Score-weighted Cox Proportional Hazards Research Articles

LONGITUDINAL USE TRAJECTORIES OF SEDATIVE-HYPNOTICS AND RISK FOR DEMENTIA AMONG MEDICARE BENEFICIARIES

Abstract Research suggests use of sedative-hypnotic medications (Benzodiazepines [BZDs; e.g., diazepam] and non-BZD hypnotics [e.g., zolpidem]) to be associated with incident Alzheimer’s disease and related dementias (ADRD). We identified longitudinal dose and duration use patterns of these medications and their associations with ADRD risk. This retrospective cohort study used 2016-2018 claims data from a 15% national sample of fee-for-service Medicare beneficiaries and included beneficiaries aged ≥65 years initiating use of a) BZDs only, b) non-BZDs only, or c) BZDs+non-BZDs concurrently. We excluded beneficiaries with ADRD diagnosis 6 months before and 12 months after first BZD/non-BZD prescription date. Based on average weekly diazepam milligram equivalent dose (low: <15, moderate: 15-30, high: >30), we used group-based multi-trajectory models to identify distinct trajectories of BZD/non-BZD use over 12 months after initiation (i.e., trajectory period). We estimated risk of time to first occurrence of ADRD after trajectory period associated with these trajectories using inverse propensity score weighted Cox proportional hazards models. Among 131,574 beneficiaries (mean age=74 years, 68% female, 89% White), we identified 11 trajectories (4 BZD only [78% of cohort], 4 non-BZD only [18%], and 3 concurrent users [4%]). Compared to beneficiaries with low-dose discontinuing non-BZD only use, trajectories associated with an increased risk of ADRD included: stable moderate-dose BZD use with concurrent stable low-dose non-BZD use (HR=2.28, 95%CI=1.62-3.21) and high-dose declining BZD only use (HR=1.57, 95%CI=1.26-1.96). Results highlight a need to assess not only patterns of BZD and non-BZD use alone, but also concurrent use, when considering risk for ADRD.

Risk of Paradoxical Eczema in Patients Receiving Biologics for Psoriasis

Biologics used for plaque psoriasis have been reported to be associated with an atopic dermatitis (AD) phenotype, or paradoxical eczema, in some patients. The risk factors for this are unknown. To explore risk of paradoxical eczema by biologic class and identify factors associated with paradoxical eczema. This prospective cohort study used data from the British Association of Dermatologists Biologics and Immunomodulators Register for adults treated with biologics for plaque psoriasis who were seen at multicenter dermatology clinics in the UK and Ireland. Included participants were registered and had 1 or more follow-up visits between September 2007 and December 2022. Duration of exposure to tumor necrosis factor (TNF) inhibitors, interleukin (IL) 17 inhibitors, IL-12/23 inhibitors, or IL-23 inhibitors until paradoxical eczema onset, treatment discontinuation, last follow-up, or death. Incidence rates of paradoxical eczema, paradoxical eczema risk by biologic class, and the association of demographic and clinical variables with risk of paradoxical eczema were assessed using propensity score-weighted Cox proportional hazards regression models. Of 56 553 drug exposures considered, 24 997 from 13 699 participants were included. The 24 997 included exposures (median age, 46 years [IQR, 36-55 years]; 57% male) accrued a total exposure time of 81 441 patient-years. A total of 273 exposures (1%) were associated with paradoxical eczema. The adjusted incidence rates were 1.22 per 100 000 person-years for IL-17 inhibitors, 0.94 per 100 000 person-years for TNF inhibitors, 0.80 per 100 000 person-years for IL-12/23 inhibitors, and 0.56 per 100 000 person-years for IL-23 inhibitors. Compared with TNF inhibitors, IL-23 inhibitors were associated with a lower risk of paradoxical eczema (hazard ratio [HR], 0.39; 95% CI, 0.19-0.81), and there was no association of IL-17 inhibitors (HR, 1.03; 95% CI, 0.74-1.42) or IL-12/23 inhibitors (HR, 0.87; 95% CI, 0.66-1.16) with risk of paradoxical eczema. Increasing age (HR, 1.02 per year; 95% CI, 1.01-1.03) and history of AD (HR, 12.40; 95% CI, 6.97-22.06) or hay fever (HR, 3.78; 95% CI, 1.49-9.53) were associated with higher risk of paradoxical eczema. There was a lower risk in males (HR, 0.60; 95% CI, 0.45-0.78). In this study, in biologic-treated patients with psoriasis, paradoxical eczema risk was lowest in patients receiving IL-23 inhibitors. Increasing age, female sex, and history of AD or hay fever were associated with higher risk of paradoxical eczema. The overall incidence of paradoxical eczema was low. Further study is needed to replicate these findings.

