A Simple and Interpretable Mortality-Based Value Metric for Condition- or Procedure-Specific Hospital Performance Reporting.

Objective: To develop a simple, interpretable value metric (VM) to assess the value of care of hospitals for specific procedures or conditions by operationalizing the value equation: Value = Quality/Cost. Patients and Methods: The present study was conducted on a retrospective cohort from 2015 to 2018 drawn from the 100% US sample of Medicare inpatient claims. The final cohort comprised 637,341 consecutive inpatient encounters with a cancer-related Medicare Severity-Diagnosis Related Grouping and 13,307 consecutive inpatient encounters with the International Classification of Diseases, Ninth Revision or International Classification of Diseases, Tenth Revision procedure code for partial or total gastrectomy. Claims-based demographic and clinical variables were used for risk adjustment, including age, sex, year, dual eligibility, reason for Medicare entitlement, and binary indicators for each of the Elixhauser comorbidities used in the Elixhauser mortality index. Risk-adjusted 30-day mortality and risk-adjusted encounter-specific costs were combined to form the VM, which was calculated as follows: number needed to treat = 1/(Mortalitynational - Mortalityhospital), and VM = number needed to treat × risk-adjusted cost per encounter. Results: Among hospitals with better-than-average 30-day cancer mortality rates, the cost to prevent 1 excess 30-day mortality for an inpatient cancer encounter ranged from $71,000 (best value) to $1.4 billion (worst value), with a median value of $543,000. Among hospitals with better-than-average 30-day gastrectomy mortality rates, the cost to prevent 1 excess 30-day mortality for an inpatient gastrectomy encounter ranged from $710,000 (best value) to $95 million (worst value), with a median value of $1.8 million. Conclusion: This simple VM may have utility for interpretable reporting of hospitals' value of care for specific conditions or procedures. We found substantial inter- and intrahospital variation in value when defined as the costs of preventing 1 excess cancer or gastrectomy mortality compared with the national average, implying that hospitals with similar quality of care may differ widely in the value of that care.

Acute pain pathways: protocol for a prospective cohort study.

INTRODUCTION: Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. METHODS AND ANALYSIS: This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients' patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. ETHICS AND DISSEMINATION: This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. TRIAL REGISTRATION NUMBER: NCT04509115.

Many Medicare Beneficiaries Do Not Fill High-Price Specialty Drug Prescriptions.

For high-price drugs, Medicare Part D beneficiaries who do not receive a low-income subsidy must pay a percentage of the drug's price for each medication fill. Without that subsidy, which lowers out-of-pocket spending, beneficiaries typically pay hundreds or thousands of dollars for a single fill. We estimated the proportion of Part D beneficiaries in fee-for-service Medicare, with and without a subsidy, who do not initiate treatment (that is, do not fill a new prescription) with high-price Part D drugs newly prescribed for four conditions. Examining 17,076 new prescriptions issued between 2012 and 2018 for Part D beneficiaries from eleven geographically diverse health systems, we found that beneficiaries receiving subsidies were nearly twice as likely to obtain the prescribed drug within ninety days as those without subsidies. Among beneficiaries without subsidies, we observed noninitiation for 30 percent of prescriptions written for anticancer drugs, 22 percent for hepatitis C treatments, and more than 50 percent for disease-modifying therapies for either immune system disorders or hypercholesterolemia. Our findings support current legislative efforts to increase the accessibility of high-price medications by reducing out-of-pocket expenses under Medicare Part D, particularly for beneficiaries without low-income subsidies.

Rates of, and factors associated with, switching among generic levothyroxine preparations in commercially insured American adults.

IMPORTANCE: Some practice guidelines warn against generic L-thyroxine preparation switching. OBJECTIVE: To examine the rates of generic L-thyroxine preparation switching within one year of initiating L-thyroxine, and to examine factors associated with switching. DESIGN AND SETTING: Retrospective study using national data from a large administrative claims database from January 2008 through November 2018. PATIENTS: Medicare or commercially insured adults (≥18 years) who filled a generic L-thyroxine preparation. MAIN OUTCOME MEASURES: At least one switch from one generic L-thyroxine preparation to another within 1 year of L-thyroxine initiation defined by prescription fills. RESULTS: From January 2008 to November 2018, we included 483,390 patients who initiated generic L-thyroxine: mean (SD) age was 61.4 years (15.2), 75.2% were female, 72.6% were white. Within 1 year of initiating therapy, 98,013 (20%) switched to another L-thyroxine generic preparation at least once. In a multivariate logistic regression analysis, factors associated with switching included the number of pharmacies visited to fill L-thyroxine (>2 vs 1 adjusted OR [aOR] 7.15, 95% confidence interval [CI] 6.97-7.34), age ≥75 vs. <45 years (aOR 1.29, 95% CI 1.26-1.33), history of thyroid surgery (aOR 1.22, 95% CI 1.13-1.31), and first L-thyroxine fill date in 2018 vs. 2008 (aOR 3.32, 95% CI 3.14-3.51). CONCLUSIONS AND RELEVANCE: One in five patients switched among generic L-thyroxine manufacturers within one year of treatment initiation. Generic L-thyroxine switching occurred more often when more pharmacies were used to fill L-thyroxine. Given existing guideline recommendations, additional studies should clarify the impact of generic L-thyroxine switching on thyroid hormone values.

