Cohort Entry Date Research Articles

Risk of aortic aneurysm and aortic dissection with the use of fluoroquinolones in Korea: a nested case\u2013control study

BackgroundRecent studies have raised concern about the association of fluoroquinolones with an increased risk of aortic aneurysm and aortic dissection. We aimed to evaluate such risk in a Korean population.MethodsWe conducted a nested case–control study using data from the National Health Insurance Service collected from 2013 to 2017 in Korea. The study cohort included patients older than 40 years and excluded patients who had used fluoroquinolones or been diagnosed with aortic aneurysm, aortic dissection, or related diseases 1 year prior to the cohort entry date. We randomly matched four controls in the risk set with each case of aortic aneurysm and aortic dissection (same sex, age, and cohort entry date). We assessed the risk of aortic aneurysm and aortic dissection from fluoroquinolones and adjusted for potential confounders using a conditional logistic regression model.ResultsA total of 29,638 aortic aneurysm and aortic dissection patients were identified between 2014 and 2017. The use of fluoroquinolones within a year was associated with a 10% increased risk of aortic aneurysm and aortic dissection (adjusted odds ratio: 1.10, 95% CI 1.07–1.14, p < 0.05) compared with nonusers. The risk was higher in patients who had used fluoroquinolones within 60 days (adjusted odds ratio: 1.53, 95% CI 1.46–1.62, p < 0.05). The risk of aortic aneurysm and aortic dissection positively correlated with the cumulative dose and duration of fluoroquinolone therapy (p < 0.001).ConclusionsOur study provides real-world evidence of the risk of aortic aneurysm and aortic dissection from fluoroquinolones in Korea. Patients and medical professionals should be aware that fluoroquinolones can increase the risk of aortic aneurysm and aortic dissection, which may be acerbated by high dosage and duration of use.

The importance of blood pressure thresholds versus predicted cardiovascular risk on subsequent rates of cardiovascular disease: a cohort study in English primary care

SummaryBackgroundFor five decades, blood pressure lowering treatment has been recommended for patients with hypertension (currently defined as blood pressure of ≥140/90 mm Hg). In the past 20 years, guidelines for treatment began incorporating predicted absolute cardiovascular disease risk (predicted risk) and reducing blood pressure thresholds. The blood pressure threshold at which to start treatment has become a secondary consideration in some countries. We aimed to provide descriptive data to assess the relative importance of blood pressure thresholds versus predicted risk on the subsequent rate of cardiovascular disease to inform treatment decisions.MethodsIn this English population-based cohort study, we used linked data from the Clinical Practice Research Datalink (CPRD) GOLD, Hospital Episode Statistics Admitted Patient Care, and the Office for National Statistics mortality data, and area-based deprivation indices (Townsend scores). Eligible patients were aged 30–79 years on Jan 1, 2011 (cohort entry date) and could be linked to hospital, mortality, and deprivation data. Patients were followed up until death, end of CPRD follow-up, or Nov 31, 2018. We examined three outcomes: cardiovascular disease, markers of potential target organ damage, and incident dementia without a known cause. The rate of each outcome was estimated and stratified by systolic blood pressure and predicted 10-year risk of cardiovascular disease (QRISK2 algorithm).FindingsBetween Jan 1, 2011, and Nov 31, 2018, 1 098 991 patients were included in the cohort and followed up for a median of 4·3 years (IQR 2·6–6·0; total follow-up of 4·6 million person-years). Median age at entry was 52 years (IQR 42–62) and 629 711 (57·3%) patients were female. There were 51 996 cardiovascular disease events and the overall rate of cardiovascular disease was 11·2 per 1000 person-years (95% CI 11·1–11·3). Median QRISK2 10-year predicted risk was 4·6% (IQR 1·4–12·0) and mean systolic blood pressure before cohort entry was 129·1 mm Hg (SD 15·7). Within strata of predicted risk, the effect of increasing systolic blood pressure on outcomes was small. For example, in the group with 10·0–19·9% predicted risk, rates of all cardiovascular disease rose from 20·1 to 23·6 per 1000 person-years between systolic blood pressures less than 110 mm Hg and 180 and higher mm Hg. But among patients with systolic blood pressure 140·0–149·9 mm Hg, rates rose from 6·9 to 52·3 per 1000 person-years between those with less than 10·0% risk and those with 30·0% or higher predicted risk.InterpretationFor a wide range of blood pressures, the rate of cardiovascular disease and effectiveness of blood pressure drug treatment was mainly determined by predicted risk, with blood pressure thresholds 140/90 mm Hg or 160/100 mm Hg—ubiquitous in most countries—adding little useful information. When medium-term predicted risk is low, there is no urgency to initiate drug treatment, allowing time to attempt non-pharmacological blood pressure reduction.FundingNational Institute for Health Research.