Influenza Vaccine Administration and Effectiveness Among Children and Adults With Glomerular Disease

IntroductionInfluenza infections contribute to excess healthcare utilization, morbidity, and mortality in individuals with glomerular disease, however influenza vaccination may not yield protective immune responses in this high-risk patient population. The objective of the present study was to describe influenza vaccine administration from 2010 to 2019 and explore the effectiveness of influenza vaccination in patients with glomerular disease. MethodsWe conducted an observational cohort study using healthcare claims for seasonal influenza vaccination (exposure) and influenza and influenza-like illness (outcomes) from commercially insured children and adults <65 years of age with primary glomerular disease in the Merative MarketScan® Research Databases. Propensity score-weighted cox proportional hazards models and ratio-of-hazard ratios (RHR) analyses were used to compare influenza infection risk in years where seasonal influenza vaccines matched or mismatched circulating viral strains. ResultsThe mean proportion of individuals vaccinated per season was 23% (range 19-24%). In pooled analyses comparing matched vs. mismatched seasons, vaccination was minimally protective for both influenza (RHR 0.86, 95% CI 0.52-1.41) and influenza-like illness (RHR 0.86, 95% CI 0.59-1.24), though estimates were limited by sample size. ConclusionsRates of influenza vaccination are suboptimal among patients with glomerular disease. Protection from influenza after vaccination may be poor, leading to excess infection-related morbidity in this vulnerable population.

Association between Fluoxetine Use and Overall Survival among Patients with Cancer Treated with PD-1/L1 Immunotherapy.

Checkpoint inhibitors can be a highly effective antitumor therapy but only to a subset of patients, presumably due to immunotherapy resistance. Fluoxetine was recently revealed to inhibit the NLRP3 inflammasome, and NLRP3 inhibition could serve as a target for immunotherapy resistance. Therefore, we evaluated the overall survival (OS) in patients with cancer receiving checkpoint inhibitors combined with fluoxetine. A cohort study was conducted among patients diagnosed with lung, throat (pharynx or larynx), skin, or kidney/urinary cancer treated with checkpoint inhibitor therapy. Utilizing the Veterans Affairs Informatics and Computing Infrastructure, patients were retrospectively evaluated during the period from October 2015 to June 2021. The primary outcome was overall survival (OS). Patients were followed until death or the end of the study period. There were 2316 patients evaluated, including 34 patients who were exposed to checkpoint inhibitors and fluoxetine. Propensity score weighted Cox proportional hazards demonstrated a better OS in fluoxetine-exposed patients than unexposed (HR: 0.59, 95% CI 0.371-0.936). This cohort study among cancer patients treated with checkpoint inhibitor therapy showed a significant improvement in the OS when fluoxetine was used. Because of this study's potential for selection bias, randomized trials are needed to assess the efficacy of the association of fluoxetine or another anti-NLRP3 drug to checkpoint inhibitor therapy.

Sex-Based Differences in Survival Among Patients with Acute Abdomen Undergoing Surgery in Malawi: A Propensity Weighted Analysis.

Sex disparities in access to health care in low-resource settings have been demonstrated. Still, there has been little research on the effect of sex on postoperative outcomes. We evaluated the relationship between sex and mortality after emergency abdominal surgery. We performed a retrospective cohort study using the acute care surgery database at Kamuzu Central Hospital (KCH) in Malawi. We included patients who underwent emergency abdominal surgery between 2013 and 2021. We created a propensity score weighted Cox proportional hazards model to assess the relationship between sex and inpatient survival. We included 2052 patients in the study, and 76% were males. The most common admission diagnosis in both groups was bowel obstruction. Females had a higher admission shock index than males (0.91 vs. 0.81, p < 0.001) and a longer delay from admission until surgery (1.47 vs. 0.79days, p < 0.001). Females and males had similar crude postoperative mortality (16.3% vs. 15.3%, p = 0.621). The final Cox proportional hazards regression model was based on the propensity-weighted cohort. The mortality hazard ratio was 0.65 among females compared to males (95% CI 0.46-0.92, p = 0.014). Our results show a survival advantage among female patients undergoing emergency abdominal surgery despite sex-based disparities in access to surgical care that favors males. Further research is needed to understand the mechanisms underlying these findings.

Association of Sodium-Glucose Cotransporter 2 Inhibitors With Time to Dementia: A Population-Based Cohort Study.

Type 2 diabetes (T2D) increases dementia risk, but clear evidence to recommend interventions that can mitigate that risk remains lacking. This population-based retrospective cohort study aimed to determine whether new use of sodium-glucose cotransporter 2 (SGLT2) inhibitors compared with dipeptidyl peptidase 4 (DPP-4) inhibitors was associated with lower dementia risk. Ontario residents aged ≥66 years who were new users of an SGLT2 inhibitor or a DPP-4 inhibitor from 1 July 2016 to 31 March 2021 entered the cohort. Incident dementia was identified using a validated algorithm for Alzheimer's disease and related dementias. Propensity score-weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and CIs for time to incident dementia. To address reverse causality and disease latency, the observation window started at 1-year lag time from cohort entry. The primary analysis followed intention-to-treat exposure definition, and a secondary as-treated analysis was performed. Among 106,903 individuals, SGLT2 inhibitors compared with DPP-4 inhibitors were associated with lower risk of dementia (14.2/1,000 person-years; aHR 0.80 [95% CI 0.71-0.89]) over a mean follow-up of 2.80 years from cohort entry. When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR 0.67 [95% CI 0.53-0.84]), followed by empagliflozin (aHR 0.78 [95% CI 0.69-0.89]), whereas canagliflozin showed no association (aHR 0.96 [95% CI 0.80-1.16]). The as-treated analysis observed a larger association (aHR 0.66 [95% CI 0.57-0.76]) than the intention-to-treat analysis. SGLT2 inhibitors showed an association with lower dementia risk in older people with T2D. Randomized controlled trials are warranted.

