Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19: A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States.

Purpose: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. Patients and Methods: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries. Patients were followed for 90 days after COVID-19 diagnosis. The primary outcomes were ATE and VTE over 90 days from diagnosis date. We measured country-level estimates of 90-day absolute risk (with 95% confidence intervals) of ATE and VTE. Results: The seven cohorts included 1,061,565 patients initially diagnosed with COVID-19 in the ambulatory setting before COVID-19 vaccines were available (through November 2020). The 90-day absolute risk of ATE during this period ranged from 0.11% (0.09-0.13%) in Canada to 1.01% (0.97-1.05%) in the US, and the 90-day absolute risk of VTE ranged from 0.23% (0.21-0.26%) in Canada to 0.84% (0.80-0.89%) in England. The seven cohorts included 3,544,062 patients with COVID-19 during vaccine availability (beginning December 2020). The 90-day absolute risk of ATE during this period ranged from 0.06% (0.06-0.07%) in England to 1.04% (1.01-1.06%) in the US, and the 90-day absolute risk of VTE ranged from 0.25% (0.24-0.26%) in England to 1.02% (0.99-1.04%) in the US. Conclusion: There was heterogeneity by country in 90-day absolute risk of ATE and VTE after ambulatory COVID-19 diagnosis both before and during COVID-19 vaccine availability.

Incidence, Microbiological Studies, and Factors Associated With Prosthetic Joint Infection After Total Knee Arthroplasty.

Importance: Despite the frequency of total knee arthroplasty (TKA) and clinical implications of prosthetic joint infections (PJIs), knowledge gaps remain concerning the incidence, microbiological study results, and factors associated with these infections. Objectives: To identify the incidence rates, organisms isolated from microbiological studies, and patient and surgical factors of PJI occurring early, delayed, and late after primary TKA. Design, Setting, and Participants: This cohort study obtained data from the US Department of Veterans Affairs (VA) Corporate Data Warehouse on patients who underwent elective primary TKA in the VA system between October 1, 1999, and September 30, 2019, and had at least 1 year of care in the VA prior to TKA. Patients who met these criteria were included in the overall cohort, and patients with linked Veterans Affairs Surgical Quality Improvement Program (VASQIP) data composed the VASQIP cohort. Data were analyzed between December 9, 2021, and September 18, 2023. Exposures: Primary TKA as well as demographic, clinical, and perioperative factors. Main Outcomes and Measures: Incident hospitalization with early, delayed, or late PJI. Incidence rate (events per 10 000 person-months) was measured in 3 postoperative periods: early (≤3 months), delayed (between >3 and ≤12 months), and late (>12 months). Unadjusted Poisson regression was used to estimate incidence rate ratios (IRRs) with 95% CIs of early and delayed PJI compared with late PJI. The frequency of organisms isolated from synovial or operative tissue culture results of PJIs during each postoperative period was identified. A piecewise exponential parametric survival model was used to estimate IRRs with 95% CIs associated with demographic and clinical factors in each postoperative period. Results: The 79 367 patients (median (IQR) age of 65 (60-71) years) in the overall cohort who underwent primary TKA included 75 274 males (94.8%). A total of 1599 PJIs (2.0%) were identified. The incidence rate of PJI was higher in the early (26.8 [95% CI, 24.8-29.0] events per 10 000 person-months; IRR, 20.7 [95% CI, 18.5-23.1]) and delayed periods (5.4 [95% CI, 4.9-6.0] events per 10 000 person-months; IRR, 4.2 [95% CI, 3.7-4.8]) vs the late postoperative period (1.3 events per 10 000 person-months). Staphylococcus aureus was the most common organism isolated overall (489 [33.2%]); however, gram-negative infections were isolated in 15.4% (86) of early PJIs. In multivariable analyses, hepatitis C virus infection, peripheral artery disease, and autoimmune inflammatory arthritis were associated with PJI across all postoperative periods. Diabetes, chronic kidney disease, and obesity (body mass index of ≥30) were not associated factors. Other period-specific factors were identified. Conclusions and Relevance: This cohort study found that incidence rates of PJIs were higher in the early and delayed vs late post-TKA period; there were differences in microbiological cultures and factors associated with each postoperative period. These findings have implications for postoperative antibiotic use, stratification of PJI risk according to postoperative time, and PJI risk factor modification.

