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We recently nominated cytokine signaling through the Janus-kinase–signal transducer and activator of transcription (JAK/STAT) pathway as a potential AD drug target. As hydroxychloroquine (HCQ) has recently been shown to inactivate STAT3, we hypothesized that it may impact AD pathogenesis and risk. Among 109,124 rheumatoid arthritis patients from routine clinical care, HCQ initiation was associated with a lower risk of incident AD compared to methotrexate initiation across 4 alternative analyses schemes addressing specific types of biases including informative censoring, reverse causality, and outcome misclassification (hazard ratio [95% confidence interval] of 0.92 [0.83–1.00], 0.87 [0.81–0.93], 0.84 [0.76–0.93], and 0.87 [0.75–1.01]). We additionally show that HCQ exerts dose-dependent effects on late long-term potentiation (LTP) and rescues impaired hippocampal synaptic plasticity prior to significant accumulation of amyloid plaques and neurodegeneration in APP/PS1 mice. Additionally, HCQ treatment enhances microglial clearance of Aβ1-42, lowers neuroinflammation, and reduces tau phosphorylation in cell culture-based phenotypic assays. Finally, we show that HCQ inactivates STAT3 in microglia, neurons, and astrocytes suggesting a plausible mechanism associated with its observed effects on AD pathogenesis. HCQ, a relatively safe and inexpensive drug in current use may be a promising disease-modifying AD treatment. This hypothesis merits testing through adequately powered clinical trials in at-risk individuals during preclinical stages of disease progression.

Given the absence of guidelines for use of virtual visits for primary care delivery, a framework is needed to inform the most appropriate use of virtual visits.We conducted in-depth, structured interviews of 18 patients, primary care clinicians, and other select informants. They were asked to discuss optimal, acceptable, and suboptimal uses of telemedicine for delivering care relative to in-person care delivery. The concepts expressed informed our development of a framework about appropriate use of virtual visits.The 103 concepts supported 5 main themes that emerged as a framework: clinical situations which are optimal for in-person care; situations optimal for virtual visits; situations that might be exchangeable between sites; contextual factors favoring in-person care; and contextual factors favoring virtual visits.After further validation, we expect that this framework may guide future research and practice: it may be valuable for clinical practice redesign, for designing evaluations of the outcomes of virtual visits, for outcomes research, for patient education, for triage, and possibly for reimbursement considerations.

Telemedicine has been implemented in many health systems by necessity, yet evidence is sparse about its appropriate use for the delivery of primary care. We sought to understand what clinicians and patients consider to be appropriate use of telemedicine in primary care to inform future development of a framework that should be valuable to diverse stakeholders.We conducted in-depth, structured interviews of patients, clinicians who deliver primary care, and other select informants. They were asked to discuss optimal, acceptable, and suboptimal uses of telemedicine for delivering care relative to in-person care delivery. Audio was transcribed and paired reviewers analyzed the content to identify the key concepts that motivated the informants. The reviewers did thematic analysis to organize the concepts into unifying themes.Our 18 key informants generated 103 unique concepts. The unique concepts aggregated into themes suggesting the clinical situations in which telemedicine is appropriately used in primary care and clinical situations in which it should be avoided. We also learned of motivators toward expanded, or at least continued, use of telemedicine and motivators away from telemedicine's continued use. The informants expressed their expectations regarding decision making about telemedicine use and who should make these decisions.These key concepts and themes are expected to be a valuable starting point for the development of a framework to inform appropriate use of telemedicine in primary care.

Anticoagulation among patients with cancer and atrial fibrillation is challenging due to elevated risk of bleeding and stroke. We characterized use of oral anticoagulants among patients with cancer and non-valvular atrial fibrillation (NVAF).We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data and included patients with cancer aged ≥66 years with an incident diagnosis of NVAF from 2010 to 2016. We used a Cox proportional hazard model and multivariable logistic regression to identify factors associated with anticoagulant use versus no use and direct oral anticoagulants (DOACs) versus warfarin use, respectively.Of 27,702 patients with cancer and NVAF, 4469 (16.1%) used DOACs and 3577 (12.9%) used warfarin. Among 8046 anticoagulant users, DOACs use increased from 21.8% in 2011 to 76.2% in 2016, with a corresponding decline in warfarin use from 78.2% to 23.8%. Nearly 7 out of 10 patients with cancer and NVAF did not initiate anticoagulation in 2016. Anticoagulant use was more likely among those with higher CHA₂DS₂-VASc scores (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.27-1.90 for score ≥6 vs. 1) or with lower HAS-BLED scores (HR 1.96, 95% CI 1.67-2.30 for score 1 vs. ≥6). Among anticoagulant users, DOAC use was less likely than warfarin in those with higher CHA₂DS₂-VASc scores (odds ratio [OR] 0.53, 95% CI 0.33-0.84 for score ≥6 vs. 1).Nearly 7 out of 10 patients with cancer and NVAF did not receive anticoagulation. Use of DOACs increased from 2010 to 2016, with a corresponding decline in warfarin use. DOACs are used less than warfarin among those at higher risk of stroke.

Background: While clinical guidelines recommend direct-acting oral anticoagulants (DOAC) over warfarin to treat isolated nonvalvular atrial fibrillation, guidelines are silent regarding nonvalvular atrial fibrillation treatment among individuals with cancer, reflecting the paucity of evidence in this setting. We quantified relative risk of ischemic stroke or systemic embolism and major bleeding (primary outcomes), and all-cause and cardiovascular death (secondary outcomes) among older individuals with cancer and nonvalvular atrial fibrillation comparing DOACs and warfarin. Methods: This retrospective cohort study used Surveillance, Epidemiology, and End Results cancer registry and linked US Medicare data from 2010 through 2016, and included individuals diagnosed with cancer and nonvalvular atrial fibrillation who newly initiated DOAC or warfarin. We used inverse probability of treatment weighting to control confounding. We used competing risk regression for primary outcomes and cardiovascular death, and Cox proportional hazard regression for all-cause death. Results: Among 7675 individuals included in the cohort, 4244 (55.3%) received DOACs and 3431 (44.7%) warfarin. In the inverse probability of treatment weighting analysis, there was no statistically significant difference among DOAC and warfarin users in the risk of ischemic stroke or systemic embolism (1.24 versus 1.19 events per 100 person-years, adjusted hazard ratio 1.41 [95% CI, 0.92–2.14]), major bleeding (3.08 versus 4.49 events per 100 person-years, adjusted hazard ratio 0.90 [95% CI, 0.70–1.17]), and cardiovascular death (1.88 versus 3.14 per 100 person-years, adjusted hazard ratio 0.82 [95% CI, 0.59–0.1.13]). DOAC users had significantly lower risk of all-cause death (7.09 versus 13.3 per 100 person-years, adjusted hazard ratio 0.81 [95% CI, 0.69–0.94]) compared to warfarin users. Conclusions: Older adults with cancer and atrial fibrillation exposed to DOACs had similar risks of stroke and systemic embolism and major bleeding as those exposed to warfarin. Relative to warfarin, DOAC use was associated with a similar risk of cardiovascular death and a lower risk of all-cause death.