Comparative Safety and Attributable Healthcare Expenditures Following Inappropriate Versus Appropriate Outpatient Antibiotic Prescriptions Among Adults With Upper Respiratory Infections.

Little is known about the clinical and financial consequences of inappropriate antibiotics. We aimed to estimate the comparative risk of adverse drug events and attributable healthcare expenditures associated with inappropriate versus appropriate antibiotic prescriptions for common respiratory infections. We established a cohort of adults aged 18 to 64 years with an outpatient diagnosis of a bacterial (pharyngitis, sinusitis) or viral respiratory infection (influenza, viral upper respiratory infection, nonsuppurative otitis media, bronchitis) from 1 April 2016 to 30 September 2018 using Merative MarketScan Commercial Database. The exposure was an inappropriate versus appropriate oral antibiotic (ie, non-guideline-recommended vs guideline-recommended antibiotic for bacterial infections; any vs no antibiotic for viral infections). Propensity score-weighted Cox proportional hazards models were used to estimate the association between inappropriate antibiotics and adverse drug events. Two-part models were used to calculate 30-day all-cause attributable healthcare expenditures by infection type. Among 3 294 598 eligible adults, 43% to 56% received inappropriate antibiotics for bacterial and 7% to 66% for viral infections. Inappropriate antibiotics were associated with increased risk of several adverse drug events, including Clostridioides difficile infection and nausea/vomiting/abdominal pain (hazard ratio, 2.90; 95% confidence interval, 1.31-6.41 and hazard ratio, 1.10; 95% confidence interval, 1.03-1.18, respectively, for pharyngitis). Thirty-day attributable healthcare expenditures were higher among adults who received inappropriate antibiotics for bacterial infections ($18-$67) and variable (-$53 to $49) for viral infections. Inappropriate antibiotic prescriptions for respiratory infections were associated with increased risks of patient harm and higher healthcare expenditures, justifying a further call to action to implement outpatient antibiotic stewardship programs.

Association of Inappropriate Outpatient Pediatric Antibiotic Prescriptions With Adverse Drug Events and Health Care Expenditures

Nonguideline antibiotic prescribing for the treatment of pediatric infections is common, but the consequences of inappropriate antibiotics are not well described. To evaluate the comparative safety and health care expenditures of inappropriate vs appropriate oral antibiotic prescriptions for common outpatient pediatric infections. This cohort study included children aged 6 months to 17 years diagnosed with a bacterial infection (suppurative otitis media [OM], pharyngitis, sinusitis) or viral infection (influenza, viral upper respiratory infection [URI], bronchiolitis, bronchitis, nonsuppurative OM) as an outpatient from April 1, 2016, to September 30, 2018, in the IBM MarketScan Commercial Database. Data were analyzed from August to November 2021. Inappropriate (ie, non-guideline-recommended) vs appropriate (ie, guideline-recommended) oral antibiotic agents dispensed from an outpatient pharmacy on the date of infection. Propensity score-weighted Cox proportional hazards models were used to estimate hazards ratios (HRs) and 95% CIs for the association between inappropriate antibiotic prescriptions and adverse drug events. Two-part models were used to calculate 30-day all-cause attributable health care expenditures by infection type. National-level annual attributable expenditures were calculated by scaling attributable expenditures in the study cohort to the national employer-sponsored insurance population. The cohort included 2 804 245 eligible children (52% male; median [IQR] age, 8 [4-12] years). Overall, 31% to 36% received inappropriate antibiotics for bacterial infections and 4% to 70% for viral infections. Inappropriate antibiotics were associated with increased risk of several adverse drug events, including Clostridioides difficile infection and severe allergic reaction among children treated with a nonrecommended antibiotic agent for a bacterial infection (among patients with suppurative OM, C. difficile infection: HR, 6.23; 95% CI, 2.24-17.32; allergic reaction: HR, 4.14; 95% CI, 2.48-6.92). Thirty-day attributable health care expenditures were generally higher among children who received inappropriate antibiotics, ranging from $21 to $56 for bacterial infections and from -$96 to $97 for viral infections. National annual attributable expenditure estimates were highest for suppurative OM ($25.3 million), pharyngitis ($21.3 million), and viral URI ($19.1 million). In this cohort study of children with common infections treated in an outpatient setting, inappropriate antibiotic prescriptions were common and associated with increased risks of adverse drug events and higher attributable health care expenditures. These findings highlight the individual- and national-level consequences of inappropriate antibiotic prescribing and further support implementation of outpatient antibiotic stewardship programs.