S92 Diabetes Progression and Chronic Pancreatitis Are Associated With an Increased Risk for Pancreatic Ductal Adenocarcinoma

Introduction: Chronic pancreatitis (CP) and diabetes (DM) are independent risk factors for pancreatic ductal adenocarcinoma (PDAC). DM is also a common sequelae of CP, and DM progression may not only be an indicator of CP disease but also of increased risk of PDAC. The primary aim was to evaluate the risk of PDAC in patients with CP and various stages of DM progression. Methods: This retrospective study was conducted on outpatients 50 years and older between 2000 and 2016 at the Veterans Administration. Patients were required to have DM progression defined as: new insulin prescription, combination oral hyperglycemia treatment, or 1% or more increase in hemoglobin A1c with the final measurement over 8% in a 15-month period. In these patients, patients with CP were identified based on diagnosis codes and were required to have a diagnosis of CP prior to cohort entry date. Patients with PDAC were identified through the VA Central Cancer Registry, or the presence of at least two encounters or two Medicare claims with the diagnosis of PDAC. Median follow-up and cumulative incidence estimates of PDAC were calculated following Kaplan-Meier method where time to event is defined as time from DM progression to diagnosis to PDAC and patients who did not develop PDAC were censored at death or December 31, 2017. Results: Of the 824,089 patients who met criteria for diabetes progression, 6,883 patients (0.8%) were found to have CP in whom PDAC developed in 125 CP patients (1.8%) over a median follow-up 108 months. CP-DM patients who developed PDAC were significantly older, leaner, predominantly White, and were less likely to be on a statin compared to CP-DM patients who did not develop PDAC (Table). The 5-year incidence of PDAC in patients with CP was 1.4% as compared to 0.5% in diabetes patients without CP. Incidence rate was steeper in the first two years of diabetes progression then thereafter (Figure 1). When PDAC incidence was compared by duration of CP diagnosis at the time of diabetes progression, the 5-year PDAC incidence in CP patients was highest within the first year of CP diagnosis at 2.4%, compared to 1.6% in patients with CP duration of 1-3 years, and 1.5% in patients with CP duration greater than 3 years. Conclusion: Patients with DM progression and CP have a nearly 3-fold higher risk of PDAC development compared to patients without CP. The highest rate for PDAC is within the first year of CP diagnosis and the first year of diabetes progression.Figure 1.: Cumulative incidence function curve estimating the incidence of PDAC in patients without CP (blue/bottom curve) and patients with CP (red/top curve), starting at time of diabetes progression.Table 1.: Baseline patient characteristics in patients with CP and diabetes progression with or without PDAC.

313Long-acting bronchodilators and risk of acute coronary syndrome

Abstract Background There is concern that long-acting bronchodilators (long-acting muscarinic antagonists [LAMAs]) and long-acting beta2-agonists [LABAs]) may further increase the already elevated risk of cardiovascular events in patients with chronic obstructive pulmonary disease (COPD). Guidelines recommend stepwise escalation from one to two long-acting bronchodilators in patients with uncontrolled symptoms, but information about the impact of this treatment intensification on acute coronary syndrome (ACS) risk is limited. Methods We undertook a nested case-control study using national administrative data to estimate the risk of ACS in users of dual LAMA and LABA therapy, and users of LABA monotherapy, relative to users of LAMA monotherapy. The underlying study cohort comprised patients aged &amp;gt;45 years who initiated long-acting bronchodilator therapy for COPD between 2006 and 2013 (n = 83,417). Cases were patients diagnosed with fatal or non-fatal ACS after cohort entry (n = 5,399). Up to 10 controls per case, matched by age, sex, date of cohort entry, and COPD severity, were randomly selected from the study cohort using risk set sampling. Odd ratios and 95% confidence intervals were estimated using conditional logistic regression. Results Relative to current use of LAMA monotherapy, the adjusted odds ratios for current use of dual LAMA and LABA therapy, and of LABA monotherapy, were 1.28 (95% CI 1.13–1.44) and 1.0 (95% CI 0.91–1.10), respectively. Conclusions Use of two long-acting bronchodilators rather than LAMA monotherapy, is associated with a higher risk of ACS, while the risks associated with LAMA and LABA monotherapy are comparable. Key messages The clinical benefit of adding a second long-acting bronchodilator to LAMA or LABA monotherapy is modest and, at the same time, is associated with an increased risk of ACS in a patient group already at high risk.

Dual versus single long-acting bronchodilator use could raise acute coronary syndrome risk by over 50%: A population-based nested case-control study.