Background Patients with sickle cell disease (SCD) have vaso-occlusive crises (VOCs). Infusion centers (ICs) are alternatives to emergency department (ED) care and may improve patient outcomes. Objective To assess whether care in ICs or EDs leads to better outcomes for the treatment of uncomplicated VOCs. Design Prospective cohort. (ClinicalTrials.gov: NCT02411396). Setting 4 U.S. sites, with recruitment between April 2015 and December 2016. Participants Adults with SCD living within 60 miles of a study site. Measurements Participants were followed for 18 months after enrollment. Outcomes of interest were time to first dose of parenteral pain medication, whether pain reassessment was completed within 30 minutes after the first dose, and patient disposition on discharge from the acute care visit. Treatment effects for ICs versus EDs were estimated using a time-varying propensity score adjustment. Results Researchers enrolled 483 participants; the 269 who had acute care visits on weekdays are included in this report. With inverse probability of treatment-weighted adjustment, the mean time to first dose was 62 minutes in ICs and 132 minutes in EDs; the difference was 70 minutes (95% CI, 54 to 98 minutes; E-value, 2.8). The probability of pain reassessment within 30 minutes of the first dose of parenteral pain medication was 3.8 times greater (CI, 2.63 to 5.64 times greater; E-value, 4.7) in the IC than the ED. The probability that a participant's visit would end in admission to the hospital was smaller by a factor of 4 (0.25 [CI, 0.18 to 0.33]) with treatment in an IC versus an ED. Limitation The study was restricted to participants with uncomplicated VOCs. Conclusion In adults with SCD having a VOC, treatment in an IC is associated with substantially better outcomes than treatment in an ED. Primary funding source Patient-Centered Outcomes Research Institute.

BACKGROUND: Older adults have many comorbidities contributing to mortality. OBJECTIVE: To develop a summary Elixhauser (S-Elixhauser) comorbidity score to predict 30-day, in-hospital, and 1-year mortality in older adults using the 38 comorbidities operationalized by the Agency for Healthcare Research and Quality (AHRQ). DESIGN: Retrospective cohort study. SETTING: Medicare beneficiaries from 2017 to 2019. PATIENTS: Persons hospitalized in 2018 (n = 899 844) and 3 disease-specific hospitalized cohorts. MEASUREMENTS: Weights were derived for 38 comorbidities to predict 30-day, in-hospital, and 1-year mortality. The S-Elixhauser score was internally validated and calibrated. Individual Elixhauser comorbidity indicators (38 comorbidities), the modified application of the AHRQ-derived Elixhauser summary score, the Charlson comorbidity indicators (17 comorbidities), and the Charlson summary score were externally validated. The c-statistic was used to evaluate discrimination of a comorbidity score model. RESULTS: The S-Elixhauser score was well calibrated and internally validated, with a c-statistic of 0.705 (95% CI, 0.703 to 0.707) in predicting 30-day mortality, 0.654 (CI, 0.651 to 0.657) for in-hospital mortality, and 0.743 (CI, 0.741 to 0.744) for 1-year mortality. In external validation of other comorbidity indices for 30-day mortality, the c-statistic was 0.711 (CI, 0.709 to 0.713) for the individual Elixhauser comorbidity indicators, 0.688 (CI, 0.686 to 0.690) for the AHRQ Elixhauser score, 0.696 (CI, 0.694 to 0.698) for the Charlson comorbidity indicators, and 0.690 (CI, 0.688 to 0.693) for the Charlson summary score. In 3 disease-specific populations, the discrimination of the S-Elixhauser score in predicting 30-day mortality ranged from 0.657 to 0.732. LIMITATIONS: Validation of the S-Elixhauser comorbidity score and head-to-head comparison with other comorbidity scores in an external population are needed to evaluate comparative performance. CONCLUSION: The S-Elixhauser comorbidity score is well calibrated and internally validated but its advantage over the AHRQ Elixhauser and Charlson summary scores is unclear. PRIMARY FUNDING SOURCE: National Institute on Aging.

Evidence suggests that an apixaban-based strategy to treat acute venous thromboembolism (VTE) in patients with End-Stage Kidney Disease (ESKD) may be safer than a warfarin-based strategy. Apixaban has an additional advantage of not requiring bridging with heparin which often necessitates long hospitalizations for patients with ESKD. We sought to determine if an apixaban-based strategy is associated with less healthcare utilization than a warfarin-based strategy.We employed a new-user, active-comparator retrospective cohort study using inverse probability of treatment weights (IPTW) to adjust for confounding demographic and clinical variables. Patients with ESKD newly initiated on either apixaban or warfarin for an acute VTE between 2014 and 2018 in the United States Renal Data System were included. Outcomes were presence of index hospitalization, length of index hospitalization, total hospital days, total hospital days excluding index hospitalization, total emergency department (ED) visits that did not result in hospitalization, and total skilled nursing facility days.At six months, patients who received apixaban were less likely to have an index hospitalization, had a shorter index hospitalization (median of 4.0 vs 8.0 days, p 0.001), and had fewer total hospital days. The IPTW and index year-adjusted incidence rate ratios of total hospital days at one, three, and six months were 0.83 (95 % confidence intervals (CI) 0.79-0.86), 0.84 (95 % CI 0.81-0.88), and 0.88 (95 % CI 0.83-0.92) for apixaban compared to warfarin.Among patients with ESKD and VTE, resource utilization for an apixaban-based strategy appears to be lower than for a warfarin-based strategy.

