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Background: Hidradenitis suppurativa (HS) has been associated with auto‐inflammatory conditions, yet the risk of developing connective tissue disease (CTD), morphoea and systemic vasculitis has not been well‐characterized. Objectives: We sought to evaluate the risk of developing CTD, morphoea and systemic vasculitis in patients with HS. Methods: Using claims data, we identified patients with HS and used 2 : 1 risk‐set sampling to identify patients without HS. Patients with existing CTD were excluded. Patient follow‐up lasted until first occurrence of the following events: the occurrence of outcome (i.e. systemic lupus erythematosus, morphoea, systemic sclerosis, Sjogren's Syndrome and systemic vasculitis), death, disenrolment or end of data stream. Hazard ratios (HR) of developing CTD, morphoea and systemic vasculitis were computed after 1 : 1 propensity score (PS) matching. Results: After 2 : 1 risk‐set sampling, we identified 78 122 HS patients and 156 247 non‐HS comparators. The mean follow‐up was 540 days. After PS matching, HS patients had an increased risk of systemic lupus erythematosus HR = 1.63 (1.31–2.03) and morphoea HR = 2.02 (1.32–3.11), compared to non‐HS patients. We did not observe an increased risk for systemic sclerosis HR = 0.90 (0.59–1.44), Sjogren's Syndrome HR = 0.91 (0.73–1.14) or systemic vasculitis HR = 0.87 (0.64–1.20). Conclusion: In this population‐based study, we observed an increased risk of developing systemic lupus erythematous and morphoea subsequent to a first‐recorded diagnosis of hidradenitis suppurativa. [ABSTRACT FROM AUTHOR]

Analyses of healthcare databases (claims, electronic health records [EHRs]) are useful supplements to clinical trials for generating evidence on the effectiveness, harm, use, and value of medical products in routine care. A constant stream of data from the routine operation of modern healthcare systems, which can be analyzed in rapid cycles, enables incremental evidence development to support accelerated and appropriate access to innovative medicines. Evidentiary needs by regulators, Health Technology Assessment, payers, clinicians, and patients after marketing authorization comprise (1) monitoring of medication performance in routine care, including the materialized effectiveness, harm, and value; (2) identifying new patient strata with added value or unacceptable harms; and (3) monitoring targeted utilization. Adaptive biomedical innovation (ABI) with rapid cycle database analytics is successfully enabled if evidence is meaningful, valid, expedited, and transparent. These principles will bring rigor and credibility to current efforts to increase research efficiency while upholding evidentiary standards required for effective decision-making in healthcare. [ABSTRACT FROM AUTHOR]

A central question in the assessment of benefit/harm of new treatments is: how does the average outcome on the new treatment (the factual) compare to the average outcome had patients received no treatment or a different treatment known to be effective (the counterfactual)? Randomized controlled trials (RCTs) are the standard for comparing the factual with the counterfactual. Recent developments necessitate and enable a new way of determining the counterfactual for some new medicines. For select situations, we propose a new framework for evidence generation, which we call 'threshold-crossing.' This framework leverages the wealth of information that is becoming available from completed RCTs and from real world data sources. Relying on formalized procedures, information gleaned from these data is used to estimate the counterfactual, enabling efficacy assessment of new drugs. We propose future (research) activities to enable 'threshold-crossing' for carefully selected products and indications in which RCTs are not feasible. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration's Sentinel system has developed the capability to conduct active safety surveillance of marketed medical products in a large network of electronic healthcare databases. We assessed the extent to which the newly developed, semiautomated Sentinel Propensity Score Matching (PSM) tool could produce the same results as a customized protocol-driven assessment, which found an adjusted hazard ratio (HR) of 3.04 (95% confidence interval [CI], 2.81-3.27) comparing angioedema in patients initiating angiotensin-converting enzyme (ACE) inhibitors vs. beta-blockers. Using data from 13 Data Partners between 1 January 2008, and 30 September 2013, the PSM tool identified 2,211,215 eligible ACE inhibitor and 1,673,682 eligible beta-blocker initiators. The tool produced an HR of 3.14 (95% CI, 2.86-3.44). This comparison provides initial evidence that Sentinel analytic tools can produce findings similar to those produced by a highly customized protocol-driven assessment. [ABSTRACT FROM AUTHOR]

Health insurance claims and electronic health records (EHR) databases have been considered the preferred data sources with which to study drug safety and effectiveness in routine care. Linking claims data to EHR allows researchers to leverage the complementary advantages of each data source to enhance study validity. We propose a framework to evaluate the need for supplementing claims data with EHR and vice versa to optimize outcome ascertainment, exposure assessment, and confounding adjustment. [ABSTRACT FROM AUTHOR]

Big healthcare data-electronically recorded longitudinal data generated during the provision and administration of healthcare for millions of patients-have become essential for understanding the effectiveness and safety of therapeutics. They are most effectively used in concert with experimental and laboratory research throughout the life cycle of a drug. Applications range from providing phenotype and health outcomes information in genome-wide association studies to postmarketing studies that assure prescribers of the safety of approved drugs (Figure ). [ABSTRACT FROM AUTHOR]

Background Recent data suggest that acid suppressive medications may alter factors central to the pathophysiology of inflammatory bowel diseases ( IBD), whether through shifts in the intestinal microbiome due to acid suppression or effects on immune function. Aim To assess the relationship between the use of proton pump inhibitors ( PPIs) or histamine2-receptor antagonists ( H2 Ra) and incidence of 'flares' (hospitalisation/surgery and change in medication). Methods We conducted a new user cohort study including individuals diagnosed with IBD in British Columbia using linked healthcare utilisation databases (available from July 1996 through April 2006). Propensity-score matched incidence rates during a 6-month follow-up period and rate ratios ( RR) and 95% CI were calculated. Results Among 16 151 IBD patients, 1307 Crohn's disease ( CD) and 996 ulcerative colitis ( UC) patients experienced a new use of PPIs, whereas 741 CD and 738 UC used H2 Ra. All IBD subgroups were matched separately to an equal number of unexposed IBD patients. H2 Ra use in CD doubled the risk of hospitalisation/surgery ( RR = 1.94; 95% CI 1.24-3.10) and numerically less so in UC patients ( RR = 1.11) with widely overlapping CIs (0.61-2.03). Proton pump inhibitors use was associated with medication change in UC ( RR = 1.39; 95% CI 1.20-1.62), but without meaningfully, increased risk of hospitalisation/surgery for UC or CD patients. Extending follow-up showed persistence, but attenuation, of all effects. Conclusions Initiation of PPIs or H2 Ra may be associated with short-term changes in the course of IBD. Although confounding by indication was adjusted using propensity score matching, residual confounding may persist and findings need to be interpreted cautiously. [ABSTRACT FROM AUTHOR]