BackgroundCoronary heart disease occurs more frequently among patients with chronic obstructive pulmonary disease (COPD) compared to those without COPD. While some research suggests that long‐acting bronchodilators might confer an additional risk of acute coronary syndrome (ACS), information from real‐world clinical practice about the cardiovascular impact of using two versus one long‐acting bronchodilator for COPD is limited. We undertook a population‐based nested case–control study to estimate the risk of ACS in users of both a long‐acting muscarinic antagonist (LAMA) and a long‐acting beta2‐agonist (LABA) relative to users of a LAMA.MethodsThe study was based on the primary care PREDICT Cardiovascular Disease Cohort and linked data from regional laboratories and the New Zealand Ministry of Health's national data collections. The underlying cohort (n = 29,993) comprised patients aged 45–84 years, who initiated treatment with a LAMA and/or LABA for COPD between 1 February 2006 and 11 October 2016. 1490 ACS cases were matched to 13,550 controls by date of birth, sex, date of cohort entry (first long‐acting bronchodilator dispensing), and COPD severity.ResultsRelative to current use of LAMA therapy, current use of LAMA and LABA dual therapy was associated with a significantly higher risk of ACS (adjusted OR = 1.72; [95% CI: 1.28–2.31]).ConclusionDual long‐acting bronchodilator therapy, rather than LAMA mono‐therapy, could increase the risk of ACS by more than 50%. This has important implications for decisions about the potential benefit/harm ratio of COPD treatment intensification, given the modest benefits of dual therapy.

Association between Airport-Related Ultrafine Particles and Risk of Malignant Brain Cancer: A Multiethnic Cohort Study

Ultrafine particles (UFP; diameter less than or equal to 100 nm) may reach the brain via systemic circulation or the olfactory tract and have been implicated in the risk of brain tumors. The effects of airport-related UFP on the risk of brain tumors are not known. Here we determined the association between airport-related UFP and risk of incident malignant brain cancer (n = 155) and meningioma (n = 420) diagnosed during 16.4 years of follow-up among 75,936 men and women residing in Los Angeles County from the Multiethnic Cohort study. UFP exposure from aircrafts was estimated for participants who lived within a 53 km × 43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993-1996) through December 31, 2013. Cox proportional hazards models were used to estimate the effects of time-varying, airport-related UFP exposure on risk of malignant brain cancer and meningioma, adjusting for sex, race/ethnicity, education, and neighborhood socioeconomic status. Malignant brain cancer risk in all subjects combined increased 12% [95% confidence interval (CI), 0.98-1.27] per interquartile range (IQR) of airport-related UFP exposure (∼6,700 particles/cm3) for subjects with any address in the grid area surrounding the LAX airport. In race/ethnicity-stratified analyses, African Americans, the subgroup who had the highest exposure, showed a HR of 1.32 (95% CI, 1.07-1.64) for malignant brain cancer per IQR in UFP exposure. UFP exposure was not related to risk of meningioma overall or by race/ethnicity. These results support the hypothesis that airport-related UFP exposure may be a risk factor for malignant brain cancers. SIGNIFICANCE: Malignant brain cancer risk increases with airport-related UFP exposure, particularly among African Americans, suggesting UFP exposure may be a modifiable risk factor for malignant brain cancer.

PCV3 Risk of Obstructive Sleep Apnea in Adults with Treatment Resistant Hypertension: A Population-Based Cohort Study

Prior research has demonstrated an association between Obstructive sleep apnea (OSA) and Treatment Resistant Hypertension (TRH), defined as occurrence of overlapping use of ≥4 antihypertensives for a period of greater than 60 days. However, the risk of OSA in patients with TRH has not been quantified accurately. We sought to evaluate OSA risk in patients with TRH compared to those with treated, but non-resistant hypertension (non-TRH) using a time dependent exposure analysis. We conducted a retrospective cohort study of patients with treated hypertension (hypertension diagnosis + ≥2 antihypertensive drug claims within 1 year) using IBM MarketScan® commercial claims database from January 2008 to December 2018. We excluded beneficiaries without 12 months of continuous enrollment before the second antihypertensive fill date (index date of cohort entry) and those having the outcome (OSA: identified by ICD codes) in the 12-month pre-index period. Follow-up started from the index date until the earliest of: first occurrence of OSA, end of continuous enrollment, or study end date (December 31st, 2018). The primary analysis was via Cox proportional hazard regression with OSA as the dependent variable, and time-dependent exposure (non-TRH vs. TRH) and baseline covariates (demographic, clinical comorbidities, prescription medication use and healthcare utilization patterns) as independent variables. Of 2,354,346 patients with treated hypertension (mean-age: 50 years, 52% male), 49,542 met TRH criteria. The crude incidence rates of OSA were 34.2 and 17.7 per 1,000 person-years in TRH patients and non-TRH patients, respectively. In the adjusted Cox Proportional Hazard Regression model, TRH remained associated with a 72% increased risk of OSA (Hazard Ratio (HR): 1.72; 95% CI, 1.67-1.78) compared to non-TRH. Our data suggests that patients with TRH are at higher risk of incident OSA. More frequent OSA screening and regular monitoring is needed in this population.

Late thrombotic complications after SARS-CoV-2 infection in hemodialysis patients.