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

BACKGROUND: Overactive bladder (OAB) is a common non-motor symptom of Parkinson disease (PD), often treated with antimuscarinics or beta-3 agonists. There is lack of evidence to guide OAB management in PD. OBJECTIVES: To assess the comparative safety of antimuscarinics versus beta-3 agonists for OAB treatment in PD. METHODS: We employed a new-user, active-comparator cohort study design. We included Medicare beneficiaries age ≥65 years with PD who were new users of either antimuscarinic or beta-3 agonist. The primary outcome was any acute care encounter (i.e., non-elective hospitalization or emergency department visit) within 90 days of OAB drug initiation. The main secondary outcome was a composite measure of acute care encounters for anticholinergic related adverse events (AEs). Matching on high-dimensional propensity score (hdPS) was used to address potential confounding. We used Cox proportional hazards models to examine the association between OAB drug category and outcomes. We repeated analyses for 30- and 180-day follow-up periods. RESULTS: We identified 27,091 individuals meeting inclusion criteria (mean age: 77.8 years). After hdPS matching, antimuscarinic users had increased risks for any acute care encounter (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.12-1.37) and encounters for anticholinergic related AEs (HR 1.18, 95% CI 1.04-1.34) compared to beta-3 agonist users. Similar associations were observed for sensitivity analyses. CONCLUSIONS: Among persons with PD, anticholinergic initiation was associated with a higher risk of acute care encounters compared with beta-3 agonist initiation. The long-term safety of anticholinergic vs. beta-3 agonist therapy in the PD population should be evaluated in a prospective study.

Hepatitis B care cascade among people with HIV/HBV coinfection in the North American AIDS Cohort Collaboration on Research and Design, 2012-2016.

A care cascade is a critical tool for evaluating delivery of care for chronic infections across sequential stages, starting with diagnosis and ending with viral suppression. However, there have been few data describing the hepatitis B virus (HBV) care cascade among people living with HIV infection who have HBV coinfection. We conducted a cross-sectional study among people living with HIV and HBV coinfection receiving care between January 1, 2012 and December 31, 2016 within 13 United States and Canadian clinical cohorts contributing data to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). We evaluated each of the steps in this cascade, including: 1) laboratory-confirmed HBV infection, 2) tenofovir-based or entecavir-based HBV therapy prescribed, 3) HBV DNA measured during treatment, and 4) viral suppression achieved via undetectable HBV DNA. Among 3,953 persons with laboratory-confirmed HBV (median age, 50 years; 6.5% female; 43.8% were Black; 7.1% were Hispanic), 3,592 (90.9%; 95% confidence interval, 90.0-91.8%) were prescribed tenofovir-based antiretroviral therapy or entecavir along with their antiretroviral therapy regimen, 2,281 (57.7%; 95% confidence interval, 56.2-59.2%) had HBV DNA measured while on therapy, and 1,624 (41.1%; 95% confidence interval, 39.5-42.6) achieved an undetectable HBV DNA during HBV treatment. Our study identified significant gaps in measurement of HBV DNA and suppression of HBV viremia among people living with HIV and HBV coinfection in the United States and Canada. Periodic evaluation of the HBV care cascade among persons with HIV/HBV will be critical to monitoring success in completion of each step.

Potentially inappropriate medications in older adults with Parkinson disease before and after hospitalization for injury.

BACKGROUND: Parkinson disease (PD) patients are at increased risk of serious injury, such as fall-related fractures. Prescription medications are a modifiable factor for injury risk. OBJECTIVES: To determine the extent to which a serious injury requiring hospitalization affects prescribing of potentially inappropriate medications (PIMs) among older adults with PD. METHODS: We conducted a quasi-experimental difference-in-difference (DID) study using 2013-2017 Medicare data. The cohort consisted of beneficiaries with PD hospitalized for injury versus for other reasons. PIMs were classified into PD and injury-relevant categories (CNS-active PIMs, PD motor symptom PIMs, PD non-motor symptom PIMs, PIMs that reduce bone mineral density). We estimated mean standardized daily doses (SDDs) of medications within each PIM category before and at 3, 6, and 12 months after hospitalization. We used generalized linear regression models to compare changes in mean SDDs for each PIM category between the injury and non-injury group at each timepoint, adjusting for biological, clinical and social determinants of health variables. RESULTS: Both groups discontinued PIMs and/or reduced PIM doses after hospitalization. There were no between-group differences in mean SDD changes, after covariate adjustment, for any PIM category, except for the CNS-active PIMs category at 3 months (DID p-value = 0.00) and for the category of PIMs that reduce bone mineral density at all timepoints (DID p-values = 0.02, 0.04, 0.02 at 3, 6, and 12 months). CONCLUSIONS: Similar patterns of PIM among persons with PD after hospitalization for serious injury versus for other reasons may represent a missed opportunity to deprescribe high-risk medications during care transitions.

Use of Immunosuppression and the Risk of Subsequent Overall or Cancer Mortality.