We developed a semi-automated active monitoring system that uses sequential matched-cohort analyses to assess drug safety across a distributed network of longitudinal electronic health-care data. In a retrospective analysis, we show that the system would have identified cerivastatin-induced rhabdomyolysis. In this study, we evaluated whether the system would generate alerts for three drug-outcome pairs: rosuvastatin and rhabdomyolysis (known null association), rosuvastatin and diabetes mellitus, and telithromycin and hepatotoxicity (two examples for which alerting would be questionable). Over >5 years of monitoring, rate differences (RDs) in comparisons of rosuvastatin with atorvastatin were −0.1 cases of rhabdomyolysis per 1,000 person-years (95% confidence interval (CI): −0.4, 0.1) and −2.2 diabetes cases per 1,000 person-years (95% CI: −6.0, 1.6). The RD for hepatotoxicity comparing telithromycin with azithromycin was 0.3 cases per 1,000 person-years (95% CI: −0.5, 1.0). In a setting in which false positivity is a major concern, the system did not generate alerts for the three drug-outcome pairs. [ABSTRACT FROM AUTHOR]

Comparative-effectiveness research (CER) aims to produce actionable evidence regarding the effectiveness and safety of medical products and interventions as they are used outside of controlled research settings. Although CER evidence regarding medications is particularly needed shortly after market approval, key methodological challenges include (i) potential bias due to channeling of patients to the newly marketed medication because of various patient-, physician-, and system-related factors; (ii) rapid changes in the characteristics of the user population during the early phase of marketing; and (iii) lack of timely data and the often small number of users in the first few months of marketing. We propose a mix of approaches to generate comparative-effectiveness data in the early marketing period, including sequential cohort monitoring with secondary health-care data and propensity score (PS) balancing, as well as extended follow-up of phase III and phase IV trials, indirect comparisons of placebo-controlled trials, and modeling and simulation of virtual trials. [ABSTRACT FROM AUTHOR]

We sought to estimate the risk of seizure-related events associated with refilling prescriptions for antiepileptic drugs (AEDs) and to estimate the effect of switching between brand-name and generic drugs or between two generic versions of the same drug. We conducted a case–crossover study using health-care databases from British Columbia, Canada, among AED users who had an emergency room visit or hospitalization for seizure (index seizure-related event), defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes 345.xx (epilepsy and recurrent seizures) and 780.3x (convulsions), between 1997 and 2005. AED prescription refilling itself was associated with 2.3-fold elevated odds of seizure-related events when the refill occurred within 21 days before the index event (odds ratio (OR) 2.31; 95% confidence interval (CI) 1.56–3.44). The OR was 2.75 (95% CI 0.88–8.64) for refills that involved switching, yielding a refill-adjusted OR for switching of 1.19 (95% CI 0.35–3.99). Refilling the same AED prescription was associated with an elevated risk of seizure-related events whether or not the refill involved switching from a brand-name to a generic product. [ABSTRACT FROM AUTHOR]

OBJECTIVE: People in rural areas live farther away from hospitals than do people in urban areas. Thus, there is concern that people living in rural areas may be less willing or able to undergo elective surgical procedures. This study was undertaken to determine whether Medicare beneficiaries in rural areas were less likely to have elective total knee or hip replacement surgeries compared with their urban counterparts. METHODS: We performed a cross-sectional study of Medicare beneficiaries, controlling for age, sex, race/ethnicity, and economic status. Beneficiaries were assigned to rural versus urban areas based on their zip code of residence and the 10-point Rural-Urban Commuting Area designation. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Compared with urban beneficiaries, rural beneficiaries were 27% more likely to have total knee or hip replacement surgeries (OR 1.27 [95% CI 1.26-1.28]). After adjusting for age, sex, race/ethnicity, median household income, average house value, mean poverty ratio, and state of residence, rural beneficiaries were still 14% more likely to have total joint replacement surgeries (OR 1.14 [95% CI 1.13-1.16]). Differential use of surgery before and after receiving Medicare eligibility did not explain the findings. While significant sex, racial, and ethnic disparities were present in both rural and urban areas, for the most part these disparities were ameliorated rather than accentuated in rural areas. CONCLUSION: Contrary to expectations, our findings indicate that Medicare beneficiaries living in rural areas are more likely to undergo total knee or hip replacement surgeries. [ABSTRACT FROM AUTHOR]

Background There remain concerns about the safety of infliximab therapy in patients with inflammatory bowel disease (IBD). Aim To assess the association between the initiation of infliximab and other immunomodulating drugs and the risk of serious bacterial infection in the treatment of IBD. Methods We assembled a cohort study of patients with IBD, including Crohn’s disease (CD) and ulcerative colitis (UC). All patients initiating an immunomodulating drug between January 2001 and April 2006 were identified in British Columbia from linked health care utilization databases. Exposure of interest was initiation of infliximab or corticosteroids compared with initiation of other immunosuppressive agents, including azathioprine, mercaptopurine (MP) and methotrexate (MTX). Outcome of interest was serious bacterial infections requiring hospitalization, including Clostridium difficile. Results Among 10 662 IBD patients, the incidence rate of bacteriaemia ranged from 3.8 per 1000 person-years (95% confidence interval 2.1–6.2) for other immunosuppressive agents to 7.4 (3.3–19.3) for infliximab with slightly higher rate for serious bacterial infections resulting in an adjusted relative risk 1.4 (0.47–4.24). Clostridium difficile infections occurred in 0/1000 (0–5.4) among 521 infliximab initiations and 14/1000 (10.6–18.2) for corticosteroids. Corticosteroid initiation tripled the risk of C. difficile infections (RR = 3.4; 1.9–6.1) compared with other immunosuppressant agents. This corticosteroid effect was neither dose-dependent nor duration-dependent. Bacteriaemia and other serious bacterial infections were not increased by corticosteroids or infliximab (5 events). Conclusions In a population-based cohort of patients with IBD, we found no meaningful association between infliximab and serious bacterial infections, although some subgroups had few events. Corticosteroid initiation increased the risk for C. difficile infections in these patients. [ABSTRACT FROM AUTHOR]

