Five-year survival prognosis of young, middle-aged, and elderly adult female invasive breast cancer patients by clinical and lifestyle characteristics.

PURPOSE: Early-onset breast cancer incidence has been increasing globally and in Taiwan. However, previous studies have not comprehensively examined how clinical and lifestyle characteristics influence the 5-year survival of breast cancer diagnosed at different stages of adulthood. METHODS: We analyzed the Taiwan National Cancer Registry and Cause of Death datasets to understand how clinical factors (including tumor and treatment characteristics) and lifestyle factors (including body mass index, cigarette smoking, and alcohol consumption) were associated with the 5-year survival of 8471 young, 57,695 middle-aged, and 14,074 elderly female adult invasive breast cancer patients respectively diagnosed at age 20-39, 40-64, and ≥ 65 years between 2002 and 2015, with mortality follow-up to 2020. Poisson regression was used for obtaining the crude and adjusted 5-year survival risk ratios. RESULTS: Clinical and lifestyle characteristics were distributed differently but had mostly similar direction of association with 5-year survival for the three age groups. Receiving any treatment was associated with better survival, especially for elderly patients. Being underweight at initial cancer treatment was associated with worse survival than having normal weight, especially for elderly patients. Current smokers had worse survival than never smokers for middle-aged and elderly patients. The 5-year breast cancer-specific survival was not significantly higher for those of age 45-49 years than 40-44 years, despite the recommended starting screening age is 45 years in Taiwan. CONCLUSION: Our findings contribute to the understanding of early-onset and later-onset female breast cancer characteristics and prognosis, which may inform surveillance and treatment strategies to achieve better breast cancer prognosis.

Risk of circulatory diseases associated with proton-pump inhibitors: a retrospective cohort study using electronic medical records in Thailand.

Background: Proton-pump inhibitors (PPIs) are prescribed to treat gastric acid-related diseases, while they may also have potential risks to population health. Recent studies suggested that a potential mechanism explaining the association between PPIs and cardiovascular diseases (CVD) includes the inhibition of the nitrate-nitrite-nitric oxide (NO) pathway. However, previous observational studies showed controversial results of the association. In addition, the inhibition of the NO pathway due to PPIs use may lead to peripheral vascular diseases (PVD); however, none of the studies explore the PPI-PVD association. Therefore, this study aimed to evaluate the association of PPIs with circulatory diseases (CVD, ischemic strokes or IS, and PVD). Methods: We conducted a retrospective hospital-based cohort study from Oct 2010 to Sep 2017 in Songkhla province, Thailand. PPIs and histamine 2-receptor antagonists (H2RAs) prescriptions were collected from electronic pharmacy records, while diagnostic outcomes were retrieved from electronic medical records at Songklanagarind hospital. Patients were followed up with an on-treatment approach. Cox proportional hazard models were applied to measure the association comparing PPIs vs H2RAs after 1:1 propensity-score-matching. Sub-group analysis, multi-bias E-values, and array-based sensitivity analysis for some covariates were used to assess the robustness of associations. Results: A total of 3,928 new PPIs and 3,928 H2RAs users were included in the 1:1 propensity score-matched cohort. As compared with H2RAs, the association of PPIs with CVD, IS, and PVD, the hazard ratios were 1.76 95% CI = [1.40-2.20] for CVD, 3.53 95% CI = [2.21-5.64] for ischemic strokes, and 17.07 95% CI = [13.82-76.25] for PVD. The association between PPIs and each outcome was significant with medication persistent ratio of over 50%. In addition, the association between PPIs and circulatory diseases was robust to unmeasured confounders (i.e., smoking and alcohol). Conclusion: PPIs were associated with circulatory diseases, particularly ischemic strokes in this hospital-based cohort study, whereas, the strength of associations was robust to unmeasured confounders.

Association Between Use of Fluoroquinolones and Risk of Mitral or Aortic Valve Regurgitation: A Nationwide Cohort Study.