IntroductionThere is an increased risk of thrombotic complications in patients with COVID‐19. Hemodialysis patients are already at an increased risk for thromboembolic events such as stroke and pulmonary embolism. The aim of our study was to determine the incidence of late thrombotic complications (deep vein thrombosis, pulmonary embolism, stroke, new‐onset vascular access thrombosis) in maintenance hemodialysis patients after recovery from COVID‐19.MethodsWe performed a retrospective cohort study of 200 prevalent hemodialysis patients in our center at the start of the pandemic. We excluded incident patients after the cohort entry date and those who required hemodialysis for acute kidney injury, and excluded patients with less than 1 month follow‐up due to kidney transplantation or death from non‐thrombotic causes.FindingsOne‐hundred and eighty five prevalent hemodialysis patients finally met the inclusion criteria; 37 patients (17.6%) had SARS‐CoV‐2 infection, out of which 10 (27%) died during the acute phase of disease without evidence of thrombotic events. There was an increased risk of thrombotic events in COVID‐19 survivors compared to the non‐infected cohort (18.5% vs. 1.9%, p = 0.002) after a median follow‐up of 7 months. Multivariate regression analysis showed that COVID‐19 infection increased risk for late thrombotic events adjusted for age, sex, hypertension, diabetes, antithrombotic treatment, and previous thrombotic events (Odds Ratio (OR) 26.4, 95% confidence interval 2.5–280.6, p = 0.01). Clinical and laboratory markers did not predict thrombotic events.ConclusionsThere is an increased risk of late thrombotic complications in hemodialysis patients after infection with COVID‐19. Further studies should evaluate the benefit of prolonged prophylactic anticoagulation in hemodialysis patients after recovery from COVID‐19.

MO721THROMBOTIC EVENTS AFTER COVID-19 INFECTION IN HEMODIALYSIS PATIENTS*

Background and AimsThere is an increased risk of thrombotic complications in patients with COVID-19. Hemodialysis patients are already at an increased risk for thromboembolic events such as stroke and pulmonary embolism. The aim of our study was to determine the incidence of late thrombotic complications (deep vein thrombosis, pulmonary embolism, stroke, new-onset vascular access thrombosis) in maintenance hemodialysis patients after recovery from COVID-19.MethodWe performed a retrospective cohort study of 200 prevalent hemodialysis patients in our center at the start of the pandemic. We excluded incident patients after the cohort entry date and those who required hemodialysis for acute kidney injury, and excluded patients with less than 1 month follow-up due to kidney transplantation or death from non-thrombotic causes.Results185 prevalent hemodialysis patients finally met the inclusion criteria; 37 patients (17.6%) had SARS-CoV-2 infection, out of which 10 (27%) died during the acute phase of disease without evidence of thrombotic events. There was an increased risk of thrombotic events in COVID-19 survivors compared to the non-infected cohort (18.5% vs 1.9%, p=0.002) after a median follow-up of 7 months. Stroke incidence was 38.9 episodes/1000 patient-years in patients infected with SARS-CoV-2, compared to an incidence of 2.8 episodes/1000 patient-years in non-infected patients during the follow-up period. The median time from diagnosis of SARS-CoV-2 to the first thrombotic event was 62 days (interquartile range 5-118 days). Survival analysis with Kaplan-Meier curves revealed an increase in the rate of thrombotic events after SARS-CoV-2 compared to non-infected patients (see Figure 1). Mean survival from thrombotic event was 6.1±0.4 months in the COVID-infected group, compared to 6.97±0.04 months in the non-infected group (p<0.001). Multivariate regression analysis showed that COVID-19 infection increased risk for late thrombotic events adjusted for age, sex, hypertension, diabetes, antithrombotic treatment and previous thrombotic events (OR 26.4, 95% CI 2.5-280.6, p=0.01). Clinical and laboratory markers did not predict thrombotic events.MO721 Figure 1:Kaplan-Meier survival curves for freedom from thrombotic events, stratified by COVID-19 infection statusConclusionThere is an increased risk of late thrombotic complications in hemodialysis patients after infection with COVID-19. Further studies should evaluate the benefit of prolonged prophylactic anticoagulation in hemodialysis patients after recovery from COVID-19.