Comparative Risk of Serious Infections With Tumor Necrosis Factor α Antagonists vs Vedolizumab in Patients With Inflammatory Bowel Diseases.

BACKGROUND AND AIMS: We conducted a retrospective cohort study comparing the risk of serious infections between patients treated with tumor necrosis factor-a (TNFa) antagonists vs. vedolizumab in patients with inflammatory bowel diseases (IBD). METHODS: Using an administrative claims database, we identified patients with IBD who were new-users of either TNFa antagonists or vedolizumab between 2014-2018 and had insurance coverage for at least 1y before and after treatment initiation. We compared the risk of serious infections (infections requiring hospitalization) between patients treated with vedolizumab or TNFa antagonists using marginal structural Cox proportional hazard models adjusted for baseline disease characteristics, healthcare utilization, comorbidities, and time-varying use of corticosteroids, immunomodulators and opiates. RESULTS: We included 4881 patients treated with TNFa antagonists (age, 41 ± 15y, 60% with Crohn's disease [CD]) of whom 434 developed serious infections over 5786 person-year [PY] follow-up, and 1106 patients treated with vedolizumab (age, 44 ± 16y, 39% with CD) of whom 86 developed serious infections over 1040-PY follow-up. Vedolizumab was associated with 46% lower risk of serious infections as compared with TNFa antagonists in patients with ulcerative colitis (HR,0.54 [95% CI,0.35-0.83), but no significant differences were observed in patients with CD (HR,1.30 [0.80-2.11]). Vedolizumab was associated with lower risk of extra-intestinal serious infections in patients with UC, but higher risk of gastrointestinal serious infections in patients with CD. CONCLUSIONS: In an observational study of patients with IBD, vedolizumab was associated with lower risk of serious infections as compared with TNFa antagonists, in patients with UC, but not in patients with CD.

Hypoglycemic and Hyperglycemic Crises Among U.S. Adults With Diabetes and End-stage Kidney Disease: Population-Based Study, 2013-2017.

OBJECTIVE: We characterized annual trends of severe hypoglycemic and hyperglycemic crises (diabetic ketoacidosis/hyperglycemic hyperosmolar state) in patients with diabetes and end-stage kidney disease (ESKD). RESEARCH DESIGN AND METHODS: This was a nationwide, retrospective study of adults (≥18 years old) with diabetes/ESKD, from the United States Renal Data System registry, between 2013 and 2017. Primary outcome was annual rates of emergency department visits or hospitalizations for hypoglycemic and hyperglycemic crises, reported as number of events/1,000 person-years. Event rates and risk factors were adjusted for patient age, sex, race/ethnicity, dialysis modality, comorbidities, treatment regimen, and U.S. region. RESULTS: Among 521,789 adults with diabetes/ESKD (median age 65 years [interquartile range 57-73], 56.1% male, and 46% White), overall adjusted rates of hypoglycemic and hyperglycemic crises were 53.64 and 18.24 per 1,000 person-years, respectively. For both hypoglycemia and hyperglycemia crises, respectively, the risks decreased with age and were lowest in older patients (≥75 vs. 18-44 years old: incidence rate ratio 0.35, 95% CI 0.33-0.37, and 0.03, 0.02-0.03), women (1.09, 1.06-1.12, and 1.44, 1.35-1.54), and those with smoking (1.36, 1.28-1.43, and 1.71, 1.53-1.91), substance abuse (1.27, 1.15-1.42, and 1.53, 1.23-1.9), retinopathy (1.10, 1.06-1.15, and 1.36, 1.26-1.47), and insulin therapy (vs. no therapy; 0.60, 0.59-0.63, and 0.44, 0.39-0.48). For hypoglycemia, specifically, additional risk was conferred by Black race (1.11, 1.08-1.15) and amputation history (1.20, 1.13-1.27). CONCLUSIONS: In this nationwide study of patients with diabetes/ESKD, hypoglycemic crises were threefold more common than hyperglycemic crises, greatly exceeding national reports in nondialysis patients with chronic kidney disease. Young, Black, and female patients were disproportionately affected.