Physicians and insurers need to weigh the effectiveness of new drugs against existing therapeutics in routine care to make decisions about treatment and formularies. Because Food and Drug Administration (FDA) approval of most new drugs requires demonstrating efficacy and safety against placebo, there is limited interest by manufacturers in conducting such head-to-head trials. Comparative effectiveness research seeks to provide head-to-head comparisons of treatment outcomes in routine care. Health-care utilization databases record drug use and selected health outcomes for large populations in a timely way and reflect routine care, and therefore may be the preferred data source for comparative effectiveness research. Confounding caused by selective prescribing based on indication, severity, and prognosis threatens the validity of non-randomized database studies that often have limited details on clinical information. Several recent developments may bring the field closer to acceptable validity, including approaches that exploit the concepts of proxy variables using high-dimensional propensity scores, within-patient variation of drug exposure using crossover designs, and between-provider variation in prescribing preference using instrumental variable (IV) analyses.Clinical Pharmacology & Therapeutics (2007) 82, 143–156. doi:10.1038/sj.clpt.6100249; published online 6 June 2007 [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the association between the initiation of anti-tumor necrosis factor alpha (anti-TNFalpha) therapy and the risk of serious bacterial infections in routine care. METHODS: This was a cohort study of patients with rheumatoid arthritis (RA) in whom specific disease-modifying antirheumatic drugs (DMARDs) were initiated. Patients were Medicare beneficiaries ages 65 years and older (mean age 76.5 years) who were concurrently enrolled in the Pharmaceutical Assistance Contract for the Elderly provided by the state of Pennsylvania. A total of 15,597 RA patients in whom a DMARD was initiated between January 1, 1995 and December 31, 2003 were identified using linked data on all prescription drug dispensings, physician services, and hospitalizations. Initiation of anti-TNFalpha therapy, cytotoxic agents other than methotrexate (MTX), noncytotoxic agents, and glucocorticoids was compared with initiation of MTX. The main outcome measure was serious bacterial infections that required hospitalization. RESULTS: The incidence of serious bacterial infections was, on average, 2.2 per 100 patient-years in this population (95% confidence interval [95% CI] 2.0-2.4). Glucocorticoid use doubled the rate of serious bacterial infections as compared with MTX use, independent of previous DMARD use (rate ratio [RR] 2.1 [95% CI 1.5-3.1]), with a clear dose-response relationship for dosages >5 mg/day (for /=20 mg/day, RR 5.48 [P for trend < 0.0001]). Adjusted models showed no increase in the rate of serious infections among initiators of anti-TNFalpha therapy (RR 1.0 [95% CI 0.6-1.7]) or other DMARDs as compared with initiators of MTX. CONCLUSION: In a large cohort of patients with RA, we found no increase in serious bacterial infections among users of anti-TNFalpha therapy compared with users of MTX. Glucocorticoid use was associated with a dose-dependent increase in such infections. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To simultaneously assess the short-term reduction in risk of gastrointestinal (GI) complications and increase in risk of acute myocardial infarction (MI) by celecoxib compared with rofecoxib and several nonselective nonsteroidal antiinflammatory drugs (NSAIDs) using instrumental variable analysis. METHODS: A population of 49,711 Medicare beneficiaries ages 65 years and older who initiated nonselective NSAID or selective cyclooxygenase 2 inhibitor therapy between January 1, 1999, and December 31, 2002, was identified. The increase in risk of GI complications and MI within 180 days after initiation of NSAID (rofecoxib, diclofenac, ibuprofen, and naproxen compared with celecoxib) therapy was assessed using instrumental variable analysis. RESULTS: Compared with nonselective NSAIDs, celecoxib reduced the risk of GI complications by 1.4 per 100 users but increased the risk of MI by 0.3 per 100 users. Rofecoxib decreased GI complications by 1.1 per 100 users and increased the risk of MI by 0.3 per 100 users. Using celecoxib as the reference exposure showed an increase in the MI risk for rofecoxib (risk difference [RD] 1.40, 95% confidence interval [95% CI] -0.20, 3.01) and diclofenac (RD 6.07, 95% CI -0.02, 12.15). The RD for naproxen as well as its upper 95% CI was the lowest of all NSAIDs (RD -0.30, 95% CI -2.74, 2.14) and there was no significant difference in GI complication rates among all NSAIDs. CONCLUSION: In this instrumental variable analysis, diclofenac and rofecoxib had the least favorable benefit-risk balance among NSAIDs in older adults. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Concerns persist about a possible association between tumor necrosis factor alpha (TNFalpha) antagonist treatment and development of cancers in patients with rheumatoid arthritis (RA). This study was undertaken to estimate the association between treatment with biologic disease-modifying antirheumatic drugs (DMARDs) and development of cancer in patients with RA. METHODS: We conducted a cohort study pooling administrative databases from 2 US states and 1 Canadian province. A cohort of patients who had received a diagnosis of RA on >/=1 occasion and had been prescribed DMARDs was identified. We categorized patients with a prescription for a biologic DMARD as biologic DMARD users, and those with a prescription for methotrexate (MTX) but no biologic DMARD as MTX users. We used time-varying propensity scores to adjust for the large number of possible confounders and stratified proportional hazards regression to estimate the effects of biologic DMARDs on cancer. The primary end points were hematologic malignancies (lymphoma, multiple myeloma, and leukemia) and common solid tumors (colorectal, lung, stomach, breast, prostate, uterine, ovarian, urinary tract/bladder, and melanoma). RESULTS: The pooled cohort included 1,152 biologic DMARD users and 7,306 MTX users. We identified 11 hematologic malignancies and 46 solid tumors during 2,940 person-years of biologic DMARD use, and 88 hematologic malignancies and 558 solid tumors during 30,300 person-years of MTX use. Comparing biologic DMARD users with MTX users, the propensity score-adjusted pooled hazard ratio was 1.37 (95% confidence interval 0.71-2.65) for hematologic malignancies and 0.91 (95% confidence interval 0.65-1.26) for solid tumors. CONCLUSION: Our results indicate that users of biologic agents are unlikely to have a substantial increase in the risk of hematologic malignancies and solid tumors as compared with MTX users. Despite the use of large combined data sets, studying the effect of an infrequent exposure (biologic DMARDs) on rare diseases (hematologic malignancies) remains a challenge. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Controversy persists regarding the cardiovascular risks of treatment with selective cyclooxygenase 2 inhibitors (coxibs) and nonselective nonsteroidal antiinflammatory drugs (NSAIDs). This study was undertaken to examine, in a large group of new users of coxibs and NSAIDs, the rate of cardiovascular events, their time course, and whether baseline cardiovascular risk modified the rate ratios (RRs) for future events. METHODS: This cohort study included Medicare beneficiaries who enrolled in a state-run prescription drug plan that fully covered NSAIDs and coxibs without restriction. All study patients started use of a coxib or NSAID after January 1, 1999. The primary composite end point was a hospital admission for either myocardial infarction or ischemic stroke. Predefined exposure groups included the 3 coxibs available in the US during the study period (celecoxib, rofecoxib, and valdecoxib), as well as oral formulations of diclofenac, ibuprofen, naproxen, and a composite of all other NSAIDs. We compared the rate of cardiovascular events associated with each of these agents with that in a reference group of patients who did not use NSAIDs or coxibs, but started other medications unrelated to cardiovascular risk. Daily exposure to all study drugs was assessed based on filled prescription data. A Cox proportional hazards model stratified on calendar year that included other baseline cardiovascular risk factors constituted the primary analysis. RESULTS: We identified 74,838 users of NSAIDs or coxibs, and 23,532 comparable users of other drugs comprised the reference group. Adjusted models demonstrated a significant elevation in the event rate for rofecoxib (RR 1.15, 95% confidence interval [95% CI] 1.06-1.25) and a significant reduction in the rate for naproxen (RR 0.75, 95% CI 0.62-0.92). No other coxib or NSAID was associated with a significant increase or decrease in cardiovascular event rate. The increased rate associated with rofecoxib was seen in the first 60 days of use (adjusted RR 1.14, 95% CI 1.01-1.29) and thereafter (adjusted RR 1.14, 95% CI 1.02-1.28). Kaplan-Meier event curves showed a similar pattern of risk (early and persistent separation of the event curves) among long-term rofecoxib users at low or high baseline cardiovascular risk. CONCLUSION: We found an increased cardiovascular event rate among users of rofecoxib, and a decreased rate with naproxen use. Other coxibs and NSAIDs did not appear to be associated with a difference in event rate compared with users of other drugs. The increase in rate associated with rofecoxib was seen within the first 60 days and persisted. There was no important modification of the event rate based on the patient's baseline cardiovascular risk. [ABSTRACT FROM AUTHOR]

Presents studies exposing problems in the treatment of late-life depression. Dosages of antidepressants given to older people; Availability of selective serotonin reuptake inhibitors; Establishment of guidelines for geriatric prescribing.