Biological plausibility suggests that fluoroquinolones may lead to mitral valve regurgitation or aortic valve regurgitation (MR/AR) through a collagen degradation pathway. However, available real-world studies were limited and yielded inconsistent findings. We estimated the risk of MR/AR associated with fluoroquinolones compared with other antibiotics with similar indications in a population-based cohort study. We identified adult patients who initiated fluoroquinolones or comparison antibiotics from the nationwide Taiwanese claims database. Patients were followed for up to 60 days after cohort entry. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of MR/AR comparing fluoroquinolones to comparison antibiotics after 1:1 propensity score (PS) matching. All analyses were conducted by type of fluoroquinolone (fluoroquinolones as a class, respiratory fluoroquinolones, and non-respiratory fluoroquinolones) and comparison antibiotic (amoxicillin/clavulanate or ampicillin/sulbactam, extended-spectrum cephalosporins). Among 6,649,284 eligible patients, the crude incidence rates of MR/AR ranged from 1.44 to 4.99 per 1,000 person-years across different types of fluoroquinolones and comparison antibiotics. However, fluoroquinolone use was not associated with an increased risk in each pairwise PS-matched comparison. HRs were 1.00 (95% CI, 0.89-1.11) for fluoroquinolones as a class, 0.96 (95% CI, 0.83-1.12) for respiratory fluoroquinolones, and 0.87 (95% CI, 0.75-1.01) for non-respiratory fluoroquinolones, compared with amoxicillin/clavulanate or ampicillin/sulbactam. Results were similar when fluoroquinolones were compared with extended-spectrum cephalosporins (HRs of 0.96, 95% CI, 0.82-1.12, HR, 1.05, 95% CI, 0.86-1.28, and HR, 0.88, 95% CI, 0.75-1.03, respectively). This large-scale cohort study did not find a higher risk of MR/AR with different types of fluoroquinolones in the adult population.

Comparative cardiovascular safety of LABA/LAMA FDC versus LABA/ICS FDC in patients with chronic obstructive pulmonary disease: a population-based cohort study with a target trial emulation framework.

BACKGROUND: Use of combinations of long-acting ß2 agonists/long-acting muscarinic antagonists (LABA/LAMA) in patients with chronic obstructive pulmonary disease (COPD) is increasing. Nevertheless, existing evidence on cardiovascular risk associated with LABA/LAMA versus another dual combination, LABA/inhaled corticosteroids (ICS), was limited and discrepant. AIM: The present cohort study aimed to examine comparative cardiovascular safety of LABA/LAMA and LABA/ICS with a target trial emulation framework, focusing on dual fixed-dose combination (FDC) therapies. METHODS: We identified patients with COPD who initiated LABA/LAMA FDC or LABA/ICS FDC from a nationwide Taiwanese database during 2017-2020. The outcome of interest was a hospitalized composite cardiovascular events of acute myocardial infarction, unstable angina, heart failure, cardiac dysrhythmia, and ischemic stroke. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for composite and individual cardiovascular events after matching up to five LABA/LAMA FDC initiators to one LABA/ICS FDC initiator using propensity scores (PS). RESULTS: Among 75,926 PS-matched patients, use of LABA/LAMA FDC did not show a higher cardiovascular risk compared to use of LABA/ICS FDC, with a HR of 0.89 (95% CI, 0.78-1.01) for the composite events, 0.80 (95% CI, 0.61-1.05) for acute myocardial infarction, 1.48 (95% CI, 0.68-3.25) for unstable angina, 1.00 (95% CI, 0.80-1.24) for congestive heart failure, 0.62 (95% CI, 0.37-1.05) for cardiac dysrhythmia, and 0.82 (95% CI, 0.66-1.02) for ischemic stroke. The results did not vary substantially in several pre-specified sensitivity and subgroup analyses. CONCLUSION: Our findings provide important reassurance about comparative cardiovascular safety of LABA/LAMA FDC treatment among patients with COPD.

Prescription Patterns of New Use of Fixed-Dose Combination Inhalers in Patients with Chronic Obstructive Pulmonary Disease: Long-Acting ß2 Agonists Plus Long-Acting Muscarinic Antagonists versus Long-Acting ß2 Agonists Plus Inhaled Corticosteroids.

Background: The clinical guideline recommends use of long-acting ß2 agonists/long-acting muscarinic antagonists (LABA/LAMA) or long-acting ß2 agonists/inhaled corticosteroids (LABA/ICS) combination therapies for patients with severe chronic obstructive pulmonary disease (COPD). The fixed-dose combination (FDC) inhalers of LABA/LAMA and LABA/ICS were reimbursed in Taiwan in 2015 and in 2002, respectively. This study aimed to examine prescription patterns of new use of either FDC therapy in real-world practice. Methods: We identified COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC between 2015 and 2018 from a population-based Taiwanese database with 2 million, randomly sampled beneficiaries enrolled in a single-payer health insurance system. We compared number of LABA/LAMA FDC and LABA/ICS FDC initiators in each calendar year, from different hospital accreditation levels, and cared for by different physician specialties. We also compared baseline patient characteristics between LABA/LAMA FDC and LABA/ICS FDC initiators. Results: A total of 12,455 COPD patients who initiated LABA/LAMA FDC (n=4019) or LABA/ICS FDC (n=8436) were included. Number of LABA/LAMA FDC initiators increased apparently (n=336 in 2015 versus n=1436 in 2018), but number of LABA/ICS FDC initiators decreased obviously (n=2416 in 2015 versus n=1793 in 2018) over time. The preference of use of LABA/LAMA FDC varied across clinical environments. The proportions of LABA/LAMA FDC initiators were more than 30% in the setting of non-primary care clinics (eg, medical centers) and in the services of chest physicians; but were only less than 10% in primary care clinics and non-chest physicians' services (eg, family medicine physicians). LABA/LAMA FDC initiators appeared to be older, male, to have more comorbidities, and to utilize resources more frequently compared to LABA/ICS FDC initiators. Conclusion: This real-world study found evident temporal trends, variations in healthcare provider, and differences in patient characteristics among COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC.

