Exposure-Response to High PM 2.5 Levels for Cardiovascular Events in High-risk Older Adults in Taiwan.

Background: Multiple studies from countries with relatively lower PM 2.5 level demonstrated that acute and chronic exposure even at lower than recommended level, e.g., 9 µg/m 3 in the US increased the risk of cardiovascular (CV) events. However, limited studies using individual level data exist from countries with a wider range of PM levels to illustrate shape of the exposure-response curve throughout the range including > 20 µg/m 3 PM 2·5 concentrations. Taiwan with its policies reduced PM 2.5 over time provide opportunities to illustrate the dose response curves and how reductions of PM 2.5 over time correlated with CV events incidence in a nationwide sample. Methods: Using data from the 2009-2019 Taiwan National Health Insurance Database linked to nationwide PM2.5 data. We examined the shape and magnitude of the exposure-response curve between seasonal average PM 2·5 level and CV events-related hospitalizations among older adults at high-risk for CV events. We used history-adjusted marginal structural models including potential confounding by individual demographic factors, baseline comorbidities, and health service measures. To quantify the risk below and above 20 µg/m 3 we conducted stratified Cox regression. We also plotted PM 2.5 and CV events from 2009-2019 as well as average temperature as a comparison. Findings: Using the PM 2.5 concentration <15 µg/m 3 (Taiwan regulatory standard) as a reference, the seasonal average PM 2.5 concentration (15-23.5µg/m 3 and > 23.5 µg/m 3 ) were associated with hazard ration of 1.13 (95%CI 1.09-1.18) and 1.19 (95%CI 1.14-1.24), 1.07 (95%CI 1.03-1.11) and 1.14 (95%CI 1.10-1.18), 1.22 (95%CI 1.08-1.38) and 1.31 (95%CI 1.16-1.48), 1.04 (95%CI 0.98-1.10) and 1.10 (95%CI 1.04-1.16) respectively for HF, IS/TIA,PE/DVT and MI/ACS. A nonlinear relationship between PM 2·5 and CV events outcomes was observed at PM 2·5 levels above 20 µg/m 3 . Interpretation: A nonlinear exposure-response relationship between PM2·5 concentration and the incidence of cardiovascular events exists when PM2.5 is higher than the levels recommended by WHO Air Quality Guidelines. Further lowering PM2·5 levels beyond current regulatory standards may effectively reduce the incidence of cardiovascular events, particularly HF and DVT, and can lead to tangible health benefits in high-risk elderly population.

Ambient heat exposure patterns and emergency department visits and hospitalizations among medicare beneficiaries 2008-2019.

OBJECTIVE: To assess the association between ambient heat and all-cause and cause-specific emergency department (ED) visits and acute hospitalizations among Medicare beneficiaries in the conterminous United States. DESIGN: Retrospective cohort study. SETTING: Conterminous US from 2008 and 2019. PARTICIPANTS: 2% random sample of all Medicare fee-for-service beneficiaries eligible for Parts A, B, and D. MAIN OUTCOME MEASURES: All-cause and cause-specific (cardiovascular, renal, and heat-related) ED visits and unplanned hospitalizations were identified using primary ICD-9 or ICD-10 diagnosis codes. We measured the association between ambient temperature - defined as daily mean temperature percentile of summer (June through September) - and the outcomes. Hazard ratios and their associated 95% confidence intervals were estimated using multivariable Cox proportional hazards regression, adjusting for individual level demographics, comorbidities, healthcare utilization factors and zip-code level social factors. RESULTS: Among 809,636 Medicare beneficiaries (58% female, 81% non-Hispanic White, 24% <65), older beneficiaries (aged ≥65) exposed to >95th percentile temperature had a 64% elevated adjusted risk of heat-related ED visits (HR [95% CI], 1.64 [1.46,1.85]) and a 4% higher risk of all-cause acute hospitalization (1.04 [1.01,1.06]) relative to <25th temperature percentile. Younger beneficiaries (aged <65) showed increased risk of heat-related ED visits (2.69 [2.23,3.23]) and all-cause ED visits (1.03 [1.01,1.05]). The associations with heat related events were stronger in males and individuals dually eligible for Medicare and Medicaid. No significant differences were observed by climatic region. We observed no significant relationship between temperature percentile and risk of CV-related ED visits or renal-related ED visits. CONCLUSIONS: Among Medicare beneficiaries from 2008 to 2019, exposure to daily mean temperature ≥ 95th percentile was associated with increased risk of heat-related ED visits, with stronger associations seen among beneficiaries <65, males, and patients with low socioeconomic position. Further longitudinal studies are needed to understand the impact of heat duration, intensity, and frequency on cause-specific hospitalization outcomes.

