Publications by authors named "Virginia Pate"

74 Publications

Long-Term Outcomes After Midurethral Mesh Sling Surgery for Stress Urinary Incontinence.

Female Pelvic Med Reconstr Surg 2021 Sep 30. Epub 2021 Sep 30.

From the Department of Epidemiology, Gillings School of Global Public Health Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Objectives: Although midurethral mesh slings are the criterion standard surgical treatment for stress urinary incontinence (SUI), limited data exist regarding long-term outcomes. Thus, our objectives were to evaluate the long-term risk of sling revision and the risk of repeat SUI surgery up to 15 years after the initial sling procedure and to identify predictors of these outcomes.

Methods: Using a population-based cohort of commercially insured individuals in the United States, we identified women aged 18 years or older who underwent a sling procedure between 2001 and 2018. For sling revision, we evaluated indications (mesh exposure or urinary retention). We estimated the cumulative risks of sling revision and repeat SUI surgery annually using Kaplan-Meier survival curves and evaluated predictors using Cox proportional hazards models.

Results: We identified 334,601 mesh sling surgical procedures. For sling revision, the 10-year and 15-year risks were 6.9% (95% confidence interval [CI], 6.7-7.0) and 7.9% (95% CI, 7.5-8.3), with 48.7% of sling revisions associated with mesh exposure. The 10-year and 15-year risks of repeat SUI surgery were 14.5% (95% CI, 14.2-14.8) and 17.9% (95% CI, 17.3-18.6). Women aged 18-29 years had an elevated risk for both sling revision (hazard ratio, 1.20; 95% CI, 1.15-1.25) and repeat SUI surgery (hazard ratio, 1.30; 95% CI, 1.25-1.37) compared with women 70 years and older.

Conclusions: In our study population, the 15-year risk of sling revision was 7.9%, with nearly half of revisions due to mesh exposure. These findings provide critical long-term data to support informed decisions for women and health care providers considering midurethral mesh slings.
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http://dx.doi.org/10.1097/SPV.0000000000001094DOI Listing
September 2021

Vedolizumab Is Associated With a Lower Risk of Serious Infections Than Anti-TNF Agents in Older Adults.

Clin Gastroenterol Hepatol 2021 Sep 3. Epub 2021 Sep 3.

Center for Gastrointestinal Disease and Biology, University of North Carolina, Chapel Hill, North Carolina; Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

Background & Aims: Despite the increased numbers of older adults with inflammatory bowel diseases (IBDs), there are few studies regarding the safety and effectiveness of IBD treatments in older adults. The aim of this study was to compare the safety and effectiveness of anti-tumor necrosis factor (TNF)-α agents and vedolizumab in older adults with IBD.

Methods: We conducted a retrospective cohort study using an active comparator, new-user design for adults age 65 years and older with IBD initiating anti-TNF-α agents and vedolizumab in the Medicare claims database from 2014 to 2017. The primary safety outcome was infection-related hospitalization (excluding intra-abdominal and perianal abscesses). Co-primary outcomes to estimate effectiveness were IBD-related hospitalization, IBD-related surgery, and new corticosteroid use 60 days or more after biologic initiation. We performed propensity score weighting to control for confounding and estimated adjusted hazard ratios and 95% CIs using standardized morbidity ratio-weighted variables.

Results: We identified 1152 anti-TNF-α new users and 480 vedolizumab new users. The median age was 71 years in both cohorts and 11% were age 80 years or older. Crohn's disease patients comprised 54% of the anti-TNF-α cohort and 57% of the vedolizumab cohort. There was no significant difference in demographics, health care utilization, or frailty in both cohorts. More than half of both cohorts had a Charlson comorbidity index of 2 or higher. Vedolizumab users had a decreased risk of infection-related hospitalization (adjusted hazard ratio, 0.47; 95% CI, 0.25-0.86). There was no significant difference in the outcomes approximating effectiveness.

Conclusions: Older IBD patients treated with vedolizumab had a lower risk of infection-related hospitalization compared with those initiating anti-TNFs. We observed no difference in effectiveness defined by hospitalizations, surgery, or new corticosteroid use.
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http://dx.doi.org/10.1016/j.cgh.2021.08.047DOI Listing
September 2021

Perinatal morbidity and health utilization among mothers of medically fragile infants.

J Perinatol 2021 Aug 10. Epub 2021 Aug 10.

School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Objective: To determine the burden of perinatal morbidity among mothers of medically fragile infants.

Study Design: We conducted a retrospective cohort study of 6849 mothers who delivered liveborn infants at a quaternary care hospital during a two-year period. We compared mothers of well babies with mothers of infants admitted to the Neonatal Intensive Care Unit (NICU), and we used logistic regression to model predictors of postpartum acute care utilization among NICU mothers.

Results: Rates of obstetric morbidity were highest for mothers of infants staying ≥72 h in the NICU; 54.2% underwent cesarean birth, 7.5% experienced severe maternal morbidity, and 6.6% required a blood transfusion. Factors independently associated with postpartum acute care use included gestational age <28 weeks, ever smoking, non-Hispanic Black race, temperature >38 °C and receiving psychiatric medication during the birth hospitalization.

Conclusion: Focused support for mothers of NICU infants has the potential to reduce maternal morbidity and improve health.
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http://dx.doi.org/10.1038/s41372-021-01171-xDOI Listing
August 2021

Effects of anticholinergic and sedative medication use on fractures: A self-controlled design study.

J Am Geriatr Soc 2021 Jul 22. Epub 2021 Jul 22.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background/objectives: Unintentional falls are a leading cause of injury for older adults, and evidence is needed to understand modifiable risk factors. We evaluated 1-year fall-related fracture risk and whether dispensing of medications with anticholinergic/sedating properties is temporally associated with an increased odds of these fractures.

Design: A retrospective cohort study with nested self-controlled analyses conducted between January 1, 2014, and December 31, 2016.

Setting: Twenty percent nationwide, random sample of US Medicare beneficiaries.

Participants: New users of medications with anticholinergic/sedating properties who were 66+ years old and had Medicare Parts A, B, and D coverage but no claims for medications with anticholinergic/sedating properties in the year before initiation were eligible.

Measurements: We followed new users of medications with anticholinergic/sedating properties until first non-vertebral, fall-related fracture (primary outcome), Medicare disenrollment, death, or end of study data. We estimated the 1-year risk with corresponding 95% confidence intervals (CIs) of first fracture after new use. We applied the self-controlled case-crossover and case-time-control designs to estimate odds ratios (ORs) and 95% CIs by comparing anticholinergic and/or sedating medication exposure (any vs. none) during a 14-day hazard period preceding the fracture to exposure to these medications during an earlier 14-day control period.