Risk of major adverse limb events in patients with type 2 diabetes mellitus receiving sodium glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists: A population-based retrospective cohort study.

Background: Both sodium glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular protective effects in patients with type 2 diabetes mellitus. However, the comparative risk of GLP-1RA versus SGLT-2i for major adverse limb events remains unknown. Materials and methods: We studied a nationwide cohort involving 123,048 diabetes patients 20-100 years of age who initiated a SGLT-2i or GLP-1RA during 2012 and 2017. The patients in the two groups were matched by propensity score (PS), and incidence rates for hospitalization for major adverse limb events, critical limb ischemia (CLI) and lower extremity amputation (LEA), were assessed. Cox proportional hazards regression was applied to estimate hazard ratios (HRs) between patients receiving SGLT-2i as compared with GLP-1RA. The modification effects of age, a history of established cardiovascular disease, and chronic kidney disease were examined. In addition, use of dipeptidyl peptidase-4 inhibitor (DPP-4i) was chosen as a second active comparator. Results: After PS-matching, a total of 13,378 SGLT-2i and 13,378 GLP-1RA initiators were identified. Use of SGLT-2i was not associated with an increased risk for hospitalization for CLI and LEA, either compared with GLP-1RA (HR, 1.13; 95% CI, 0.77-1.65 and 1.27; 95% CI, 0.63-2.55, respectively) or compared with DPP-4i use (HR, 1.06; 95% CI, 0.75-1.50 and HR, 0.80; 95% CI, 0.42-1.53, respectively). Although the study was underpowered to explore potential effect modification, a trend of higher risks for LEA was noted among SGLT-2i users with cardiovascular disease as compared with either GLP-1RA or DPP-4i. Conclusion: Use of SGLT-2i was not associated with higher risks for hospitalization for CLI and LEA as compared with reference drugs. Further large-scale studies are needed for a precise risk estimation.

Association between glucagon-like peptide-1 receptor agonists and biliary-related diseases in patients with type 2 diabetes: A nationwide cohort study.

STUDY OBJECTIVE: Clinical trials have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may be associated with a higher risk of biliary-related diseases in patients with type 2 diabetes. Limited real-world studies have examined the comparative biliary safety of GLP-1RAs versus other antihyperglycemic drugs. We aimed to estimate the comparative risk of biliary-related diseases between GLP-1RAs and sodium glucose cotransporter 2 inhibitors (SGLT2is), which are indicated for patients with similar diabetes severity in Taiwan. DESIGN: Retrospective cohort study. DATA SOURCE: Taiwan National Health Insurance Database during 2011 to 2018. PATIENTS: Patients with type 2 diabetes who initiated GLP-1RAs or SGLT2is. INTERVENTION: GLP-1RAs versus SGLT2is. MEASUREMENTS AND MAIN RESULTS: We used an on-treatment approach to examine the effect of continuous use and an intention-to-treat approach to assess the effect of initiation of GLP-1RAs versus SGLT2is. We used Coxregression models to estimate the hazard ratios (HRs) and 95% confidenceintervals (CIs) for the composite hospitalized biliary-related diseases, including acute cholecystitis or cholecystectomy, choledocholithiasis, and acute cholangitis, after matching each GLP-1RA initiator to up to 10 SGLT2iinitiators using propensity scores (PSs). Among 78,253 PS-matched patients, GLP-1RA use was associated with a numerically higher risk of biliary-related diseases versus SGLT2i use in the on-treatment analysis, with an HR of 1.20 (95% CI, 0.93-1.56) for the composite outcome, an HR of 1.22 (95% CI, 0.92-1.62) for acute cholecystitis or cholecystectomy, an HR of 1.20 (95% CI, 0.69-2.07) for choledocholithiasis, and an HR of 1.14 (95% CI,0.82-2.42) for acute cholangitis. The HRs were more pronounced in theintention-to-treat analysis (1.27 [95% CI, 1.05-1.53] for the composite outcome, 1.29 [95% CI, 1.04-1.58] foracute cholecystitis or cholecystectomy, 1.74 [95% CI, 1.23-2.46] for choledocholithiasis, and 1.31 [95% CI, 0.89-1.94] for acute cholangitis). The increased risk of the composite outcome associated with GLP-1RAs was more evident in patients aged 〉60 years, women, and 120 days after treatment initiation. Liraglutide, but not dulaglutide, was associated with an elevated risk. CONCLUSIONS: GLP-1RAs might be associated with an elevated risk of biliary-related diseases compared to SGLT2is in Asian patients with type 2 diabetes.

