aged at least 18 years who underwent hysterectomy. For opioid use, we identified filled prescriptions for opioid medications. We excluded women with prevalent opioid use, defined as an opioid prescription filled 180 to 30 days preoperatively or at least two prescriptions filled in the 30 days before surgery. We defined perioperative opioid use as any opioid prescription filled within 30 days before or 7 days after surgery. We used log-binomial regression to identify independent predictors of perioperative opioid prescription fill. To assess the risk of long-term opioid use, we estimated the proportion of women with ongoing monthly opioid prescriptions through 12 months after surgery and the proportion of women with any opioid prescription 3-6 months after surgery, mimicking published estimates. RESULTS: Among 569,634 women who underwent hysterectomy during the study period, 176,537 (30.9%) were excluded owing to prevalent opioid use. We found that 331,322 (84.3%) women filled a perioperative opioid prescription, with median quantity of 30 pills (interquartile range 25-40), and that younger (adjusted risk ratio [adjRR]18-24 0.91) and older (adjRR65-74 0.84; adjRR75+ 0.70) patients were less likely to receive a perioperative prescription compared with women aged 45-54. The proportion of women with continuous monthly fills of opioids through 2, 3, 6, and 12 months after surgery was 1.40%, 0.34%, 0.06%, and 0.02%, respectively. CONCLUSION: Most women who underwent hysterectomy in the United States from 2005 to 2015 filled a perioperative opioid prescription with a median quantity of 30 pills. The risk of prolonged opioid use through 6 months is quite low, at 0.06% or 1 in 1,547.

Medical Use of Long-term Extended-release Opioid Analgesics in Commercially Insured Adults in the United States.

OBJECTIVES: We examined the proportion of patients initiating extended-release (ER) opioids who become long-term users and describe how pain-related diagnoses before initiation of opioid therapy vary between drugs and over time. METHODS: Using MarketScan (2006-2015), a US national commercial insurance database, we examined pain-related diagnoses in the 182-day baseline period before initiation of ER opioid therapy to characterize indications for opioid initiation. We report the proportion who became long-term users, the median length of opioid therapy, and the proportion with cancer and other noncancer chronic pain, by active ingredient. RESULTS: Among 1,077,566 adults initiating ER opioids, 31% became long-term users, with a median length of use of 209 days. The most common ER opioids prescribed were oxycodone (26%) and fentanyl (23%), and the most common noncancer pain diagnoses were back pain (65%) and arthritis (48%). Among all long-term users, 16% had a diagnosis of cancer. We found notable variation by drug. Eighteen percent of patients initiating drugs approved by the Food and Drug Administration >10 years ago had evidence of cancer during baseline compared with only 8% of patients who received newer drugs. CONCLUSIONS: In a national sample of adults with private insurance, back pain was the most common diagnosis preceding initiation of opioid therapy. Opioids that have been approved within the last 10 years were more frequently associated with musculoskeletal pains and less frequently associated with cancer. Amid increasing concerns regarding long-term opioid therapy, our findings provide context regarding the conditions for which long-term opioid therapy is prescribed.

Cigarette smoking intensity informs outcomes after open revascularization for peripheral artery disease.

OBJECTIVE: Cigarette smoking is the leading risk factor for peripheral artery disease (PAD). Existing literature often defines smoking history in broad categories of current, former, and never smokers, which may not sufficiently identify patients at the highest risk for poor outcomes. The purpose of this study was to examine the use of more informative categorization of smoking and to determine the association with important revascularization outcomes. METHODS: We conducted a retrospective review of all patients undergoing open lower extremity revascularization for symptomatic PAD, defined as claudication (Rutherford 3) or critical limb ischemia (Rutherford 4-6), during a 5-year period (2013-2017). Smoking history, demographics, and comorbidities were abstracted from electronic health records from seven hospitals within our health care system. Smoking history was defined by intensity (packs/day), duration (years), pack-year history, and cessation time. Outcomes included major adverse limb events (MALEs), death, limb loss, and amputation-free survival. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (CIs) for each parameter adjusted for patients' demographics and comorbidities. Cumulative incidence is reported for outcomes at 30, 180, and 365 days of follow-up. RESULTS: We identified 693 patients undergoing open lower extremity revascularization for PAD (66% critical limb ischemia; 46% diabetes). The 1-year cumulative incidence of MALEs was 29.9% (95% CI, 26.4-33.9), whereas the 1-year incidence of death was 9.8% (95% CI, 7.5-12.7). The broad classification of current and former smokers identified no statistically significant differences in any measured outcomes. Patients who smoked more than one pack/day had 1.48 (95% CI, 1.01-2.16) times increase in risk of MALEs at 1 year compared with patients who smoked one or fewer packs/day. Patients who smoked more than one pack/day also had the highest 1-year amputation incidence (12.7%). Each of the four parameters was associated with increased risk of poor outcomes, although small sample size limited the precision of our estimates. CONCLUSIONS: We found that smoking intensity is particularly informative of outcomes of patients undergoing open lower extremity revascularization for symptomatic PAD. These findings lay the groundwork for future research on relevant smoking history parameters and benefits of smoking reduction and cessation for clinicians to discuss with patients and to better understand and inform patients of intervention risks and expected outcomes.