Long-term Persistence of First-line Biologics for Patients With Psoriasis and Psoriatic Arthritis in the French Health Insurance Database

Treatment options for psoriasis (PsO) and psoriatic arthritis (PsA) have evolved significantly throughout the era of biologics. Clinical trials are inadequate to assess the relative long-term efficacy of biologics and are often insufficient regarding safety. To assess the long-term persistence of different biologic classes to treat PsO and PsA. This nationwide cohort study involved the administrative health care database of the French health insurance scheme linked to the hospital discharge database. All adults with PsO and PsA who were new users of biologics (not in the year before the index date) from January 1, 2015, to May 31, 2019, were included and followed up through December 31, 2019. Patients hospitalized for PsA in the PsO cohort and for PsO in the PsA cohort in the year before the index date were excluded. Data were analyzed from June 1 to October 31, 2021. Persistence was defined as the time from biologic therapy initiation to discontinuation and was estimated using the Kaplan-Meier method. Comparison of persistence by biologic class involved using propensity score-weighted Cox proportional hazards regression models and adjustment on specific systemic nonbiologics (time-dependent variables). A total of 16 892 patients with PsO were included in the analysis (mean [SD] age, 48.5 [13.8] years; 9152 men [54.2%] men). Of these, 10 199 patients (60.4%) started therapy with a tumor necrosis factor (TNF) inhibitor; 3982 (23.6%), with an interleukin 12 and interleukin 23 (IL-12/23) inhibitor; and 2711 (16.0%), with an interleukin 17 (IL-17) inhibitor. An additional 6531 patients with PsA (mean [SD] age, 49.1 [12.8] years; 3565 [54.6%] women) were included; of these, 4974 (76.2%) started therapy with a TNF inhibitor; 803 (12.3%), with an IL-12/23 inhibitor; and 754 (11.5%), with an IL-17 inhibitor. Overall 3-year persistence rates were 40.9% and 36.2% for PsO and PsA, respectively. After inverse probability of treatment weighting and adjustment, the IL-17 inhibitor was associated with higher persistence compared with the TNF inhibitor for PsO (weighted hazard ratio [HR], 0.78 [95% CI, 0.73-0.83]) and PsA (weighted HR, 0.70 [95% CI, 0.58-0.85]) and compared with the IL-12/23 inhibitor for PsA (weighted HR, 0.69 [95% CI, 0.55-0.87]). No difference between the IL-17 inhibitor and IL-12/23 inhibitor for PsO was noted. The IL-12/23 inhibitor was associated with higher persistence than the TNF inhibitor for PsO (weighted HR, 0.76 [95% CI, 0.72-0.80]), with no difference observed for PsA. The findings of this cohort study suggest that IL-17 inhibitors are associated with higher treatment persistence than the TNF inhibitor for PsO and PsA. Interleukin 17 inhibitors were also associated with higher persistence than the IL-12/23 inhibitor for PsA, with no difference for PsO. However, the persistence rates of all biologics remained globally low at 3 years.

Utilization and survival benefit of adjuvant immunotherapy in resected high-risk stage II melanoma

The risk of locoregional and distant recurrence of stage IIB/IIC cutaneous melanoma is high, and limited evidence exists on the clinical benefit of adjuvant immunotherapy (aIMT). This is the first retrospective study to evaluate the utilization and survival benefit of adjuvant immunotherapy (aIMT) for high-risk stage II cutaneous melanoma. The National Cancer Database (NCDB) was queried for stage IIB/IIC melanoma patients who underwent resection and sentinel lymph node biopsy. Chi-square tests and multivariable logistic regression examined associations between utilization of aIMT and socioeconomic and clinical characteristics. Propensity score weighted Cox proportional hazards model assessed impact of aIMT on overall survival. Of the 8,549 patients with pathologic stage IIB/IIC melanoma, 344 (4.02%) patients received aIMT. Patients with pT4b disease or positive surgical margins were more likely to receive aIMT than patients with pT3b disease or negative margins (OR=3.10, OR=2.71, respectively, all P <0.001). Females or patients less than age 65 were more likely to receive aIMT (OR=1.36, OR=2.77, respectively, P <0.05). The Cox proportional hazard model demonstrated that receiving aIMT was associated with longer survival (HR=0.66, P <0.01). This study observed a survival advantage with utilization of immunotherapy for patients with resectable stage IIB/IIC melanoma. Sociodemographic differences on the receipt of aIMT warrant further attention.

Predictors and Outcomes of Minimally Invasive Surgery for Small Bowel Neuroendocrine Tumors

BackgroundOpen surgical resection with regional lymphadenectomy is the standard of care for small bowel neuroendocrine tumors (SBNETs). There is no consensus on the role of minimally invasive surgery (MIS). This study aims to evaluate the current national trends for MIS in treating SBNETs and its association with lymph node (LN) yield. MethodsThe National Cancer Database was queried for patients with Stage I-III SBNETs who underwent surgery from 2010–2017. Time trends were examined using the Cochran–Armitage test. Chi-square tests, t test, and multivariable logistic regression assessed associations of surgical approach with patient, clinical, and facility characteristics. Kaplan–Meier curves and propensity score weighted Cox proportional hazards model were used to examine survival. ResultsOf the 11,367 patients with Stage I-III SBNETs, 46.5% (N = 5,298) underwent MIS. From 2010–2017, the proportion of MIS increased from 35.6% to 57.7% (P < 0.001). Patients of Stage I disease (OR = 1.23), Caucasian race (OR = 1.18), private insurance (OR = 1.29), and higher volume centers (OR = 1.29) were more likely to undergo MIS (all P < 0.02). The average number of LN harvested in the MIS cohort was greater than in the open surgery cohort (13.3 vs 11.8 LN, P < 0.001). MIS patients had shorter length of stay by 2 days compared to open surgery (5.4 vs 7.6 days, P < 0.001). LN yield ≥ 8 was associated with better survival (HR = 0.77, P < 0.001). ConclusionThe utilization of a MIS approach to treat Stage I-III SBNETs has increased, especially at higher volume centers. We did not observe an inferior LN harvest with the MIS cohort compared to the open surgery cohort.