Comparative cardiovascular effectiveness of glucagon-like peptide-1 receptor agonists versus sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes: A population-based cohort study.

AIMS: To examine the comparative effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors for select cardiovascular outcomes and to examine whether the relative risks varied across different patient subgroups in patients with type 2 diabetes. MATERIALS AND METHODS: We conducted a nationwide cohort study of patients with type 2 diabetes who initiated GLP-1RAs or SGLT2 inhibitors between 2012 and 2018 in Taiwan. The study outcomes included myocardial infarction and total stroke, further classified into ischaemic or haemorrhagic stroke. We estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for each outcome, comparing GLP-1RAs with SGLT2 inhibitors using Cox proportional hazards models after 1:1 propensity-score (PS) matching. We also examined if there was effect modification by age, underlying chronic kidney disease, or coexisting cardiovascular disease in prespecified subgroup analyses. RESULTS: Among 26 032 PS-matched patients, GLP-1RA initiators and SGLT2 inhibitor initiators showed similar risks of myocardial infarction (HR 0.99, 95% CI 0.65-1.52), total stroke (HR 0.90, 95% CI 0.69-1.17), ischaemic stroke (HR 0.86, 95% CI 0.65-1.14) and haemorrhagic stroke (HR 0.88, 95% CI 0.63-1.25). However, GLP-1RA treatment was associated with an increased risk of total stroke (HR 1.76, 95% CI 1.06-2.94) and ischaemic stroke (HR 1.88, 95% CI 1.09-3.23) among patients with chronic kidney disease, but not among patients without chronic kidney disease. GLP-1RA therapy seemed to have a lower risk of haemorrhagic stroke among patients with cardiovascular disease (HR 0.64, 95% CI 0.43-0.97), but not in patients without cardiovascular disease. CONCLUSIONS: Glucagon-like peptide-1 receptor agonists and SGLT2 inhibitors appeared to have comparable effectiveness with regard to several cardiovascular outcomes overall, but their comparative effectiveness may vary in certain patient subgroups.

Post-Intracranial Hemorrhage Antithrombotic Therapy in Patients With Atrial Fibrillation.

Background To investigate the effectiveness and safety of withholding or restarting antithrombotic agents, and different antithrombotic therapies among patients with atrial fibrillation post-intracranial hemorrhage. Methods and Results This is a nationwide retrospective cohort study involving patients with atrial fibrillation receiving antithrombotic therapies who subsequently developed intracranial hemorrhage between January 1, 2011 and December 31, 2017. The risk of ischemic stroke (IS), recurrent intracerebral hemorrhage (ICH), and all-cause mortality were investigated between patients receiving no treatment versus patients reinitiating oral anticoagulants (OACs) or antiplatelet agents, and warfarin versus non-vitamin K antagonist OACs. We applied inverse probability of treatment weighting to balance the baseline characteristics and Cox proportional hazards model to estimate the hazard ratios (HRs) of different outcomes of interest. Compared with no treatment, OACs reduced the risk of IS (HR, 0.61; 0.42-0.89), without increase in the risk of ICH (1.15, 0.66-2.02); antiplatelet agent users showed a similar risk of IS (1.13, 0.81-1.56) and increased risk of ICH (1.81, 1.07-3.04). Use of OACs or antiplatelet agents did not reduce the risk of all-cause mortality (0.85, 0.72-1.01; and 0.88, 0.75-1.03, respectively). Compared with warfarin, non-vitamin K antagonist OAC users showed a similar risk of IS (0.92, 0.50-1.70), non-significantly reduced risk of ICH (0.53, 0.22-1.30), and significantly reduced all-cause mortality (0.60, 0.43-0.84). Conclusions OACs are recommended in patients with atrial fibrillation and intracranial hemorrhage because they reduced the risk of IS with no increase in the risk of subsequent ICH. Non-vitamin K antagonist OACs are recommended over warfarin owing to their survival benefits.

Young adult cancer incidence trends in Taiwan and the U.S. from 2002 to 2016.