Air pollution and serious bleeding events in high-risk older adults.

IMPORTANCE: Despite biological plausibility, very few epidemiologic studies have investigated the risks of clinically significant bleeding events due to particulate air pollution. OBJECTIVE: To measure the independent and synergistic effects of PM2.5 exposure and anticoagulant use on serious bleeding events. DESIGN: Retrospective cohort study (2008-2016). SETTING: Nationwide Medicare population. PARTICIPANTS: A 50% random sample of Medicare Part D-eligible Fee-for-Service beneficiaries at high risk for cardiovascular and thromboembolic events. EXPOSURES: Fine particulate matter (PM2.5) and anticoagulant drugs (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin). MAIN OUTCOMES AND MEASURES: The outcomes were acute hospitalizations for gastrointestinal bleeding, intracranial bleeding, or epistaxis. Hazard ratios and 95% CIs for PM2.5 exposure were estimated by fitting inverse probability weighted marginal structural Cox proportional hazards models. The relative excess risk due to interaction was used to assess additive-scale interaction between PM2.5 exposure and anticoagulant use. RESULTS: The study cohort included 1.86 million high-risk older adults (mean age 77, 60% male, 87% White, 8% Black, 30% anticoagulant users, mean PM2.5 exposure 8.81 µg/m3). A 10 µg/m3 increase in PM2.5 was associated with a 48% (95% CI: 45%-52%), 58% (95% CI: 49%-68%) and 55% (95% CI: 37%-76%) increased risk of gastrointestinal bleeding, intracranial bleeding, and epistaxis, respectively. Significant additive interaction between PM2.5 exposure and anticoagulant use was observed for gastrointestinal and intracranial bleeding. CONCLUSIONS: Among older adults at high risk for cardiovascular and thromboembolic events, increasing PM2.5 exposure was significantly associated with increased risk of gastrointestinal bleeding, intracranial bleeding, and epistaxis. In addition, PM2.5 exposure and anticoagulant use may act together to increase risks of severe gastrointestinal and intracranial bleeding. Thus, clinicians may recommend that high-risk individuals limit their outdoor air pollution exposure during periods of increased PM2.5 concentrations. Our findings may inform environmental policies to protect the health of vulnerable populations.

Ambient Heat and Risk of Serious Hypoglycemia in Older Adults With Diabetes Using Insulin in the U.S. and Taiwan: A Cross-National Case-Crossover Study.

OBJECTIVE: To measure the association between ambient heat and hypoglycemia-related emergency department visit or hospitalization in insulin users. RESEARCH DESIGN AND METHODS: We identified cases of serious hypoglycemia among adults using insulin aged ≥65 in the U.S. (via Medicare Part A/B/D-eligible beneficiaries) and Taiwan (via National Health Insurance Database) from June to September, 2016-2019. We then estimated odds of hypoglycemia by heat index (HI) percentile categories using conditional logistic regression with a time-stratified case-crossover design. RESULTS: Among ∼2 million insulin users in the U.S. (32,461 hypoglycemia case subjects), odds ratios of hypoglycemia for HI >99th, 95-98th, 85-94th, and 75-84th percentiles compared with the 25-74th percentile were 1.38 (95% CI, 1.28-1.48), 1.14 (1.08-1.20), 1.12 (1.08-1.17), and 1.09 (1.04-1.13) respectively. Overall patterns of associations were similar for insulin users in the Taiwan sample (∼283,000 insulin users, 10,162 hypoglycemia case subjects). CONCLUSIONS: In two national samples of older insulin users, higher ambient temperature was associated with increased hypoglycemia risk.

Retrospective cohort study investigating synergism of air pollution and corticosteroid exposure in promoting cardiovascular and thromboembolic events in older adults.