Association Between Biologics Use and Risk of Serious Infection in Patients With Psoriasis

Biologics and targeted therapies, such as apremilast, are efficient treatments to manage moderate to severe psoriasis. More information about the risk of serious infection is needed for the newest treatment options in a real-world setting. To assess the risk of serious infection among biologics and apremilast used to treat psoriasis, with etanercept as the comparator. This nationwide cohort study from France involved data from the National Health Data System covering approximately 99% of the French population. All adults with psoriasis, defined as receiving at least 2 prescriptions of a topical vitamin D derivative within a 2-year period, registered in the database between January 1, 2008, and May 31, 2019, were eligible. The study population included those who were new users of biologic agents or apremilast (ie, without any prescriptions of a biologic or apremilast during the previous year). Patients with HIV infection or a history of cancer, transplant, or serious infection were excluded. End of follow-up was January 31, 2020. The primary end point was a serious infection in a time-to-event analysis using propensity score-weighted Cox proportional hazards regression models, estimating weighted hazard ratios (wHRs) and 95% CIs. A total of 44 239 new users of biologic treatment were identified (mean [SD] age, 48.4 [13.8] years; 22 866 [51.7%] men; median follow-up, 12 months [interquartile range, 7-24 months]). A total of 29 618 (66.9%) were prescribed a tumor necrosis factor inhibitor first, 6658 (15.0%) an interleukin (IL) 12/23 inhibitor, 4093 (9.3%) an IL-17 inhibitor, 526 (1.2%) an IL-23 inhibitor, and 3344 (7.6%) apremilast. The total number of serious infections was 1656, and the overall crude incidence rate was 25.0 (95% CI, 23.8-26.2) per 1000 person-years. The most frequent serious infections were gastrointestinal infections (645 patients [38.9%]). After adjusting for time-dependent covariables, risk of serious infections was higher for new users of adalimumab (wHR, 1.22; 95% CI, 1.07-1.38) or infliximab (wHR, 1.79; 95% CI 1.49-2.16) vs etanercept, whereas ustekinumab was associated with a lower risk of having a serious infection (wHR, 0.79; 95% CI, 0.67-0.94). Risk of serious infections was not increased for new users of IL-17 and the IL-23 inhibitor guselkumab or apremilast vs etanercept. Risk of serious infections was increased with concomitant nonsteroidal anti-inflammatory drugs or systemic corticosteroids. In this cohort study of individuals with moderate to severe psoriasis, risk of serious infections was increased in new users of infliximab and adalimumab vs etanercept, whereas ustekinumab users had lower risk of having a serious infection but not new users of IL-17 and IL-23 inhibitors or apremilast. Other observational studies are needed to confirm results for the most recent drugs.

Survival Benefit of Guideline-Concordant Postoperative Radiation for Local Merkel Cell Carcinoma

BackgroundPostoperative radiation therapy (RT) for early-stage Merkel Cell Carcinoma (MCC) decreases the risk of locoregional recurrence and improve overall survival. However, concordance with RT guidelines is unknown. Materials and MethodsThe National Cancer Database was queried for stage I/II MCC patients receiving surgical intervention from 2006-2017. The cohort was stratified by patients who had and did not have indication(s) for adjuvant RT of the primary tumor site based on National Comprehensive Cancer Network guidelines. We captured the use of RT, patient demographics, socioeconomic characteristics, and clinical characteristics. Logistic regression, Kaplan-Meier method, and propensity score weighted Cox proportional hazards model examined associations and survival benefits of RT. Results2,330 stage I/II MCC patients underwent surgical intervention. 1,858 (79.7%) met National Comprehensive Cancer Network criteria for RT of the primary tumor site, of which 1,062 (57.2%) received RT. 472 (20.3%) did not meet criteria for RT, of which 203 (43.0%) received RT. Five-year overall survival advantage was identified for patients who received RT when it was indicated (P < 0.003). There was no evidence of overall survival advantage when patients received guideline-discordant RT (P = 0.478). ConclusionsSurgical resection with adjuvant RT of the primary tumor site has an overall survival benefit for local MCC when patients meet criteria for RT. This study found a group who received guideline-discordant RT with no survival advantage. Further investigation is warranted to identify the socio-demographic and oncologic reasons for guideline discordance in the treatment of MCC for both under- and over-treatment.

Severe Hypoglycemia Risk With Long-Acting Insulin Analogs vs Neutral Protamine Hagedorn Insulin

