Risk of myocarditis and pericarditis following coronavirus disease 2019 messenger RNA Vaccination-A nationwide study.

BACKGROUND: An extended interval between the two primary doses may reduce the risk of myocarditis/pericarditis after COVID-19 mRNA vaccination. Taiwan has implemented a two-dose regimen with a 12-week interval for adolescents. Here we present nationwide data of myocarditis/pericarditis following COVID-19 vaccinations. METHODS: Data on adverse events of myocarditis/pericarditis were from the Taiwan Vaccine Adverse Events Reporting System between March 22, 2021, and February 9, 2022. The reporting rates according to sex, age, and vaccine type were calculated. We investigated the rates among young individuals under different two-dose intervals and among those who received two doses of different vaccines. RESULTS: Among 204 cases who met the case definition of myocarditis/pericarditis, 75 cases occurred after the first dose and 129 after the second. The rate of myocarditis/pericarditis after COVID-19 vaccination varied across sex and age groups and was highest after the second dose in males aged 12-17 years (126.79 cases per million vaccinees) for the BNT162b2 vaccine and in males aged 18-24 years (93.84 cases per million vaccinees) for the mRNA-1273 vaccine. The data did not suggest an association between longer between-dose interval and lower rate of myocarditis/pericarditis among males and females aged 18-24 or 25-29 years who received two doses of the BNT162b2 or mRNA-1273 vaccine. Rates of myocarditis/pericarditis in males and females aged 18-49 years after receiving ChAdOx1-S - mRNA-1273 vaccination was significantly higher than after ChAdOx1-S - ChAdOx1-S vaccination. CONCLUSIONS: Myocarditis and pericarditis are rare following mRNA vaccination, with higher risk occurring in young males after the second dose.

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.

The Association Between Body Mass Index and the Risk of Hospitalization and Mortality due to Infection: A Prospective Cohort Study.

BACKGROUND: We aim to determine whether obesity increases the risk of various infections using a large prospective population-based cohort. METHODS: A total of 120 864 adults were recruited from the New Taipei City health screening program from 2005 to 2008. Statistics for hospitalization and mortality due to infection were obtained from the National Health Insurance Database and the National Death Registry in Taiwan. RESULTS: During a mean follow-up period of 7.61 years, there were 438, 7582, 5298, and 1480 first hospitalizations due to infection in the underweight, normal, overweight, and obese groups, respectively. Obesity significantly increases the risk of hospitalization for intra-abdominal infections (adjusted hazard ratio [aHR], 1.19; 95% CI, 1.00-1.40), including diverticulitis, liver abscess, acute cholecystitis and anal and rectal abscess, reproductive and urinary tract infection (aHR, 1.38; 95% CI, 1.26-1.50), skin and soft tissue infection (aHR, 2.46; 95% CI, 2.15-2.81), osteomyelitis (aHR, 1.70; 95% CI, 1.14-2.54), and necrotizing fasciitis (aHR, 3.54; 95% CI,1.87-6.67), and this relationship is dose-dependent. This study shows that there is a U-shaped association between body mass index (BMI) and hospitalization for lower respiratory tract infection, septicemia, and the summation of all infections and that underweight people are at the greatest risk, followed by obese people. There is a clear negative relationship between BMI and infection-related mortality. CONCLUSIONS: The pattern that BMI affects the risk of hospitalization and mortality due to infection varies widely across infection sites. It is necessary to tailor preventive and therapeutic measures against different infections in hosts with different BMIs.

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.

Stratified risks of infection-related hospitalization in patients with chronic kidney disease - A prospective cohort study.