PURPOSE: To determine the incidence of all-cause and cancer mortality (CM) in association with immunosuppression. DESIGN: Retrospective cohort study at ocular inflammatory disease (OID) subspecialty centers. We harvested exposure and covariate data retrospectively from clinic inception (earliest in 1979) through 2010 inclusive. Then we ascertained overall and cancer-specific mortalities by National Death Index linkage. We constructed separate Cox models to evaluate overall and CM for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression. PARTICIPANTS: Patients with noninfectious OID, excluding those with human immunodeficiency infection or preexisting cancer. METHODS: Tumor necrosis factor (TNF) inhibitors (mostly infliximab, adalimumab, and etanercept); antimetabolites (methotrexate, mycophenolate mofetil, azathioprine); calcineurin inhibitors (cyclosporine); and alkylating agents (cyclophosphamide) were given when clinically indicated in this noninterventional cohort study. MAIN OUTCOME MEASURES: Overall mortality and CM. RESULTS: Over 187 151 person-years (median follow-up 10.0 years), during which 15 938 patients were at risk for mortality, we observed 1970 deaths, 435 due to cancer. Both patients unexposed to immunosuppressants (standardized mortality ratio [SMR] = 0.95, 95% confidence interval [CI], 0.90-1.01) and those exposed to immunosuppressants but free of systemic inflammatory diseases (SIDs) (SMR = 1.04, 95% CI, 0.95-1.14) had similar mortality risk to the US population. Comparing patients exposed to TNF inhibitors, antimetabolites, calcineurin inhibitors, and alkylating agents with patients not exposed to any of these, we found that overall mortality (adjusted hazard ratio [aHR] = 0.88, 0.89, 0.90, 1.11) and CM (aHR = 1.25, 0.89, 0.86, 1.23) were not significantly increased. These results were stable in sensitivity analyses whether excluding or including patients with SID, across 0-, 3-, or 5-year lags and across quartiles of immunosuppressant dose and duration. CONCLUSIONS: Our results, in a cohort where the indication for treatment was proven unassociated with mortality risk, found that commonly used immunosuppressants-especially the antimetabolites methotrexate, mycophenolate mofetil, and azathioprine; the TNF inhibitors adalimumab and infliximab, and cyclosporine-were not associated with increased overall and CM over a median cohort follow-up of 10.0 years. These results suggest the safety of these agents with respect to overall and CM for patients treated with immunosuppression for a wide range of inflammatory diseases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Hepatitis C Care Cascade During the Direct-Acting Antiviral Era in a United States Commercially Insured Population.

Background: Periodic surveillance of the hepatitis C virus (HCV) care cascade is important for tracking progress toward HCV elimination goals, identifying gaps in care, and prioritizing resource allocation. In the pre-direct-acting antiviral (DAA) era, it was estimated that 50% of HCV-infected individuals were diagnosed and that 16% had been prescribed interferon-based therapy. Since then, few studies utilizing nationally representative data from the DAA era have been conducted in the United States. Methods: We performed a cross-sectional study to describe the HCV care cascade in the United States using the Optum de-identified Clinformatics® Data Mart Database to identify a nationally representative sample of commercially insured beneficiaries between January 1, 2014 and December 31, 2019. We estimated the number of HCV-viremic individuals in Optum based on national HCV prevalence estimates and determined the proportion who had: (1) recorded diagnosis of HCV infection, (2) recorded HCV diagnosis and underwent HCV RNA testing, (3) DAA treatment dispensed, and (4) assessment for cure. Results: Among 120,311 individuals estimated to have HCV viremia in Optum during the study period, 109,233 (90.8%; 95% CI, 90.6%-91.0%) had a recorded diagnosis of HCV infection, 75,549 (62.8%; 95% CI, 62.5%-63.1%) had a recorded diagnosis of HCV infection and underwent HCV RNA testing, 41,102 (34.2%; 95% CI, 33.9%-34.4%) were dispensed DAA treatment, and 25,760 (21.4%; 95% CI, 21.2%-21.6%) were assessed for cure. Conclusions: Gaps remain between the delivery of HCV-related care and national treatment goals among commercially insured adults. Efforts are needed to increase HCV treatment among people diagnosed with chronic HCV infection to achieve national elimination goals.

Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation.

BACKGROUND & AIMS: Cases of acute liver injury (ALI) have been reported among chronic HCV-infected patients receiving protease inhibitor (PI)-based direct-acting antiviral (DAA) regimens, but no analyses have compared the risk of ALI in patients receiving PI- vs. non-PI-based DAAs. Thus, we compared the risk of 3 ALI outcomes between patients (by baseline Fibrosis-4 [FIB-4] group) receiving PI-based or non-PI-based DAAs. METHODS: We conducted a cohort study of 18,498 patients receiving PI-based DAA therapy (paritaprevir/ritonavir/ombitasvir±dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) matched 1:1 on propensity score to those receiving non-PI-based DAAs (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). During exposure to DAA therapy, we determined development of: i) alanine aminotransferase (ALT) >200 U/L, ii) severe hepatic dysfunction (coagulopathy with hyperbilirubinemia), and iii) hepatic decompensation. We used Cox regression to determine hazard ratios (HRs) with 95% CIs for each ALI outcome within groups defined by baseline FIB-4 (≤3.25; >3.25). RESULTS: Among patients with baseline FIB-4 ≤3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR 3.98; 95% CI 2.37-6.68), but not severe hepatic dysfunction (HR 0.67; 95% CI 0.19-2.39) or hepatic decompensation (HR 1.01; 95% CI 0.29-3.49), compared to those receiving non-PI-based regimens. For those with baseline FIB-4 >3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR, 2.15; 95% CI 1.09-4.26), but not severe hepatic dysfunction (HR, 1.23 [0.64-2.38]) or hepatic decompensation (HR, 0.87; 95% CI 0.41-1.87), compared to those receiving non-PI-based regimens CONCLUSION: While risk of incident ALT elevations was increased in those receiving PI-based DAAs in both FIB-4 groups, the risk of severe hepatic dysfunction and hepatic decompensation did not differ between patients receiving PI- or non-PI-based DAAs in either FIB-4 group. LAY SUMMARY: Cases of liver injury have been reported among patients treated with protease inhibitor-based direct-acting antivirals for hepatitis C infection, but it is not clear if the risk of liver injury among people starting these drugs is increased compared to those starting non-protease inhibitor-based therapy. In this study, patients receiving protease inhibitor-based treatment had a higher risk of liver inflammation than those receiving a non-protease inhibitor-based treatment, regardless of the presence of pre-treatment advanced liver fibrosis/cirrhosis. However, the risk of severe liver dysfunction and decompensation were not higher for patients treated with protease inhibitor-based regimens.