BACKGROUND: Previous studies have not examined young adult cancer incidence trends in Taiwan, or comprehensively compared these trends at two nations with different population genetics, environmental exposures, and health care. Therefore, we compared the incidence rates and trends of the most common young adult cancers diagnosed at 20-39 years of age in Taiwan and the U.S. METHODS: Incidence rates from 2002 to 2016 were calculated from the Taiwan National Health Insurance Research Datasets and the U.S. Surveillance, Epidemiology, and End Results Program. For trend assessment, average annual percent change (AAPC) values were calculated from 15 years of data using Joinpoint Regression Program. We also obtained sex or age of diagnosis stratified estimates. RESULTS: The age-standardized overall young adult cancer incidence rate significantly increased from 2002 to 2016 in both Taiwan (AAPC=1.1%, 95% CI: 0.8-1.5%) and the U.S. (AAPC=1.8%, 95% CI: 1.1-2.4%). Cancers with significantly decreasing trends in Taiwan included cancers of the nasopharynx, liver, and tongue, which were not among the most common young adult cancers in the U.S. Cancers with significantly increasing trends in both Taiwan and the U.S. included colorectal, thyroid, and female breast cancers. Lymphoma, ovarian cancer, and lung and bronchus cancer had significantly increasing trends in Taiwan but not in the U.S. Although cervical cancer had significantly decreasing trends in both nations among those 30-39 years of age, its trend was significantly increasing in Taiwan but decreasing in the U.S. among those 20-29 years of age. CONCLUSION: The types of common young adult cancers as well as their incidence rates and trends differed in Taiwan and the U.S. Future studies should further understand the etiological factors driving these trends.

Risk of COPD Exacerbations Associated with Statins versus Fibrates: A New User, Active Comparison, and High-Dimensional Propensity Score Matched Cohort Study.

BACKGROUND: Several observational studies have found that statins may materially decrease the risk of chronic obstructive pulmonary disease (COPD) exacerbations. However, most of these studies used a prevalent user, non-user comparison approach, which may lead to overestimation of the clinical benefits of statins. We aimed to explore the risk of COPD exacerbations associated with statins with a new user, active comparison approach to address potential methodological concerns. We selected fibrates, another class of lipid-lowering agents, as the reference group because no evidence suggests that fibrates have an effect on COPD exacerbations. METHODS: We identified patients with COPD who initiated statins or fibrates from a nationwide Taiwanese database. Patients were followed from cohort entry to the earliest of the following: hospitalization for COPD exacerbations, death, end of the data, or 180 days after cohort entry. Stratified Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of COPD exacerbations comparing statins with fibrates after variable-ratio propensity score (PS) matching and high-dimensional PS (hd-PS) matching, respectively. RESULTS: We identified a total of 134,909 eligible patients (110,726 initiated statins; 24,183 initiated fibrates); 1979 experienced COPD exacerbations during follow-up. The HRs were 1.10 (95% CI, 0.96 to 1.26) after PS matching and 1.08 (95% CI, 0.94 to 1.24) after hd-PS matching. The results did not differ materially by type of statins and patient characteristic and did not change with longer follow-up durations. CONCLUSION: This large-scale, population-based cohort study did not show that use of statins was associated with a reduced risk of acute exacerbations in patients with COPD using state-of-the-art pharmacoepidemiologic approaches. The findings emphasize the importance of applying appropriate methodology in exploring statin effectiveness in real-world settings.

Association of Infections and Use of Fluoroquinolones With the Risk of Aortic Aneurysm or Aortic Dissection.

Importance: Prior observational studies have suggested that fluoroquinolone use may be associated with more than 2-fold increased risk of aortic aneurysm or aortic dissection (AA/AD). These studies, however, did not fully consider the role of coexisting infections and the risk of fluoroquinolones relative to other antibiotics. Objective: To estimate the risk of AA/AD associated with infections and to assess the comparative risk of AA/AD associated with fluoroquinolones vs other antibiotics with similar indication profiles among patients with the same types of infections. Designs, Settings, and Participants: This nested case-control study identified 21 651 176 adult patients from a nationwide population-based health insurance claims database from January 1, 2009, to November 30, 2015. Each incident case of AA/AD was matched with 10 control individuals by age, sex, and follow-up duration in the database using risk-set sampling. Analysis of the data was conducted from April 2019 to March 2020. Exposures: Infections and antibiotic use within a 60-day risk window before the occurrence of AA/AD. Main Outcomes and Measures: Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% CIs comparing infections for which fluoroquinolones are commonly used with no infection within a 60-day risk window before outcome occurrence, adjusting for baseline confounders and concomitant antibiotic use. The adjusted ORs comparing fluoroquinolones with antibiotics with similar indication profiles within patients with indicated infections were also estimated. Results: A total of 28 948 cases and 289 480 matched controls were included (71.37% male; mean [SD] age, 67.41 [15.03] years). Among these, the adjusted OR of AA/AD for any indicated infections was 1.73 (95% CI, 1.66-1.81). Septicemia (OR, 3.16; 95% CI, 2.63-3.78) and intra-abdominal infection (OR, 2.99; 95% CI, 2.45-3.65) had the highest increased risk. Fluoroquinolones were not associated with an increased AA/AD risk when compared with combined amoxicillin-clavulanate or combined ampicillin-sulbactam (OR, 1.01; 95% CI, 0.82-1.24) or with extended-spectrum cephalosporins (OR, 0.88; 95% CI, 0.70-1.11) among patients with indicated infections. The null findings for fluoroquinolone use remained robust in different subgroup and sensitivity analyses. Conclusions and Relevance: These results highlight the importance of accounting for coexisting infections while examining the safety of antibiotics using real-world data; the findings suggest that concerns about AA/AD risk should not deter fluoroquinolone use for patients with indicated infections.