Patients with chronic kidney disease (CKD) are at high risk of infection, but whether the risks are attenuated in different patient groups remains unclear. This study enrolled participants with CKD stages 1-3 in the New Taipei City Health Screening Program between 2005 and 2008. A proportional hazard regression model was employed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for infection-related hospitalization and mortality in younger (<50-year-old) and older (≥50-year-old) CKD patients. Of 119,871 adults, there were 14,207 cases of first hospitalization for infection during a median follow-up of 8.14 years; 45.5% of these cases were younger patients. Unlike CKD stage 1 and 2 patients, the risk of infection-related hospitalization in younger CKD stage 3 patients is as high as for older CKD stage 3 patients. Proteinuria increases the risk of infection-related hospitalization independent of estimated glomerular filtration rate (eGFR) levels in older CKD patients but this relationship is weak in their younger counterparts. In conclusion, the risk of infection-related hospitalization is high in subgroups of CKD patients. Prevention and treatment of infections in these patients merit more attention.

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.

Diabetes, Glycemic Control, and Risk of Infection Morbidity and Mortality: A Cohort Study.

OBJECTIVE: Diabetic patients have an elevated risk of infection, but the optimal level of glycemic control with the lowest infection risk remains unclear, especially among the elderly. We aimed to investigate the relation between fasting plasma glucose (FPG) level and risk of infection-related morbidity and mortality. METHOD: The participants were from a community-based health screening program in northern Taiwan during 2005-2008 (n = 118 645) and were followed up until 2014. Incidence of hospitalization for infection and infection-related death was ascertained from the National Health Insurance Database and National Death Registry. Cox proportional hazards regression modelling was used to estimate the hazard ratio (HR) between FPG and risk of infection. RESULTS: During a median follow-up of 8.1 years, the incidence rate of hospitalization for any infection was 36.33 and 14.26 per 1000 person-years among diabetics and nondiabetics, respectively, in the total study population, but increased to 70.02 and 45.21 per 1000 person-years, respectively, in the elderly. In the Cox regression analysis, the adjusted HR comparing diabetics to nondiabetics was 1.59 (95% confidence interval [CI], 1.52-1.67) for any hospitalization for infection and 1.71 (95% CI, 1.36-2.16) for infection-related mortality. The hazard for infection morbidity and mortality was higher at both extremes (<90 and >200 mg/dl) of FPG. The excess risk associated with FPG ≤ 90 mg/dl was attenuated after controlling for multiple comorbidities. CONCLUSIONS: Poor glycemic control (FPG > 200 mg/dl) was associated with a higher risk of infection-related morbidity and mortality, especially in the elderly population where the baseline infection risk was high.

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.

Thiazolidinediones and reduced risk of incident bacterial abscess in adults with type 2 diabetes: A population-based cohort study.

AIM: Previous research has suggested that peroxisome proliferator-activated receptor-gamma (PPAR-γ) may play an important role in immunomodulation. We aimed to examine the association between thiazolidinediones, PPAR-γ agonists and incidence of bacterial abscess among patients with type 2 diabetes. MATERIALS AND METHODS: This retrospective cohort study between 2000 and 2010 included 46 986 propensity (PS)-matched patients diagnosed with type 2 diabetes. We compared the incidence of bacterial abscess, including liver and non-liver abscesses, between patients treated with metformin plus a thiazolidinedione (M + T, N = 7831) or metformin plus a sulfonylurea (M + S, N = 39 155). Data were retrieved from a population-based Taiwanese database. We applied Cox proportional hazard regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), comparing M + T and M + S after PS matching. RESULTS: During a median follow-up of 4.5 years, the incidence rate of bacterial abscess was lower with M + T than with M + S treatment (1.89 vs 3.15 per 1000 person-years) in the PS-matched cohort. M + T was associated with a reduced risk of bacterial abscess (HRs after PS matching, 0.58; 95% CI, 0.42-0.80 for total bacterial abscess; 0.54; 95% CI, 0.28-1.07 for liver abscess; 0.59; 95% CI, 0.41-0.85 for non-liver abscess). Results did not change materially after accounting for unmeasured confounding factors using high-dimenional PS matching and differential censoring between regimen groups. Rosiglitazone and pioglitazone, in combination with metformin, produced similar reductions in risk of all abscess outcomes. CONCLUSION: We found that M + T may provide a protective benefit in reducing the incidence of bacterial abscesses. These findings merit further investigation.