The article focuses on the challenges faced by the current health care system of the U. S. in the treatment of the growing number of elderly patients with severe mental illness (SMI). SMI patients include those with schizophrenia, other psychotic-spectrum disorders, bipolar disorder and treatment-refractory severe depression. According to Stephen J. Bartels, M. D., M. S., there are two main challenges: One is providing rehabilitation and associated skills that will enhance their ability to live in the community and improve their health behaviors and the other is to address the high rates of medical comorbidity, which appears to be associated with poor health care habits and poor health care.

A response by J. J. Gagne and colleagues to a letter to the editor about their article "Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events" in the 2010 issue is presented.

Background: A direct comparison of the gastrointestinal (GI) and cardiac safety of NSAIDs in elderly patients is not possible based on randomized trials since different trials employed non-overlapping patient populations and comparison exposures. We sought to estimate the risk reduction of GI complications and risk increase in acute myocardial infarction (MI) by celecoxib and rofecoxib compared with several non-selective NSAIDs addressing confounding by using instrumental variable methods.Methods: We identified 49,731 Medicare beneficiaries who initiated non-selective NSAIDs or selective COX2 inhibitors between 1/1/99 and 7/31/03. Risk increase of GI complications and MI in 180 days after initiation of NSAID therapy (rofecoxib, diclofenac, ibuprofen, and naproxen compared with celecoxib) was assessed using instrumental variable analysis adjusting un/measured confounders.Results: Compared with celecoxib, a tendency for increased risk of GI complications was observed for ibuprofen (risk difference = 0.93 events per 100 patients; -1.88; 3.73) and diclofenac (RD=5.20; -1.07;11.5). We found a clear increase in the risk of MI for rofecoxib (RD=2.17; 0.12;4.21) and diclofenac (RD=7.63; 0.24;15.0), while naproxen had the lowest risk (RD = -1.59; -4.62;1.44).Conclusions: Diclofenac appears to have the least favorable safety profile among NSAIDs, while naproxen has the lowest risk of MI with no meaningful increase in risk for GI complications, making it a viable alternative to celecoxib.Clinical Pharmacology & Therapeutics (2005) 79, P83–P83; doi: 10.1016/j.clpt.2005.12.296 [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors have improved the clinical outcomes of several cancers but have also been associated with a greater risk of immune-related adverse effects, especially when combined. The objective of this study was to investigate the incidence of myocarditis in relation to the use of dual concurrent versus single immune checkpoint inhibitors therapies., Methods and Results: A cohort study was conducted using medical and pharmacy claims data (2011-2022) from a large US commercial insurer. Cox regression quantified the comparative risks of myocarditis or heart failure in patients with cancer receiving treatment with combination therapy (nivolumab and ipilimumab) in comparison to taking a single immune checkpoint inhibitor only. Mean follow-up time in 53 018 patients was 226 days (interquartile range, 93-495 days). There were 148 cases of myocarditis (0.3%), 33 (0.7%) in patients on combination therapy, and 115 (0.2%) in patients on monotherapy. The risk of myocarditis per 1000 patients was 7.40 in the combination therapy group and 2.37 in the monotherapy group (risk ratio, 3.12 [95% CI, 2.12-4.60]). Using multivariable regression analysis, the hazard ratio for myocarditis in the combination therapy group was 2.38 (1.57-3.63). No difference in the risk of heart failure was found between combination and single therapy., Conclusions: Therapy with 2 immune checkpoint inhibitors was associated with an increased risk of myocarditis compared with monotherapy, with most cases occurring in the first 6 months of therapy.

Aim: Non-randomized studies on bariatric surgery have reported large reductions in mortality within 6-12 months after surgery compared with non-surgical patients. It is unclear whether these findings are the result of bias., Study Design and Setting: We searched PubMed to identify all non-randomized studies investigating the effect of bariatric surgery on all-cause mortality compared with non-surgical patients. We assessed these studies for potential confounding and time-related biases. We conducted bias analyses to quantify the effect of these biases., Results: We identified 21 cohort studies that met our inclusion criteria. Among those, 11 were affected by immortal time bias resulting from the misclassification or exclusion of relevant follow-up time. Five studies were subject to potential confounding bias because of a lack of adjustment for body mass index (BMI). All studies used an inadequate comparator group that lacked indications for bariatric surgery. Bias analyses to correct for potential confounding from BMI shifted the effect estimates towards the null [reported hazard ratio (HR): 0.78 vs. bias-adjusted HR: 0.92]. Bias analyses to correct for the presence of immortal time also shifted the effect estimates towards the null (adjustment for 2-year wait time: reported HR: 0.57 vs. bias-adjusted HR: 0.81)., Conclusion: Several important sources of bias were identified in non-randomized studies of the effectiveness of bariatric surgery versus non-surgical comparators on mortality. Future studies should ensure that confounding by BMI is accounted for, considering the choice of the comparator group, and that the design or analysis avoids immortal time bias from the misclassification or exclusion., (© 2024 John Wiley & Sons Ltd.)

Introduction: Early in COVID-19, continuing professional development (CPD) providers quickly made decisions about program content, design, funding and technology. Although experiences during an earlier pandemic cautioned providers to make disaster plans, CPD was not entirely prepared for this event. We sought to better understand how CPD organisations make decisions about CPD strategy and operations during a crisis., Methods: This is a descriptive qualitative research study of decision making in two organisations: CPD at the University of Toronto (UofT) and the US-based Society for Academic Continuing Medical Education (SACME). In March 2021, using purposive and snowball sampling, we invited faculty and staff who held leadership positions to participate in semi-structured interviews. The interview focused on the individual's role and organisation, their decision-making process and reflections on how their units had changed because of COVID-19. Transcripts were reviewed, coded and analysed using thematic analysis. We used Mazmanian et al.'s Ecological Framework as a further conceptual tool., Results: We conducted eight interviews from UofT and five from SACME. We identified that decision making during the pandemic occurred over four phases of reactions and impact from COVID-19, including shutdown, pivot, transition and the 'new reality'. The decision-making ability of CPD organisations changed throughout the pandemic, ranging from having little or no independent decision-making ability early on to having considerable control over choosing appropriate pathways forward. Decision making was strongly influenced by the creativity, adaptability and flexibility of the CPD community and the need for social connection., Conclusions: This adds to literature on the changes CPD organisations faced due to COVID-19, emphasising CPD organisations' adaptability in making decisions. Applying the Ecological Framework further demonstrates the importance of time to decision-making processes and the relational aspect of CPD. To face future crises, CPD will need to embrace creative, flexible and socially connected solutions. Future scholarship could explore an organisation's ability to rapidly adapt to better prepare for future crises., (© 2023 The Authors. Medical Education published by Association for the Study of Medical Education and John Wiley & Sons Ltd.)