Comparison of Different Case-Crossover Variants in Handling Exposure-Time Trend or Persistent-User Bias: Using Dipeptidyl Peptidase-4 Inhibitors and the Risk of Heart Failure as an Example.

OBJECTIVES: Inappropriate use of the case-crossover design, which is efficient for examining associations between brief exposure and abrupt outcomes, in evaluating the effects of medications in the presence of exposure-time trends or persistent drug use may generate spurious associations. We compared different approaches to adjusting for these sources of bias by examining the risk of heart failure hospitalization (HFH) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors. Overall, existing evidence does not suggest a higher risk of HFH associated with DPP-4 inhibitors; however, case-crossover analyses of these medications may be susceptible to bias. METHODS: We conducted case-crossover; age, sex, risk-set (ASR) matched case-time-control; disease risk score (DRS)-matched case-time-control; and case-case-time-control analyses to assess the association between DPP-4 inhibitors and HFH among patients with diabetes mellitus (DM) in a population-based Taiwanese database. We also examined metformin and sulfonylureas, both with assumed null associations. RESULTS: Among 362 022 DM patients, 4105 (case-crossover), 4103 (ASR-matched case-time-control), 3957 (DRS-matched case-time-control), and 2812 (case-case-time-control) HFH cases were identified. The OR for DPP-4 inhibitors and HFH was elevated in the case-crossover analysis (1.52; 95% confidence interval [95% CI] 0.95-2.42). The ASR-matched case-time control, DRS-matched case-time-control, and case-case-time control analyses yielded near-null associations (0.90 [95% CI 0.45-1.83], 0.96 [95% CI 0.46-2.02], and 0.92 [95% CI 0.39-2.21], respectively). Null effects were observed for metformin across designs and for sulfonylureas in the case-case-time control analysis. CONCLUSIONS: Our case-crossover analysis suggested DPP-4 inhibitors may be associated with HFH; however, each method for adjusting for exposure-time and persistent user bias attenuated the findings. The case-case-time-control analysis had the least precision.

Comparative Performance of Comorbidity Measures in Predicting Health Outcomes in Patients with Chronic Obstructive Pulmonary Disease.

Purpose: Multiple studies have suggested that comorbidities pose negative impacts on the survival of patients with chronic obstructive pulmonary disease (COPD); few have applied comorbidity measures driven from health insurance claims databases to predict various health outcomes. We aimed to examine the performance of commonly used comorbidity measures based on diagnosis and pharmacy dispensing claims information in predicting future death and hospitalization in COPD patients. Methods: We identified COPD patients in a population-based Taiwanese database. We built logistic regression models with age, sex, and baseline comorbidities measured by either diagnosis or pharmacy claims information as predictors of subsequent-year death or hospitalization in a random 50% sample and validated the discrimination in the other 50%. The diagnosis-based comorbidity measures included the Charlson Index and the Elixhauser comorbidity measure; the pharmacy-based comorbidity measures included the updated Chronic Disease Score (CDS) and the Pharmacy-Based Comorbidity Index (PBDI). Results: We identified 428,251 eligible patients. For overall death, the Elixhauser comorbidity measure showed the best predictive performance (c-statistic=0.832), followed by the PBDI (c-statistic=0.822), the Charlson Index (c-statistic=0.815), and the updated CDS (c-statistic=0.808). For overall hospitalization, the PBDI (c-statistics=0.730) and the Elixhauser comorbidity measure (c-statistics=0.724) outperformed the updated CDS (c-statistics=0.714) and the Charlson Index (c-statistics=0.710). For hospitalization due to cardiovascular, cerebrovascular, or respiratory diseases, the comorbidity models showed similar predictive ranks and demonstrated c-statistics higher than 0.75. However, none of the models could adequately predict hospitalization due to other reasons (c-statistics < 0.60). Conclusion: Our study comprehensively compared the predictive performance of comorbidity measures. The Elixhauser comorbidity measure and the PBDI are useful tools for describing comorbid conditions and predicting health outcomes in COPD patients.

Comparative Safety and Effectiveness of Inhaled Corticosteroid and Long-Acting ß2-Agonist Combinations in Patients With COPD.