Results: A total of 1,097,989 Medicare beneficiaries initiated medications with anticholinergic/sedating properties in the study period. The 1-year cumulative incidence of fall-related fracture, accounting for death as a competing risk, was 5.0% (95% CI: 5.0%-5.0%). Using the case-crossover design (n = 41,889), the adjusted OR for the association between anticholinergic/sedating medications and fractures was 1.03 (95% CI: 0.99, 1.08). Accounting for the noted temporal trend using the case-time-control design (n = 209,395), the adjusted OR was 1.60 (95% CI: 1.52, 1.69).

Conclusion: Use of anticholinergic/sedating medication was temporally associated with an increased odds of fall-related fractures. Patients and their healthcare providers should consider pharmacologic and non-pharmacologic treatments for the target condition that are safer.
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http://dx.doi.org/10.1111/jgs.17377DOI Listing
July 2021

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

Anesth Analg 2021 Jul 14. Epub 2021 Jul 14.

From the Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

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.
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http://dx.doi.org/10.1213/ANE.0000000000005656DOI Listing
July 2021

Comparative Effectiveness and Harms of Antibiotics for Outpatient Diverticulitis : Two Nationwide Cohort Studies.

Ann Intern Med 2021 06 23;174(6):737-746. Epub 2021 Feb 23.

Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, North Carolina (L.A.B., R.S.S., A.F.P.).

Background: Outpatient diverticulitis is commonly treated with either a combination of metronidazole and a fluoroquinolone (metronidazole-with-fluoroquinolone) or amoxicillin-clavulanate alone. The U.S. Food and Drug Administration advised that fluoroquinolones be reserved for conditions with no alternative treatment options. The comparative effectiveness of metronidazole-with-fluoroquinolone versus amoxicillin-clavulanate for diverticulitis is uncertain.

Objective: To determine the effectiveness and harms of metronidazole-with-fluoroquinolone versus amoxicillin-clavulanate for outpatient diverticulitis.

Design: Active-comparator, new-user, retrospective cohort studies.

Setting: Nationwide population-based claims data on U.S. residents aged 18 to 64 years with private employer-sponsored insurance (2000 to 2018) or those aged 65 years or older with Medicare (2006 to 2015).

Participants: Immunocompetent adults with diverticulitis in the outpatient setting.

Intervention: Metronidazole-with-fluoroquinolone or amoxicillin-clavulanate.

Measurements: 1-year risks for inpatient admission, urgent surgery, and infection (CDI) and 3-year risk for elective surgery.

Results: In MarketScan (IBM Watson Health), new users of metronidazole-with-fluoroquinolone ( = 106 361) and amoxicillin-clavulanate ( = 13 160) were identified. There were no differences in 1-year admission risk (risk difference, 0.1 percentage points [95% CI, -0.3 to 0.6]), 1-year urgent surgery risk (risk difference, 0.0 percentage points [CI, -0.1 to 0.1]), 3-year elective surgery risk (risk difference, 0.2 percentage points [CI, -0.3 to 0.7]), or 1-year CDI risk (risk difference, 0.0 percentage points [CI, -0.1 to 0.1]) between groups. In Medicare, new users of metronidazole-with-fluoroquinolone ( = 17 639) and amoxicillin-clavulanate ( = 2709) were identified. There were no differences in 1-year admission risk (risk difference, 0.1 percentage points [CI, -0.7 to 0.9]), 1-year urgent surgery risk (risk difference, -0.2 percentage points [CI, -0.6 to 0.1]), or 3-year elective surgery risk (risk difference, -0.3 percentage points [CI, -1.1 to 0.4]) between groups. The 1-year CDI risk was higher for metronidazole-with-fluoroquinolone than for amoxicillin-clavulanate (risk difference, 0.6 percentage points [CI, 0.2 to 1.0]).

Limitation: Residual confounding is possible, and not all harms associated with these antibiotics, most notably drug-induced liver injury, could be assessed.

Conclusion: Treating diverticulitis in the outpatient setting with amoxicillin-clavulanate may reduce the risk for fluoroquinolone-related harms without adversely affecting diverticulitis-specific outcomes.

Primary Funding Source: National Institutes of Health.
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http://dx.doi.org/10.7326/M20-6315DOI Listing
June 2021

Trends in Opioid and Psychotropic Prescription in Pregnancy in the United States From 2001 to 2015 in a Privately Insured Population : A Cross-sectional Study.

Ann Intern Med 2020 12;173(11 Suppl):S19-S28

University of Utah Health, Salt Lake City, Utah (M.C.S.).

Background: Opioid and psychotropic prescriptions are common during pregnancy. Little is known about coprescriptions of both medications in this setting.

Objective: To describe opioid prescription among women who are prescribed psychotropics compared with women who are not.

Design: Cross-sectional study.

Setting: U.S. commercial insurance beneficiaries from MarketScan (2001 to 2015).

Participants: Pregnant women at 22 weeks' gestation or greater who were insured continuously for 3 months or more before pregnancy through delivery.

Measurements: Opioid prescription, dosage thresholds (morphine milligram equivalents [MME] of ≥50/day and ≥90/day), number of opioid agents (≥2), and duration (≥30 days) among those with and without prescription of psychotropics, from 2011 to 2015.

Results: Among 958 980 pregnant women, 10% received opioids only, 6% psychotropics only, and 2% opioids with coprescription of psychotropics. Opioid prescription was higher among women prescribed psychotropics versus those who were not (26.5% vs. 10.7%). From 2001 to 2015, psychotropic prescription overall increased from 4.4% to 7.6%, opioid prescription without coprescription of psychotropics decreased from 11.9% to 8.4%, and opioids with coprescription decreased from 28.1% to 22.0%. Morphine milligram equivalents of 50 or greater per day decreased for women with and without coprescription (29.6% to 17.3% and 22.8% to 18.5%, respectively); MME of 90 or greater per day also decreased in both groups (15.0% to 4.7% and 11.5% to 4.2%, respectively). Women prescribed opioids only were more likely to have an antepartum hospitalization compared with those with neither prescription, as were women with coprescription versus those prescribed psychotropics only. Compared with those prescribed opioids only, women with coprescriptions were more likely to exceed MME of 90 or greater per day and to be prescribed 2 or more opioid agents and for 30 days or longer. Number and duration of opioids increased with benzodiazepine and gabapentin coprescription.

Limitation: Inability to determine appropriateness of prescribing or overdose events.

Conclusion: Opioids are frequently coprescribed with psychotropic medication during pregnancy and are associated with antepartum hospitalization. A substantial proportion of pregnant women are prescribed opioids at doses that increase overdose risk and exceed daily recommendations.

Primary Funding Source: None.
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http://dx.doi.org/10.7326/M19-3249DOI Listing
December 2020

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

Inj Epidemiol 2020 Oct 19;7(1):53. Epub 2020 Oct 19.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, McGavran Greenberg Hall, CB #7435, Chapel Hill, NC, 27599-7435, USA.

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.
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http://dx.doi.org/10.1186/s40621-020-00282-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570098PMC
October 2020

The comparative risk of acute kidney injury of vancomycin relative to other common antibiotics.