Background Many patients with cirrhosis have concurrent nonvalvular atrial fibrillation (NVAF). Data are lacking regarding recent oral anticoagulant (OAC) usage trends among US patients with cirrhosis and NVAF. Methods and Results Using MarketScan claims data (2012-2019), we identified patients with cirrhosis and NVAF eligible for OACs (CHA 2 DS 2 -VASc score ≥2 [men] or ≥3 [women]). We calculated the yearly proportion of patients prescribed a direct OAC (DOAC), warfarin, or no OAC. We stratified by high-risk features (decompensated cirrhosis, thrombocytopenia, coagulopathy, chronic kidney disease, or end-stage renal disease). Among 32 487 patients (mean age=71.6 years, 38.5% women, 15.1% with decompensated cirrhosis, mean CHA 2 DS 2 -VASc=4.2), 44.6% used OACs within 180 days of NVAF diagnosis, including DOACs (20.2%) or warfarin (24.4%). Compared with OAC nonusers, OAC users were less likely to have decompensated cirrhosis (18.6% versus 10.7%), thrombocytopenia (19.5% versus 12.5%), or chronic kidney disease/end-stage renal disease (15.5% versus 14.0%). Between 2012 and 2019, warfarin use decreased by 21.0% (32.0% to 11.0%), whereas DOAC use increased by 30.6% (7.4% to 38.0%), and among all DOACs between 2012 and 2019, apixaban was the most commonly prescribed (46.1%). Warfarin use decreased and DOAC use increased in all subgroups, including in compensated and decompensated cirrhosis, thrombocytopenia, coagulopathy, chronic kidney disease/end-stage renal disease, and across CHA 2 DS 2 -VASc categories. Among OAC users (2012-2019), DOAC use increased by 58.9% (18.7% to 77.6%). Among DOAC users, the greatest proportional increase was with apixaban (61.2%; P <0.001). Conclusions Among US patients with cirrhosis and NVAF, DOAC use has increased substantially and surpassed warfarin, including in decompensated cirrhosis. Nevertheless, >55% of patients remain untreated, underscoring the need for clearer treatment guidance.

Aim: To investigate effectiveness and safety outcomes among patients with type 2 diabetes (T2D) initiating empagliflozin versus dipeptidyl peptidase-4 (DPP-4) inhibitor treatment across the broad spectrum of cardiovascular risk., Methods: In a population-based cohort study we identified 39 072 pairs of 1:1 propensity score-matched adult patients with T2D initiating empagliflozin or DPP-4 inhibitors, using data from 2 US commercial insurance databases and Medicare between August 2014 and September 2017. The primary outcomes were a composite of myocardial infarction (MI)/stroke, and hospitalization for heart failure (HHF). Safety outcomes were bone fractures, lower-limb amputations (LLAs), diabetic ketoacidosis (DKA), and acute kidney injury (AKI). We estimated pooled hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for more than 140 baseline covariates., Results: Study participants had a mean age of 60 years and only 28% had established cardiovascular disease. Compared to DPP-4 inhibitors, empagliflozin was associated with similar risk of MI/stroke (HR 0.99 [95% CI 0.81-1.21]), and lower risk of HHF (HR 0.48 [95% CI 0.35-0.67] and 0.63 [95% CI 0.54-0.74], based on a primary and any heart failure discharge diagnosis, respectively). The HR was 0.52 (95% CI 0.38-0.72) for all-cause mortality (ACM) and 0.83 (95% CI 0.70-0.98) for a composite of MI/stroke/ACM. Empagliflozin was associated with a similar risk of LLA and fractures, an increased risk of DKA (HR 1.71 [95% CI 1.08-2.71]) and a decreased risk of AKI (HR 0.60 [95% CI 0.43-0.85])., Conclusions: In clinical practice, the initiation of empagliflozin versus a DPP-4 inhibitor was associated with a lower risk of HHF, ACM and MI/stroke/ACM, a similar risk of MI/stroke, and a safety profile consistent with documented information., (© 2021 John Wiley & Sons Ltd.)

Aim: To determine whether body mass index (BMI) can be accurately identified in epidemiological studies using claims databases., Materials and Methods: Using the Mass General Brigham Research Patient Data Repository-Medicare-linked database, we identified a cohort of patients with a BMI measurement for the periods January 1 to June 31, 2014 or January 1 to June 31, 2016, to capture both the International Classification of Disease (ICD)-9 and ICD-10 eras. Patients were divided into two groups, with or without an obesity-related ICD code in the 6 months before or after the BMI measurement date. We created two binary measures, first for composite overweight, obesity, or severe obesity (BMI ≥25 kg/m 2 ), and second for obesity or severe obesity (BMI ≥30 kg/m 2 ). We calculated accuracy measures (sensitivity, specificity, positive predictive value [PPV] and negative predictive value [NPV]) for each obesity category for the overall cohort, and stratified by type 2 diabetes and ICD-code era., Results: The cohort included 73 644 patients with a BMI measurement in 2014 or 2016, of whom 16 280 had an obesity-related ICD code. The specificity of obesity-related ICD codes (ICD-9 and ICD-10) was 99.7% for underweight/normal weight, 97.4% for overweight, 99.7% for obese and 98.9% for severely obese. For binary categories capturing BMI ≥25 kg/m 2 and BMI ≥30 kg/m 2 , specificity was 97.0% and 98.2%, and PPV was 86.9% and 97.3%. Sensitivity was low overall (<40%). Codes for patients with type 2 diabetes and codes in the ICD-10 era had higher sensitivity, PPV and NPV., Conclusion: Obesity-related ICD codes can accurately identify patients with obesity in epidemiological studies using claims databases., (© 2021 John Wiley & Sons Ltd.)

Aims: To determine whether adiposity modified the effect on the cardiovascular safety of sulphonylureas as a first-line therapy compared with metformin among patients with type 2 diabetes., Materials and Methods: Using the UK Clinical Practice Research Datalink, we conducted a cohort study among 13 862 new sulphonylurea users matched on body mass index (BMI) and propensity score, in a 1:1 ratio, to new metformin users between April 1, 1998 and December 31, 2016. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of major adverse cardiovascular events (MACE), individual components of MACE (myocardial infarction [MI], ischaemic stroke, cardiovascular mortality), and all-cause mortality, comparing use of sulphonylureas with use of metformin, overall and within BMI categories (≤24.9 kg/m 2 , 25.0-29.9 kg/m 2 , ≥30 kg/m 2 )., Results: Compared with metformin, sulphonylureas were not associated with an increased risk of MACE either overall (HR 1.08, 95% CI 0.94-1.23) or by BMI category. Similar findings were observed for MI and ischaemic stroke. By contrast, sulphonylureas were associated with an increased risk of cardiovascular mortality (HR 1.24, 95% CI 1.04-1.48), primarily among obese patients (HR 1.52, 95% CI 1.08-2.13), and not among normal-weight patients (HR 1.00, 95% CI 0.72-1.39; P-interaction 0.21). Similar results were observed for all-cause mortality (HR 1.47, 95% CI 1.32-1.62), where an increased risk was observed among obese patients (HR 1.83, 95% CI 1.49-2.25), but not normal-weight patients (HR 1.18, 95% CI 0.99-1.42; P-interaction: 0.006)., Conclusion: The findings of this study suggest that adiposity may have a modifying effect on the association between sulphonylureas and cardiovascular and all-cause mortality compared with metformin., (© 2021 John Wiley & Sons Ltd.)