Stroke associated with non-adherence and non-persistence with direct oral anticoagulants in Germany

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Daiichi Sankyo Europe GmbH Background Based on results of multiple randomised controlled trials, direct oral anticoagulants (DOACs) are frequently used to reduce stroke risk in patients with atrial fibrillation (AF). The hypothesis is that in the real-world setting DOACs are effective in reducing the risk of stroke but ensuring continuous use is essential because of the rapid decline in anticoagulation activity when doses are omitted. Purpose The aim of this study was to assess the relationship between non-adherence, discontinuation of DOAC treatment and incidence of ischaemic stroke. Methods A nested case-control study was conducted in the InGef database, an anonymised healthcare claims database in Germany. AF patients starting DOACs between drug approval date and 31/12/2018 were included. We restricted to patients aged ≥45, ≥1 year database history, ≥1 year follow-up and at least two DOAC dispensings after cohort entry date (CED) (date of first dispensing). Patients with an ischaemic stroke during follow-up were selected as cases and compared with matched controls (matched on age +/- 5 years, sex, year of CED and CHA₂DS₂-VASc-score at CED). Controls were assigned the index date (date of first stroke diagnosis) of the corresponding case. Adherence to treatment was assessed among current users (DOAC use at or within 30 days before index date) and defined as proportion of days covered (PDC) ≥80% during CED and index date. Persistent users were defined as those with continuous DOAC use from CED to index date. We also assessed the effect of current, recent (DOAC use within 30-365 days before index date) and past use (DOAC use more than 1 year before index date). Odds ratios (ORs) with 95% confidence intervals (CIs) for ischaemic stroke were determined in logistic regression models. Results 900 cases and 3,570 controls were included. Among cases and controls, mean ± sd age was 80 ± 8 years and 49% were male. Current users who were non-adherent had a significant 1.21 higher odds (95% CI 1.01-1.45) of ischaemic stroke compared to adherent users. Similar results were observed in twice-daily (BID) users (OR 1.42 (1.15-1.75)). However, among once-daily (QD) users, the odds was not different between the adherent and non-adherent users (OR 0.99 (95% CI 0.58-1.69)). The risk of ischaemic stroke was significantly higher among non-persistent users compared to persistent users (OR 1.91 (95% CI 1.64-2.22)). Similar findings were observed among QD and BID users. The comparison of past and recent users to current users showed that the OR became higher the longer a patient had stopped DOAC use. Conclusion Both non-adherence and non-persistence were found to increase the risk of ischaemic stroke, showing that continuous use is essential for both BID and QD users. In BID users, there seems to be a stronger association between non-adherence and risk of stroke than in QD users. An explanation might be the higher degree of difficulty in adhering to a BID than QD regimen.

Effect of Statin Use on the Risk of Osteoporotic Fracture in Patients With Metabolic Syndrome: A Nested Case-Control Study

Statins may have advantageous pleiotropic effects on bone metabolism, however, the clinical evidence about the association is still unclear. Although many studies have already evaluated this association, they have performed mostly in a general population with limitation of between-study heterogeneity. Statin may not be equally effective for bone metabolism to every patient, but it can give some benefits for some patients especially with metabolic syndrome (MetS). However, no recent study assessing this relationship, to best our knowledge, has evaluated specifically on patients with MetS. It is also unclear whether the association between statin and osteoporotic fracture differ by statin intensity, dose (cumulative defined daily dose), and duration. This study aimed to investigate the association of statin use with the risk of major osteoporotic fracture in MetS patients from a population-based cohort (NHIS-HEALS, 2002–2015). A nested case-control study was performed in patients with MetS (≥50 years) who had no history of previous osteoporotic fracture. This study included 17,041 cases diagnosed as new-onset osteoporotic fractures and controls matched in a 1:1 ratio by age, sex, body mass index, cohort entry date, and follow-up duration. Conditional logistic regression analysis was used to evaluate covariate-adjusted odds ratio (OR) and 95% confidence interval (CI). During the 4-year follow up period, statin users had a significantly lower risk of major osteoporotic fractures by 9% (OR, 0.91; 95% CI, 0.85 to 0.97) compared with non-users. Among subtypes of major osteoporotic fracture, a risk reduction of vertebral fracture was significant (OR, 0.86; 95% CI, 0.79 to 0.94), but not non-vertebral fracture (OR, 0.97; 95% CI, 0.88 to 1.06) with statin use. Longer duration (OR, 0.97 per 1 year) and cumulative dose (OR, 0.97 per 365 defined daily dose) of statin was negatively associated with the risk of major osteoporotic fracture. There was no difference in risk of major osteoporotic fractures among groups according to statin intensity. In conclusion, this study supports the hypothesis that statin treatment has a beneficial effect on major osteoporotic fracture, especially for vertebral fracture, in patients with MetS with a possibly dose-effect relationship.