Risk of Malignancy with Vedolizumab Versus Tumor Necrosis Factor-α Antagonists in Patients with Inflammatory Bowel Diseases.

BACKGROUND AND AIMS: We conducted a retrospective cohort study comparing the risk of malignancy between patients treated with vedolizumab vs. tumor necrosis factor-α (TNFα) antagonists in patients with inflammatory bowel diseases (IBD). METHODS: Using an administrative claims database, we identified patients with IBD without prior malignancy who were new users of either vedolizumab or TNFα antagonists between 2014-2018, with no prior exposure to either biologic or in preceding 1 y and had insurance coverage for at least 1 y after treatment initiation. We estimated incidence rate of malignancy (solid organ, hematological or skin cancers) in patients treated with vedolizumab and TNFα antagonists, and compared risk using Cox proportional hazard analysis. RESULTS: We included 4807 patients treated with TNFα antagonists (age, 41 ± 15 y, 60% with Crohn's disease [CD]) of whom 65 developed malignancy over 7214 person-year [PY] follow-up (incidence rate [IR], 9.0 per 1000-PY), and 759 patients treated with vedolizumab (age, 46 ± 16y, 42% CD) of whom 11 developed malignancy over 950-PY follow-up (IR, 11.6). No difference was observed in the incidence of malignancy between vedolizumab versus TNFα antagonists (incidence rate ratio, 1.28; 95% CI, 0.61-2.45). After adjusting for age, sex, race, comorbidity burden, disease phenotype and concomitant use of immunomodulators, no difference was observed in time to incident malignancy between vedolizumab versus TNFα antagonists (HR, 1.15; 95% CI, 0.61-2.19). Similar results were observed on stratified analysis by age and concomitant immunomodulators, and after excluding non-melanoma skin cancers. CONCLUSIONS: In an observational study of patients with IBD, no differences were observed in the risk of incident malignancy in patients treated with vedolizumab versus TNFα antagonists.

A Clinical Decision Aid to Support Personalized Treatment Selection for Patients with Clinical T1 Renal Masses: Results from a Multi-institutional Competing-risks Analysis.

BACKGROUND: Personalized treatment for clinical T1 renal cortical masses (RCMs) should take into account competing risks related to tumor and patient characteristics. OBJECTIVE: To develop treatment-specific prediction models for cancer-specific mortality (CSM), other-cause mortality (OCM), and 90-d Clavien grade ≥3 complications across radical nephrectomy (RN), partial nephrectomy (PN), thermal ablation (TA), and active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS: Pretreatment clinical and radiological features were collected for consecutive adult patients treated with initial RN, PN, TA, or AS for RCMs at four high-volume referral centers (2000-2019). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prediction models used competing-risks regression for CSM and OCM and logistic regression for 90-d Clavien grade ≥3 complications. Performance was assessed using bootstrap validation. RESULTS AND LIMITATIONS: The cohort comprised 5300 patients treated with RN (n = 1277), PN (n = 2967), TA (n = 476), or AS (n = 580). Over median follow-up of 5.2 yr (interquartile range 2.5-8.7), there were 117 CSM, 607 OCM, and 198 complication events. The C index for the predictive models was 0.80 for CSM, 0.77 for OCM, and 0.64 for complications. Predictions from the fitted models are provided in an online calculator (https://small-renal-mass-risk-calculator.fredhutch.org). To illustrate, a hypothetical 74-yr-old male with a 4.5-cm RCM, body mass index of 32 kg/m2, estimated glomerular filtration rate of 50 ml/min, Eastern Cooperative Oncology Group performance status of 3, and Charlson comorbidity index of 3 has predicted 5-yr CSM of 2.9-5.6% across treatments, but 5-yr OCM of 29% and risk of 90-d Clavien grade 3-5 complications of 1.9% for RN, 5.8% for PN, and 3.6% for TA. Limitations include selection bias, heterogeneity in practice across treatment sites and the study time period, and lack of control for surgeon/hospital volume. CONCLUSIONS: We present a risk calculator incorporating pretreatment features to estimate treatment-specific competing risks of mortality and complications for use during shared decision-making and personalized treatment selection for RCMs. PATIENT SUMMARY: We present a risk calculator that generates personalized estimates of the risks of death from cancer or other causes and of complications for surgical, ablation, and surveillance treatment options for patients with stage 1 kidney tumors.