BACKGROUND: The differential risk of pneumonia among inhaled corticosteroid (ICS) use in patients with COPD requires more investigation, especially regarding beclomethasone-containing inhalers. The goal of this study was to compare the risk and benefit profile of different ICS/long-acting ß2-agonist (LABA) combinations in patients with COPD. METHODS: This retrospective cohort study was conducted by using national health insurance claims data from the years 2009 to 2015 in Taiwan and included patients with COPD with new ICS/LABA use. Propensity score matching and Cox regression models were used to estimate the hazard ratios of severe pneumonia and acute exacerbation for different ICS/LABA users. RESULTS: Both budesonide/formoterol (BUD/FOR) dry-powder inhalers and beclomethasone/formoterol (BEC/FOR) metered-dose inhalers, compared with fluticasone propionate/salmeterol (FLU/SAL) delivered via the same device type, were associated with a lower risk of severe pneumonia (BUD/FOR hazard ratio [HR], 0.83 [95% CI, 0.70-0.98]; BEC/FOR HR, 0.69 [95% CI, 0.58-0.81]) and severe acute exacerbation (BUD/FOR HR, 0.88 [95% CI, 0.78-0.99]; BEC/FOR HR, 0.82 [95% CI, 0.72-0.93]). After additionally adjusting for the average daily ICS dose, BUD/FOR dry-powder inhaler users continued to have a significantly decreased risk of severe pneumonia (18%), although BEC/FOR metered-dose inhaler users did not. The results were consistent in most of the prespecified subgroups and across all the sensitivity analyses. CONCLUSIONS: This study augments the existing evidence concerning the different safety and effectiveness outcomes of ICS/LABA combinations in patients with COPD, which may be considered when making clinical treatment decisions.

Incidence of hospitalization for infection among patients with hepatitis B or C virus infection without cirrhosis in Taiwan: A cohort study.

BACKGROUND: Infection is a major complication in liver cirrhosis and causes major morbidity and mortality. However, the incidence and mortality related to these conditions in patients infected with hepatitis C virus (HCV) are unclear, as is whether antiviral therapy could change their infection risk. METHODS AND FINDINGS: In this community-based cohort study, a total of 115,336 adults (mean age 52.2 years; 35.6% men) without cirrhosis participating in the New Taipei City Health Screening in 2005-2008 were classified as having noncirrhotic HCV (NC-HCV) (n = 2,839), noncirrhotic hepatitis B virus (NC-HBV) (n = 8,316), or no HBV or HCV infection (NBNC) (n = 104,181). Participants were followed to their first hospitalization for infection or death after data linkage with the Taiwan National Health Insurance Research Database (NHIRD) and Death Registry. A Cox proportional hazard regression model, adjusted for age, sex, body mass index (BMI), smoking, alcohol consumption, education level, diabetes, renal function, systemic steroids, and history of hospitalization, was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and individual sites of infection and infection-related mortality. The reference group was NBNC participants with normal to mildly elevated alanine aminotransferase (ALT) (<1.5 times upper normal limit [UNL]) levels. To further address the impact of antiviral treatment on infection risk, we conducted analyses of data from the nationwide NHIRD and compared the risks for hospitalization because of infections and infection-related deaths between patients with HCV who received antiviral therapy (n = 20,264) and those who remained untreated (n = 104,360). During a median 8.2-year follow-up, the incidence of hospitalization for infection was substantially higher in NC-HCV patients. Compared to the reference group, NC-HCV was associated with a significantly higher risk for hospitalization because of overall infections (adjusted HR: 1.22; 95% CI: 1.12-1.33), but we observed no increased risk for patients in the NC-HBV (adjusted HR: 0.94; 95% CI: 0.88-1.01) or NBNC group with moderate to markedly elevated ALT levels (adjusted HR: 1.03; 95% CI: 0.93-1.14). For specific sites of infection, the NC-HCV group had increased risks for septicemia and lower respiratory tract, reproductive, and urinary tract infections. We noted no increased risk for infection-related death among patients with NC-HCV. Patients with HCV who received antiviral therapy had significantly reduced infection-related hospitalization and death risks (adjusted HR: 0.79; 95% CI: 0.73-0.84 for infection-related hospitalization and adjusted HR: 0.08; 95% CI: 0.04-0.16 for infection-related deaths). Study limitations include the exclusion of patients with cirrhosis from the cohort, the possibility of unmeasured confounding, and the lack of information on direct-acting antiviral agents (DAAs). CONCLUSIONS: In this study, patients with NC-HCV were at increased risk for hospitalization for infection, while no increased risk was observed for NC-HBV-infected patients.

Re-evaluating Safety and Effectiveness of Dabigatran Versus Warfarin in a Nationwide Data Environment: A Prevalent New-User Design Study.