The proliferation of “ultra-expensive” drugs has sparked debate on their sustainability and affordability. Medicare Part D’s share of annual spending on these drugs increased by 1,170 percent betwe...

Patients with end-stage kidney disease (ESKD) are at significantly increased risk for both thrombosis and bleeding relative to those with normal renal function. The optimal therapy of venous thromboembolism (VTE) in patients with ESKD is unknown.To compare the safety and effectiveness of apixaban relative to warfarin in patients with ESKD and acute VTE.New-user, active-comparator retrospective United States population-based cohort with inverse probability of treatment weighting, using the United States Renal Data System data from 2014 to 2018. We included adults with ESKD on hemodialysis or peritoneal dialysis who were newly initiated on apixaban or warfarin for an acute VTE.The coprimary outcomes were major bleeding, recurrent VTE, and all-cause mortality within 6 months of anticoagulant initiation. Secondary outcomes were intracranial hemorrhage and gastrointestinal bleeding. The primary analyses were based on intent-to-treat defined by the first drug received and accounted for competing risks of death. Sensitivity analyses included varied follow-up time, as-treated analyses, and dose-specific apixaban subgroups.The apixaban and warfarin cohorts included 2302 and 9263 patients, respectively. Apixaban was associated with a lower risk of major bleeding (hazard ratio [HR] 0.81, 95% confidence interval [CI]: 0.70-0.94), intracranial bleeding (HR 0.69, 95% CI 0.48-0.98), and gastrointestinal bleeding (HR 0.82, 95% CI 0.69-0.96). Recurrent VTE and all-cause mortality were not significantly different between the groups.Apixaban was associated with a lower risk of bleeding relative to warfarin when used to treat acute VTE in patients with ESKD on dialysis.

Multiple real-world studies have confirmed the safety and efficacy of hepatitis C (HCV) direct-acting antivirals (DAAs); however, few studies have provided data on long-term outcomes of patients without cirrhosis after achieving sustained virologic response (SVR).

Objectives To estimate the effect of filgrastim-sndz market entry on patient out-of-pocket costs and claim payments for filgrastim products. Methods This study used a single interrupted time series design with longitudinal, nationally representative, individual-level claims data from IBM MarketScan. Analyses included all outpatient and prescription claims for branded filgrastim (filgrastim and tbo-filgrastim) and biosimilar filgrastim (filgrastim-sndz) from January 1, 2014, to December 31, 2017. Outcomes of interest included changes in monthly claim payments and monthly patient out-of-pocket costs for filgrastim products. Results In the baseline period (January 2014 to February 2016), insurers paid an average of $472.21 (95% confidence interval [CI]: 465.38-479.03) for 480 mcg of branded filgrastim, whereas patients paid an average of $49.26 (CI: 34.25-64.27). Filgrastim-sndz market entry was associated with a statistically significant and immediate 1-month decrease in insurer payment of $30.77 (95% CI: –40.59 to –20.94) and a significant decrease in monthly insurer payment trend of $3.10 per month (95% CI: –3.90 to –2.31) relative to baseline. Long-term changes in patient out-of-pocket costs were modest and restricted to beneficiaries enrolled in high cost sharing plans. Conclusions Biosimilar filgrastim availability led to significant immediate and long-term decreases in claims payments for filgrastim products, supporting efforts to facilitate biosimilar adoption in the United States. Nevertheless, there were only slight changes in patient out-of-pocket costs, restricted to beneficiaries enrolled in high cost sharing plans, suggesting the importance of further work assessing the relationship between biosimilar availability and patient out-of-pocket costs.

We recently nominated cytokine signaling through the Janus-kinase-signal transducer and activator of transcription (JAK/STAT) pathway as a potential AD drug target. As hydroxychloroquine (HCQ) has recently been shown to inactivate STAT3, we hypothesized that it may impact AD pathogenesis and risk. Among 109,124 rheumatoid arthritis patients from routine clinical care, HCQ initiation was associated with a lower risk of incident AD compared to methotrexate initiation across 4 alternative analyses schemes addressing specific types of biases including informative censoring, reverse causality, and outcome misclassification (hazard ratio [95% confidence interval] of 0.92 [0.83-1.00], 0.87 [0.81-0.93], 0.84 [0.76-0.93], and 0.87 [0.75-1.01]). We additionally show that HCQ exerts dose-dependent effects on late long-term potentiation (LTP) and rescues impaired hippocampal synaptic plasticity prior to significant accumulation of amyloid plaques and neurodegeneration in APP/PS1 mice. Additionally, HCQ treatment enhances microglial clearance of Aβ

Objectives It is unclear on what basis Medicare drug plans impose coverage restrictions on orphan drugs. This study aims to investigate the factors associated with utilization controls in Medicare fee-for-service Part D formularies. Study design Cross-sectional analysis. Methods We used multivariate logistic regression to assess the association between orphan drug characteristics and use of formulary utilization controls in 2016. We controlled for number of beneficiaries per drug, exclusivity expiration, and the number of plans and beneficiaries per formulary. We conducted sensitivity analyses using fixed and random effects. Results On average, 85% of orphan drugs on a formulary were placed on its highest cost-sharing tier and 76% were subject to prior authorization (PA). Orphan drugs with annual costs of $50,000 or more had twice the odds of having PA requirements compared with less expensive ones. Relative to orphan drugs with a single indication, drugs with multiple indications were more likely to have restrictions. Less effective drugs had 1.5 times the odds of highest tier placement relative to more effective drugs. The presence of black box warnings and patient assistance programs were associated with more restricted access. Orphan drugs with generics were less likely to undergo restrictions than those without generics (all P Conclusions Plans are making evidence-based decisions by rewarding more clinically effective and safer orphan drugs. They are penalizing drugs with multiple indications. Surprisingly, plans place fewer restrictions on orphan drugs that have a generic equivalent, which may further discourage generic entry into the orphan space, where competition is already sparse.

Summary Whereas generic drugs offer a cost-effective alternative to brand name drugs, regulators need a method to assess therapeutic equivalence in a post-market setting. We develop such a method in the context of assessing the therapeutic equivalence of immediate release venlafaxine, based on a large insurance claims data set provided by OptumLabs\circledR. To address this question properly, our methodology must deal with issues of non-adherence, secular trends in health outcomes and lack of treatment overlap due to sharp uptake of the generic drug once it becomes available. We define, identify (under assumptions) and estimate (using G-computation) a causal effect for a time-to-event outcome by extending regression discontinuity to survival curves. We do not find evidence for a lack of therapeutic equivalence of brand and generic immediate release venlafaxine.