Association Between Area-Level Socioeconomic Deprivation and Diabetes Care Quality in US Primary Care Practices.

Importance: Diabetes management operates under a complex interrelationship between behavioral, social, and economic factors that affect a patient's ability to self-manage and access care. Objective: To examine the association between 2 complementary area-based metrics, area deprivation index (ADI) score and rurality, and optimal diabetes care. Design, Setting, and Participants: This cross-sectional study analyzed the electronic health records of patients who were receiving care at any of the 75 Mayo Clinic or Mayo Clinic Health System primary care practices in Minnesota, Iowa, and Wisconsin in 2019. Participants were adults with diabetes aged 18 to 75 years. All data were abstracted and analyzed between June 1 and November 30, 2020. Main Outcomes and Measures: The primary outcome was the attainment of all 5 components of the D5 metric of optimal diabetes care: glycemic control (hemoglobin A1c <8.0%), blood pressure (BP) control (systolic BP <140 mm Hg and diastolic BP <90 mm Hg), lipid control (use of statin therapy according to recommended guidelines), aspirin use (for patients with ischemic vascular disease), and no tobacco use. The proportion of patients receiving optimal diabetes care was calculated as a function of block group-level ADI score (a composite measure of 17 US Census indicators) and zip code-level rurality (calculated using Rural-Urban Commuting Area codes). Odds of achieving the D5 metric and its components were assessed using logistic regression that was adjusted for demographic characteristics, coronary artery disease history, and primary care team specialty. Results: Among the 31 934 patients included in the study (mean [SD] age, 59 [11.7] years; 17 645 men [55.3%]), 13 138 (41.1%) achieved the D5 metric of optimal diabetes care. Overall, 4090 patients (12.8%) resided in the least deprived quintile (quintile 1) of block groups and 1614 (5.1%) lived in the most deprived quintile (quintile 5), while 9193 patients (28.8%) lived in rural areas and 2299 (7.2%) in highly rural areas. The odds of meeting the D5 metric were lower for individuals residing in quintile 5 vs quintile 1 block groups (odds ratio [OR], 0.72; 95% CI, 0.67-0.78). Patients residing in rural (OR, 0.84; 95% CI, 0.73-0.97) and highly rural (OR, 0.81; 95% CI, 0.72-0.91) zip codes were also less likely to attain the D5 metric compared with those in urban areas. Conclusions and Relevance: This cross-sectional study found that patients living in more deprived and rural areas were significantly less likely to attain high-quality diabetes care compared with those living in less deprived and urban areas. The results call for geographically targeted population health management efforts by health systems, public health agencies, and payers.

Real-world Cardiovascular Outcomes Associated With Degarelix vs Leuprolide for Prostate Cancer Treatment.

Importance: With a growing interest in the use of real-world evidence for regulatory decision-making, it is important to understand whether real-world data can be used to emulate the results of randomized clinical trials. Objective: To use electronic health record and administrative claims data to emulate the ongoing PRONOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease). Design, Setting, and Participants: This retrospective, propensity-matched cohort study included adult men with a diagnosis of prostate cancer and cardiovascular disease who initiated either degarelix or leuprolide between December 24, 2008, and June 30, 2019. Participants were commercially insured individuals and Medicare Advantage beneficiaries included in a large US administrative claims database. Exposures: Degarelix or leuprolide. Main Outcomes and Measures: The primary end point was time to first occurrence of a major adverse cardiovascular event (MACE), defined as death due to any cause, myocardial infarction, or stroke, analogous to the PRONOUNCE trial. Secondary end points were time to death due to any cause, myocardial infarction, stroke, and angina. Cox proportional hazards regression was used to evaluate primary and secondary end points. Results: A total of 32 172 men initiated degarelix or leuprolide for prostate cancer; of them, 9490 (29.5%) had cardiovascular disease, and 7800 (24.2%) met the PRONOUNCE trial eligibility criteria and were included in this study. Overall, 165 participants (2.1%) were Asian, 1390 (17.8%) were Black, 663 (8.5%) were Hispanic, and 5258 (67.4%) were White. The mean (SD) age was 74.4 (7.4) years. Among 2226 propensity score-matched patients, no significant difference was observed in the risk of MACE for patients taking degarelix vs those taking leuprolide (10.18 vs 8.60 events per 100 person-years; hazard ratio [HR], 1.18; 95% CI, 0.86-1.61). Degarelix was associated with a higher risk of death from any cause (HR, 1.48; 95% CI, 1.01-2.18) but not of myocardial infarction (HR, 1.16; 95% CI, 0.60-2.25), stroke (HR, 0.92; 95% CI, 0.45-1.85), or angina (HR, 1.36; 95% CI, 0.43-4.27). Conclusions and Relevance: In this emulation of a clinical trial of men with cardiovascular disease undergoing treatment for prostate cancer, degarelix was not associated with a lower risk of cardiovascular events than leuprolide. Comparison of these data with PRONOUNCE trial results, when published, will help enhance our understanding of the appropriate role of using real-world data to emulate clinical trials.