503 Cardio-Vascular Burden of Narcolepsy Disease (CV-BOND): a Real-World Evidence Study

Abstract Introduction Narcolepsy is a rare, lifelong disorder that requires long-term treatment and is associated with multiple comorbidities, including cardiovascular conditions. Many available treatments have cardiovascular-related warnings and precautions in their labels. The objective of this study was to estimate the incidence of cardiovascular comorbidities in adult patients with a narcolepsy diagnosis in the US. Methods Claims from IBM® MarketScan®, an administrative claims database, between January 2014 and June 2019 were analyzed. Eligible patients were ≥18 years and had continuous medical and prescription coverage (gaps &amp;lt;30 days allowed). The narcolepsy cohort was defined by ≥2 outpatient claims containing a diagnosis of narcolepsy type 1 or type 2 on separate days and no more than 6 months apart, with ≥1 non-diagnostic office-visit. Non-narcolepsy patients were matched 3:1 to narcolepsy patients by calendar date of cohort entry, age, gender, US geographic region, and insurance type. Each incidence calculation required a 6 month wash-out period prior to cohort entry. Differences between cohorts were evaluated using a Cox proportional hazard model adjusted for age, gender, region, insurance type, and relevant morbidities/comorbidities and medications in the baseline period. Results Of 54,239,110 adults in the database, 12,816 and 38,441 were included in the narcolepsy and matched non-narcolepsy cohort. Approximately 67% were female patients and mean age was approximately 38 years in both cohorts. Incidence rates (per 1,000 person-years) for newly recorded cardiovascular comorbidities or events in narcolepsy/non-narcolepsy were: CVD without hypertension (13.29/7.99), MACE+ (11.75/6.86), heart failure (5.72/3.41), stroke (4.28/2.17), ischemic stroke (3.69/1.91), edema (9.84/4.22), and a composite of stroke, atrial fibrillation, and edema (17.73/8.88). Conclusion Physicians should consider the increased cardiovascular risk when considering risk modification strategies and treatment options for narcolepsy patients. Further research is needed to understand treatment-specific risks. Support (if any) Jazz Pharmaceuticals

Exploratory research on asthma exacerbation risk factors using the Japanese claims database and machine learning: a retrospective cohort study

Objective: Analytical studies of risk factor assessment using machine learning have recently been reported. We performed an exploratory detection study of asthma exacerbation-related factors using health insurance claims data and machine learning to explore risk factors that have high generalizability and can be easily obtained in daily practice. Methods: A dataset of asthma patients during May 2014-April 2019 from the Japanese insurance claims database, MediScope® (DB) was used. Patient characteristics and disease information were extracted, and association with occurrence of asthma exacerbation was evaluated to comprehensively search for exacerbation risk factors. Asthma exacerbations were defined as the co-occurrence of emergency medical procedures, such as emergency transport and intravenous steroid injections, with asthma claims, which were recorded in the database. Results: In total, 5,844 (13.7%) subjects had exacerbations in 42,685 eligible cases from the DB. Information on approximately 3,300 diseases was subjected to a machine learning, and 25 variables were extracted as variable importance and targeted for risk assessment. As a result, sex, days without exacerbation from cohort entry date at look-back period, Charlson Comorbidity Index, allergic rhinitis, chronic sinusitis, acute airway disease (upper airway), acute airway disease (lower airways), Chronic obstructive pulmonary disease/chronic bronchitis, gastroesophageal reflux disease, and hypertension were significantly associated with exacerbation. Dyslipidemia and periodontitis were detected as associated factors of reduced exacerbation risk. Conclusions: A comprehensive analysis of claims data using machine learning showed asthma exacerbation risk factors mostly consistent with those in previous studies. Further examination in other fields is warranted. Supplemental data for this article is available online at https://doi.org/10.1080/02770903.2021.1923740 .

Mortality, Falls, and Fracture Risk Are Positively Associated With Frailty: A SIDIAP Cohort Study of 890 000 Patients.

BackgroundFrail subjects are at increased risk of adverse outcomes. We aimed to assess their risk of falls, all-cause mortality, and fractures.MethodWe used a retrospective cohort study using the Sistema d’Informació per al Desenvolupament de l’Investigació en Atenció Primària database (>6 million residents). Subjects aged 75 years and older with ≥1 year of valid data (2007–2015) were included. Follow-up was carried out from (the latest of) the date of cohort entry up to migration, end of the study period or outcome (whichever came first). The eFRAGICAP classified subjects as fit, mild, moderate, or severely frail. Outcomes (10th revision of the International Classification of Diseases) were incident falls, fractures (overall/hip/vertebral), and all-cause mortality during the study period. Statistics: hazard ratios (HRs), 95% CI adjusted (per age, sex, and socioeconomic status), and unadjusted cause-specific Cox models, accounting for competing risk of death (fit group as the reference).ResultsA total of 893 211 subjects were analyzed; 54.4% were classified as fit, 34.0% as mild, 9.9% as moderate, and 1.6% as severely frail. Compared with the fit, frail had an increased risk of falls (adjusted HR [95% CI] of 1.55 [1.52–1.58], 2.74 [2.66–2.84], and 5.94 [5.52–6.40]), all-cause mortality (adjusted HR [95% CI] of 1.36 [1.35–1.37], 2.19 [2.16–2.23], and 4.29 [4.13–4.45]), and fractures (adjusted HR [95% CI] of 1.21 [1.20–1.23], 1.51 [1.47–1.55], and 2.36 [2.20–2.53]) for mild, moderate, and severe frailty, respectively. Severely frail had a high risk of vertebral (HR of 2.49 [1.99–3.11]) and hip fracture (HR [95% CI] of 1.85 [1.50–2.28]). Accounting for competing risk of death did not change results.ConclusionFrail subjects are at increased risk of death, fractures, and falls. The eFRAGICAP tool can easily assess frailty in electronic primary care databases in Spain.