Background Emergency department (ED) visits or hospitalizations should prompt review of the patient’s medications after discharge and targeted deprescribing to reduce ongoing risks. Objective To see if this is happening, we sought to examine the proportion of serious falls and delirium that were followed by a prescription fill for a bladder antimuscarinic. Our secondary objective was to identify concurrent use of other anticholinergics, cholinesterase inhibitors (ChEIs), and diuretics among people with dementia taking bladder antimuscarinics. Methods Retrospective descriptive study using data from the National Health and Aging Trends Study (2011–2014) linked with Medicare claims from 2010–2014. The primary outcome was the proportion of serious falls or delirium that were followed by a bladder antimuscarinic prescription fill within 12 months. The secondary outcome was the proportion of individuals concurrently receiving prescriptions for bladder antimuscarinics, other strong anticholinergics, ChEIs, and diuretics. Results During the observation period, 8.88% of people with dementia filled a bladder antimuscarinic prescription. Over one-third (35%) initiated use after being identified as having dementia. Many used bladder antimuscarinics concurrently with other strong anticholinergics (19%), diuretics (42%), and ChEIs (32%). The majority (76%) of serious falls or delirium among people with dementia and bladder antimuscarinic use were followed by a bladder antimuscarinic prescription within 12 months. Conclusions In this descriptive study, bladder antimuscarinic prescriptions were often filled irrespective of dementia status, serious falls, or delirium. Concurrent use of other anticholinergics, diuretics, and ChEIs was common. Falls and delirium should trigger review of the medication list after discharge and targeted deprescribing in people with dementia.

We evaluated the hypothesis that phosphodiesterase-5 inhibitors, including sildenafil and tadalafil, may be associated with reduced incidence of Alzheimer’s disease and related dementia using a patient-level cohort study of Medicare claims and cell culture-based phenotypic assays. We compared incidence of Alzheimer’s disease and related dementia after phosphodiesterase-5 inhibitor initiation versus endothelin receptor antagonist initiation among patients with pulmonary hypertension after controlling for 76 confounding variables through propensity score matching. Across four separate analytic approaches designed to address specific types of biases including informative censoring, reverse causality, and outcome misclassification, we observed no evidence for a reduced risk of Alzheimer’s disease and related dementia with phosphodiesterase-5 inhibitors;hazard ratio (95% confidence interval): 0.99 (0.69–1.43), 1.00 (0.71–1.42), 0.67 (0.43–1.06), and 1.15 (0.57–2.34). We also did not observe evidence that sildenafil ameliorated molecular abnormalities relevant to Alzheimer’s disease in most cell culture-based phenotypic assays. These results do not provide support to the hypothesis that phosphodiesterase-5 inhibitors are promising repurposing candidates for Alzheimer’s disease and related dementia.

BACKGROUND Medical care overuse is a significant source of patient harm and wasteful spending. Understanding the drivers of overuse is essential to the design of effective interventions. OBJECTIVE We tested the association between structural factors of the health care delivery system and regional differences systemic overuse. RESEARCH DESIGN We conducted a retrospective analysis of deidentified claims for 18- to 64-year-old adults from the IBM MarketScan Commercial Claims and Encounters Database. We calculated a semiannual Johns Hopkins Overuse Index for each of the 375 Metropolitan Statistical Areas in the United States, from January 2011 to June 2015. We fit an ordinary least squares regression to model the Johns Hopkins Overuse Index as a function of regional characteristics of the health care system, adjusted for confounders and time. RESULTS The supply of regional health care resources was associated with systemic overuse in commercially insured beneficiaries. Regional characteristics associated with systemic overuse included number of physicians per 1000 residents (P=0.001) and higher Medicare malpractice geographic price cost index (P

Summary Background Many individuals take long-term immunosuppressive medications. We evaluated whether these individuals have worse outcomes when hospitalised with COVID-19 compared with non-immunosuppressed individuals. Methods We conducted a retrospective cohort study using data from the National COVID Cohort Collaborative (N3C), the largest longitudinal electronic health record repository of patients in hospital with confirmed or suspected COVID-19 in the USA, between Jan 1, 2020, and June 11, 2021, within 42 health systems. We compared adults with immunosuppressive medications used before admission to adults without long-term immunosuppression. We considered immunosuppression overall, as well as by 15 classes of medication and three broad indications for immunosuppressive medicines. We used Fine and Gray's proportional subdistribution hazards models to estimate the hazard ratio (HR) for the risk of invasive mechanical ventilation, with the competing risk of death. We used Cox proportional hazards models to estimate HRs for in-hospital death. Models were adjusted using doubly robust propensity score methodology. Findings Among 231 830 potentially eligible adults in the N3C repository who were admitted to hospital with confirmed or suspected COVID-19 during the study period, 222 575 met the inclusion criteria (mean age 59 years [SD 19]; 111 269 [50%] male). The most common comorbidities were diabetes (23%), pulmonary disease (17%), and renal disease (13%). 16 494 (7%) patients had long-term immunosuppression with medications for diverse conditions, including rheumatological disease (33%), solid organ transplant (26%), or cancer (22%). In the propensity score matched cohort (including 12 841 immunosuppressed patients and 29 386 non-immunosuppressed patients), immunosuppression was associated with a reduced risk of invasive ventilation (HR 0·89, 95% CI 0·83–0·96) and there was no overall association between long-term immunosuppression and the risk of in-hospital death. None of the 15 medication classes examined were associated with an increased risk of invasive mechanical ventilation. Although there was no statistically significant association between most drugs and in-hospital death, increases were found with rituximab for rheumatological disease (1·72, 1·10–2·69) and for cancer (2·57, 1·86–3·56). Results were generally consistent across subgroup analyses that considered race and ethnicity or sex, as well as across sensitivity analyses that varied exposure, covariate, and outcome definitions. Interpretation Among this cohort, with the exception of rituximab, there was no increased risk of mechanical ventilation or in-hospital death for the rheumatological, antineoplastic, or antimetabolite therapies examined. Funding None.