Previous studies have found that the risk of severe hypoglycemia does not differ between long-acting insulin analogs and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. However, these studies did not focus on patients 65 years or older, who are at an increased risk for hypoglycemia, or did not include patients with concomitant prandial insulin use. To examine the risk of emergency department (ED) visits or hospitalizations for hypoglycemia among older community-residing patients with type 2 diabetes who initiated long-acting insulin or NPH insulin in real-world settings. This retrospective, new-user cohort study assessed Medicare beneficiaries 65 years or older who initiated insulin glargine (n = 407 018), insulin detemir (n = 141 588), or NPH insulin (n = 26 402) from January 1, 2007, to July 31, 2019. Insulin glargine, insulin detemir, and NPH insulin. The primary outcome was time to first ED visit or hospitalization for hypoglycemia, defined using a modified validated algorithm. Propensity score-weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs. The risk of recurring hypoglycemia events was estimated using the Andersen-Gill model. Post hoc analyses were conducted investigating possible effect modification by age. Of the 575 008 patients initiating use of insulin (mean [SD] age 74.9 [6.7] years; 53% female), 407 018 used glargine, 141 588 used detemir, and 26 402 used NPH insulin. The study included 7347 ED visits or hospitalizations for hypoglycemia (5194 for glargine, 1693 for detemir, and 460 for NPH insulin, with a median follow-up across the 3 cohorts of 0.37 years (interquartile range, 0.20-0.76 years). Initiation of glargine and detemir use was associated with a reduced risk of hypoglycemia compared with NPH insulin use (HR for glargine vs NPH insulin, 0.71; 95% CI, 0.63-0.80; HR, detemir vs NPH insulin, 0.72; 95% CI, 0.63-0.82). The HRs were similar for the recurrent event analysis. The protective association of long-acting insulin analogs varied by age and was not seen with concomitant prandial insulin use. In this cohort study, initiation of long-acting analogs was associated with a lower risk of ED visits or hospitalizations for hypoglycemia compared with NPH insulin in older patients with type 2 diabetes in Medicare. However, this association was not seen with concomitant prandial insulin use.

Frequency and Timing of Complications and Catastrophic Events After Same-Day Discharge Compared With Inpatient Total Hip Arthroplasty

BackgroundSame-day discharge total hip arthroplasty (THA) has grown in utilization although concerns exist regarding early complications and catastrophic events. We sought to compare the risk of complications and catastrophic events for same-day and inpatient stay THA. MethodsA cohort study was conducted using Kaiser Permanente’s total joint replacement registry. Primary elective THA were identified (2017-2018). Propensity score–weighted Cox proportional hazards regression was used to evaluate risk for 90-day incident events, including emergency department (ED) visit, unplanned readmission, cardiac complication, deep infection, venous thromboembolism (VTE), and mortality, by in-hospital length of stay: same-day vs 1-2-night inpatient stay. ResultsThe study sample comprised 13,646 THA, 6033 (44.1%) with a same-day discharge. Median days-to-events for same-day vs inpatient was 11 vs 12 for ED visit, 23 vs 20 for readmission, 38 vs 12 for cardiac complication, 28 vs 24 for deep infection, 14.5 vs 23.5 for VTE, and 7 vs 35.5 for mortality. In propensity score–weighted models, same-day discharge THA had a lower risk for 90-day ED visit (HR = 0.82, 95% CI = 0.72-0.94), readmission (HR = 0.75, 95% CI = 0.61-0.92), and cardiac complication (HR = 0.60, 95% CI = 0.47-0.76), compared with inpatient stay THA; no difference was observed for deep infection (HR = 1.59, 95% CI = 0.81-3.12), VTE (HR = 0.90, 95% CI = 0.52-1.58), or mortality (HR = 0.81, 95% CI = 0.27-2.40). ConclusionWe observed a lower or no difference in risk for complications and catastrophic events after same-day THA than an inpatient stay. Catastrophic events were more likely to occur early in the 90-day period, but an inpatient stay did not preclude events.

Society for Vascular Surgery femoral runoff score is associated with limb-based patency after aortofemoral bypass

ObjectiveDespite advancements, aortofemoral bypass (AFB) remains the most durable option for aortoiliac occlusive disease. Although runoff has been shown to be associated with AFB patency, the association of the Society for Vascular Surgery (SVS) thigh runoff scoring system with patency has not been assessed. The aim of the present study was to evaluate the association between the SVS runoff scoring system and limb-based primary patency after AFB. MethodsInstitutional data for patients undergoing AFB with preoperative runoff imaging available from 2000 to 2017 were queried. Runoff scores were assigned according to the presence of occlusive disease in the superficial femoral artery and profunda femoris artery (minimum, 1; maximum, 10) as described by the 1997 SVS reporting standards for lower extremity ischemia. Limb-based patency was the primary endpoint. Kaplan-Meier analysis was used to compare the long-term limb-based patency and freedom from reintervention between limbs with runoff scores ≥6 and those with runoff scores <6. Propensity score-weighted Cox proportional hazards modeling was used to evaluate the association between a runoff score of ≥6 and primary patency loss, controlling for other factors associated with primary patency. ResultsIn 161 patients, 316 limbs had undergone revascularization. The mean patient age was 66.7 ± 11.3 years, and 51.6% were women. Most limbs had undergone revascularization for claudication (56.5%). Most (89.4%) had TransAtlantic InterSociety Consensus class D lesions, 27.3% had required suprarenal or higher clamping, and 11.2% had undergone concomitant mesenteric intervention. A femoral outflow adjunct and concurrent lower extremity bypass was required in 41.8% and 2.9% of limbs, respectively. Those with a runoff score of ≥6 had experienced greater rates of 30-day myocardial infarction (11% vs 1%; P = .005), respiratory failure (11% vs 1%; P = .005), and mortality (8% vs 0%; P ≤ .006). The median follow-up period was 4.0 years (interquartile range, 6.5 years). The 1-, 3-, and 5-year primary patency was 94.6% (95% confidence interval [CI], 91.9%-97.3%), 89.2% (95% CI, 85.4%-93.2%), and 81.4% (95% CI, 76.0%-87.1%), respectively. The 5-year primary-assisted patency, secondary patency, and freedom from reintervention were 84.9% (95% CI, 79.7%-90.5%), 91.7% (95% CI, 87.3%-96.3%), and 83.3% (95% CI, 78.3%-88.7%), respectively. Patients with a runoff score of ≥6 had lower primary (log-rank P < .01), primary-assisted (P < .01), and secondary patency (P = .01). The factors associated with the loss of primary patency included a high runoff score (runoff score of ≥6: hazard ratio [HR], 4.1; 95% CI, 2.1-8.0; P < .01), simultaneous mesenteric endarterectomy (HR, 13.5; 95% CI, 1.9-97.8; P = .01), and chronic kidney disease (HR, 4.6; 95% CI, 1.5-14.6; P = .01). Increasing age (HR, 0.94 per year; 95% CI, 0.91-0.97; P < .01) and hyperlipidemia (HR, 0.44; 95% CI, 0.23-0.85; P = .01) were protective. ConclusionsThe SVS femoral runoff score is an important factor associated with long-term AFB limb patency. Scores of ≥6 portend for worse limb outcomes and a greater incidence of operative complications. The SVS score can be determined from preoperative axial imaging studies and serve as a guide in decision-making and operative planning.