Association of Bcr-Abl Tyrosine Kinase Inhibitors With Hepatitis B Virus Reactivation Requiring Antiviral Treatment in Taiwan

The US Food and Drug Administration (FDA) highlighted the potential risk of hepatitis B reactivation that was associated with Bcr-Abl tyrosine kinase inhibitor (TKI) treatment and has required updated product labels. To examine the association between hepatitis B flare and exposure to Bcr-Abl TKIs compared with non-Bcr-Abl TKIs. This nested case-control study included patients who entered a hepatitis B carrier cohort in Taiwan after January 1, 2005. Patients who received their first antiviral agents for hepatitis B flare for more than 28 days after the cohort entry date were included as case patients. For each case, a corresponding risk set was formed that included all eligible patients in the study cohort who had the same age (within 1 year), same sex, and were at risk of developing hepatitis B flare at the case date. As many as 10 control patients were randomly selected from the risk set for each case patient. TKIs were evaluated before the hepatitis B flare for case patients and before the corresponding index date for control patients. Data were collected from the Taiwan National Health Insurance research database from January 2000 to 2015. Data analysis was conducted from January to June 2019. Use of Bcr-AbL TKIs. Conditional logistic regression was used to estimate the rate ratio for the association between hepatitis B flare and exposure to Bcr-Abl TKIs compared with non-Bcr-Abl TKIs. Among 698 342 patients who carried incident hepatitis B virus, 66 702 patients with hepatitis B flare that required antiviral treatment (47 492 [71.2%] men; mean [SD] age at index date, 50.2 [13.8] years) were included as case patients, and 666 989 age and sex-matched patients (474 903 [71.2%] men; mean [SD] age, 50.2 [13.8] years) were included as control patients. Analysis revealed that Bcr-Abl TKI use during the previous 90 days was independently associated with a 56% higher risk of hepatitis B flare (adjusted rate ratio [aRR], 1.56; 95% CI, 1.11-2.20), and the aRR increased to 1.66 (95% CI, 1.20-2.28) for Bcr-Abl TKI use during the previous 365 days. Use of Bcr-AbL TKIs during the previous 60 days was associated with a significantly increased risk of flare among women (aRR, 3.20; 95% CI, 1.70-6.03) but not among men (aRR, 1.14; 95% CI, 0.72-1.81). These findings suggest that sex-specific strategies may be needed to monitor for hepatitis B reactivation among patients receiving Bcr-Abl TKIs.

Identifying prescribing cascades in Alzheimer's disease and related dementias: The calcium channel blocker-diuretic prescribing cascade.

Prescribing cascades occur when a physician prescribes a new drug to address the side-effect of another drug. Persons with Alzheimer's disease and related dementias (ADRD) are at increased risk for prescribing cascades. Our objective was to develop an approach to estimating the proportion of calcium channel blocker-diuretic (CCB-diuretic) prescribing cascades among persons with ADRD in two U.S. health plans. We identified patients aged ≥50 on January 1, 2017, dispensed a drug to treat ADRD in the 365-days prior to/on cohort entry date. Patients had medical/pharmacy coverage for 1 year before and through cohort entry. We excluded individuals with an institutional stay encounter in the 45 days prior to cohort entry and censored patients based on: disenrollment from coverage, death, or end of data. We identified incident and prevalent CCB use in the 183-days following cohort entry, and identified subsequent incident diuretic use among incident and prevalent CCB-users within 365-days from cohort entry. There were 121 538 eligible patients. Approximately 62% were female, with a mean age of 79.5 (SD ±8.6). Overall 2.1% of the cohort experienced a prevalent CCB-diuretic prescribing cascade with 1586 incident diuretic-users among 36 462 prevalent CCB-users (4.3%, 95% CI 4.1-4.6%]); and there were161 incident diuretic-users among 3304 incident CCB-users (4.9%, 95% CI 4.2-5.7%) (incident CCB-diuretic cascade). We describe an approach to identify prescribing cascades in persons with ADRD, which can be used to assess the proportion of prescribing cascades in large cohorts. We determined the proportion of CCB-diuretic prescribing cascades was low.