Given the renewed policy focus on drug pricing and pharmaceutical innovation, this article examines the historical backdrop of efforts to integrate comparative effectiveness research into the FDA drug review process. Noting previous policy efforts over a decade ago, we characterize industry challenges and suggest a path forward.

The incidence of diabetes in the general US population (6.7 per 1000 adults in 2018) has not changed significantly since 2000, suggesting that individuals with prediabetes are not connecting to evidence-based interventions.We sought to describe the clinical care of individuals with prediabetes, determine patient factors associated with this care, and evaluate risk for diabetes development.Retrospective cohort study using linked claims and electronic health record data.We created a cohort of adults with prediabetes based on laboratory measures. We excluded patients with a prior history of diabetes, pregnancy in prior 6 months, or recent steroid use.We measured ordering and completion of clinical services targeting prediabetes management and diabetes incidence within 12 months following cohort entry. We tested the strength of the association between individuals' characteristics and outcomes of interest using bivariate and multiple logistic regression.Our cohort included 3888 patients with a laboratory diagnosis of prediabetes (incident or prevalent prediabetes). Within 12 months, 63.4% had repeat glycemic testing, yet only 10.4% had coded diagnoses of prediabetes, 1.0% were referred for nutrition services, and 5.4% were prescribed metformin. Most patients completed labs and nutrition visits when referred and filled metformin when prescribed. Individuals with a higher glycemic level or BMI were more likely to receive prediabetes clinical care. Six percent of individuals developed diabetes within 12 months of cohort entry and had higher glycemic levels and BMI ≥ 30 kg/mRates of prediabetes clinical care activities are low and have not improved. Strategies are urgently needed to improve prediabetes care delivery thereby preventing or delaying incident diabetes.

Clinical trials investigating cardiovascular safety of dipeptidyl peptidase-IV inhibitors (DPP-4i) among patients with cardiovascular and renal disease rarely recruit patients with renal impairment, despite associations with increased risk for major adverse cardiovascular events (MACE). We investigated the risk of MACE associated with the use of DPP-4i among these high-risk patients. Using a new-user, retrospective, cohort design, we analyzed 2010–2015 IBM MarketScan Commercial Claims and Encounters for patients with diabetes, comorbid with cardiovascular disease and/or renal impairment. We compared time to first MACE for DPP-4i versus sulfonylurea and versus metformin. Of 113,296 individuals, 9146 (8.07%) were new DPP-4i users, 17,481 (15.43%) were new sulfonylurea users, and 88,596 (78.20%) were new metformin users. Exposure groups were not mutually exclusive. DPP-4i was associated with lower risk for MACE than sulfonylurea (aHR 0.84; 95% CI 0.74, 0.93) and similar risk for MACE to metformin (aHR 1.07; 95% CI [1.04, 1.16]). DPP-4i use was associated with lower risk for MACE compared to sulfonylureas and similar risk for MACE compared to metformin. This association was most evident in the first year of therapy, suggesting that DPP-4i is a safer choice than sulfonylurea for diabetes treatment initiation in high-risk patients.

Background and aims Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. Approach and results We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. Conclusions This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

The proliferation of "ultra-expensive" drugs has sparked debate on their sustainability and affordability. Medicare Part D's share of annual spending on these drugs increased by 1,170 percent between 2012 and 2018, largely because the number of beneficiaries receiving them increased during this period.

Objective To determine if there are differences in opioid prescribing among generalist physicians, nurse practitioners (NPs), and physician assistants (PAs) to Medicare Part D beneficiaries. Design Serial cross-sectional analysis of prescription claims from 2013 to 2016 using publicly available data from the Centers for Medicare and Medicaid Services. Subjects All generalist physicians, NPs, and PAs who provided more than 10 total prescription claims between 2013 and 2016 were included. These prescribers were subsetted as practicing in a primary care, urgent care, or hospital-based setting. Methods The main outcomes were total opioid claims and opioid claims as a proportion of all claims in patients treated by these prescribers in each of the three settings of interest. Binomial regression was used to generate marginal estimates to allow comparison of the volume of claims by these prescribers with adjustment for practice setting, gender, years of practice, median income of the ZIP code, state fixed effects, and relevant interaction terms. Results There were 36,999 generalist clinicians (physicians, NPs, and PAs) with at least one year of Part D prescription drug claims data between 2013 and 2016. The number of adjusted total opioid claims across these four years for physicians was 660 (95% confidence interval [CI] = 660–661), for NPs was 755 (95% CI = 753–757), and for PAs was 812 (95% CI = 811–814). Conclusions We find relatively high rates of opioid prescribing among NPs and PAs, especially at the upper margins. This suggests that well-designed interventions to improve the safety of NP and PA opioid prescribing, along with that of their physician colleagues, could be especially beneficial.

Aim There is conflicting evidence regarding the safety and effectiveness of warfarin for atrial fibrillation (AF) treatment among older end-stage renal disease (ESRD) patients, and differences among subgroups are unclear. Methods Older dialysis patients who were newly diagnosed with AF (7/2007-12/2011) were identified in the United States Renal Data System. The adjusted hazard ratios (HR) of the outcomes (any stroke, ischaemic stroke, major bleeding, severe gastrointestinal bleeding, and death) by time-varying warfarin use were estimated using Cox regression accounting for the inverse probability of treatment weight. Results Among 5765 older dialysis patients with incident AF, warfarin was associated with significantly increased risk of major bleeding (HR = 1.50, 95% CI 1.33-1.68), but was not statistically associated with any stroke (HR = 0.92, 95% CI 0.75-1.12), ischaemic stroke (HR = 0.88, 95%CI 0.70-1.11) or gastrointestinal bleeding (HR = 1.03, 95% CI 0.80-1.32). Warfarin use was associated with a reduced risk of mortality (HR = 0.72, 95%CI 0.65-0.80). The association between warfarin and major bleeding differed by sex (male: HR = 1.29; 95%CI 1.08-1.55; female: HR = 1.67; 95%CI 1.44-1.93; P-value for interaction = 0.03). Conclusion Older ESRD patients with AF who were treated with warfarin had a no difference in stroke risk, lower mortality risk, but increased major bleeding risk. The bleeding risk associated with warfarin was greater among women than men. The risk/benefit ratio of warfarin may be less favourable among older women.