Sci Rep 2020 10 14;10(1):17282. Epub 2020 Oct 14.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, 135 Dauer Drive, 2101 McGavran-Greenberg Hall, CB #7435, Chapel Hill, NC, USA.

The glycopeptide antibiotic vancomycin is a mainstay in the treatment of Gram-positive infection. While its association with acute kidney injury (AKI) has waxed and waned, recent data suggest nephrotoxicity, even as mono-therapy. Our study aimed to evaluate the 2-week risk of AKI after at least 3 days of intravenous vancomycin mono-therapy initiated within 5 days of hospitalization compared to other intravenous antibiotics used for similar indications. We used a new user-active comparator study design and identified patients with a first hospitalization during which they received vancomycin or comparator, from commercial claims based in the United States. We estimated incidence rates, hazard ratios using adjusted cox-regression models, and standardized mortality/morbidity ratio weighted cox-regression models. In the 32,997 patients vancomycin was used in 17% of patients and 129 cases of AKI were observed. Overall incidence of AKI was 9.3 (95% CI 0.78-1.22) per 100 person-years. The adjusted hazard ratio for vancomycin versus all other comparators was 0.74 (95% CI 0.45-1.21). Separate models for respective comparators resulted in hazard ratios below the null, except for vancomycin vs. cefazolin. Intravenous vancomycin mono-therapy does not increase the risk of AKI compared to other intravenous antibiotics used for similar indication in this cohort of hospitalized patients.
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http://dx.doi.org/10.1038/s41598-020-73687-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560595PMC
October 2020

Quantifying cumulative anticholinergic and sedative drug load among US Medicare Beneficiaries.

Pharmacoepidemiol Drug Saf 2021 02 15;30(2):144-156. Epub 2020 Oct 15.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Purpose: Medications with anticholinergic and sedative properties are widely used among older adults despite strong evidence of harm. The drug burden index (DBI), a pharmacological screening tool, measures these properties across drug classes, and higher DBI drug exposure (DBI > 1) has been associated with certain physical function-related adverse events. Our aim was to quantify mean daily DBI drug exposure among older adults in the United States (US).

Methods: We screened medications for DBI properties and operationalized the DBI for US Medicare claims. We then conducted a retrospective cohort study of a 20% random, nationwide sample of 4 137 384 fee-for-service Medicare beneficiaries aged 66+ years (134 757 039 person-months) from January 2013 to December 2016. We measured the monthly distribution based on mean daily DBI, categorized as (a) >0 vs 0 (any use) and (b) 0, 0 < DBI ≤ 1, 1 < DBI ≤ 2, and DBI > 2, and examined temporal trends. We described patient-level factors (eg, demographics, healthcare use) associated with high (>2) vs low (0 < DBI≤1) DBI drug exposure.

Results: The distribution of the mean daily DBI, aggregated at the month-level, was: 58.1% DBI = 0, 29.0% 0 < DBI≤1, 9.3% 1 < DBI≤2, and 3.7% DBI > 2. Predictors of high monthly DBI drug exposure (DBI > 2) included certain indicators of increased healthcare use (eg, high number of drug claims), white race, younger age, frailty, and a psychosis diagnosis code.

Conclusions: The predictors of high DBI drug exposure can inform discussions between patients and providers about medication appropriateness and potential de-prescribing. Future Medicare-based studies should assess the association between the DBI and adverse events.
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http://dx.doi.org/10.1002/pds.5144DOI Listing
February 2021

Gender Disparities in Surgical Treatment of Axis Fractures in Older Adults.

Global Spine J 2021 Jan 25;11(1):71-75. Epub 2019 Nov 25.

2331University of North Carolina, Chapel Hill, NC, USA.

Study Design: Retrospective cohort study.

Objectives: Gender appears to play in important role in surgical outcomes following acute cervical spine trauma, with current literature suggesting males have a significantly higher mortality following spine surgery. However, no well-adjusted population-based studies of gender disparities in incidence and outcomes of spine surgery following acute traumatic axis injuries exist to our knowledge. We hypothesized that females would receive surgery less often than males, but males would have a higher 1-year mortality following isolated traumatic axis fractures.

Methods: We performed a retrospective cohort study using Medicare claims data that identified US citizens aged 65 and older with ICD-9 (International Classification of Diseases, Ninth Revision) code diagnosis corresponding to isolated acute traumatic axis fracture between 2007 and 2014. Our primary outcome was defined as cumulative incidence of surgical treatment, and our secondary outcome was 1-year mortality. Propensity weighted analysis was performed to balance covariates between genders. Our institutional review board approved the study (IRB #16-0533).

Results: There was no difference in incidence of surgery between males and females following acute isolated traumatic axis fractures (7.4 and 7.5 per 100 fractures, respectively). Males had significantly higher 1-year weighted mortality overall (41.7 and 28.9 per 100 fractures, respectively, < .001).

Conclusion: Our well-adjusted data suggest there was no significant gender disparity in incidence of surgical treatment over the study period. The data also support previous observations that males have worse outcomes in comparison to females in the setting of axis fractures and spinal trauma regardless of surgical intervention.
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http://dx.doi.org/10.1177/2192568219890573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734274PMC
January 2021

Newer second-line glucose-lowering drugs versus thiazolidinediones on cirrhosis risk among older US adult patients with type 2 diabetes.

J Diabetes Complications 2020 11 5;34(11):107706. Epub 2020 Aug 5.

Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, United States of America; Durham Veterans Affairs Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham, NC, United States of America.

Aims: Type 2 diabetes (T2D) accelerates progression of chronic liver disease to cirrhosis, yet the effects of most glucose-lowering drugs (GLDs) on cirrhosis risk in T2D are unknown. To address this gap, we compared cirrhosis risk following initiation of newer second-line GLDs vs. thiazolidinediones (TZDs), which improve histology in non-alcoholic fatty liver disease.

Materials And Methods: Using the US Medicare Fee-for-Service database (2007-2015) and an active comparator, new-user design, we estimated crude incidence rates (IRs) and propensity-score adjusted hazard ratios (aHR) for incident cirrhosis, comparing newer GLDs (dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1RA), and sodium-glucose co-transporter 2 inhibitors (SGLT2i)) vs. TZDs.

Results: Among 239,549 total initiators, we observed 318, 151, and < 30 cirrhosis events when comparing DPP4i vs. TZD, GLP1RA vs. TZD, and SGLT2i vs. TZD, respectively. IRs ranged from 1.7 [95% CI, 0.8-3.6] to 3.6 [2.5-5.2] events per 1000 person-years. Point aHR estimates for cirrhosis were elevated among newer GLD initiators vs. TZD (DPP4i: 1.15 [0.89-1.50]; GLP1RA: 1.34 [0.82-2.20]; SGLT2i: 1.16, [0.44-3.08]), although estimates were imprecise due to short durations of drug exposure.