Uptake of evidence by physicians: De-adoption of erythropoiesis-stimulating agents after the TREAT trial.

BACKGROUND: Variation in de-adoption of ineffective or unsafe treatments is not well-understood. We examined de-adoption of erythropoiesis-stimulating agents (ESA) in anemia treatment among patients with chronic kidney disease (CKD) following new clinical evidence of harm and ineffectiveness (the TREAT trial) and the FDA's revision of its safety warning. METHOD: We used a segmented regression approach to estimate changes in use of epoetin alfa (EPO) and darbepoetin alfa (DPO) in the commercial, Medicare Advantage (MA) and Medicare fee-for-service (FFS) populations. We also examined how changes in both trends and levels of use were associated with physicians' characteristics. RESULTS: Use of DPO and EPO declined over the study period. There were no consistent changes in DPO trend across insurance groups, but the level of DPO use decreased right after the FDA revision in all groups. The decline in EPO use trend was faster after the TREAT trial for all groups. Nephrologists were largely more responsive to evidence than primary care physicians. Differences by physician's gender, and age were not consistent across insurance populations and types of ESA. CONCLUSIONS: Physician specialty has a dominant role in prescribing decision, and that specializations with higher use of treatment (nephrologists) were more responsive to new evidence of unsafety and ineffectiveness.

Drug labeling changes and pediatric hematology/oncology prescribing: Measuring the impact of U.S. legislation.

BACKGROUND/AIMS: The Pediatric Research Equity Act and Best Pharmaceuticals for Children Act are intended to promote the conduct of clinical trials that generate pediatric-specific evidence about drug safety and efficacy. This study assesses the quality of evidence generated through Pediatric Research Equity Act-mandated and Best Pharmaceuticals for Children Act-incentivized clinical trials of hematology/oncology drugs and characterizes subsequent changes in pediatric drug utilization rates. METHODS: Trial characteristics (blinding, randomization, and comparator group) were determined for clinical trials that supported pediatric label changes. Using data from OptumLabs® Data Warehouse, a de-identified administrative claims database, we calculated pediatric utilization rates for each drug. We calculated monthly utilization rates from January 2003 (or from the first month in which data were available) to December 2018. RESULTS: We identified 11 hematology/oncology drugs that underwent pediatric label changes under the Pediatric Research Equity Act Pediatric Research Equity Act and/or Best Pharmaceuticals for Children Act, and we identified 15 trials supporting these changes. Of these trials, 36% (5/14) were randomized, 31% (4/13) were blinded, and 36% (5/14) used a comparator group. A median of 49 children (interquartile range 29.5) received the drug under investigation across these trials. Pediatric label changes were not associated with subsequent changes in pediatric drug utilization. Although some drugs saw increased pediatric use after gaining new pediatric indications, this pattern was not consistently observed. In addition, there was no evidence to suggest that drugs were utilized less frequently after they failed to receive pediatric indications. CONCLUSIONS: Clinical trials of hematology/oncology drugs conducted under the Pediatric Research Equity Act Pediatric Research Equity Act and Best Pharmaceuticals for Children Act generally have low methodological rigor, and the resulting label changes are not consistently associated with changes in pediatric utilization. Alternative regulatory strategies and study designs may be necessary to maximize the impact of newly generated knowledge on drug utilization.

Outcomes for hospitalized patients with idiopathic pulmonary fibrosis treated with antifibrotic medications.