Comparative cardiovascular safety of nonsteroidal anti-inflammatory drugs in patients with hypertension: a population-based cohort study.

AIMS: Previous studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with higher cardiovascular risks. However, few have been active comparison studies that directly assessed the potential differential cardiovascular risk between NSAID classes or across individual NSAIDs. We compared the risk of major cardiovascular events between cyclooxygenase 2 (COX-2)-selective and nonselective NSAIDs in patients with hypertension. METHODS: We conducted a cohort study of patients with hypertension who initiated COX-2-selective or nonselective NSAIDs in a population-based Taiwanese database. The outcomes included hospitalization for the following major cardiovascular events: ischaemic stroke, acute myocardial infarction, congestive heart failure, transient ischaemic attack, unstable angina or coronary revascularization. We followed patients for up to 4 weeks, based on the as-treated principle. We used inverse probability weighting to control for baseline and time-varying covariates, and estimated the on-treatment hazard ratios (HRs) and 95% conservative confidence interval (CIs). RESULTS: We identified 2749 eligible COX-2-selective NSAID users and 52 880 eligible nonselective NSAID users. The HR of major cardiovascular events comparing COX-2-selective with nonselective NSAIDs after adjusting for baseline and time-varying covariates was 1.07 (95% CI 0.65, 1.74). We did not observe a differential risk when comparing celecoxib to diclofenac (HR 1.17; 95% CI 0.61, 2.25), ibuprofen (HR 1.36; 95% CI 0.58, 3.18) or naproxen (HR 0.75; 95% CI 0.23, 2.44). There was an increased risk with COX-2-selective NSAIDs, however, when comparing COX-2-selective NSAIDs with mefenamic acid (HR 2.11; 95% CI 1.09, 4.09). CONCLUSIONS: Our results provide important information about the comparative cardiovascular safety of NSAIDs in patients with hypertension.

Risk of Heart Failure Hospitalization Associated With Cilostazol in Diabetes: A Nationwide Case-Crossover Study.

Background and Objective: It has been suggested to avoid cilostazol, the first-line therapy for peripheral arterial disease, in patients with congestive heart failure (HF). The objective of this study was to evaluate the risk of hospitalization for heart failure (HHF) associated with cilostazol use in the patients of diabetes mellitus. Methods: This case-crossover study retrieved records on diabetic patients > 20 years of age who were hospitalized for heart failure during the period of 2009-2011 from the Taiwan National Health Insurance Database. The "current" period was defined as 1-30 days prior to HHF whereas the 91-120 days prior to HHF served as the "reference" period. The exposure status just preceding the event is compared with exposure of the same person in one or more referent remote to the event. Adjusted odds ratios (OR) were used to estimate time-varying discordant exposure by the ratio of the number exposed to cilostazol only during the case period to the number exposed to cilostazol only during the control period. Results: A total of 47,506 diabetic patients were included in the analysis (average age: 72.7 ± 12.4, percentage of males: 48%). A total of 399 patients (0.84%) received cilostazol only in the current period, and 252 (0.53%) received cilostazol only in the reference period. After adjustment for other medications, a significant association was found between cilostazol and HHF (OR: 1.35, 95% CI: 1.14-1.59). After further adjustment for time-varying co-morbidities the ORs remained essentially the same. Sensitivity analyses using different definitions of control period (ranging from 31-60, 61-90, to 121-150 days before index date) yielded adjusted ORs of 1.43 (95% CI: 1.14-1.79), 1.31 (95% CI: 1.09-1.57) and 1.23 (95% CI: 1.06-1.44), respectively suggesting the robustness of our study findings. Conclusion: Use of cilostazol may be positively related to the risk of HHF. Further studies are warranted to explore the underlying mechanisms and to confirm the association.