The Association Between Cement Viscosity and Revision Risk After Primary Total Knee Arthroplasty

BackgroundRecent case series have reported early failure with the use of high-viscosity cement (HVC) in total knee arthroplasty (TKA). We evaluated revision risk after TKA with HVC compared with medium-viscosity cement (MVC) in a large cohort. MethodsWe conducted a cohort study using data from Kaiser Permanente’s Total Joint Replacement Registry. Patients who underwent fully cemented primary TKA for osteoarthritis were identified (2001-2018). Only posterior-stabilized, fixed-mobility designs of the 3 highest-volume implant systems (DePuy PFC, Zimmer NexGen, and Zimmer Persona) were included to mitigate confounding from implant characteristics. Palacos (Zimmer/Heraeus) and Simplex (Stryker) cements comprised the HVC and MVC exposure groups, respectively. Propensity score–weighted Cox proportional hazards regression was used to evaluate risk for any revision during follow-up and risk for revision from aseptic loosening specifically. ResultsThe final cohort comprised 76,052 TKAs, 41.1% using MVC. The crude 14-year cumulative revision probability was 4.55% and 5.12% for TKA with MVC and HVC, respectively. In propensity score–weighted Cox models, MVC compared with HVC had a lower risk of any revision (hazard ratio = 0.82, 95% confidence interval = 0.70-0.95) while no difference was observed for revision from aseptic loosening (hazard ratio = 0.80, 95% confidence interval = 0.56-1.13). ConclusionWhile we observed a lower risk for any revision with the use of Simplex MVC compared with Palacos HVC, we did not observe a difference in revision for aseptic loosening specifically. Given the widespread use of HVC, additional research to investigate other HVC and potential mechanisms for failure outside of loosening is warranted. Level of EvidenceLevel III.

Comparative Effectiveness of Renin-Angiotensin System Inhibitors and Calcium Channel Blockers in Individuals With Advanced CKD: A Nationwide Observational Cohort Study

It is unknown whether initiating renin-angiotensin system (RAS) inhibitor therapy in patients with advanced chronic kidney disease (CKD) is superior to alternative antihypertensive agents such as calcium channel blockers (CCBs). We compared the risks for kidney replacement therapy (KRT), mortality, and major adverse cardiovascular events (MACE) in patients with advanced CKD in routine nephrology practice who were initiating either RAS inhibitor or CCB therapy. Observational study in the Swedish Renal Registry, 2007 to2017. 2,458 new users of RAS inhibitors and 2,345 CCB users with estimated glomerular filtration rates<30mL/min/1.73m2 (CKD G4-G5 without KRT) who were being followed up by a nephrologist. As a positive control cohort, new users of the same drugs with CKD G3 (estimated glomerular filtration rate, 30-60mL/min/1.73m2) were evaluated. RAS inhibitor versus CCB therapy initiation. Initiation of KRT (maintenance dialysis or transplantation), all-cause mortality, and MACE (composite of cardiovascular death, myocardial infarction, or stroke). HRs with 95% CIs were estimated using propensity score-weighted Cox proportional hazards regression adjusting for demographic, clinical, and laboratory covariates. Median age was 74 years, 38% were women, and median follow-up was 4.1 years. After propensity score weighting, there was significantly lower risk for KRT after new use of RAS inhibitors compared with new use of CCBs (adjusted HR, 0.79 [95% CI, 0.69-0.89]) but similar risks for mortality (adjusted HR, 0.97 [95% CI, 0.88-1.07]) and MACE (adjusted HR, 1.00 [95% CI, 0.88-1.15]). Results were consistent across subgroups and in as-treated analyses. The positive control cohort of patients with CKD G3 showed similar KRT risk reduction (adjusted HR, 0.67 [95% CI, 0.56-0.80]) with RAS inhibitor therapy compared with CCBs. Potential confounding by indication. Our findings provide evidence from real-world clinical practice that initiation of RAS inhibitor therapy compared with CCBs may confer kidney benefits among patients with advanced CKD, with similar cardiovascular protection.