Risk of HCC With Hepatitis B Viremia Among HIV/HBV-Coinfected Persons in North America.

BACKGROUND AND AIMS: Chronic HBV is the predominant cause of HCC worldwide. Although HBV coinfection is common in HIV, the determinants of HCC in HIV/HBV coinfection are poorly characterized. We examined the predictors of HCC in a multicohort study of individuals coinfected with HIV/HBV. APPROACH AND RESULTS: We included persons coinfected with HIV/HBV within 22 cohorts of the North American AIDS Cohort Collaboration on Research and Design (1995-2016). First occurrence of HCC was verified by medical record review and/or cancer registry. We used multivariable Cox regression to determine adjusted HRs (aHRs [95% CIs]) of factors assessed at cohort entry (age, sex, race, body mass index), ever during observation (heavy alcohol use, HCV), or time-updated (HIV RNA, CD4+ percentage, diabetes mellitus, HBV DNA). Among 8,354 individuals coinfected with HIV/HBV (median age, 43 years; 93% male; 52.4% non-White), 115 HCC cases were diagnosed over 65,392 person-years (incidence rate, 1.8 [95% CI, 1.5-2.1] events/1,000 person-years). Risk factors for HCC included age 40-49 years (aHR, 1.97 [1.22-3.17]), age ≥50 years (aHR, 2.55 [1.49-4.35]), HCV coinfection (aHR, 1.61 [1.07-2.40]), and heavy alcohol use (aHR, 1.52 [1.04-2.23]), while time-updated HIV RNA >500 copies/mL (aHR, 0.90 [0.56-1.43]) and time-updated CD4+ percentage <14% (aHR, 1.03 [0.56-1.90]) were not. The risk of HCC was increased with time-updated HBV DNA >200 IU/mL (aHR, 2.22 [1.42-3.47]) and was higher with each 1.0 log10 IU/mL increase in time-updated HBV DNA (aHR, 1.18 [1.05-1.34]). HBV suppression with HBV-active antiretroviral therapy (ART) for ≥1 year significantly reduced HCC risk (aHR, 0.42 [0.24-0.73]). CONCLUSION: Individuals coinfected with HIV/HBV on ART with detectable HBV viremia remain at risk for HCC. To gain maximal benefit from ART for HCC prevention, sustained HBV suppression is necessary.

Association of Longitudinal Changes in Symptoms and Urinary Biomarkers in Patients with Urological Chronic Pelvic Pain Syndrome: A MAPP Research Network Study.

PURPOSE: We analyzed a series of novel noninvasive urinary biomarkers for their ability to objectively monitor the longitudinal clinical status of patients with urological chronic pelvic pain syndrome. MATERIALS AND METHODS: Baseline, 6 and 12-month urine samples were collected (216) and used to quantify vascular endothelial growth factor, vascular endothelial growth factor (VEGF) receptor 1 (R1), neutrophil gelatinase associated lipocalin (NGAL), matrix metalloproteinase-2, matrix metalloproteinase (MMP)-9, and MMP-9/NGAL complex by enzyme-linked immunosorbent assays. Patient symptom changes were classified as improved, stable or worse using a functional clustering algorithm. Proportional odds models were used to evaluate the association between symptom change and urinary biomarkers. RESULTS: Across all sampled participants, longitudinal decreases in normalized VEGF concentration (pg/µg) were associated with pain severity improvement, and decreases in MMP-9, NGAL and VEGF-R1 concentration (pg/ml) as well as NGAL normalized concentration were associated with improved urinary symptoms. Longitudinal decreases in normalized VEGF-R1 were associated with pain improvement in patients with moderate widespreadness, no bladder symptoms and no painful filling. Lower baseline normalized VEGF-R1 concentration was associated with pain improvement in patients with pelvic pain only. Higher baseline MMP-9/NGAL levels were associated with pain and urinary improvement across all participants. Moreover, longitudinal increases in MMP-2 concentration was associated with improved pain in men and patients with painful filling. CONCLUSIONS: Our results suggest these urinary biomarkers may be useful in monitoring urological chronic pelvic pain syndrome symptom changes with respect to both urinary severity and pain severity. With further testing, they may represent objective biological measures of urological chronic pelvic pain syndrome progression and/or resolution while also providing insight into the pathophysiology of urological chronic pelvic pain syndrome.