Conclusions: We observed mildly elevated cirrhosis risk with newer GLDs vs. TZD; however, uncertainty remains due to imprecise and statistically non-significant effect estimates.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657660PMC
November 2020

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

Am J Obstet Gynecol 2020 12 9;223(6):894.e1-894.e9. Epub 2020 Jul 9.

Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Center for Women's Health Research, University of North Carolina at Chapel Hill, Chapel Hill, NC.

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.
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http://dx.doi.org/10.1016/j.ajog.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704807PMC
December 2020

Decreased Antihyperglycemic Drug Use Driven by High Out-of-Pocket Costs Despite Medicare Coverage Gap Closure.

Diabetes Care 2020 09 8;43(9):2121-2127. Epub 2020 Jul 8.

Department of Epidemiology, Gillings School of Public Health, University of North Carolina, Chapel Hill, NC.

Objective: Using the 2016 Medicare Part D coverage gap as an example, we explored effects of increased out-of-pocket costs on adherence to branded dipeptidyl peptidase 4 inhibitors (DPP-4i) in patients without financial subsidies relative to subsidized patients who do not experience increased spending during the gap. We also explored seasonality of reinitiation, because discontinuers may be more likely to reinitiate in January when benefits reset.

Research Design And Methods: We identified DPP-4i or sulfonylurea initiators, aged ≥66 years, from a 20% sample of 2015-2016 Medicare claims. Difference-in-differences Poisson regression was used to compare adherence before and after entering the coverage gap between nonsubsidized and subsidized patients. Among discontinuers, monthly hazard ratios (HRs) for reinitiation relative to January 2016 were derived with Cox models. As a second control, we repeated analyses using sulfonylureas, generic low-cost alternatives.

Results: In 2016, 8,096 subsidized and 6,173 nonsubsidized DPP-4i initiators entered the coverage gap. For nonsubsidized patients, copayment in the coverage gap was 45% ($227 per DPP-4i prescription), and adherence decreased from 68.4% to 49.0% after gap entry. Accounting for adherence differences in subsidized patients, nonsubsidized patients demonstrated reduced adherence to DPP-4i (difference-in-difference: -16.9%; 95% CI -18.7%, -15.1%) but not sulfonylureas (-1.6%; 95% CI -3.4%, 0.2%). Reinitiation was lowest in the months before January (HR 0.4-0.5) among nonsubsidized DPP-4i patients, demonstrating a strong seasonal pattern.

Conclusions: Increased out-of-pocket costs negatively affect adherence and reinitiation of branded antihyperglycemic drugs among patients without financial subsidies. Despite closure of the coverage gap, affordability remains a concern given increasing list prices for many drugs on Medicare and the growing use of deductibles and coinsurance by commercial health plans.
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http://dx.doi.org/10.2337/dc19-1880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440898PMC
September 2020

1-Year Mortality and Surgery Incidence in Older US Adults with Cervical Spine Fracture.

World Neurosurg 2020 09 12;141:e858-e863. Epub 2020 Jun 12.

Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background: Traumatic cervical spinal cord injuries (SCIs) can be lethal and are especially dangerous for older adults. Falls from standing and risk factors for a cervical fracture and spinal cord injury increase with age. This study estimates the 1-year mortality for patients with a cervical fracture and resultant SCI and compares the mortality rate with that from an isolated cervical fracture.

Methods: We performed a retrospective cohort study of U.S. Medicare patients older than 65 years of age. International Classification of Diseases (ICD)-9 codes were used to identify patients with a cervical fracture without SCI and patients with a cervical fracture with SCI between 2007 and 2014. Our primary outcome was 1-year mortality cumulative incidence rate; our secondary outcome was the cumulative incidence rate of surgical intervention. Propensity weighted analysis was performed to balance covariates between the groups.

Results: The SCI cohort had a 1-year mortality of 36.5%, compared with 31.1% in patients with an isolated cervical fracture (risk difference 5.4% (2.9%-7.9%)). Patients with an SCI were also more likely to undergo surgical intervention compared with those without a SCI (23.1% and 10.3%, respectively; risk difference 12.8% (10.8%-14.9%)).

Conclusions: Using well-adjusted population-level data in older adults, this study estimates the 1-year mortality after SCI in older adults to be 36.5%. The mortality after a cervical fracture with SCI was 5 percentage points higher than in patients without SCI, and this difference is smaller than one might expect, likely representing the frailty of this population and unmeasured covariates.
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http://dx.doi.org/10.1016/j.wneu.2020.06.070DOI Listing
September 2020

Comparative Propensity-Weighted Mortality After Isolated Acute Traumatic Axis Fractures in Older Adults.

Geriatr Orthop Surg Rehabil 2020 30;11:2151459320911867. Epub 2020 Mar 30.

Department of Neurosurgery, UNC School of Medicine, NC, USA.

Introduction: In older patients with axis fractures, the survival benefit from surgery is unclear due to high baseline mortality. Comparative effectiveness research can provide evidence from population level cohorts. Propensity weighting is the preferred methodology for reducing bias when analyzing national administrative cohort data for these purposes but has not yet been utilized for this important surgical conundrum. We estimate the effect of surgery on mortality after isolated acute traumatic axis fracture in older adults.

Materials And Methods: We used a retrospective population-based cohort of Medicare patients and generated a propensity score-weighted nonsurgical cohort and compared mortality with and without surgery. This balanced the comorbid conditions of the treatment groups. Incident fractures were defined using a predetermined algorithm based on enrollment, code timing, and billing location. The primary outcome was adjusted all-cause 1-year mortality.

Results: From 12 372 beneficiaries with 1-year continuous enrollment and a coded axis fracture, 2676 patients met final inclusion/exclusion criteria. Estimated incidence was 16.5 per 100 000 person-years overall in 2014 (95% confidence interval [CI]: 15.0-18.0) and was stable from 2008 through 2014. Patients with axis fracture had a mean age of 82.8 years, 30.2% were male, and 91.9% were Caucasian. Mortality was 3.8 times higher (CI 3.6-4.1) compared with the general population of older US adults. Propensity-weighted mortality at 1 year for nonsurgical patients was 26.7 of 100 (CI: 24.5-29.0). Mortality for surgical patients was significantly lower (19.7/100; CI 14.5-25.0). Risk difference was 7.0 fewer surgical deaths per 100 patients (CI: 1.3-12.7). Surgical patients aged 65 to 74 years had the largest difference in mortality with 11.2 fewer deaths per 100 (CI: 1.1-21.3).

Discussion: Patients with axis fractures are predominantly older Caucasian women and have a higher mortality rate than the general population. Propensity-weighted mortality at 1-year was lower in the surgical patients with the largest risk difference occurring in patients 65 to 74 years old.

Conclusions: Surgery may provide an independent survival benefit in patients aged 65 to 75 years, and the mortality difference diminishes thereafter.
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http://dx.doi.org/10.1177/2151459320911867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133078PMC
March 2020

Real-world evidence on sodium-glucose cotransporter-2 inhibitor use and risk of Fournier's gangrene.