Aim: To assess the effectiveness and safety of sodium-glucose cotransporter-2 (SGLT2) inhibitors in treatment-naïve patients compared with metformin., Participants and Methods: We conducted a cohort study of US adults with type 2 diabetes mellitus who had not filled a prescription for a diabetes medication in the preceding year. We then identified patients who newly filled a prescription for an SGLT2 inhibitor or metformin between 2013 and 2018. The primary outcome was a composite of heart failure, myocardial infarction or stroke. Safety outcomes included hypoglycaemia, diabetic ketoacidosis, genital infection, lactic acidosis and acute kidney injury. After 1:1 propensity-score (PS) matching, proportional hazards models were fit to estimate hazard ratios (HRs) with 95% confidence intervals (CIs)., Results: We identified 9964 individuals newly prescribed an SGLT2 inhibitor who were PS-matched to 9964 individuals newly prescribed metformin. The mean age was 54 years, 52% were women, and the duration of follow-up was 213 days for metformin and 147 days for SGLT2 inhibitors. The primary outcome occurred in 54 patients (7.2 events per 1000 person-years) who received an SGLT2 inhibitor, compared to 84 patients (8.5 per 1000 person-years) who received metformin (HR  0.82, 95% CI 0.58, 1.15). Similar results (HR 0.87, 95% CI 0.69, 1.09) were observed in an analysis with longer follow-up (ie, approximately 600 days). The rates of genital infection (HR 2.28, 95% CI 1.87, 2.78) and diabetic ketoacidosis (HR 1.58, 95% CI 0.92, 2.70) were higher for patients prescribed an SGLT2 inhibitor compared to metformin, while the rates of acute kidney injury (HR 0.94, 95% CI 0.60, 1.47) or hypoglycaemia (HR 0.83, 95% CI 0.48, 1.42) were not., Conclusions: We observed a numerically lower rate of short-/mid-term cardiovascular events for patients newly prescribed an SGLT2 inhibitor compared to metformin, albeit with wide CIs that include the possibility of a null effect. SGLT2 inhibitors were associated with a higher rate of genital infection and diabetic ketoacidosis. Larger cohort studies and long-term clinical trials powered to assess cardiovascular events are necessary to understand the risk-benefit profile of SGLT2 inhibitors as first-line therapy for adults with type 2 diabetes mellitus., (© 2021 John Wiley & Sons Ltd.)

Aim: To reproduce and correct studies on bariatric surgery and the reduction in major adverse cardiovascular events (MACE) among patients with obesity and type 2 diabetes (T2D)., Methods: We used electronic healthcare records (EHR) from in and outpatient facilities around the United States to identify a cohort of patients with T2D, aged 18 to 80 years and with a body mass index (BMI) of 30 kg/m 2 or higher undergoing bariatric surgery. We compared against hip/knee arthroplasty to establish an active comparison group that reduced bias from differential information and confounding. The main outcome was six-point MACE. Pre-exposure characteristics were adjusted in propensity score (PS) models with 1:2 matching plus high-dimensional PS matching., Results: After a range of exclusions, the final cohort included 344 bariatric surgery patients (65% female; mean age 58 years) and 551 PS-matched patients undergoing arthroplasty (65% female; 59 years). Median follow-up was 2.5 years in both groups. Bariatric surgery patients showed a sustained 20% weight reduction and an HbA1c reduction by 1% point. We found no benefits of bariatric surgery for six-point MACE (HR = 0.99; 95% CI 0.76-1.30). We observed known increases in risks for vitamin B 12 deficiency anaemia (HR = 3.06; 1.10-8.49) and cholelithiasis (HR = 1.72; 0.94-3.13)., Conclusions: This real-world evidence study found reductions in HbA1c and BMI following bariatric surgery similar to trials, and no meaningful cardiovascular benefit compatible with the underpowered trials but in contrast to earlier EHR studies. We showed how information bias typical in EHR analyses and confounding may cause substantial bias., (© 2021 John Wiley & Sons Ltd.)

Aim: To assess the trends in the prescribing of antiobesity medications and the characteristics of patients recently initiating antiobesity drugs., Materials and Methods: We conducted a population-based cohort study using claims data from commercial health insurances in the United States. Patients initiating an antiobesity drug between January 2004 and December 2018 were included. Trends in the utilization of antiobesity medications were plotted by year, as a proportion of any antiobesity treatment, and as initiation rates per 100 000. Descriptive statistics were used to summarize the characteristics of antiobesity initiators., Results: From 2004 to 2018, 626 216 patients started an antiobesity medication (two per 100 000). Phentermine was the most frequently prescribed (50% in 2018). In recent years (2015-2018), among 227 692 patients who initiated an antiobesity drug, 51% started phentermine, 19% naltrexone-bupropion, and 13% liraglutide 3.0 mg. Compared to other agents, the use of liraglutide 3.0 mg increased between 2015 and 2018. The average age of initiators was 45 years, 81% of initiators were female, 32% had hypertension, 25% had dyslipidaemia, and 6% had type 2 diabetes. Time on treatment was generally short (mean 81 days)., Conclusion: The overall use of antiobesity medications remained low over the past 15 years and phentermine was the preferred antiobesity agent. Although the use of potentially safer antiobesity agents, for example, liraglutide 3.0 mg, has increased in recent years, phentermine remained the most frequently prescribed agent among middle-aged adults with a moderate burden of comorbidities., (© 2021 John Wiley & Sons Ltd.)

Several cohorts have shown that long-term tenofovir-containing combination antiretroviral therapy (cART) leads to higher HBsAg seroclearance rates in HIV/HBV coinfected patients vs HBV-monoinfected patients under tenofovir disoproxil fumarate (TDF)-based therapy. We have analysed data on determinants of HBsAg loss in a retrospective multicentric cohort of 359 HIV/HBV coinfected patients. Median CD4 T-cell count at baseline was 359/ul (321-404), CDC stage was C in 20% (n = 70). Most patients (68%) were ART-naïve when TDF- or tenofovir alafenamide (TAF)-containing cART was initiated (baseline). After a median follow-up of 11 years HBsAg loss had occurred in 66/359 (18%) patients. However, patients with stage CDC C (P ≤ .001), lower CD4 gain (P = .043) and not receiving TDF/FTC (P = .008) were less likely to lose HBsAg. Long-term TDF-containing cART appears to achieve higher rates of HBsAg seroclearance compared to published data for HBV monoinfected subjects. However, late presentation for HIV and poor immune recovery significantly impair HBV seroconversion rates., (© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.)

Transparency of real-world evidence (RWE) studies is critical to understanding how findings of a specific study were derived and is a necessary foundation to assessing validity and determination of whether decisions should be informed by the findings. In the present paper, we lay out strategies to improve clarity in the reporting of comparative effectiveness studies using real-world data that were generated by the routine operation of a healthcare system. This may include claims data, electronic health records, wearable devices, patient-reported outcomes or patient registries. These recommendations were discussed with multiple stakeholders, including regulators, payers, academics and journal editors, and endorsed by two professional societies that focus on RWE. We remind readers interested in diabetes research of the utility of conceptualizing a target trial that is then emulated by a RWE study when planning and communicating about RWE study implementation. We recommend the use of a graphical representation showcasing temporality of key longitudinal study design choices. We highlight study elements that should be reported to provide the clarity necessary to make a study reproducible. Finally, we suggest registering study protocols to increase process transparency. With these tools the readership of diabetes RWE studies will be able to more efficiently understand each study and be more able to assess a study's validity with reasonably high confidence before making decisions based on its findings., (© 2019 John Wiley & Sons Ltd.)