Exudative Retinal Detachment in Ocular Inflammatory Diseases: Risk and Predictive Factors.

PURPOSE: This study evaluated the risk and risk factors for exudative retinal detachment (ERD) in ocular inflammatory diseases. DESIGN: Retrospective cohort study. METHODS: Patients with noninfectious ocular inflammation had been followed longitudinally between 1978 and 2007 at 4 US subspecialty uveitis centers. The main outcome measurements were occurrences of ERD and predictive factors. RESULTS: A total of 176 of 14,612 eyes with ocular inflammation presented with ERD. Among uveitis cases, Vogt-Koyanagi-Harada syndrome (VKH) (odds ratio [OR] = 109), undifferentiated choroiditis (OR = 9.18), sympathetic ophthalmia (OR = 8.43), primary or secondary panuveitis (OR = 7.09), multifocal choroiditis with panuveitis (OR = 4.51), and "other" forms of posterior uveitis (OR = 16.9) were associated with a higher prevalence of ERD. Among the 9,209 uveitic or scleritic eyes initially free of ERD and followed, 137 incident ERD cases were observed over 28,949 eye-years at risk (incidence rate = 0.47% [0.40%-0.56%/eye-year]). VKH (HR = 13.2), sympathetic ophthalmia (HR = 5.82), undifferentiated choroiditis (HR = 6.03), primary or secondary panuveitis (HR = 4.21), and rheumatoid arthritis (HR = 3.30) were significantly associated with incident ERD. A significant dose-response relationship with the prevalence and incidence of ERD were observed for AC cells and vitreous cell activity. African Americans had significantly higher prevalence and incidence of ERD. CONCLUSIONS: Other ocular inflammatory conditions in addition to VKH syndrome and posterior scleritis were associated with increased risk of ERD, indicating that ERD does not necessarily dictate a diagnosis of VKH or posterior scleritis. In addition, the relationship between ERD and inflammatory severity factors implies that inflammation is a key predictive factor associated with developing ERD and requires early and vigorous control.

Opioid Prescribing After Surgery in the United States, Canada, and Sweden.

Importance: Small studies and anecdotal evidence suggest marked differences in the use of opioids after surgery internationally; however, this has not been evaluated systematically across populations receiving similar procedures in different countries. Objective: To determine whether there are differences in the frequency, amount, and type of opioids dispensed after surgery among the United States, Canada, and Sweden. Design, Setting, and Participants: This cohort study included patients without previous opioid prescriptions aged 16 to 64 years who underwent 4 low-risk surgical procedures (ie, laparoscopic cholecystectomy, laparoscopic appendectomy, arthroscopic knee meniscectomy, and breast excision) between January 2013 and December 2015 in the United States, between July 2013 and March 2016 in Canada, and between January 2013 and December 2014 in Sweden. Data analysis was conducted in all 3 countries from July 2018 to October 2018. Main Outcomes and Measures: The main outcome was postoperative opioid prescriptions filled within 7 days after discharge; the percentage of patients who filled a prescription, the total morphine milligram equivalent (MME) dose, and type of opioid dispensed were compared. Results: The study sample consisted of 129 379 patients in the United States, 84 653 in Canada, and 9802 in Sweden. Overall, 52 427 patients (40.5%) in the United States were men, with a mean (SD) age of 45.1 (12.7) years; in Canada, 25 074 patients (29.6%) were men, with a mean (SD) age of 43.5 (13.0) years; and in Sweden, 3314 (33.8%) were men, with a mean (SD) age of 42.5 (13.0). The proportion of patients in Sweden who filled an opioid prescription within the first 7 days after discharge for any procedure was lower than patients treated in the United States and Canada (Sweden, 1086 [11.1%]; United States, 98 594 [76.2%]; Canada, 66 544 [78.6%]; P < .001). For patients who filled a prescription, the mean (SD) MME dispensed within 7 days of discharge was highest in United States (247 [145] MME vs 169 [93] MME in Canada and 197 [191] MME in Sweden). Codeine and tramadol were more commonly dispensed in Canada (codeine, 26 136 patients [39.3%]; tramadol, 12 285 patients [18.5%]) and Sweden (codeine, 170 patients [15.7%]; tramadol, 315 patients [29.0%]) than in the United States (codeine, 3210 patients [3.3%]; tramadol, 3425 patients [3.5%]). Conclusions and Relevance: The findings indicate that the United States and Canada have a 7-fold higher rate of opioid prescriptions filled in the immediate postoperative period compared with Sweden. Of the 3 countries examined, the mean dose of opioids for most surgical procedures was highest in the United States.

Concordance of hospitalizations between Clinical Practice Research Datalink and linked Hospital Episode Statistics among patients treated with oral antidiabetic therapies.