OBJECTIVE: To evaluate the synergistic effects created by fine particulate matter (PM2.5) and corticosteroid use on hospitalisation and mortality in older adults at high risk for cardiovascular thromboembolic events (CTEs). DESIGN AND SETTING: A retrospective cohort study using a US nationwide administrative healthcare claims database. PARTICIPANTS: A 50% random sample of participants with high-risk conditions for CTE from the 2008-2016 Medicare Fee-for-Service population. EXPOSURES: Corticosteroid therapy and seasonal-average PM2.5. MAIN OUTCOME MEASURES: Incidences of myocardial infarction or acute coronary syndrome (MI/ACS), ischaemic stroke or transient ischaemic attack, heart failure (HF), venous thromboembolism, atrial fibrillation and all-cause mortality. We assessed additive interactions between PM2.5 and corticosteroids using estimates of the relative excess risk due to interaction (RERI) obtained using marginal structural models for causal inference. RESULTS: Among the 1 936 786 individuals in the high CTE risk cohort (mean age 76.8, 40.0% male, 87.4% white), the mean PM2.5 exposure level was 8.3±2.4 µg/m3 and 37.7% had at least one prescription for a systemic corticosteroid during follow-up. For all outcomes, we observed increases in risk associated with corticosteroid use and with increasing PM2.5 exposure. PM2.5 demonstrated a non-linear relationship with some outcomes. We also observed evidence of an interaction existing between corticosteroid use and PM2.5 for some CTEs. For an increase in PM2.5 from 8 µg/m3 to 12 µg/m3 (a policy-relevant change), the RERI of corticosteroid use and PM2.5 was significant for HF (15.6%, 95% CI 4.0%, 27.3%). Increasing PM2.5 from 5 µg/m3 to 10 µg/m3 yielded significant RERIs for incidences of HF (32.4; 95% CI 14.9%, 49.9%) and MI/ACSs (29.8%; 95% CI 5.5%, 54.0%). CONCLUSION: PM2.5 and systemic corticosteroid use were independently associated with increases in CTE hospitalisations. We also found evidence of significant additive interactions between the two exposures for HF and MI/ACSs suggesting synergy between these two exposures.

Racial differences in setting of implantable cardioverter-defibrillator placement in older adults with heart failure and association with disparate post-implant outcomes.

Background: Implantable cardioverter-defibrillator (ICD) placement in heart failure (HF) patients during or early after (≤90 days) unplanned cardiovascular hospitalizations has been associated with poor outcomes. Racial and ethnic differences in this "peri-hospitalization" ICD placement have not been well described. Methods: Using a 20% random sample of Medicare beneficiaries, we identified older (≥66 years) patients with HF who underwent ICD placement for primary prevention from 2008 to 2018. We investigated racial and ethnic differences in frequency of peri-hospitalization ICD placement using modified Poisson regression. We utilized Kaplan-Meier analyses and Cox regression to investigate the association of peri-hospitalization ICD placement with differences in all-cause mortality and hospitalization (HF, cardiovascular and all-cause) within and between race and ethnicity groups for up to 5-year follow-up. Results: Among the 61,710 beneficiaries receiving ICDs (35% female, 82% White, 10% Black, 6% Hispanic), 44% were implanted peri-hospitalization. Black [adjusted rate ratio (RR) 95% Confidence Interval (95% CI): 1.16 (1.12, 1.20)] and Hispanic [RR (95% CI): 1.10 (1.06, 1.14)] beneficiaries were more likely than White beneficiaries to have ICD placement peri-hospitalization. Peri-hospitalization ICD placement was associated with an at least 1.5× increased risk of death, 1.5× increased risk of re-hospitalization and 1.7× increased risk of HF hospitalization during 3-year follow-up in fully adjusted models. Although beneficiaries with peri-hospitalization placement had the highest mortality and readmission rates 1- and 3-year post-implant (log-rank p < 0.0001), the magnitude of the associated risk did not differ significantly by race and ethnicity (p = NS for interaction). Conclusions: ICD implantation occurring during the peri-hospitalization period was associated with worse prognosis and occurred at higher rates among Black and Hispanic compared to White Medicare beneficiaries with HF during the period under study. The risk associated with peri-hospitalization ICD placement did not differ by race and ethnicity. Future paradigms aimed at enhancing real-world effectiveness of ICD therapy and addressing disparate outcomes should consider timing and setting of ICD placement in HFrEF patients who otherwise meet guideline eligibility.

Validity of International Classification of Diseases (ICD)-10 Diagnosis Codes for Identification of Acute Heart Failure Hospitalization and Heart Failure with Reduced Versus Preserved Ejection Fraction in a National Medicare Sample.