Brief Report: Maternal Opioid Prescription from Preconception Through Pregnancy and the Odds of Autism Spectrum Disorder and Autism Features in Children.

Opioid use during pregnancy is associated with suboptimal pregnancy outcomes. Little is known about child neurodevelopmental outcomes. We examined associations between maternal opioid prescriptions preconception to delivery (peri-pregnancy) and child's risk of ASD, developmental delay/disorder (DD) with no ASD features, or ASD/DD with autism features in the Study to Explore Early Development, a case-control study of neurodevelopment. Preconception opioid prescription was associated with 2.43 times the odds of ASD [95% confidence interval (CI) 0.99, 6.02] and 2.64 times the odds of ASD/DD with autism features (95% CI 1.10, 6.31) compared to mothers without prescriptions. Odds for ASD and ASD/DD were non-significantly elevated for first trimester prescriptions. Work exploring mechanisms and timing between peri-pregnancy opioid use and child neurodevelopment is needed.

Opioid tolerance and clinically recognized opioid poisoning among patients prescribed extended-release long-acting opioids.

BACKGROUND: In recognition of potential for increased overdose risk, drug labels for extended-release and long-acting (ER/LA) opioids emphasize the need for established opioid tolerance prior to initiating high dosages. OBJECTIVES: Describe the proportion of patients with opioid tolerance prior to initiation of 90 morphine milligram equivalents (MME) ER/LA opioids and examine subsequent risk of opioid poisoning. METHODS: We used Truven Health Analytics' MarketScan Databases (2006-2015) to identify patients initiating ER/LA opioids ≥90 MME. We examined prescription histories and describe the proportion of initiators with opioid tolerance (defined as ≥7 days of 60 MME in the prior 14 days). We adjusted for age, sex, year of initiation, and baseline comorbidities using inverse probability of treatment weighted Cox proportional hazards models. We estimated adjusted hazard ratios and 95% confidence intervals for the effect of opioid tolerance on the risk of clinically recognized opioid poisoning (based on diagnosis codes) in specific periods (0-7, 8-30, 31-90, and 91-365 days) following initiation. RESULTS: Among 372 038 initiators, 38% did not meet opioid tolerance criteria. The proportion of nontolerant initiators was highest among those initiating methadone (44%) and fentanyl (42%). Nontolerant patients were 37% more likely to be diagnosed with opioid poisoning (adjusted hazard ratios = 1.37 [1.07, 1.76]) in the week following ER/LA initiation. CONCLUSIONS: Over one-third of patients initiating ≥90 MME ER/LA opioids did not have evidence of opioid tolerance. The 7 days following high dose ER/LA initiation may represent a high-risk period for clinically diagnosed opioid poisoning in patients who do not have prior opioid tolerance.

Correction to: Brief Report: Maternal Opioid Prescription from Preconception Through Pregnancy and the Odds of Autism Spectrum Disorder and Autism Features in Children.

The original version of this article unfortunately contained a mistake in Table 2. The "Time of use" should be the column header with the corresponding row with "N = 126" belonging to the "Peri-pregnancy" row. The "Preconception" row should be the row with "N = 17", "Trimester 1" should be the "N = 29" row, "Trimester 2" should be the "N = 25" row, and "Trimester 3" should be the "N = 47" row.

Measurement error and misclassification in electronic medical records: methods to mitigate bias.

PURPOSE OF REVIEW: We sought to: 1) examine common sources of measurement error in research using data from electronic medical records (EMR), 2) discuss methods to assess the extent and type of measurement error, and 3) describe recent developments in methods to address this source of bias. RECENT FINDINGS: We identified eight sources of measurement error frequently encountered in EMR studies, the most prominent being that EMR data usually reflect only the health services and medications delivered within the specific health facility/system contributing to the EMR data. Methods for assessing measurement error in EMR data usually require gold standard or validation data, which may be possible using data linkage. Recent methodological developments to address the impact of measurement error in EMR analyses were particularly rich in the multiple imputation literature. SUMMARY: Presently, sources of measurement error impacting EMR studies are still being elucidated, as are methods for assessing and addressing them. Given the magnitude of measurement error that has been reported, investigators are urged to carefully evaluate and rigorously address this potential source of bias in studies based in EMR data.