PURPOSE: The ability of the Clinical Practice Research Datalink (CPRD) to ascertain all-cause hospitalizations remains unknown. We determined the proportion of hospitalizations in CPRD that were also recorded in Hospital Episode Statistics (HES), and vice versa, among patients initiating oral antidiabetic (OAD) therapy. METHODS: We conducted a retrospective cohort study from October 2009 to September 2012 among OAD-treated patients registered with general practitioners who contribute to CPRD and consent to HES linkage. In CPRD, we identified initial hospitalizations for each calendar year by an Inpatient Referral, Consultation Type code, or Read code indicating an inpatient episode and determined if an admission date was recorded in HES within ±30 days. We then identified initial HES admission dates and determined if a hospitalization was documented in CPRD within ±30 days. Sensitivity analyses were conducted utilizing HES discharge, rather than admission, dates. RESULTS: Among 8574 OAD-treated HES-linked patients in CPRD, 6574 initial hospitalizations across the study period were identified in CPRD, and 5188 (78.9% [95% CI, 77.9%-79.9%]) were confirmed by a HES admission date within ±30 days (median difference, ±3 days [IQR, 1-7 days]). Among 8609 initial hospital admissions in HES, 4803 (55.7% [95% CI, 54.7%-56.8%]) hospitalizations were recorded in CPRD within ±30 days (median difference, ±4 days [IQR, 1-9 days]). Similar results were observed using HES discharge dates. CONCLUSION: A substantial minority of patient-level hospitalization data are nonconcordant between HES and CPRD. Pharmacoepidemiologic studies within CPRD that seek to identify hospitalizations should consider linkage with HES to ensure adequate ascertainment of inpatient events.

Comparison Between Methotrexate and Mycophenolate Mofetil Monotherapy for the Control of Noninfectious Ocular Inflammatory Diseases.

PURPOSE: To compare mycophenolate mofetil (MMF) to methotrexate (MTX) as corticosteroid-sparing therapy for ocular inflammatory diseases. DESIGN: Retrospective analysis of cohort study data. METHODS: Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained via medical record review. The study included 352 patients who were taking single-agent immunosuppression with MTX or MMF at 4 tertiary uveitis clinics. Marginal structural models (MSM)-derived statistical weighting created a virtual population with covariates and censoring patterns balanced across alternative treatments. With this methodological approach, the results estimate what would have happened had none of the patients stopped their treatment. Survival analysis with stabilized MSM-derived weights simulated a clinical trial comparing MMF vs MTX for noninfectious inflammatory eye disorders. The primary outcome was complete control of inflammation on prednisone ≤10 mg/day, sustained for ≥30 days. RESULTS: The time to success was shorter (more favorable) for MMF than MTX (hazard ratio = 0.68, 95% confidence interval: 0.46-0.99). Adjusting for covariates, the proportion achieving success was higher at every point in time for MMF than MTX from 2 to 8 months, then converges at 9 months. The onset of corticosteroid-sparing success took more than 3 months for most patients in both groups. Outcomes of treatment (MMF vs MTX) were similar across all anatomic sites of inflammation. The incidence of stopping therapy for toxicity was similar in both groups. CONCLUSIONS: Our results suggest that, on average, MMF may be faster than MTX in achieving corticosteroid-sparing success in ocular inflammatory diseases.

Determinants of Liver Complications Among HIV/Hepatitis B Virus-Coinfected Patients.

BACKGROUND: Hepatitis B virus (HBV) infection is a leading cause of end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) in HIV. Factors contributing to the high rates of liver complications among HIV/HBV-coinfected individuals remain unknown. SETTING: North American AIDS Cohort Collaboration on Research and Design. METHODS: We performed a retrospective cohort study among HIV/HBV-coinfected patients in 10 US and Canadian cohorts of the North American AIDS Cohort Collaboration on Research and Design that validated ESLD (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, and/or hepatic encephalopathy) and HCC diagnoses from 1996 to 2010. Multivariable Cox regression was used to examine adjusted hazard ratios [aHRs with 95% confidence interval (CIs)] of liver complications (first occurrence of ESLD or HCC) associated with hypothesized determinants and with increasing durations of HIV suppression (≤500 copies/mL). RESULTS: Among 3573 HIV/HBV patients with 13,790 person-years of follow-up, 111 liver complications occurred (incidence rate = 8.0 [95% CI: 6.6 to 9.7] events/1000 person-years). Rates of liver complication were increased with non-black/non-Hispanic race [aHR = 1.76 (1.13-2.74)], diabetes mellitus [aHR = 2.07 (1.20-3.57)], lower time-updated CD4 cell count [<200 cells/mm: aHR = 2.59 (1.36-4.91); 201-499 cells/mm: aHR = 1.75 (1.01-3.06) versus ≥500 cells/mm], heavy alcohol use [aHR = 1.58 (1.04-2.39)], and higher FIB-4 at start of follow-up [>3.25: aHR = 9.79 (5.73-16.74); 1.45-3.25: aHR = 3.20 (1.87-5.47) versus FIB-4 <1.45]. HIV suppression for ≥6 months was associated with lower liver complication rates compared with those with unsuppressed HIV [aHR = 0.56 (0.35-0.91)]. CONCLUSIONS: Non-black/non-Hispanic race, diabetes, lower CD4 cell count, heavy alcohol use, and advanced liver fibrosis were determinants of liver complications among HIV/HBV patients. Sustained HIV suppression should be a focus for HIV/HBV-coinfected patients to reduce the risks of ESLD/HCC.