Background It is unclear whether chronic use of immunosuppressive drugs worsens or improves the severity of coronavirus disease 2019 (COVID-19), with plausible mechanisms for both. Methods Retrospective cohort study in 2121 consecutive adults with acute inpatient hospital admission between 4 March and 29 August 2020 with confirmed or suspected COVID-19 in a large academic health system, with adjustment for confounding with propensity score–derived stabilized inverse probability of treatment weights. Chronic immunosuppression was defined as prescriptions for immunosuppressive drugs current at the time of admission. Outcomes included mechanical ventilation, in-hospital mortality, and length of stay. Results There were 2121 patients admitted with laboratory-confirmed (1967, 93%) or suspected (154, 7%) COVID-19 during the study period, with a median age of 55 years (interquartile range, 40–67). Of these, 108 (5%) were classified as immunosuppressed before COVID-19, primarily with prednisone (>7.5 mg/day), tacrolimus, or mycophenolate mofetil. Among the entire cohort, 311 (15%) received mechanical ventilation; the median (interquartile range) length of stay was 5.2 (2.5–10.6) days, and 1927 (91%) survived to discharge. After adjustment, there were no significant differences in the risk of mechanical ventilation (hazard ratio [HR], .79; 95% confidence interval [CI], .46–1.35), in-hospital mortality (HR, .66; 95% CI, .28–1.55), or length of stay (HR, 1.16; 95% CI, .92–1.47) among individuals with immunosuppression and counterparts. Conclusions Chronic use of immunosuppressive drugs was neither associated with worse nor better clinical outcomes among adults hospitalized with COVID-19 in one US health system., Among adults with confirmed or suspected coronavirus disease 2019 (COVID-19), chronic use of immunosuppressive drugs was neither associated with worse nor better clinical outcomes such as mechanical ventilation, in-hospital mortality, or length of stay.

Given the renewed policy focus on drug pricing and pharmaceutical innovation, this article examines the historical backdrop of efforts to integrate comparative effectiveness research into the FDA drug review process. Noting previous policy efforts over a decade ago, we characterize industry challenges and suggest a path forward.

Clinical trials are primarily conducted to understand the average effects treatments have on patients. However, patients are heterogeneous in the severity of the condition and in ways that affect what treatment effect they can expect. It is therefore important to understand and characterize how treatment effects vary. The design and analysis of clinical studies play critical roles in evaluating and characterizing heterogeneous treatment effects. This panel discussed considerations in design and analysis under the recognition that there are heterogeneous treatment effects across subgroups of patients. Panel members discussed many questions including: What is a good estimate of the treatment effect in me, a 65-year-old, bald, Caucasian-American, male patient? What magnitude of heterogeneity of treatment effects (HTE) is sufficiently large to merit attention? What role can prior evidence about HTE play in confirmatory trial design and analysis? Is there anything described in the 21st Century Cures Act that would benefit from greater attention to HTE? An example of a Bayesian approach addressing multiplicity when testing for treatment effects in subgroups will be provided. We can do more or better at understanding heterogeneous treatment effects and providing the best information on heterogeneous treatment effects.

Rigorous evidence about the broad range of harms that might be experienced by a patient in the course of testing and treatment is sparse. We aimed to generate recommendations for how researchers might more comprehensively evaluate potential harms of healthcare interventions, to allow clinicians and patients to better include this evidence in clinical decision-making. We propose seven domains of harms of tests and treatments that are relevant to patients: (1) physical impairment, (2) psychological distress, (3) social disruption, (4) disruption in connection to healthcare, (5) labeling, (6) financial impact, and (7) treatment burden. These domains will include a range of severity of harms and variation in timing after testing or treatment, attributable to the service itself or a resulting care cascade. Although some new measures may be needed, diverse data and tools are available to allow the assessment of harms comprehensively across these domains. We encourage researchers to evaluate harms in sub-populations, since the harms experienced may differ importantly by demographics, social determinants, presence of comorbid illness, psychological state, and other characteristics. Regulators, funders, and editors might require either assessment or reporting of harms in each domain or require justification for inclusion and exclusion of different domains. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06597-9.

We aim to help inform the choice of estimand (i.e., target of inference) and analysis method to be used in future COVID-19 treatment trials. To this end, we describe estimands for outcome types of particular interest in these trials (ordinal and time-to-event). When the outcome is ordinal, the estimands that we consider are the difference between study arms in the mean outcome, the Mann-Whitney (rank--based) estimand, and the average of the cumulative log odds ratios over the levels of the outcome. For time-to-event outcomes, we consider the difference between arms in the restricted mean survival time, the difference between arms in the cumulative incidence, and the relative risk. Advantageously, the interpretability of these estimands does not rely on a proportional odds or proportional hazards assumptions. For each estimand, we evaluate the potential value added by using estimators that leverage information in baseline variables to improve precision and reduce the required sample size to achieve a desired power. These are called covariate adjusted estimators. To evaluate the performance of the covariate adjusted and unadjusted estimators that we present, we simulate two-arm, randomized trials comparing a hypothetical COVID-19 treatment versus standard of care, where the primary outcome is ordinal or time-to-event. Our simulated distributions are derived from two sources: longitudinal data on over 500 patients hospitalized at Weill Cornell Medicine New York Presbyterian Hospital prior to March 28, 2020, and a CDC preliminary description of 2449 cases reported to the CDC from February 12 to March 16, 2020. We focus on hospitalized, COVID-19 positive patients and consider the following outcomes: intubation, ventilator use, and death. We conduct simulations using all three estimands when the outcome is ordinal, but only evaluate the restricted mean survival time when the outcome is time to event. Our simulations showed that, in trials with at least 200 participants, the precision gains due to covariate adjustment are equivalent to requiring 10-20% fewer participants to achieve the same power as a trial that uses the unadjusted estimator; this was the case for each outcome and estimand that we considered.