Evidence of potential bias in a comparison of ß blockers and calcium channel blockers in patients with chronic obstructive pulmonary disease and acute coronary syndrome: results of a multinational study.

OBJECTIVES: A number of observational studies have reported that, in patients with chronic obstructive pulmonary disease (COPD), ß blockers (BBs) decrease risk of mortality and COPD exacerbations. To address important methodological concerns of these studies, we compared the effectiveness and safety of cardioselective BBs versus non-dihydropyridine calcium channel blockers (non-DHP CCBs) in patients with COPD and acute coronary syndromes (ACS) using a propensity score (PS)-matched, active comparator, new user design. We also assessed for potential unmeasured confounding by examining a short-term COPD hospitalisation outcome. SETTING AND PARTICIPANTS: We identified 22 985 patients with COPD and ACS starting cardioselective BBs or non-DHP CCBs across 5 claims databases from the USA, Italy and Taiwan. PRIMARY AND SECONDARY OUTCOME MEASURES: Stratified Cox regression models were used to estimate HRs for mortality, cardiovascular (CV) hospitalisations and COPD hospitalisations in each database after variable-ratio PS matching. Results were combined with random-effects meta-analyses. RESULTS: Cardioselective BBs were not associated with reduced risk of mortality (HR, 0.90; 95% CI 0.78 to 1.02) or CV hospitalisations (HR, 1.06; 95% CI 0.91 to 1.23), although statistical heterogeneity was observed across databases. In contrast, a consistent, inverse association for COPD hospitalisations was identified across databases (HR, 0.54; 95% CI 0.47 to 0.61), which persisted even within the first 30 days of follow-up (HR, 0.55; 95% CI 0.37 to 0.82). Results were similar across a variety of sensitivity analyses, including PS trimming, high dimensional-PS matching and restricting to high-risk patients. CONCLUSIONS: This multinational study found a large inverse association between cardioselective BBs and short-term COPD hospitalisations. The persistence of this bias despite state-of-the-art pharmacoepidemiologic methods calls into question the ability of claims data to address confounding in studies of BBs in patients with COPD.

Comparing the risks of hospitalized heart failure associated with glinide, sulfonylurea, and acarbose use in type 2 diabetes: A nationwide study.

BACKGROUND: Increasing evidence suggests that certain newer anti-diabetic drugs are associated with an increased risk of hospitalized heart failure (HHF). However, the potential risks associated with the use of sulfonylurea and glinide have not been carefully evaluated. METHODS: A retrospective cohort study using the Taiwan National Health Insurance claims database was conducted to examine the risks of HHF among newly diagnosed type 2 diabetic patients who initiated glinide, sulfonylurea, or acarbose therapy during 2006-2012. The outcome of interest was hospitalization due to heart failure after treatment initiation, defined by ICD-9-CM code. A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) using acarbose as the reference group. RESULTS: A total of 25,638 glinide, 272,140 sulfonylurea, and 29,376 acarbose initiators were included in the analysis. Patients who initiated glinide had the highest crude HHF incidence. In the analysis adjusted for baseline differences, a significantly higher risk of HHF was found for glinide (adjusted HR, 1.53; 95% CI, 1.24-1.88), but not for sulfonylurea (adjusted HR, 0.94; 95% CI, 0.80-1.11), as compared with acarbose. The elevated risk remained consistent across different subgroups of patients as well as several sensitivity analyses including exploring the impact of potential unmeasured confounding. CONCLUSIONS: These findings indicated that, as compared with acarbose, glinide may be associated with a higher risk of HHF for type 2 diabetic patients. Further researchis needed to fully evaluate the risks and benefits of glinide therapy relative to other oral anti-diabetic agents.

Stent revascularization versus bypass surgery for peripheral artery disease in type 2 diabetic patients - an instrumental variable analysis.