Levosimendan use in patients with acute heart failure and reduced ejection fraction with or without severe renal dysfunction in critical cardiac care units: a multi-institution database study

BackgroundAcute heart failure is a life-threatening clinical condition. Levosimendan is an effective inotropic agent used to maintain cardiac output, but its usage is limited by the lack of evidence in patients with severely abnormal renal function. Therefore, we analyzed data of patients with acute heart failure with and without abnormal renal function to examine the effects of levosimendan.MethodsWe performed this retrospective cohort study using data from the Chang Gung Research Database (CGRD) of Chang Gung Memorial Hospital (CGMH). Patients admitted for heart failure with LVEF ≤ 40% between January 2013 and December 2018 who received levosimendan or dobutamine in the critical cardiac care units (CCU) were identified. Patients with extracorporeal membrane oxygenation (ECMO) were excluded. Outcomes of interest were mortality at 30, 90, and 180 days after the cohort entry date.ResultsThere were no significant differences in mortality rate at 30, 90, and 180 days after the cohort entry date between the levosimendan and dobutamine groups, or between subgroups of patients with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and eGFR < 30 mL/min/1.73 m2 or on dialysis. The results were consistent before and after propensity score matching.ConclusionsLevosimendan did not increase short- or long-term mortality rates in critical patients with acute heart failure and reduced ejection fraction compared to dobutamine, regardless of their renal function. An eGFR less than 30 mL/min/1.73 m2 was not necessarily considered a contraindication for levosimendan in these patients.

Antidopaminergic-Antiparkinsonian Medication Prescribing Cascade in Persons with Alzheimer's Disease.

Persons living with Alzheimer's disease (AD) may be at increased risk for prescribing cascades due to greater multimorbidity, polypharmacy, and the need for more complex care. Our objective was to assess the proportion of the antidopaminergic-antiparkinsonian medication prescribing cascades among persons living with Alzheimer's disease. Two large administrative claims databases in the United States. We identified patients aged ≥50 on January 1, 2017, who were dispensed a drug used to treat Alzheimer's disease for at least 1 day in the 365 days prior to or on cohort entry date and who had medical and pharmacy coverage in the 365 days prior to the cohort entry date. We excluded individuals with a recent institutional stay. We identified incident antidopaminergic (antipsychotic/metoclopramide) use in the 183 days following cohort entry and identified subsequent incident antiparkinsonian drug use within 8 to 365 days. There were 121,538 patients with Alzheimer's disease eligible for inclusion. Approximately 62% were women with a mean age of 79.5 (SD ± 8.6). The mean number of drugs dispensed was 9.2 (SD ± 4.9). There were 36 incident antiparkinsonian users among 4,534 incident antipsychotic/metoclopramide users (0.8%). We determined that the proportion of antidopaminergic-antiparkinsonian medication prescribing cascades, widely considered as high-priority, was low. Our approach can be used to assess the proportion of prescribing cascades in populations considered to be at high risk and to prioritize system-level interventional efforts to improve medication safety in these patients.

Long-term Clinical Outcome of Major Adverse Vascular Events After Hypertensive Disorders of Pregnancy.

To assess the association between hypertensive disorders of pregnancy and adverse events after pregnancy, including chronic kidney disease and major adverse cardiovascular events (cerebrovascular accident, coronary artery disease, or death). A nationwide, population-based cohort study was conducted analyzing women with hypertensive disorders of pregnancy identified from Taiwan National Health Insurance Research Database from 2004 to 2015. Hypertensive disorders of pregnancy were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification codes. The study cohort was comprised of women aged 20-40 years diagnosed with hypertensive disorders of pregnancy from 2006 to 2013. The comparison group comprised of four randomly selected women without hypertensive disorders of pregnancy, matched for age and index date for each woman with hypertensive disorders of pregnancy. All the women were followed from the date of cohort entry until they developed chronic kidney disease or major adverse cardiovascular events or until the end of 2015, whichever occurred first. A Cox proportional hazard model was used to estimate the risk of chronic kidney disease and major adverse cardiovascular events. We identified 29,852 women with a diagnosis of hypertensive disorders of pregnancy and 119,408 matched women without hypertensive disorders of pregnancy who fit the inclusion criteria. The crude hazard ratios (HRs) were 5.22 (95% CI 4.67-5.83) and 2.26 (95% CI 1.99-2.57) for chronic kidney disease and major adverse cardiovascular events. After adjusting for potential confounders, hypertensive disorders of pregnancy was associated with a higher risk of chronic kidney disease (adjusted HR, 4.26; 95% CI 3.80-4.78), and major adverse cardiovascular events (adjusted HR, 2.15; 95% CI 1.89-2.45). This population-based cohort study indicated that women with hypertensive disorders of pregnancy are at a higher risk of chronic kidney disease and major adverse cardiovascular events than women without hypertensive disorders of pregnancy. Further studies are required to clarify the nature of these associations and to improve public health interventions.

Is the use of two versus one long-acting bronchodilator by patients with COPD associated with a higher risk of acute coronary syndrome in real-world clinical practice?

BackgroundCardiovascular comorbidity is common among patients with chronic obstructive pulmonary disease (COPD) and there is concern that long-acting bronchodilators (long-acting muscarinic antagonists (LAMAs) and long-acting beta2 agonists (LABAs)) may further...