PURPOSE: Delays in initiating adjuvant endocrine therapy (AET) are a cause for concern among women with breast cancer and clinicians, but the impact of delayed AET on overall survival (OS) is unclear. This study seeks to describe the relationship between delayed AET and OS. METHODS: Retrospective cohort study of women with stage II and III hormone receptor positive, human epidermal receptor 2 negative, invasive breast cancer, identified from the National Cancer Database. The primary exposure delayed AET, was defined as initiation of AET more than 12 months after breast cancer diagnosis. Using logistic regression we examined predictors of delayed AET. The survival analysis with Cox proportional hazards regression adjusted for patient, tumor, and treatment characteristics. RESULTS: Among the 391,594 included women, 12,162 (3.1%) had delayed AET. Predictors of delayed AET included Black race (adjusted odds ratio [aOR]=1.61, 95% confidence interval [CI], 1.52-1.70) or Hispanic ethnicity (aOR=1.25, 95% CI 1.16-1.35) vs white race, Medicare (aOR=1.13, 95% CI 1.06-1.20) or Medicaid (aOR=1.41, 95% CI 1.32-1.50) versus private insurance, and cancer stage III (aOR=1.24, 95% CI 1.19-1.30) vs stage II. With median follow-up of 67.4 months, 67,335 (17.2%) patients died. Delayed AET had no statistically significant effect on the hazard of death (adjusted hazards ratio=1.01; 95% CI, 0.96-1.06) compared to initiation within 12 months of diagnosis. CONCLUSION: This study suggests that there may be no adverse impact on survival if initiation of AET occurs 12 to 24 months after initial diagnosis compared to within 12 months of diagnosis as currently recommended.

ObjectivesThe coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19.Design, setting and participantsCross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO’s International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers.Main outcome(s)Trial intervention, sponsorship, critical design elements and specified outcomesResultsOverall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020.ConclusionsWhile accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.

Background Medical overuse is a leading contributor to the high cost of the US health care system and is a definitive misuse of resources. Elimination of overuse could improve health care efficiency. In 2014, the State of Maryland placed the majority of its hospitals under an all-payer, annual, global budget for inpatient and outpatient hospital services. This program aims to control hospital use and spending. Objective To assess whether the Maryland global budget program was associated with a reduction in the broad overuse of health care services. Methods We conducted a retrospective analysis of deidentified claims for 18–64 year old adults from the IBM MarketScan® Commercial Claims and Encounters Database. We matched 2 Maryland Metropolitan Statistical Areas (MSAs) to 6 out-of-state comparison MSAs. In a difference-in-differences analysis, we compared changes in systemic overuse in Maryland vs the comparison MSAs before (2011–2013) and after implementation (2014–2015) of the global budget program. Systemic overuse was measured using a semiannual Johns Hopkins Overuse Index. Results Global budgets were not associated with a reduction in systemic overuse. Over the first 1.5 years of the program, we estimated a nonsignificant differential change of −0.002 points (95%CI, −0.372 to 0.369; p = 0.993) relative to the comparison group. This result was robust to multiple model assumptions and sensitivity analyses. Conclusions We did not find evidence that Maryland hospitals met their revenue targets by reducing systemic overuse. Global budgets alone may be too blunt of an instrument to selectively reduce low-value care.

This study is an evaluation of a discharge intervention that occurred in multiple hospitals across Maryland. In this program, patients received medications at their bedside before discharge with the goal of reducing the risk of primary nonadherence to prescribed medications.To test if the intervention reduced the risk of 30-day readmission for the patients who received bedside medication delivery relative to comparable patients who did not receive bedside medication delivery.This was a retrospective cohort study. Patients who received the intervention were linked to their claims data in the Maryland Health Information Exchange. These patients were matched on age, sex, diagnosis-related group, and hospital to a set of patients who did not receive the intervention. We used propensity score matching, as well as inverse-probability weighting, to account for residual differences between the treated and comparison patients. With robust Poisson regression, adjusting for hospital, we generated risk ratios for 30-day readmission and explored risk ratios in key subgroups.The cohort included 6,167 inpatients who received medications at bedside and 28,546 who did not from 10 Maryland hospitals. They were 60% female, 61% white, and 31% African American; the average age was 56 years. The risk ratio for readmission, comparing the intervention group to the propensity score-matched comparison group, was 1.21 (95% CI = 0.96-1.5). Inverse-probability weighting yielded a similar result (1.19 [95% CI = 0.98-1.45]).In this study, the isolated intervention of bedside medication delivery did not reduce 30-day readmission risk. We expect it may have favorable outcomes on other metrics such as primary nonadherence and patient satisfaction. It may also have a favorable effect when bundled with other care transition activities. As an isolated intervention, however, bedside medication delivery is unlikely to affect 30-day readmission rates.This study was funded by Walgreen Co. through unrestricted funds to Johns Hopkins University, which has received fees from Walgreens for providing consultation as an institution to Walgreens. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Segal received a grant from the National Institute on Aging during the conduct of this study. The other authors have nothing to disclose.

BACKGROUND: Some classes of drugs have lower than optimal uptake of generic products. We aimed to understand the determinants of generic drug substitution across classes. METHODS: We conducted a cross-sectional analysis of data from the 2013 MarketScan Commercial Claims and Encounters Database from Truven Health Analytics. We quantified generic substitution rates (GSR) for 26 drug classes, choosing one representative week in November 2013. We used mixed-effects logistic regression to estimate the independent relationship between the determinants of interest and generic substitution for 8 classes with low generic utilization. RESULTS: The GSRs for most classes exceeded 90%, although some were much lower including thyroid hormones (64%), androgens (74%), estrogens (71%), and hydantoin-type anticonvulsants (72%). The determinants of generic substitution varied across classes, albeit with important patterns. Patients using a mail order pharmacy had significantly less generic substitution than patients filling at retail pharmacies for 5 of the 8 studied classes; two additional classes showed no relationship between pharmacy type and generic use. Men relative to women and patients taking more medications were more likely to use generics for most classes. State substitution laws and patient consent laws were largely inconsequential regarding generic substitution. CONCLUSIONS: Policies are needed to support the use of safe, effective and often lower cost generic drugs, when available. Mail order pharmacies, as often required by pharmacy benefits managers, lessen generic use for many classes. These pharmacies may require additional regulatory oversight if this adversely impacts patients.

Drug discovery for disease‐modifying therapies for Alzheimer's disease and related dementias (ADRD) based on the traditional paradigm of experimental animal models has been disappointing. We describe the rationale and design of the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study, an innovative multidisciplinary alternative to traditional drug discovery. First, we use a systems biology perspective in the "hypothesis generation" phase to identify metabolic abnormalities that may either precede or interact with the accumulation of ADRD neuropathology, accelerating the expression of clinical symptoms of the disease. Second, in the "hypothesis refinement" phase we propose use of large patient cohorts to test whether drugs approved for other indications that also target metabolic drivers of ADRD pathogenesis might alter the trajectory of the disease. We emphasize key challenges in population‐based pharmacoepidemiologic studies aimed at quantifying the association between medication use and ADRD onset and outline robust causal inference principles to safeguard against common pitfalls. Candidate ADRD treatments emerging from this approach will hold promise as plausible disease‐modifying therapies for evaluation in randomized controlled trials.