Validity of diagnostic codes to identify hospitalizations for infections among patients treated with oral anti-diabetic drugs.

PURPOSE: Identification of hospitalizations for infection is important for post-marketing surveillance of drugs, but the validity of using diagnosis codes to identify these events is unknown. Differentiating between hospitalization for and with infection is important, as the latter is common and less likely to arise from pre-admission exposure to drugs. We determined positive predictive values (PPVs) of diagnostic coding-based algorithms to identify hospitalization for infection among patients prescribed oral anti-diabetic drugs (OADs). METHODS: We identified patients initiating OADs within 2 United States claims databases (Medicare, HealthCore Integrated Research DatabaseSM [HIRDSM ]) and 2 United Kingdom electronic medical record databases (Clinical Practice Research Datalink [CPRD], The Health Improvement Network [THIN]) from 2009 to 2014. To identify potential hospitalizations for infection, we selected patients with a hospital diagnosis of infection and, within 7 days prior to hospitalization, either an outpatient/emergency department visit with an infection diagnosis or outpatient antimicrobial treatment. Hospital records were reviewed by infectious disease specialists to adjudicate hospital admissions for infection. PPVs for confirmed outcomes were determined for each database. RESULTS: Code-based algorithms to identify hospitalization for infection had PPVs exceeding 80% within Medicare (PPV, 83% [90/109]; 95% CI, 74-89%), HIRDSM (PPV, 89% [73/82]; 95% CI, 80-95%), and THIN (PPV, 86% [12/14]; 95% CI, 57-98%) but not within CPRD (PPV, 67% [14/21]; 95% CI, 43-85%). CONCLUSIONS: Algorithms identifying hospitalization for infection utilizing hospital diagnoses along with antecedent outpatient/emergency infection diagnoses or antimicrobial therapy had sufficiently high PPVs for confirmed events within Medicare, HIRDSM , and THIN to enable their use for pharmacoepidemiologic research.

Postauthorization safety study of the DPP-4 inhibitor saxagliptin: a large-scale multinational family of cohort studies of five outcomes.

OBJECTIVE: To evaluate the risk of serious adverse events among patients with type 2 diabetes mellitus initiating saxagliptin compared with oral antidiabetic drugs (OADs) in classes other than dipeptidyl peptidase-4 (DPP-4) inhibitors. RESEARCH DESIGN AND METHODS: Cohort studies using 2009-2014 data from two UK medical record data sources (Clinical Practice Research Datalink, The Health Improvement Network) and two USA claims-based data sources (HealthCore Integrated Research Database, Medicare). All eligible adult patients newly prescribed saxagliptin (n=110 740) and random samples of up to 10 matched initiators of non-DPP-4 inhibitor OADs within each data source were selected (n=913 384). Outcomes were hospitalized major adverse cardiovascular events (MACE), acute kidney injury (AKI), acute liver failure (ALF), infections, and severe hypersensitivity events, evaluated using diagnostic coding algorithms and medical records. Cox regression was used to determine HRs with 95% CIs for each outcome. Meta-analyses across data sources were performed for each outcome as feasible. RESULTS: There were no increased incidence rates or risk of MACE, AKI, ALF, infection, or severe hypersensitivity reactions among saxagliptin initiators compared with other OAD initiators within any data source. Meta-analyses demonstrated a reduced risk of hospitalization/death from MACE (HR 0.91, 95% CI 0.85 to 0.97) and no increased risk of hospitalization for infection (HR 0.97, 95% CI 0.93 to 1.02) or AKI (HR 0.99, 95% CI 0.88 to 1.11) associated with saxagliptin initiation. ALF and hypersensitivity events were too rare to permit meta-analysis. CONCLUSIONS: Saxagliptin initiation was not associated with increased risk of MACE, infection, AKI, ALF, or severe hypersensitivity reactions in clinical practice settings. TRIAL REGISTRATION NUMBER: NCT01086280, NCT01086293, NCT01086319, NCT01086306, and NCT01377935; Results.

Risk of Acute Liver Injury With Antiretroviral Therapy by Viral Hepatitis Status.