BACKGROUND: Idiopathic Pulmonary Fibrosis is a chronic, progressive interstitial lung disease for which there is no cure. However, lung function decline, hospitalizations, and mortality may be reduced with the use of the antifibrotic medications, nintedanib and pirfenidone. Historical outcomes for hospitalized patients with Idiopathic Pulmonary Fibrosis are grim; however there is a paucity of data since the approval of nintedanib and pirfenidone for treatment. In this study, we aimed to determine the effect of nintedanib and pirfenidone on mortality following respiratory-related hospitalizations, intensive care unit (ICU) admission, and mechanical ventilation. METHODS: Using a large U.S. insurance database, we created a one-to-one propensity score matched cohort of patients with idiopathic pulmonary fibrosis treated and untreated with an antifibrotic who underwent respiratory-related hospitalization between January 1, 2015 and December 31, 2018. Mortality was evaluated at 30 days and end of follow-up (up to 2 years). Subgroup analyses were performed for all patients receiving treatment in an ICU and those receiving invasive and non-invasive mechanical ventilation during the index hospitalization. RESULTS: Antifibrotics were not observed to effect utilization of mechanical ventilation or ICU treatment during the index admission or effect mortality at 30-days. If patients survived hospitalization, mortality was reduced in the treated cohort compared to the untreated cohort when followed up to two years (20.1% vs 47.8%). CONCLUSIONS: Treatment with antifibrotic medications does not appear to directly improve 30-day mortality during or after respiratory-related hospitalizations. Post-hospital discharge, however, ongoing antifibrotic treatment was associated with improved long-term survival.

Obesity Is Not Associated With an Increased Risk of Serious Infections in Biologic-Treated Patients With Inflammatory Bowel Diseases.

INTRODUCTION: Obesity has been associated with adverse disease-related outcomes and inferior treatment response to biologic agents in patients with inflammatory bowel diseases (IBDs), but its impact on the risk of treatment-related complications is unknown. We performed a cohort study examining the association between obesity and risk of serious infections in biologic-treated patients with IBD. METHODS: Using an administrative claims database, in a cohort of biologic-treated patients with IBD between 2014 and 2018 with follow-up 1 year before and after treatment initiation, we compared the risk of serious infections (infections requiring hospitalization) between obese vs nonobese patients (based on validated administrative claims) using Cox proportional hazard analysis. RESULTS: We included 5,987 biologic-treated patients with IBD (4,881 on tumor necrosis factor-α antagonists and 1,106 on vedolizumab), of whom 524 (8.8%) were classified as obese. Of the 7,115 person-year follow-up, 520 patients developed serious infection. Risk of serious infection was comparable in obese vs nonobese patients (8.8% vs 8.5%; unadjusted hazard ratio, 1.15; 95% confidence interval, 0.86-1.54). After adjusting for age, comorbidities, disease characteristics, health care utilization, use of corticosteroids, immunomodulators, and opiates, obesity was not associated with an increased risk of serious infection (adjusted hazard ratio, 0.74 [95% confidence interval, 0.55-1.01]). Similar results were seen on stratified analysis by disease phenotype (Crohn's disease and ulcerative colitis) and index biologic therapy (tumor necrosis factor-α antagonists and vedolizumab). DISCUSSION: After adjusting for comorbid conditions and disease characteristics, obesity is not independently associated with an increased risk of serious infections in biologic-treated patients with IBD.

Cardiovascular outcomes and rates of fractures and falls among patients with brand-name versus generic L-thyroxine use.

PURPOSE: To compare cardiovascular outcomes and rates of fractures and falls among patients with persistent brand-name versus generic L-thyroxine use. METHODS: Retrospective, 1:1 propensity-matched longitudinal study using a national administrative claims database to examine adults (≥18 years) who initiated either brand or generic L-thyroxine between 2008 and 2018, censored at switch or discontinuation of L-thyroxine formulation or disenrollment from the health plan. Main outcome measures included rates of hospitalization for atrial fibrillation, myocardial infarction, congestive heart failure, stroke, spine and hip fractures, and rate of falls in the outpatient or inpatient setting. Hospitalizations for pneumonia were used as a negative control. RESULTS: 195,046 adults initiated treatment with L-thyroxine between 2008 and 2017: 87% generic and 13% brand formulations. They were mostly women (76%), young (94.6% under age 65), white (66%), and 47% had baseline thyroid stimulating hormone levels between 4.5 and 9.9 mIU/L. Among 35,667 propensity-matched patients, there were no significant differences between patients treated with brand versus generic L-thyroxine in atrial fibrillation (HR 0.96, 0.58-1.60), myocardial infarction (HR 0.66, 0.39-1.14), congestive heart failure (HR 1.30, 0.78-2.16), stroke (0.72, 0.49-1.06), spine (HR 0.87, 0.38-1.99) and hip fractures (HR 0.86, 0.26-2.82), or fall outcomes (HR 1.02, 0.14-7.32). Hospitalization rates for pneumonia (used as negative control) did not differ between groups (HR 0.85, 0.61-1.19). There were no interactions between brand versus generic L-thyroxine, these outcomes, and thyroid cancer, age, or L-thyroxine dose subgroups. CONCLUSIONS: We found no significant differences in cardiovascular outcomes and rates of falls and fractures for patients who filled brand versus generic L-thyroxine.

Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019.

Importance: After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications. Objective: To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics' original indication approvals. Design, Setting, and Participants: This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics' original indication approvals. Data analysis was performed from August to October 2020. Main Outcomes and Measures: Number and design of pivotal trials supporting both supplemental and original indication approvals. Results: From 2017 to 2019, the FDA approved 146 supplemental indications for 107 therapeutics on the basis of 181 pivotal efficacy trials. The median (interquartile range) number of trials per supplemental indication was 1 (1-1). Most trials used either placebo (77 trials [42.5%; 95% CI, 35.6%-49.8%]) or active comparators (65 trials [35.9%; 95% CI, 29.3%-43.1%]), and most of these multigroup trials were randomized (141 trials [99.3%; 95% CI, 96.0%-100.0%]) and double-blinded (106 trials [74.5%; 95% CI, 66.6%-81.0%]); 80 trials (44.2%; 95 CI, 37.2%-51.5%) used clinical outcomes as the primary efficacy end point. There was no difference between oncology therapies and those approved for other therapeutic areas to have supplemental indication approvals be based on at least 2 pivotal trials (11.5% vs 20.6%; difference, 9.1%; 95% CI, 2.9%-21.0%; P = .10). Similarly, there was no difference in use of randomization (98.3% vs 100.0%; difference, 1.7%; 95% CI, 1.6%-5.0%; P = .43) among multigroup trials, although these trials were less likely to be double-blinded (50.8% vs 92.3%; difference, 41.5%; 95% CI, 27.4%-55.5%; P < .001); overall, these trials were less likely to use either placebo or active comparators (64.9% vs 86.7%; difference, 21.8% 95% CI, 9.8%-33.9%; P < .001) or to use clinical outcomes as their primary efficacy end point (27.5% vs 61.1%; difference, 33.6%; 95% CI, 14.1%-40.9%; P < .001) and were longer (median [interquartile range], 17 [6-48] weeks vs 95 [39-146] weeks). Original approvals were more likely than supplemental indication approvals to be based on at least 2 pivotal trials (44.0% [95% CI, 33.7%-42.6%] vs 15.8% [95% CI, 10.7%-22.5%]; difference, 28.2%; 95% CI, 17.6%-39.6%; P < .001) and less likely to be supported by at least 1 trial of 12 months' duration (27.6% [95% CI, 17.9%-35.0%] vs 54.8% [95% CI, 46.7%-62.6%]; difference, 27.2%; 95% CI, 14.5%-37.8%; P < .001). Pivotal trial designs were otherwise not significantly different. Conclusions and Relevance: These findings suggest that the number and design of the pivotal trials supporting supplemental indication approvals by the FDA varied across therapeutic areas, with the strength of evidence for cancer indications weaker than that for other indications. There was little difference in the design characteristics of the pivotal trials supporting supplemental indication and original approvals.

Association of outpatient ACE inhibitors and angiotensin receptor blockers and outcomes of acute respiratory illness: a retrospective cohort study.

OBJECTIVES: Evaluate associations between ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) and clinical outcomes in acute viral respiratory illness (AVRI). DESIGN: Retrospective cohort analysis of claims data. SETTING: The USA; 2018-2019 influenza season. PARTICIPANTS: Main cohort: people with hypertension (HTN) taking an ACEi, ARB or other HTN medications, and experiencing AVRI. Falsification cohort: parallel cohort receiving elective knee or hip replacement. MAIN OUTCOME MEASURES: Main cohort: hospital admission, intensive care unit, acute respiratory distress (ARD), ARD syndrome and all-cause mortality. Falsification cohort: complications after surgery and all-cause mortality. RESULTS: The main cohort included 236 843 episodes of AVRI contributed by 202 629 unique individuals. Most episodes were in women (58.9%), 81.4% in people with Medicare Advantage and 40.3% in people aged 75+ years. Odds of mortality were lower in the ACEi (0.78 (0.74 to 0.83)) and ARB (0.64 (0.61 to 0.68)) cohorts compared with other HTN medications. On all other outcomes, people taking ARBs (but not ACEis) had a >10% reduction in odds of inpatient stays compared with other HTN medications.In the falsification analysis (N=103 353), both ACEis (0.89 (0.80 to 0.98)) and ARBs (0.82 (0.74 to 0.91)) were associated with decreased odds of complications compared with other HTN medications; ARBs (0.64 (0.47 to 0.87)) but not ACEis (0.79 (0.60 to 1.05)) were associated with lower odds of death compared with other HTN medications. CONCLUSIONS: Outpatient use of ARBs was associated with better outcomes with AVRI compared with other medications for HTN. ACEis were associated with reduced risk of death, but with minimal or no reduction in risk of other complications. A falsification analysis conducted to provide context on the possible causal implications of these findings did not provide a clear answer. Further analysis using observational data will benefit from additional approaches to assess causal relationships between these drugs and outcomes in AVRI.