BMJ Open Diabetes Res Care 2020 01;8(1)

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with increased occurrence of Fournier's gangrene (FG), a rare but serious form of necrotizing fasciitis, leading to a warning from the Food and Drug Administration. Real-world evidence on FG is needed to validate this warning.

Methods: We used data from IBM MarketScan (2013-2017) to compare the incidence of FG among adult patients who initiated either SGLT2i, a dipeptidyl peptidase-4 inhibitor (DPP4i), or any non-SGLT2i antihyperglycemic medication. FG was defined using inpatient International Classification of Diseases, Ninth Edition and Tenth Edition diagnosis codes 608.83 and N49.3, respectively, combined with procedure codes for debridement, surgery, or systemic antibiotics. We estimated crude incidence rates (IRs) using Poisson regression, and crude and adjusted HRs (aHR) and 95% CIs using standardized mortality ratio-weighted Cox proportional hazards models. Sensitivity analyses examined the impact of alternative outcome definitions.

Results: We identified 211 671 initiators of SGLT2i (n=93 197) and DPP4i (n=118 474), and 305 329 initiators of SGLT2i (n=32 868) and non-SGLT2i (n=272 461). Crude FG IR ranged from 3.2 to 3.8 cases per 100 000 person-years during a median follow-up of 0.51-0.58 years. Compared with DPP4i, SGLT2i initiation was not associated with increased risk of FG for any outcome definition, with aHR estimates ranging from 0.25 (0.04-1.74) to 1.14 (0.86-1.51). In the non-SGLT2i comparison, we observed an increased risk of FG for SGLT2i initiators when using FG diagnosis codes alone, using all diagnosis settings (aHR 1.80; 0.53-6.11) and inpatient diagnoses only (aHR 4.58; 0.99-21.21).

Conclusions: No evidence of increased risk of FG associated with SGLT2i was observed compared with DPP4i, arguably the most relevant clinical comparison. However, uncertainty remains based on potentially higher risk in the broader comparison with all non-SGLT2i antihyperglycemic agents and the rarity of FG.

Trial Registration Number: EUPAS Register Number 30018.
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http://dx.doi.org/10.1136/bmjdrc-2019-000985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039596PMC
January 2020

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

Obstet Gynecol 2020 01;135(1):123-132

Department of Epidemiology, Gillings School of Global Public Health; the Center for Women's Health Research; and the Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

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.
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http://dx.doi.org/10.1097/AOG.0000000000003612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236400PMC
January 2020

Dipeptidyl Peptidase 4 Inhibitors and Risk of Inflammatory Bowel Disease: Real-world Evidence in U.S. Adults.

Diabetes Care 2019 11 30;42(11):2065-2074. Epub 2019 Aug 30.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC

Objective: A recent study raises concerns that dipeptidyl peptidase 4 inhibitors (DPP4i) are associated with increased risk of inflammatory bowel disease (IBD). We evaluated the association between new use of DPP4i and IBD risk compared with other second-line antihyperglycemics.

Research Design And Methods: We implemented an active-comparator, new-user cohort design using two U.S. administrative claims databases for commercially insured (MarketScan) and older adult (Medicare fee-for-service, 20% random sample) patients from January 2007 to December 2016. We identified patients, aged ≥18 years, who initiated DPP4i versus sulfonylureas (SUs) or initiated DPP4i versus thiazolidinediones (TZDs) and were without prior diagnosis, treatment, or procedure for IBD. The primary outcome was incident IBD, defined by IBD diagnosis preceded by colonoscopy and biopsy and followed by IBD treatment. We performed propensity score weighting to control for measured baseline confounding, estimated adjusted hazard ratios (aHRs [95% CI]) using weighted Cox proportional hazards models, and used random-effects meta-analysis models to pool aHRs across cohorts.

Results: We identified 895,747 eligible patients initiating DPP4i, SU, or TZD; IBD incidence rates ranged from 11.6 to 32.3/100,000 person-years. Over a median treatment duration of 1.09-1.69 years, DPP4i were not associated with increased IBD risk across comparisons. The pooled aHRs for IBD were 0.82 (95% CI 0.41-1.61) when comparing DPP4i ( = 161,612) to SU ( = 310,550) and 0.76 (0.46-1.26) when comparing DPP4i ( = 205,570) to TZD ( = 87,543).

Conclusions: Our population-based cohort study of U.S. adults with diabetes suggests that short-term DPP4i treatment does not increase IBD risk.
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http://dx.doi.org/10.2337/dc19-0162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804610PMC
November 2019

Renin-Angiotensin-Aldosterone System-based Antihypertensive Agents and the Risk of Colorectal Cancer Among Medicare Beneficiaries.

Epidemiology 2019 11;30(6):867-875

From the Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Background: Biologic evidence suggests that angiotensin II may play a role in tumor progression or growth. We compared the short-term colorectal cancer (CRC) risk among initiators of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) versus guideline-recommended clinical alternatives (beta blockers, calcium channel blockers [CCB], and thiazides).

Methods: We conducted a new-user cohort study on U.S. Medicare beneficiaries aged over 65 years, who initiated antihypertensive monotherapy during 2007-2013 and were free of cancer diagnosis before drug initiation. Follow-up began 6 months postinitiation to allow time for the diagnostic delay. We estimated hazard ratios (HR) with 95% confidence intervals (CI) using propensity score weighted Cox regression, overall and stratified by time since drug initiation, and 5-year cumulative risk differences (RD) using Kaplan-Meier estimator. We assessed the potential for unmeasured confounding using supplemental data from Medicare Current Beneficiary Survey.

Results: For analyses without censoring for treatment changes, we observed 532 CRC events among 111,533 ACEI/ARB initiators. After a median follow-up of 2.2 years (interquartile range: 1.0-3.7), CRC risk was similar between ACEI/ARB and active comparators, with adjusted HRs of 1.0 (95% CI = 0.85, 1.1) for ACEI/ARB versus beta blockers, 1.2 (95% CI = 0.97, 1.4) for ACEI/ARB versus CCB and 1.0 (95% CI = 0.80, 1.3) for ACEI/ARB versus thiazide. Five-year RDs and as-treated analyses, which censored follow-up at medication changes, produced similar findings.

Conclusions: Based on real-world antihypertensive utilization patterns in Medicare beneficiaries, our study suggests no association between ACEI/ARB initiation and the short-term CRC risk.
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http://dx.doi.org/10.1097/EDE.0000000000001065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768762PMC
November 2019

Study design choices for evaluating the comparative safety of diabetes medications: An evaluation of pioglitazone use and risk of bladder cancer in older US adults with type-2 diabetes.

Diabetes Obes Metab 2019 09 17;21(9):2096-2106. Epub 2019 Jun 17.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Aim: The aim of the study was to empirically demonstrate the effect of varying study designs when evaluating the safety of pioglitazone in treating bladder cancer.