INTRODUCTION: The new user cohort design is widely used to assess the effects of a new drug, such as dabigatran, but inherently excludes some users due to prior use of the comparator drug, for example warfarin. The prevalent new-user design offers a solution that includes all eligible users of the new drug. OBJECTIVE: To evaluate the safety and effectiveness of dabigatran versus warfarin in non-valvular atrial fibrillation (NVAF) patients with prevalent new-user design. METHODS: Taiwan National Health Insurance and mortality data from 2011 through 2015 were utilized. From an incident NVAF cohort, we identified dabigatran initiators as either incident or prevalent (switchers from warfarin) new users. Time- and prescription-based exposure sets were formed for dabigatran initiators to account for prior warfarin prescriptions. A comparable warfarin user was matched on the time-conditional propensity score to the dabigatran initiator in each set. The matched patients were followed for clinical outcomes, with Cox proportional hazards model used to estimate hazard ratios (HRs). RESULTS: There were 10,811 dabigatran initiators, including 22% prevalent new users (switchers), who formed the exposure sets and were matched 1:1 to warfarin users. Dabigatran use was associated with lower risks of intracranial hemorrhage (HR 0.51; 95% confidence interval [CI] 0.39, 0.66) and gastrointestinal bleeding (HR 0.81; 95% CI 0.70, 0.92), compared with warfarin use. These effects were similar between the incident and prevalent new users. CONCLUSION: Using a design that includes both incident and prevalent new users of dabigatran, the use of dabigatran is associated with lower major bleeding risk than warfarin use among patients with incident NVAF.

Using Previous Medication Adherence to Predict Future Adherence.

BACKGROUND: Medication nonadherence is a major public health problem. Identification of patients who are likely to be and not be adherent can guide targeted interventions and improve the design of comparative-effectiveness studies. OBJECTIVE: To evaluate multiple measures of patient previous medication adherence in light of predicting future statin adherence in a large U.S. administrative claims database. METHODS: We identified a cohort of patients newly initiating statins and measured their previous adherence to other chronic preventive medications during a 365-day baseline period, using metrics such as proportion of days covered (PDC), lack of second fills, and number of dispensations. We measured adherence to statins during the year after initiation, defining high adherence as PDC ≥ 80%. We built logistic regression models from different combinations of baseline variables and previous adherence measures to predict high adherence in a random 50% sample and tested their discrimination using concordance statistics (c-statistics) in the other 50%. We also assessed the association between previous adherence and subsequent statin high adherence by fitting a modified Poisson model from all relevant covariates plus previous mean PDC categorized as < 25%, 25%-79%, and ≥ 80%. RESULTS: Among 89,490 statin initiators identified, a prediction model including only demographic variables had a c-statistic of 0.578 (95% CI = 0.573-0.584). A model combining information on patient comorbidities, health care services utilization, and medication use resulted in a c-statistic of 0.665 (95% CI = 0.659-0.670). Models with each of the previous medication adherence measures as the only explanatory variable yielded c-statistics ranging between 0.533 (95% CI = 0.529-0.537) for lack of second fill and 0.666 (95% CI = 0.661-0.671) for maximum PDC. Adding mean PDC to the combined model yielded a c-statistic of 0.695 (95% CI = 0.690-0.700). Given a sensitivity of 75%, the predictor improved the specificity from 47.7% to 53.6%. Patients with previous mean PDC < 25% were half as likely to show high adherence to statins compared with those with previous mean PDC ≥ 80% (risk ratio = 0.49, 95% CI = 0.46-0.50). CONCLUSIONS: Including measures of previous medication adherence yields better prediction of future statin adherence than usual baseline clinical measures that are typically used in claims-based studies. DISCLOSURES: This study was funded by the Patient-Centered Outcomes Research Institute (ME-1309-06274). Kumamaru, Kohsaka, and Miyata are affiliated with the Department of Healthcare Quality Assessment at the University of Tokyo, which is a social collaboration department supported by National Clinical Database. The department was formerly supported by endowments from Johnson & Johnson K.K., Nipro, Teijin Pharma, Kaketsuken K.K., St. Jude Medical Japan, Novartis Pharma K.K., Taiho Pharmaceutical, W. L. Gore & Associates, Olympus Corporation, and Chugai Pharmaceutical. Gagne has received grants from Novartis Pharmaceuticals and Eli Lilly and Company to the Brigham and Women's Hospital for unrelated work. He is a consultant to Aetion, a software company, and to Optum. Choudhry has received grants from the National Heart, Lung, and Blood Institute, PhRMA Foundation, Merck, Sanofi, AstraZeneca, CVS, and MediSafe. Schneeweiss is consultant to WHISCON and Aetion, a software manufacturer of which he also owns equity. He is principal investigator of investigator-initiated grants to the Brigham and Women's Hospital from Bayer, Genentech, and Boehringer Ingelheim unrelated to the topic of this study. He does not receive personal fees from biopharmaceutical companies. No potential conflict of interest was reported by the other authors.