The objective of this study was to use instrumental variable (IV) analyses to evaluate the clinical effectiveness of percutaneous stent revascularization versus bypass surgery in the treatment of peripheral artery disease (PAD) among type 2 diabetic patients. Type 2 diabetic patients who received peripheral artery bypass surgery (n = 5,652) or stent revascularization (n = 659) for lower extremity arterial stenosis between 2000 and 2007 were identified from the Taiwan National Health Insurance claims database. Patients were followed from the date of index hospitalization for 2 years for lower-extremity amputation, revascularization, and hospitalization for medical treatment. Analysis using treatment year, patients' monthly income level, and regional difference as IVs were conducted to reduce unobserved treatment selection bias. The crude analysis showed a statistically significant risk reduction in favor of stent placement in lower extremity amputation and in the composite endpoint of amputation, revascularization, or hospitalization for medical treatment. However, peripheral artery stent revascularization and bypass surgery had similar risk of lower limb amputation and composite endpoints in the analyses using calendar year or patients' monthly income level as IVs. These two treatment modalities had similar risk of lower limb amputation among DM patients with PAD.

No increased risk of hospitalization for heart failure for patients treated with dipeptidyl peptidase-4 inhibitors in Taiwan.

BACKGROUND: Saxagliptin has been reported to be associated with an increased risk of hospitalization for heart failure (HF). The objective of this study was to test whether the increased risk is drug specific or a class effect for dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: Diabetic patients prescribed sitagliptin, saxagliptin, and vildagliptin between 2011 and 2013 were identified from Taiwan's National Health Insurance (NHI) claims database. The outcome of interest was the first hospitalization for HF. The patients were followed for one year from drug initiation to outcome occurrence, death, or study termination (December 31, 2013). A Cox proportional hazards regression model was used to calculate the hazard ratios (HR) and their 95% confidence intervals, using sitagliptin as the reference group. RESULTS: A total of 239,669 patients, including 159,330 sitagliptin, 38,561 saxagliptin, and 41,778 vildagliptin initiators, were included in the analysis. With a follow-up period ranging from 269days (vildagliptin) to 313days (sitagliptin), the crude incidence rate of HF was 2.77, 2.63, and 1.91 per 100 person-years for sitagliptin, saxagliptin, and vildagliptin, respectively. Saxagliptin had a similar risk (HR: 0.98, 95% CI: 0.91-1.06) to sitagliptin, while vildagliptin was associated with a lower risk of HF (HR: 0.85, 95% CI: 0.78-0.93). Auxiliary analyses using acarbose (n=130,800) as a reference group consistently showed no increased risk of HF associated with DDP-4 inhibitors. CONCLUSION: Three DPP-4 inhibitors studied seem to be safe regarding the risk of HF, while the reduced risk of vildagliptin might be a spurious association or a chance finding.

Use of cardioselective ß-blockers and overall death and cardiovascular outcomes in patients with COPD: a population-based cohort study.

PURPOSE: Use of ß-blockers (BBs) in patients with chronic obstructive pulmonary disease (COPD) and cardiovascular diseases is supported by increasing evidence. However, most of these studies focused on the survival outcome and used a non-active comparison, prevalent-user design. We aimed to examine the risk of overall death and cardiovascular outcomes associated with use of cardioselective BBs using an active comparison, incident cohort approach. METHODS: We identified COPD patients initiating cardioselective BBs or non-dihydropyridine calcium channel blockers (CCBs) between 2007 and 2011 in the population-based Taiwan database. A Cox regression model was applied to estimate hazard ratios (HRs) for overall death, cardiovascular death, and cardiovascular events comparing cardioselective BBs and non-dihydropyridine CCBs after propensity score matching. We also conducted sensitivity analyses to quantify the unmeasured confounding effect from COPD severity. RESULTS: A total of 107,902 patients were included. Cardioselective BBs were associated with a modest, lower risk of overall death (HR, 0.85; 95 % CI, 0.81-0.88). The reduced risk of overall death, however, was vulnerable to distribution of COPD severity and was easily weakened with lower prevalence of severe COPD patients in the initiators of cardioselective BBs and higher prevalence of severe COPD patients in the initiators of non-dihydropyridine CCBs. No excess benefit for cardiovascular death (HR, 1.05; 95 % CI, 0.97-1.13) or cardiovascular events (HR, 0.98; 95 % CI, 0.94-1.03) was detected. CONCLUSION: The present study demonstrated a potential effect of confounding by COPD severity and therefore did not suggest an association between use of cardioselective BB and survival benefit in COPD patients.