Methods: We identified Medicare beneficiaries above 65 years of age with diabetes between 2008 and 2015 and with classified exposure (at least two claims within 180 days) to glucose-lowering drugs (GLD), pioglitazone or another drug. The effects of varying the following study design parameters on bladder cancer risk were assessed: use of a new vs existing drug, choice of referent (all non-users and users of GLDs, non-insulin GLDs and DPP-4s) and whether or not censoring accounted for treatment change. We used the Cox proportional hazards model to obtain adjusted HRs and 95% CIs.

Results: We included 1,510,212 patients classified as pioglitazone users (N = 135,188) or non-users (N = 1,375,024). Users had more diabetic complications than non-users, but fewer than insulin users. The HR ranged from 1.10 (1.01-1.20) to 1.13 (0.99-1.29) when censoring ignored treatment change, suggesting a weak association or none between pioglitazone and bladder cancer, probably under-estimating risk. However, the HR was 1.20 (1.01-1.42) when cohorts were restricted to new users, censored upon treatment change, and when DPP-4 was used as the referent, suggesting an increased risk of bladder cancer associated with pioglitazone.

Conclusions: The continued demand for new GLDs indicates the need for more robust observational methods to improve the value of generating real-world evidence in equipping clinicians to make informed prescribing decisions. Although there is no one-size-fits-all approach, we recommend active comparator new user study designs that compare therapeutically equivalent drugs and account for treatment changes during follow-up to present the least biased comparative safety estimates.
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http://dx.doi.org/10.1111/dom.13774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025290PMC
September 2019

Burden and Cost of Outpatient Hemorrhoids in the United States Employer-Insured Population, 2014.

Am J Gastroenterol 2019 05;114(5):798-803

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina.

Introduction: Although hemorrhoids are a common indication for seeking health care, there are no contemporary estimates of burden and cost. We examined data from an administrative claims database to estimate health care use and aggregate costs.

Methods: We conducted a cross-sectional study using the MarketScan Commercial Claims and Encounters Database for 2014. The analysis included 18.9 million individuals who were aged 18-64 and continuously enrolled with prescription coverage. Outpatient hemorrhoid claims were captured using the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes in the first position, as well as Common Procedural Terminology codes. Prescription medications were identified using National Drug Codes. Annual prevalence and costs were determined by summing gross payments for prescription medications, physician encounters, and facility costs. We used validated weights to standardize annual cost estimates to the US employer-insured population.

Results: In 2014, we identified 227,638 individuals with at least one outpatient hemorrhoid-related claim (annual prevalence, 1.2%). Among those, 119,120 had prescription medication claims, 136,125 had physician claims, and 28,663 had facility claims. After standardizing, we estimated that 1.4 million individuals in the US employer-insured population sought care for hemorrhoids in 2014 for a total annual cost of $770 million. This included $322 million in physician claims, $361 million in outpatient facility claims, and $88 million in prescription medication claims.

Conclusions: The estimated economic burden of hemorrhoids in the employer-insured population approaches $800 million annually. Given the substantial and rising burden and cost, expanded research attention should be directed to hemorrhoidal etiology, prevention, and treatment.
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http://dx.doi.org/10.14309/ajg.0000000000000143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502684PMC
May 2019

Sodium-glucose co-transporter-2 inhibitor use and risk of lower-extremity amputation: Evolving questions, evolving answers.

Diabetes Obes Metab 2019 05 4;21(5):1223-1236. Epub 2019 Mar 4.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina.

Aim: To examine whether sodium-glucose co-transporter-2 (SGLT2) inhibitors are associated with a higher risk of lower-extremity amputation than dipeptidyl-peptidase-4 (DPP-4) inhibitors and sulphonylureas.

Methods: We conducted a retrospective cohort study, using the MarketScan Commercial Claims and Encounters Database (2013-2015), to compare the incidence of lower-extremity amputation (LEA) between initiators of SGLT2 inhibitors and initiators of two second-line drugs, DPP-4 inhibitors and sulphonylureas (SUs). We estimated crude incidence rates (IRs) and adjusted hazard ratios (aHR), with 95% confidence intervals (CIs), before and after propensity-score weighting. We additionally conducted sensitivity analyses using a comparator group of all non-metformin, non-SGLT2 inhibitor glucose-lowering drugs, as previous studies used this approach.

Results: In a cohort of 328 150 individuals aged 18 to 64 years, the IR of LEA ranged from 1.5 to 2.4 per 1000 person-years. In as-treated analysis, the estimated hazard of LEA was increased among SGLT2 inhibitor initiators compared to DPP-4 inhibitor initiators (aHR 1.69, 95% CI 1.20-2.38), but not compared to SU initiators (aHR 1.02, 95% CI 0.67-1.55) or non-metformin, non-SGLT2 inhibitor initiators (aHR 1.02, 95% CI 0.54-1.93). Results were consistent in intention-to-treat analysis and across a number of sensitivity analyses.

Conclusions: Among commercially insured patients in the United States, our results suggest that initiation of SGLT2 inhibitors may increase the risk of LEA compared to initiation of DPP-4 inhibitors. Contrasting results when comparing SGLT2 inhibitor initiators to DPP-4 inhibitor and SU initiators highlight the importance of choosing appropriate comparator drugs when addressing comparative effectiveness and safety questions that can inform clinical decision-making.
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http://dx.doi.org/10.1111/dom.13647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459697PMC
May 2019

Impact of metformin use on the cardiovascular effects of dipeptidyl peptidase-4 inhibitors: An analysis of Medicare claims data from 2007 to 2015.

Diabetes Obes Metab 2019 04 18;21(4):854-865. Epub 2018 Dec 18.

Department of Medicine, Division of Endocrinology and Metabolism, University of North Carolina, Chapel Hill, North Carolina.

Aims: To examine the outcomes of dipeptidyl peptidase-4 (DPP-4) inhibitor initiation with and without concurrent metformin treatment.

Materials And Methods: We identified Medicare enrollees initiating a DPP-4 inhibitor, a sulphonylurea or a thiazolidinedione. Using propensity-score-weighted Poisson models, we evaluated 1-year cardiovascular (CV) outcome incidence among initiators of DPP-4 inhibitors versus comparators in subgroups with and without concurrent metformin use, and assessed the interaction between initiation drug and metformin. Outcomes included mortality, non-fatal myocardial infarction (MI), stroke, and a composite outcome.