BACKGROUND: The risk of hepatotoxicity with antiretroviral therapy (ART) remains unknown. We determined the comparative risk of acute liver injury (ALI) for antiretroviral drugs, classes, and regimens, by viral hepatitis status. METHODS: We followed a cohort of 10 083 human immunodeficiency virus (HIV)-infected persons in Kaiser Permanente Northern California (n = 2099) from 2004 to 2010 and the Veterans Aging Cohort Study (n = 7984) from 2004 to 2012. Within the first year of ART, we determined occurrence of (1) liver aminotransferases >200 U/L and (2) severe ALI (coagulopathy with hyperbilirubinemia). We used Cox regression to determine hazard ratios (HRs) with 95% confidence intervals (CIs) of endpoints among initiators of nucleos(t)ide analogue combinations, antiretroviral classes, and ART regimens, all stratified by viral hepatitis status. RESULTS: Liver aminotransferases >200 U/L developed in 206 (2%) persons and occurred more frequently among HIV/viral hepatitis-coinfected than HIV-monoinfected persons (116.1 vs 20.7 events/1000 person-years; P < .001). No evidence of differential risk was found between initiators of abacavir/lamivudine versus tenofovir/emtricitabine among coinfected (HR, 0.68; 95% CI, .29-1.57) or HIV-monoinfected (HR, 1.19; 95% CI, .47-2.97) groups. Coinfected patients had a higher risk of aminotransferases >200 U/L after initiation with a protease inhibitor than nonnucleoside reverse-transcriptase inhibitor (HR, 2.01; 95% CI, 1.36-2.96). Severe ALI (30 events; 0.3%) occurred more frequently in coinfected persons (15.9 vs 3.1 events/1000 person-years; P < .001) but was too uncommon to evaluate in adjusted analyses. CONCLUSIONS: Within the year after ART initiation, aminotransferase elevations were infrequently observed and rarely led to severe ALI. Protease inhibitor use was associated with a higher risk of aminotransferase elevations among viral hepatitis-coinfected patients.

Evaluation of methods to estimate missing days' supply within pharmacy data of the Clinical Practice Research Datalink (CPRD) and The Health Improvement Network (THIN).

PURPOSE: The extent to which days' supply data are missing in pharmacoepidemiologic databases and effective methods for estimation is unknown. We determined the percentage of missing days' supply on prescription and patient levels for oral anti-diabetic drugs (OADs) and evaluated three methods for estimating days' supply within the Clinical Practice Research Datalink (CPRD) and The Health Improvement Network (THIN). METHODS: We estimated the percentage of OAD prescriptions and patients with missing days' supply in each database from 2009 to 2013. Within a random sample of prescriptions with known days' supply, we measured the accuracy of three methods to estimate missing days' supply by imputing the following: (1) 28 days' supply, (2) mode number of tablets/day by drug strength and number of tablets/prescription, and (3) number of tablets/day via a machine learning algorithm. We determined incidence rates (IRs) of acute myocardial infarction (AMI) using each method to evaluate the impact on ascertainment of exposure time and outcomes. RESULTS: Days' supply was missing for 24 % of OAD prescriptions in CPRD and 33 % in THIN (affecting 48 and 57 % of patients, respectively). Methods 2 and 3 were very accurate in estimating days' supply for OADs prescribed at a consistent number of tablets/day. Method 3 was more accurate for OADs prescribed at varying number of tablets/day. IRs of AMI were similar across methods for most OADs. CONCLUSIONS: Missing days' supply is a substantial problem in both databases. Method 2 is easy and very accurate for most OADs and results in IRs comparable to those from method 3.

Remission of Intermediate Uveitis: Incidence and Predictive Factors.

PURPOSE: To evaluate the incidence of remission among patients with intermediate uveitis; to identify factors potentially predictive of remission. DESIGN: Retrospective cohort study. METHODS: Involved eyes of patients with primary noninfectious intermediate uveitis at 4 academic ocular inflammation subspecialty practices, followed sufficiently long to meet the remission outcome definition, were studied retrospectively by standardized chart review data. Remission of intermediate uveitis was defined as a lack of inflammatory activity at ≥2 visits spanning ≥90 days in the absence of any corticosteroid or immunosuppressant medications. Factors potentially predictive of intermediate uveitis remission were evaluated using survival analysis. RESULTS: Among 849 eyes (of 510 patients) with intermediate uveitis followed over 1934 eye-years, the incidence of intermediate uveitis remission was 8.6/100 eye-years (95% confidence interval [CI], 7.4-10.1). Factors predictive of disease remission included prior pars plana vitrectomy (PPV) (hazard ratio [HR] [vs no PPV] = 2.39; 95% CI, 1.42-4.00), diagnosis of intermediate uveitis within the last year (HR [vs diagnosis >5 years ago] =3.82; 95% CI, 1.91-7.63), age ≥45 years (HR [vs age <45 years] = 1.79; 95% CI, 1.03-3.11), female sex (HR = 1.61; 95% CI, 1.04-2.49), and Hispanic race/ethnicity (HR [vs white race] = 2.81; 95% CI, 1.23-6.41). Presence/absence of a systemic inflammatory disease, laterality of uveitis, and smoking status were not associated with differential incidence. CONCLUSIONS: Our results suggest that intermediate uveitis is a chronic disease with an overall low rate of remission. Recently diagnosed patients and older, female, and Hispanic patients were more likely to remit. With regard to management, pars plana vitrectomy was associated with increased probability of remission.