Risk of Systemic Adverse Events after Intravitreal Bevacizumab, Ranibizumab, and Aflibercept in Routine Clinical Practice

Intravitreal anti-vascular endothelial growth factor (VEGF) pharmacotherapy plays a central role in the management of neovascular age-related macular degeneration (nAMD), diabetic retinal disease (DRD), and retinal venous occlusive disease (RVO). Within clinical trials, rates of systemic serious adverse events (SAEs) after anti-VEGF treatment have been low. However, the comparative systemic safety profile of common anti-VEGF agents remains incompletely understood. The goal of this study was to compare the systemic safety of intravitreal bevacizumab, ranibizumab, and aflibercept in real-world practice. Retrospective cohort study. Using a large U.S. administrative claims database of commercially insured and Medicare Advantage enrollees, we identified adult cohorts receiving initial anti-VEGF injections for nAMD, DRD, and RVO between January 1, 2007, and June 30, 2018. We included patients with 1 year of insurance coverage before initial treatment. We compared predefined systemic outcomes between anti-VEGF agents occurring within 180 days of treatment initiation using propensity score-weighted Cox proportional hazards models. Patients were censored upon treatment with a different anti-VEGF medication or termination of health plan coverage. Primary outcomes were acute myocardial infarction (MI), acute cerebrovascular disease (CVD), major bleeding, and all-cause hospitalization. A total of 87 844 patients received initial anti-VEGF injections for nAMD, DRD, and RVO between January 1, 2007, and June 30, 2018 (69 007 bevacizumab; 10 895 ranibizumab; 7942 aflibercept). Postinjection 180-day event rates per 100 patients for MI, CVD, major bleeding, and all-cause hospitalization were similar for bevacizumab (0.64, 0.59, 0.34, and 10.41, respectively), ranibizumab (0.62, 0.53, 0.40, and 9.44, respectively), and aflibercept (0.63, 0.60, 0.20, and 9.88, respectively). No differences were identified for the risk of MI, CVD, major bleeding, or all-cause hospitalization when comparing the risk-adjusted effect of treatment initiation with bevacizumab versus ranibizumab (hazard ratio [HR], 0.96 [95% confidence interval {CI}, 0.74-1.25]; HR, 1.04 [95% CI, 0.78-1.38]; HR, 0.85 [95% CI, 0.61-1.19]; HR, 1.03 [95% CI, 0.96-1.10], all P > 0.05), bevacizumab versus aflibercept (HR, 0.95 [95% CI, 0.68-1.33], HR, 0.99 [95% CI, 0.71-1.38], HR, 1.02 [95% CI, 0.60-1.74], HR, 1.01 [95% CI, 0.93-1.10], all P > 0.05), or aflibercept versus ranibizumab (HR, 0.91 [95% CI, 0.62-1.35], HR, 1.12 [95% CI, 0.74-1.69], HR, 0.96 [95% CI, 0.53-1.73], HR, 1.02 [95% CI, 0.92-1.13], all P > 0.05). We observed no differences in the risk of acute MI, CVD, major bleeding, or all-cause hospitalization after treatment initiation with intravitreal bevacizumab, ranibizumab, or aflibercept during routine clinical practice.

Increasing antiviral treatment uptake improves survival in patients with HBV-related HCC.

Background & AimsAntiviral treatment is known to improve survival in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). Yet, the treatment uptake in CHB patients remains low. We aimed to report the secular trend in antiviral treatment uptake from 2007–2017, and to compare the effect of different nucleos(t)ide analogue (NA) initiation times (before vs. after HCC diagnosis) on survival.MethodsA 3-month landmark analysis was used to compare overall survival in patients not receiving NA treatment (i.e. no NA), patients receiving NAs after their first HCC treatment (i.e. post-HCC NA), and patients receiving NAs ≤3 months before their first HCC treatment (i.e. pre-HCC NA). A propensity score-weighted Cox proportional hazards model was used to balance clinical characteristics between the 3 groups and to estimate hazard ratios (HRs).ResultsThe uptake of antiviral treatment in HCC patients increased from 47.3% in 2007 to 98.3% in 2017. The pre-HCC NA group contributed mostly to the uptake rate, which increased from 72.7% to 96.0% in the past decade. In addition, 3,843 CHB patients (407 no NA; 2,932 pre-HCC NA; 504 post-HCC NA) with HCC, receiving at least 1 type of HCC treatment, were included in the analysis. Lack of NA treatment at the time of HCC diagnosis increased the risk of death (weighted HR 3.05; 95% CI 2.70–3.44; p <0.001). The impact of the timing of NA treatment was insignificant (weighted HR 0.90; 95% CI 0.78–1.04; p = 0.161).ConclusionsThe uptake of antiviral treatment in HCC patients increased over the past decade. NA treatment, regardless of whether it was initiated before or after HCC diagnosis, improved survival. It is never too late to initiate NA treatment, even after HCC diagnosis.Lay summaryMore and more patients who have hepatitis B-related liver cancer received antiviral treatment over the past decade. The timing of starting antiviral treatment, regardless of whether it was before or after liver cancer happens, does not really matter in terms of survival benefits.