Results: For the DPP-4 inhibitor (n = 13 391) versus sulphonylurea (n = 33 206) comparison, rate differences in composite outcome incidence favoured DPP-4 inhibitors: -2.0/100 person-years among metformin users (95% confidence interval [CI] -2.7 to -1.3) and - 1.0/100 person-years (95% CI -1.8 to -0.2) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-1.5/100 person-years [95% CI -2.1 to -0.9] and -0.7/100 person-years [95% CI -1.4 to 0.0]) and non-fatal MI (-0.5/100 person-years [95% CI -0.8, -0.3] and 0.1/100 person-years [95% CI -0.2 to 0.4]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for non-fatal MI (P = 0.008). For the DPP-4 inhibitor (n = 22 210) versus thiazolidinedione (n = 9517) comparison, rate differences in composite outcome incidence for DPP-4 inhibitor initiation were -0.6/100 person-years (95% CI -1.5 to 0.2) among metformin users and 1.0 (95% CI 0.0 to 2.0) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-0.5/100 person-years [95% CI -1.3 to 0.1] and 0.8/100 person-years [95% CI -0.0 to 1.7]) and non-fatal MI (-0.1/100 person-years [95% CI -0.4 to 0.2] and 0.2/100 person-years [95% CI -0.1 to 0.6]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for the composite outcome (P = 0.024) and mortality (P = 0.023).

Conclusion: Incidence rate differences in multiple CV outcomes appeared more favourable when DPP-4 inhibitor initiation occurred in the presence of metformin, suggesting a possible interaction between DPP-4 inhibitors and metformin.
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http://dx.doi.org/10.1111/dom.13589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527500PMC
April 2019

Who diagnosed and prescribed what? Using provider details to inform observational research.

Pharmacoepidemiol Drug Saf 2018 Dec 31;27(12):1422-1426. Epub 2018 Oct 31.

Department of Health Sciences, Northeastern University, Boston, Massachusetts, USA.

Purpose: To describe how often patients with depression initiating antidepressants receive their depression diagnosis and prescriptions from the same provider and, when simultaneously initiating benzodiazepines, how often both prescriptions come from the same provider.

Methods: Using a US healthcare claims database, we created a cohort of adults (18-64 years) with a depression diagnosis who initiated antidepressants. We examined concordance by provider specialty and provider identifier between (a) the first antidepressant prescription fill and most proximal depression diagnosis, and (b) the initial antidepressant and benzodiazepine prescription fills among simultaneous benzodiazepine and antidepressant initiators.

Results: Among 245 166 antidepressant initiators with a recent depression diagnosis (female = 67%; median age = 39), the specialty of the provider assigning the depression diagnosis matched the antidepressant prescriber's specialty in 94% of cases with known provider details (provider identifier concordance = 93%). Concordance was higher for adults diagnosed by a general practitioner (98%) or psychiatrist (92%) than for those diagnosed by a psychologist (74%). In simultaneous new users of antidepressants and benzodiazepines (n = 19 371), both prescriptions were issued by the same provider specialty and provider identifier 94% and 93% of the time, respectively.

Conclusions: The vast majority of patients who received antidepressant prescriptions and depression diagnoses appear to have received both diagnosis and antidepressants from the same provider, suggesting that when antidepressants are issued around the time a patient is diagnosed with depression, the antidepressant was likely prescribed for depression. In addition, the great majority of patients who simultaneously initiate benzodiazepines appear to do so under the direction of one provider.
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http://dx.doi.org/10.1002/pds.4685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407693PMC
December 2018

Trends in Incidence of ACL Reconstruction and Concomitant Procedures Among Commercially Insured Individuals in the United States, 2002-2014.

Sports Health 2018 Nov/Dec;10(6):523-531

Department of Orthopaedics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background:: Few population-based descriptive studies on the incidence of anterior cruciate ligament (ACL) reconstruction and concomitant pathology exist.

Hypothesis:: Incidence of ACL reconstruction has increased from 2002 to 2014.

Study Design:: Descriptive clinical epidemiology study.

Level Of Evidence:: Level 3.

Methods:: The Truven Health Analytics MarketScan Commercial Claims and Encounters database, which contains insurance enrollment and health care utilization data for approximately 158 million privately insured individuals younger than 65 years, was used to obtain records of ACL reconstructions performed between 2002 and 2014 and any concomitant pathology using Current Procedures Terminology (CPT) and International Classification of Diseases, Ninth Revision (ICD-9) codes. The denominator population was defined as the total number of person-years (PYs) for all individuals in the database. Annual rates were computed overall and stratified by age, sex, and concomitant procedure.

Results:: There were 283,810 ACL reconstructions and 385,384,623 PYs from 2002 to 2014. The overall rate of ACL reconstruction increased 22%, from 61.4 per 100,000 PYs in 2002 to 74.6 per 100,000 PYs in 2014. Rates of isolated ACL reconstruction were relatively stable over the study period. However, among children and adolescents, rates of both isolated ACL reconstruction and ACL reconstruction with concomitant meniscal surgery increased substantially. Adolescents aged 13 to 17 years had the highest absolute rates of ACL reconstruction, and their rates increased dramatically over the 13-year study period (isolated, +37%; ACL + meniscal repair, +107%; ACL + meniscectomy, +63%). Rates of isolated ACL reconstruction were similar for males and females (26.1 vs 25.6 per 100,000 PYs, respectively, in 2014), but males had higher rates of ACL reconstruction with concomitant meniscal surgery than females.

Conclusion:: Incidence rates of isolated ACL reconstruction and rates of concomitant meniscal surgery have increased, particularly among children and adolescents.

Clinical Relevance:: A renewed focus on adoption of injury prevention programs is needed to mitigate these trends. In addition, more research is needed on long-term patient outcomes and postoperative health care utilization after ACL reconstruction, with a focus on understanding the sex-based disparity in concomitant meniscal surgery.
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http://dx.doi.org/10.1177/1941738118803616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204641PMC
October 2018

Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2018.

Gastroenterology 2019 01 10;156(1):254-272.e11. Epub 2018 Oct 10.

University of North Carolina School of Medicine, Chapel Hill, North Carolina.

Background & Aims: Estimates of disease burden can inform national health priorities for research, clinical care, and policy. We aimed to estimate health care use and spending among gastrointestinal (GI) (including luminal, liver, and pancreatic) diseases in the United States.

Methods: We estimated health care use and spending based on the most currently available administrative claims from commercial and Medicare Supplemental plans, data from the GI Quality Improvement Consortium Registry, and national databases.

Results: In 2015, annual health care expenditures for gastrointestinal diseases totaled $135.9 billion. Hepatitis ($23.3 billion), esophageal disorders ($18.1 billion), biliary tract disease ($10.3 billion), abdominal pain ($10.2 billion), and inflammatory bowel disease ($7.2 billion) were the most expensive. Yearly, there were more than 54.4 million ambulatory visits with a primary diagnosis for a GI disease, 3.0 million hospital admissions, and 540,500 all-cause 30-day readmissions. There were 266,600 new cases of GI cancers diagnosed and 144,300 cancer deaths. Each year, there were 97,700 deaths from non-malignant GI diseases. An estimated 11.0 million colonoscopies, 6.1 million upper endoscopies, 313,000 flexible sigmoidoscopies, 178,400 upper endoscopic ultrasound examinations, and 169,500 endoscopic retrograde cholangiopancreatography procedures were performed annually. Among average-risk persons aged 50-75 years who underwent colonoscopy, 34.6% had 1 or more adenomatous polyps, 4.7% had 1 or more advanced adenomatous polyps, and 5.7% had 1 or more serrated polyps removed.