Antihypertensive agents and the risk of breast cancer in women aged 55 years and older: a nested case-control study.

OBJECTIVE: The study aimed to investigate the association of long-term use of different antihypertensive agents with incident breast cancer. METHODS: A total of 794 ,533 women aged at least 55 years were identified from Taiwan National Health Insurance claims database during 2001-2011. As of 31 December 2011, incident breast cancer patients were included as cases, and 1 : 4 age-matched controls were selected by risk-set sampling scheme. Logistic regression models were applied to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer incidence associated with different durations of use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, ß-blockers, and dihydropyridine calcium channel blockers (DHP CCBs). Different restriction rules were applied to reveal the potential effects of confounding by indication. RESULTS: Among the 9397 incident breast cancer patients and 37 ,588 controls, a significantly elevated risk was found for relatively short-term use of DHP CCBs (<6 years) but not in those observed for more than 6 years. There was no association between either angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or ß-blockers use and breast cancer. Although restricting our analyses to those with any prescription of antihypertensive medications in 2001 or those with diagnosis of hypertension, there was no longer a statistically significant association between any use of DHP CCBs and breast cancer (OR: 1.21, 95% CI: 0.88-1.67 for the former, and OR: 1.71, 95% CI: 0.99-2.95 for the latter). CONCLUSION: The results demonstrated the potential effect of confounding by indication, and thus, did not suggest any association of the use of antihypertensive medication and breast cancer risk.

Comparing individual angiotensin-converting enzyme inhibitors with losartan in the risk of hospitalization for pneumonia and related mortality: a nationwide cohort study.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors might decrease the risk of pneumonia, but head-to-head comparisons with angiotensin receptor blockers (ARBs) were seldom made. The objective of this study was to evaluate incidence of pneumonia and mortality for different ACE inhibitors as compared to losartan, an ARB that has similar indications. METHODS: Adult patients aged more than 20 years who initiated ACE inhibitors and losartan between 1 January 2004 and 31 December 2009 were identified from Taiwan's National Health Insurance Database. The outcomes of interest were hospitalization for pneumonia and pneumonia-related mortality. Participants were followed from treatment initiation to the earliest of outcome occurrence, death or disenrollment, treatment discontinuation, switching to other ACE inhibitors or ARBs, or study termination (31 December 31 2010). Proportional-hazards regression model was used to calculate the hazard ratios and their 95% confidence intervals (CIs), adjusted on baseline characteristics. RESULTS: A total of 1,192,082 ACE inhibitors and 175,668 losartan initiators were included. The risk of hospitalization for pneumonia was significantly higher for captopril (hazard ratio 1.94, 95% CI 1.82-2.07), enalapril (hazard ratio 1.14, 95% CI 1.07-1.22), fosinopril (hazard ratio 1.11, 95% CI 1.02-1.21), perindopril (hazard ratio 1.14, 95% CI 1.04-1.25), and ramipril (hazard ratio 1.11, 95% CI 1.02-1.22), as compared with losartan. Captopril was associated with a significantly increased risk of pneumonia mortality (hazard ratio 2.43, 95% CI 1.79-3.31). CONCLUSIONS: Treatment with ACE inhibitors is not associated with a lower risk of pneumonia incidence and mortality as compared with losartan.