Validation of prognostic indices for short term mortality in an incident dialysis population of older adults >75.

RATIONAL AND OBJECTIVE: Prognosis provides critical knowledge for shared decision making between patients and clinicians. While several prognostic indices for mortality in dialysis patients have been developed, their performance among elderly patients initiating dialysis is unknown, despite great need for reliable prognostication in that context. To assess the performance of 6 previously validated prognostic indices to predict 3 and/or 6 months mortality in a cohort of elderly incident dialysis patients. STUDY DESIGN: Validation study of prognostic indices using retrospective cohort data. Indices were compared using the concordance ("c")-statistic, i.e. area under the receiver operating characteristic curve (ROC). Calibration, sensitivity, specificity, positive and negative predictive values were also calculated. SETTING & PARTICIPANTS: Incident elderly (age ≥75 years; n = 349) dialysis patients at a tertiary referral center. ESTABLISHED PREDICTORS: Variables for six validated prognostic indices for short term (3 and 6 month) mortality prediction (Foley, NCI, REIN, updated REIN, Thamer, and Wick) were extracted from the electronic medical record. The indices were individually applied as per each index specifications to predict 3- and/or 6-month mortality. RESULTS: In our cohort of 349 patients, mean age was 81.5±4.4 years, 66% were male, and median survival was 351 days. The c-statistic for the risk prediction indices ranged from 0.57 to 0.73. Wick ROC 0.73 (0.68, 0.78) and Foley 0.67 (0.61, 0.73) indices performed best. The Foley index was weakly calibrated with poor overall model fit (p <0.01) and overestimated mortality risk, while the Wick index was relatively well-calibrated but underestimated mortality risk. LIMITATIONS: Small sample size, use of secondary data, need for imputation, homogeneous population. CONCLUSION: Most predictive indices for mortality performed moderately in our incident dialysis population. The Wick and Foley indices were the best performing, but had issues with under and over calibration. More accurate indices for predicting survival in older patients with kidney failure are needed.

Adoption of the Antifibrotic Medications Pirfenidone and Nintedanib for Patients with Idiopathic Pulmonary Fibrosis.

Rationale: In October 2014, the antifibrotic medications pirfenidone and nintedanib became the first medications approved by the U.S. Food and Drug Administration for use in patients with idiopathic pulmonary fibrosis (IPF). Since approval, there has been no nonregistry analysis of the real-world adoption of these medications in everyday clinical practice. Objectives: To evaluate the adoption, persistence, and out-of-pocket (OOP) costs of pirfenidone and nintedanib since their approval in the United States in 2014. Methods: A retrospective cohort analysis was performed by identifying privately insured and Medicare Advantage beneficiaries with IPF. We then split the patients into three cohorts: those who were untreated and those who filled a prescription for either pirfenidone or nintedanib between October 1, 2014, and July 31, 2019. The primary outcome was adoption of the medications. Secondary outcomes included medication persistence and prescription drug costs. Results: A total of 10,996 patients with IPF were identified in the data set. A minority of patients (26.4%) with IPF identified in the cohort had started either medication since approval in 2014, with the adoption of both medications being comparable at around 13.2%. Those receiving the medications were younger (72 vs. 73.9 yr; P < 0.0001) and healthier (3.9 vs. 4.9 comorbidities; P < 0.0001) than those not receiving treatment. Men were significantly more likely to receive treatment than woman (30.0% vs. 21.9%; P < 0.0001). Among treated patients, 42.8% discontinued the medications during the study period. Patients' OOP expenses per month were high for both drugs (mean, $397.51 for nintedanib; mean, $394.49 for pirfenidone). Conclusions: The adoption of both the antifibrotic medications in the United States in everyday practice has been low since approval and may be associated with the high OOP cost.