Overuse of health care is a pervasive threat to patients that requires measurement to inform the development of interventions.To measure low-value health care use within health systems in the US and explore features of the health systems associated with low-value care delivery.In this cross-sectional analysis, we identified occurrences of 17 low-value services in 3745 hospitals and affiliated outpatient sites. Hospitals were linked to 676 health systems in the US using the Agency for Healthcare Research and Quality (AHRQ) Compendium of Health Systems. The participants were 100% of Medicare beneficiaries with claims from 2016 to 2018.We identified occurrences of 17 low-value services in 3839 hospitals and affiliated outpatient sites.Hospitals were linked to health systems using AHRQ's Compendium of Health Systems. Between March and August 2021, we modeled overuse occurrences with a negative binomial regression model including the year-quarter, procedure indicator, and a health system indicator. The model included random effects for hospital and beneficiary age, sex, and comorbidity count specific to each indicator, hospital, and quarter. The beta coefficients associated with the health system term, normalized, reflect the tendency of that system to use low-value services relative to all other systems. With ordinary least squares regression, we explored health system characteristics associated with the Overuse Index (OI), expressed as a standard deviation where the mean across all health systems is 0.There were 676 unique health systems assessed in our study that included from 1 to 163 hospitals (median of 2). The mean age of eligible beneficiaries was 75.5 years and 76% were women. Relative to the lowest tertile, health systems in the upper tertile of medical groups count and bed count had an OI that was higher by 0.38 standard deviations (SD) and 0.44 SD, respectively. Health systems that were primarily investor owned had an OI that was 0.56 SD higher than those that were not investor owned. Relative to the lowest tertile, health systems in the upper tertile of primary care physicians, upper tertile of teaching intensity, and upper quartile of uncompensated care had an OI that was lower by 0.59 SD, 0.45 SD, and 0.47 SD, respectively.In this cross-sectional study of US health systems, higher amounts of overuse among health systems were associated with investor ownership and fewer primary care physicians. The OI is a valuable tool for identifying potentially modifiable drivers of overuse and is adaptable to other levels of investigation, such as the state or region, which might be affected by local policies affecting payment or system consolidation.

BACKGROUND: Overuse of health care resources has been identified as the leading contributor to waste in the US health care system. OBJECTIVE: To explore health care system factors associated with regional variation in systemic overuse of health care resources as measured by the Johns Hopkins Overuse Index (JHOI) which aggregates systemic overuse of 20 health care services. DESIGN: Using Medicare fee-for-service claims data from beneficiaries age 65 or over in 2008, we calculated the JHOI for the 306 hospital referral regions in the United States. We used ordinary least squares regression and multilevel models to estimate the association of JHOI scores and characteristics of regional health care delivery systems listed in the Area Health Resource File and Dartmouth Atlas. KEY RESULTS: Regions with a higher density of primary care physicians had lower JHOI scores, indicating less systemic overuse (P

Background: Excessive breast cancer screening with mammography or other modalities often burdens patients with false-positive results and costs. Yet, screening patients beyond the age at which they will benefit or at too frequent intervals persists. This review summarizes the factors associated with overuse of breast cancer screening. Methods: We searched Medline and Embase from January 1998 to March 2017 for articles addressing the overuse of breast cancer screening and hand-searched the reference lists of included articles. Studies were included if they were written in English, pertained to a U.S. population, and identified a factor associated specifically with overuse of breast imaging. Paired reviewers independently screened abstracts, extracted data, and assessed quality. Results: We included 15 studies: 3 cohort, 5 cross-sectional, 6 surveys, and 1 in-depth interview. White women (non-Hispanic) were less vulnerable than other racial groups to overuse in 3 of 5 studies. Physician specialty was consistently associated with screening overuse in three of three studies. Abundant access to primary care and a patient desire for screening were associated with breast cancer screening overuse. Lower self-confidence, lower risk taking tendencies, higher perception of conflict in expert recommendations, and a belief in screening effectiveness were clinician traits associated with overuse of screening in the surveys. Conclusions: The literature supports that liberal access to care and clinicians' recommendations to screen, possibly influenced by conflicting guidelines, increase excessive breast cancer screening. Overuse might conceivably be reduced with more concordance across guidelines, physician education, patient involvement in decision-making, thoughtful insurance restrictions, and limitations on the supply of services; however, these will need careful testing regarding their impact.

Rationale: Diabetes and metabolic syndrome have been associated with worsened asthma control. Metformin improves insulin resistance and metabolic function. Experimental studies suggest that metformin may improve pathologic features of asthma, but evidence of clinical benefit is limited. Objectives: To determine if treatment with metformin in a cohort of individuals with asthma and diabetes is associated with lower risk of asthma exacerbation. Methods: A 6-year retrospective cohort of individuals over age 18 with asthma and diabetes was assembled from a national administrative claims database. New users of metformin were matched to nonusers by propensity score on the basis of demographic, comorbidity, and medication-use characteristics. An exacerbation was defined as an asthma-related hospitalization, emergency department visit, or filling of a systemic corticosteroid prescription within 14 days of an asthma-related ambulatory visit. Cox proportional hazards estimated the change in hazard of asthma exacerbation associated with metformin initiation. Results: In a cohort of 23,920 individuals with asthma and diabetes, metformin initiation was associated with lower hazard of asthma exacerbation (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.86–0.98), driven by lower hazards of asthma-related emergency department visits (HR, 0.81; 95% CI, 0.74–0.88) and hospitalization (HR, 0.67; 95% CI, 0.50–0.91), without differences in corticosteroid use (HR, 0.96; 95% CI, 0.86–1.03). Conclusions: In an administrative cohort of individuals with asthma and diabetes, metformin initiation was associated with a lower hazard of asthma-related emergency department visits and hospitalizations. These findings suggest a possible benefit of metformin in more severe asthma exacerbations. Investigation within cohorts with more detailed participant characterization is necessary.