Conclusions: GI diseases contribute substantially to health care use in the United States. Total expenditures for GI diseases are $135.9 billion annually-greater than for other common diseases. Expenditures are likely to continue increasing.
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http://dx.doi.org/10.1053/j.gastro.2018.08.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689327PMC
January 2019

Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases.

Lancet Psychiatry 2018 10 13;5(10):824-835. Epub 2018 Sep 13.

Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Background: The use of medications to treat attention deficit hyperactivity disorder (ADHD) has increased, but the prevalence of ADHD medication use across different world regions is not known. Our objective was to determine regional and national prevalences of ADHD medication use in children and adults, with a specific focus on time trends in ADHD medication prevalence.

Methods: We did a retrospective, observational study using population-based databases from 13 countries and one Special Administrative Region (SAR): four in Asia and Australia, two in North America, five in northern Europe, and three in western Europe. We used a common protocol approach to define study populations and parameters similarly across countries and the SAR. Study populations consisted of all individuals aged 3 years or older between Jan 1, 2001, and Dec 31, 2015 (dependent on data availability). We estimated annual prevalence of ADHD medication use with 95% CI during the study period, by country and region and stratified by age and sex. We reported annual absolute and relative percentage changes to describe time trends.

Findings: 154·5 million individuals were included in the study. ADHD medication use prevalence in 2010 (in children aged 3-18 years) varied between 0·27% and 6·69% in the countries and SAR assessed (0·95% in Asia and Australia, 4·48% in North America, 1·95% in northern Europe, and 0·70% in western Europe). The prevalence of ADHD medication use among children increased over time in all countries and regions, and the absolute increase per year ranged from 0·02% to 0·26%. Among adults aged 19 years or older, the prevalence of any ADHD medication use in 2010 varied between 0·003% and 1·48% (0·05% in Asia and Australia, 1·42% in North America, 0·47% in northern Europe, and 0·03% in western Europe). The absolute increase in ADHD medication use prevalence per year ranged from 0·0006% to 0·12%. Methylphenidate was the most commonly used ADHD medication in most countries.

Interpretation: Using a common protocol and data from 13 countries and one SAR, these results show increases over time but large variations in ADHD medication use in multiple regions. The recommendations of evidence-based guidelines need to be followed consistently in clinical practice. Further research is warranted to describe the safety and effectiveness of ADHD medication in the short and long term, and to inform evidence-based guidelines, particularly in adults.

Funding: None.
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http://dx.doi.org/10.1016/S2215-0366(18)30293-1DOI Listing
October 2018

Incretin-Based Therapies and Diabetic Retinopathy: Real-World Evidence in Older U.S. Adults.

Diabetes Care 2018 09 16;41(9):1998-2009. Epub 2018 Jul 16.

Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC

Objective: Recent large trials yield conflicting results on the association between incretin-based therapies (IBTs) and diabetic retinopathy (DR). We examined whether IBTs increase DR risk compared with other antihyperglycemics.

Research Design And Methods: We implemented an active comparator, new-user cohort design using a nationwide 20% random sample of fee-for-service U.S. Medicare beneficiaries aged 65 years or older with Parts A, B, and D coverage between 2007 and 2015. We identified the following cohorts without prior treatment for retinopathy: dipeptidyl peptidase 4 inhibitors (DPP4i) versus sulfonylureas (SU), DPP4i versus thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonists (GLP1RA) versus long-acting insulin (LAI), and GLP1RA versus TZD. Primary outcome was advanced diabetic retinopathy requiring treatment (ADRRT), defined as a procedure code for retinopathy treatment. Incident diabetic retinopathy (IDR), identified by a diagnosis code, was a secondary outcome. We estimated propensity scores to balance confounders and adjusted hazard ratios (95% CI) using weighted Cox proportional hazards models.

Results: We identified 213,652 eligible patients. During a median duration of 0.58 to 0.87 years across comparisons, with a rate from 6.0 to 12.8 per 1,000 person-years, IBTs were not associated with increased ADRRT or IDR risk. The adjusted hazard ratios (95% CI) for ADRRT were 0.91 (0.79-1.04) by comparing DPP4i to SU ( = 39,292 and 87,073); 0.91 (0.75-1.11), DPP4i to TZD ( = 51,410 and 22,231); 0.50 (0.39-0.65), GLP1RA to LAI ( = 9,561 and 82,849); and 0.75 (0.53-1.06), GLP1RA to TZD ( = 10,355 and 27,345).

Conclusions: Our population-based cohort study of older U.S. adults with diabetes suggests that IBTs used for approximately 1 year do not increase the DR risk.
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http://dx.doi.org/10.2337/dc17-2285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105327PMC
September 2018

Classifying medical histories in US Medicare beneficiaries using fixed vs all-available look-back approaches.

Pharmacoepidemiol Drug Saf 2018 07 14;27(7):771-780. Epub 2018 Apr 14.

Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Purpose: Evaluate use of fixed and all-available look-backs to identify eligibility criteria and confounders among Medicare beneficiaries.

Methods: We identified outpatient visits (2007-2012) with recently documented (≤180 days) cardiovascular risk and classified patients according to whether the exposure (statin) was initiated within 14 days. We selected each beneficiary's first eligible visit (in each treatment group) that met criteria during the respective look-backs: continuous enrollment (1 or 3 years for fixed look-back; 180 days for all-available), no cancer history, and no statin claims. We estimated crude and standardized mortality ratio weighted hazard ratios (HRs) for the effect of statin initiation on incident 6-month cancer (a known null effect) and 2-year mortality, separately, adjusting for covariates assessed by using each look-back.

Results: Analyzing short-term cancer, the estimated HR from the all-available approach (HR = 0.90, 95% CI: 0.83, 0.98) was less biased than the 1-year look-back (HR = 0.79, 95% CI: 0.73, 0.84), which included beneficiaries with prevalent cancer. The 3-year look-back (HR = 1.05, 95% CI: 0.90, 1.21) was somewhat less biased than the all-available estimate but less precise due the exclusion of a large proportion of observations without sufficient continuous enrollment (62.0% and 59.9% of initiators and non-initiators, respectively). All approaches produced similar estimates of the effect on all-cause mortality. Alternative look-backs did not differ in their ability to control confounding.

Conclusions: The all-available look-back performed nearly as well as the 3-year fixed, which produced the least biased point estimate. If 3-year look-backs are infeasible (eg, due to power/sample), all-available look-backs may be preferable to short (1-year) fixed look-backs.
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http://dx.doi.org/10.1002/pds.4435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417795PMC
July 2018
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