Cases of a rare but serious infection called Fournier's gangrene have been reported with sodium-glucose co-transporter-2 inhibitors (SGLT-2i). To evaluate the safety signal in a population of patients with type 2 diabetes, we used administrative claims data from Horizon Blue Cross Blue Shield of New Jersey from 2014 through 2017 to estimate incidence rates of Fournier's gangrene or necrotizing fasciitis of the perineum among patients treated with a second-line antidiabetic drug. We found very low incidence rates of Fournier's gangrene or necrotizing fasciitis. While we found no indication of an increased risk among SGLT-2i users compared with similar patients treated with other second-line antidiabetic medications, the small number of events yielded wide confidence intervals., (© 2019 John Wiley & Sons Ltd.)

Aim: To evaluate the safety of linagliptin versus other glucose-lowering medications in a multi-year monitoring programme using insurance claims data., Methods: In two commercial US claims databases, we identified three pairwise 1:1 propensity-score (PS)-matched cohorts of patients with type 2 diabetes (T2D) aged ≥18 years initiating linagliptin or a comparator (other dipeptidyl peptidase-4 [DPP-4] inhibitors [n = 31 492 pairs], pioglitazone [n = 23 316 pairs], or second-generation sulphonylureas [n = 19 731 pairs]) between May 2011 and December 2015. The primary endpoint was the risk of a composite cardiovascular (CV) outcome (hospitalization for myocardial infarction, stroke, unstable angina, or coronary revascularization). We estimated pooled hazard ratios (HRs) and 95% confidence intervals (CIs), controlling for >100 baseline characteristics., Results: Patient characteristics were well balanced after PS-matching. The mean age was 55 years and mean follow-up was 0.8 years. Linagliptin conferred a similar risk of the composite CV outcome compared to other DPP-4 inhibitors (HR 0.91, 95% CI 0.79-1.05) and pioglitazone (HR 0.98, 95% CI 0.84-1.15), and showed a reduced risk of CV outcomes compared to second-generation sulphonylureas (HR 0.76, 95% CI 0.64--0.92). Key findings were signalled at the first interim analysis in June 2013 and solidified during ongoing monitoring until 2015., Conclusion: Analyses from a large monitoring programme in routine care of patients with T2D, showed that linagliptin had similar CV safety compared to other DPP-4 inhibitors and pioglitazone, and a reduced CV risk compared to sulphonylureas., (© 2019 John Wiley & Sons Ltd.)

The extent to which sodium-glucose co-transporter-2 (SGLT2) inhibitors increase the risk of genital infections in routine clinical care, compared with other antidiabetic medications, is not clear, or whether the increased risk is consistent across gender or age subgroups, within individual SGLT2 agents, or if it is more pronounced at a particular time after treatment initiation. We conducted a retrospective cohort study using two US commercial claims databases (2013-2017). In the primary analysis, 1:1 propensity score-matched cohorts of female and male subjects with type 2 diabetes mellitus initiating SGLT2 versus dipeptidyl peptidase-4 inhibitors were created. The outcome was a composite of genital candidal infections, vaginitis or vulvovaginitis in women, and genital candidal infections, balanitis, balanoposthitis, phimosis or paraphimosis in men. Among propensity score-matched cohorts of 129 994 women and 156 074 men, the adjusted hazard ratio (HR) and excess risk per 1000 person-years for SGLT2 versus DPP-4 inhibitors was 2.81 (95% confidence interval [CI], 2.64, 2.99) and 87.4 (95% CI, 79.1, 96.2) respectively for women, and was 2.68 (95% CI, 2.31, 3.11) and 11.9 (95% CI, 9.3-15.0) for men. Findings were similar in the SGLT2 inhibitor versus GLP-1 agonist comparison, more pronounced in the subgroup of patients aged ≥60 (HR, 4.45 [95% CI, 3.83-5.17] in women and 3.30 [95% CI, 2.56-4.25] in men), and no meaningful difference across individual SGLT2 inhibitors was identified. This increase in risk was evident in the first month of treatment initiation and remained elevated throughout the course of therapy. SGLT2 inhibitors were associated with an approximately 3-fold increase in risk of genital infections., (© 2018 John Wiley & Sons Ltd.)

Aim: To evaluate the extent to which balance in unmeasured characteristics of patients with type 2 diabetes (T2DM) was achieved in claims data, by comparing against more detailed information from linked electronic health records (EHR) data., Methods: Within a large US commercial insurance database and using a cohort design, we identified patients with T2DM initiating linagliptin or a comparator agent within class (ie, another dipeptidyl peptidase-4 inhibitor) or outside class (ie, pioglitazone or a sulphonylurea) between May 2011 and December 2012. We focused on comparators used at a similar stage of diabetes to linagliptin. For each comparison, 1:1 propensity score (PS) matching was used to balance >100 baseline claims-based characteristics, including proxies of diabetes severity and duration. Additional clinical data from EHR were available for a subset of patients. We assessed representativeness of the claims-EHR-linked subset, evaluated the balance of claims- and EHR-based covariates before and after PS-matching via standardized differences (SDs), and quantified the potential bias associated with observed imbalances., Results: From a claims-based study population of 166 613 patients with T2DM, 7219 (4.3%) patients were linked to their EHR data. Claims-based characteristics in the EHR-linked and EHR-unlinked patients were similar (SD < 0.1), confirming the representativeness of the EHR-linked subset. The balance of claims-based and EHR-based patient characteristics appeared to be reasonable before PS-matching and generally improved in the PS-matched population, to be SD < 0.1 for most patient characteristics and SD < 0.2 for select laboratory results and body mass index categories, which was not large enough to cause meaningful confounding., Conclusion: In the context of pharmacoepidemiological research on diabetes therapy, choosing appropriate comparison groups paired with a new-user design and 1:1 PS matching on many proxies of diabetes severity and duration improves balance in covariates typically unmeasured in administrative claims datasets, to the extent that residual confounding is unlikely., (© 2017 John Wiley & Sons Ltd.)

Background: Real-time monitoring is used to the ends of postmarketing observational research on newly marketed drugs. We implemented a pilot near-real-time monitoring program on the test case of oral anticoagulants. Specifically, we evaluated the safety and effectiveness of direct oral anticoagulants compared to vitamin K antagonists in nonvalvular atrial fibrillation secondary prevention during 2013-2015 in the Lazio Region, Italy., Methods and Results: A cohort study was conducted using a sequential propensity-score-matched new user parallel-cohort design. Sequential analyses were performed using Cox models. Overall, 10 742 patients contributed to the analyses. Compared with vitamin K antagonists, direct oral anticoagulant use was associated with a reduction of all-cause mortality (0.81; 95% confidence interval [CI] 0.66-0.99), cardiovascular mortality (0.71; 95% CI 0.54-0.93), myocardial infarction (0.67; 95% CI 0.43-1.04), ischemic stroke (0.87; 95% CI 0.52-1.45), hemorrhagic stroke (0.25; 95% CI 0.07-0.88), and with a nonsignificant increase of gastrointestinal bleeding (1.26; 95% CI 0.69-2.30)., Conclusions: The present pilot study is a cornerstone to develop real-time monitoring for new drugs in our region., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Time in the therapeutic range (TTR) is associated with the effectiveness and safety of vitamin K antagonist (VKA) therapy. To optimize prescribing of VKA, we aimed to develop and validate a prediction model for TTR in older adults taking VKA for nonvalvular atrial fibrillation and venous thromboembolism., Methods and Results: The study cohort comprised patients aged ≥65 years who were taking VKA for atrial fibrillation or venous thromboembolism and who were identified in the 2 US electronic health record databases linked with Medicare claims data from 2007 through 2014. With the predictors identified from a systematic review and clinical knowledge, we built a prediction model for TTR, using one electronic health record system as the training set and the other as the validation set. We compared the performance of the new models to that of a published prediction score for TTR, SAMe-TT 2 R 2 . Based on 1663 patients in the training set and 1181 in the validation set, our optimized score included 42 variables and the simplified model included 7 variables, abbreviated as PROSPER (Pneumonia, Renal dysfunction, Oozing blood [prior bleeding], Staying in hospital ≥7 days, Pain medication use, no Enhanced [structured] anticoagulation services, Rx for antibiotics). The PROSPER score outperformed SAMe-TT 2 R 2 when predicting both TTR ≥70% (area under the receiver operating characteristic curve 0.67 versus 0.55) and the thromboembolic and bleeding outcomes (area under the receiver operating characteristic curve 0.62 versus 0.52)., Conclusions: Our geriatric TTR score can be used as a clinical decision aid to select appropriate candidates to receive VKA therapy and as a research tool to address confounding and treatment effect heterogeneity by anticoagulation quality., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Older-generation anticonvulsants that highly induce cytochrome P450 enzyme system activity produce metabolic abnormalities that may increase cardiovascular risk. The objective of this study was to evaluate the risk of ischemic cerebrovascular and coronary events in adult new users of anticonvulsants that highly induce cytochrome P450 activity compared with other anticonvulsant agents, as observed in a routine care setting., Methods and Results: This was a cohort study of patients 40 to 64 years old from the HealthCore Integrated Research Database who had initiated an anticonvulsant medication between 2001 and 2006 and had no recorded major coronary or cerebrovascular condition in the 6 months before treatment initiation. Propensity score (PS) matching was used to evaluate ischemic cerebrovascular and coronary risk among anticonvulsant new users. High-dimensional propensity score (hdPS)-matched analyses were used to confirm adjusted findings. The study identified 913 events in 166 031 unmatched new treatment episodes with anticonvulsant drugs. In a PS-matched population of 22 864 treatment episodes, the rate ratio (RR) for ischemic coronary or cerebrovascular events associated with highly inducing agents versus other agents was 1.22 (95% CI, 0.90-1.65). The RR moved to 0.99 (95% CI, 0.73-1.33) with adjustment for hdPS matching (RR, 1.47; 95% CI, 0.95-2.28 for cerebrovascular events; RR, 0.70; 95% CI, 0.47-1.05 for coronary events)., Conclusions: In this exploratory analysis, there was no evidence of a consistent and statistically significant effect of initiating anticonvulsants that highly induce cytochrome P450 activity on ischemic coronary or cerebrovascular outcomes compared with other agents, given routine care utilization patterns.

Objective: Previous study findings have suggested that patients with chronic diseases such as rheumatoid arthritis (RA) do not receive optimal preventive medical services, including cancer screening tests. This study was undertaken to evaluate cancer screening rates in RA patients compared to non-RA control populations., Methods: Using data from a large US commercial insurance plan, we examined rates of screening tests for cervical, breast, and colon cancer in patients with RA compared to control subjects without RA (non-RA controls) or control subjects with hypertension. Individuals were included in the RA cohort if they had at least 2 visits coded for a diagnosis of RA and had received at least 1 prescription for a disease-modifying antirheumatic drug during the study period. Multivariable Cox proportional hazards models were used to compare the rates of different cancer screening tests between RA patients and non-RA controls., Results: RA patients (n = 13,314) and control subjects (non-RA and hypertension controls) (n = 212,324) were screened, on average, once every 3 years for cervical cancer and once every 2 years for breast cancer during the followup period (mean 2.3 years of followup). In the age-adjusted Cox regression model, women with RA were more likely to receive ≥ 1 Papanicolaou smear (hazard ratio [HR] 1.21, 95% confidence interval [95% CI] 1.17-1.24), ≥ 1 mammogram (HR 1.49, 95% CI 1.45-1.53), and ≥ 1 colonoscopy (HR 1.69, 95% CI 1.61-1.77) compared to female non-RA control subjects. Men with RA were also more likely to receive at least 1 colonoscopy (HR 1.52, 95% CI 1.40-1.64) than were male non-RA control subjects. These results were robust in multivariable analyses adjusted for age, number of physician visits, percentage of visits made to primary care physicians, and the Charlson Comorbidity Index., Conclusion: Patients with RA did not appear to be at risk for receiving fewer cancer screening tests when compared to individuals without RA. The majority of both RA patients and non-RA control subjects were screened regularly for cervical, breast, and colon cancer, in accordance with current recommendations., (Copyright © 2012 by the American College of Rheumatology.)

Objective: The risk of cardiovascular disease (CVD) is increased in patients with rheumatoid arthritis (RA), most likely because of increased systemic inflammation. Prior research suggests that immunosuppressive medications may reduce the risk of CVD among RA patients. This study was undertaken to investigate the effects of various immunosuppressive medications on the risk of cardiovascular events among a group of older patients with RA., Methods: In this nested case-control study, the source cohort was derived from Medicare beneficiaries receiving a drug benefit from the state of Pennsylvania. These individuals were required to have been diagnosed as having RA on at least 2 visits and to have filled a prescription for an immunosuppressive agent. Cases were defined as those patients who were hospitalized for a cardiovascular event such as myocardial infarction or stroke, and 10 control subjects were matched to each case by age, sex, and calendar year of the index date (the time of the first cardiovascular event in each case). Current use of an immunosuppressive medication was defined as having filled a prescription for these agents within the 90 days prior to the index date. Multivariate logistic regression models that included important covariates were assessed to determine the risk of cardiovascular events associated with immunosuppressive agents and their combinations., Results: Among the study cohort, we identified 3,501 RA patients who fulfilled our eligibility criteria. During followup of this cohort, 946 patients were hospitalized for a cardiovascular event. Although the 95% confidence intervals (95% CIs) were wide in adjusted risk regression models with methotrexate (MTX) monotherapy as the reference group, biologic immunosuppressive agents showed neither protective nor deleterious effects (with biologics monotherapy, odds ratio [OR] 1.0, 95% CI 0.5-1.9; with biologics plus MTX combination therapy, OR 0.8, 95% CI 0.3-2.0; and with biologics plus other immunosuppressive agents, OR 1.2, 95% CI 0.7-2.2). Monotherapy with oral glucocorticoids was associated with an increased risk of cardiovascular events (OR 1.5, 95% CI 1.1-2.1), and a similar trend in the direction of risk was seen with glucocorticoid combination therapy (OR 1.3, 95% CI 0.8-2.0). Cytotoxic immunosuppressive agents other than MTX (azathioprine, cyclosporine, and leflunomide) were also associated with an increased risk of cardiovascular events (with both monotherapy and combination treatment, OR 1.8, 95% CI 1.1-3.0)., Conclusion: When compared with RA patients receiving MTX monotherapy, those receiving biologic immunosuppressive agents had neither an increased nor decreased risk of experiencing a cardiovascular event, whereas use of oral glucocorticoids and cytotoxic immunosuppressive agents was associated with significant increases in the risk of cardiovascular events.