BACKGROUND: Heart failure (HF) is a leading cause of hospitalization in older adults. Medicare data have been used to assess HF outcomes. However, the validity of ICD-10 diagnosis codes (used since 2015) to identify acute HF hospitalization or distinguish reduced (heart failure with reduced ejection fraction) versus preserved ejection fraction (HFpEF) is unknown in Medicare data. METHODS: Using Medicare data (2015-2017), we randomly sampled 200 HF hospitalizations with ICD-10 diagnosis codes for HF in the first/second claim position in a 1:1:2 ratio for systolic HF (I50.2), diastolic HF (I50.3), and other HF (I50.X). The primary gold standards included recorded HF diagnosis by a treating physician for HF hospitalization, ejection fraction (EF)≤50 for heart failure with reduced ejection fraction, and EF>50 for HFpEF. If the quantitative EF was not present, then qualitative descriptions of EF were used for heart failure with reduced ejection fraction/HFpEF gold standards. Multiple secondary gold standards were also tested. Gold standard data were extracted from medical records using standardized forms and adjudicated by cardiology fellows/staff. We calculated positive predictive values with 95% CIs. RESULTS: The 200-chart validation sample included 50 systolic, 50 diastolic, 47 combined dysfunction, and 53 unspecified HF patients. The positive predictive values of acute HF hospitalization was 98% [95% CI, 95-100] for first-position ICD-10 HF diagnosis and 66% [95% CI, 58-74] for first/second-position diagnosis. Quantitative EF was available for ≥80% of patients with systolic, diastolic, or combined dysfunction ICD-10 codes. The positive predictive value of systolic HF codes was 90% [95% CI, 82-98] for EFs≤50% and 72% [95% CI, 60-85] for EFs≤40%. The positive predictive value was 92% [95% CI, 85-100] for HFpEF for EFs>50%. The ICD-10 codes for combined or unspecified HF poorly predicted heart failure with reduced ejection fraction or HFpEF. CONCLUSIONS: ICD-10 principal diagnosis identified acute HF hospitalization with a high positive predictive value. Systolic and diastolic ICD-10 diagnoses reliably identified heart failure with reduced ejection fraction and HFpEF when EF 50% was used as the cutoff.

Disparate Cardiovascular Hospitalization Trends Among Young and Middle-Aged Adults Within and Across Race and Ethnicity Groups in Four States in the United States.

Background Inpatient hospitalizations for cardiovascular disease (CVD) decreased nationally in the past decade. However, data are lacking on whether national declines represent trends within and across race and ethnicity populations from different US regions. Methods and Results Using State Inpatient Databases, Census Bureau and Behavioral Risk Factor Surveillance System data for Florida, Kentucky, New Jersey, and North Carolina, we identified all CVD hospitalizations and population characteristics for adults aged 18 to 64 years between January 1, 2009 and December 31, 2018. We calculated yearly CVD hospitalization rates for each state for the overall population, by sex, race, and ethnicity. We modeled yearly trends in age-adjusted CVD hospitalization rate in each state using negative binomial regression. State base populations were similar by age (mean age: 40-42 years) and sex (50%-51% female) throughout the study period. There were 314 973 and 288 843 total CVD hospitalizations among the 4 states in 2009 and 2018, respectively. Crude hospitalization rates declined in all states (age 18-44 years NJ: -33.4%; KY: -17.0%; FL: -11.9%; NC: -11.2%; age 45-64 years NJ: -29.8%; KY: -20.3%; FL: -12.2%; NC: -11.6%) over the study period. In age-adjusted models, overall hospitalization rates declined significantly in NJ -2.5%/y (95% CI, -2.9 to -2.1) and in KY -1.6%/y (-1.9 to -1.2) with no significant declining trend in FL and NC. Similar findings were present by sex. Among non-Hispanic White populations, mean yearly decline in hospitalization rate was significant in all states except FL, with the greatest declines in NJ (-3.8%/y [-4.4 to -3.2], P values for state-year interaction <0.0001). By contrast, a significant declining trend was present for non-Hispanic Black and Hispanic populations only in NJ (P values for state-year interaction <0.001). We found similar differences in trend between states in sensitivity analyses incorporating additional demographic and comorbid characteristics. Conclusions Decreases in CVD hospitalization rates in the past decade among nonelderly adults varied considerably by state and appeared largely driven by declines among non-Hispanic White populations. Overall declines did not represent divergent trends between states within non-Hispanic Black and Hispanic populations. Recognition of differences not just between but also within race and ethnicity populations should inform national and local policy initiatives aimed at reducing disparities in CVD outcomes.

Diabetes mellitus and Alzheimer's disease: shared pathology and treatment?

Epidemiological and basic science evidence suggest a possible shared pathophysiology between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). It has even been hypothesized that AD might be 'type 3 diabetes'. The present review summarizes some of the evidence for the possible link, putative biochemical pathways and ongoing clinical trials of antidiabetic drugs in AD patients. The primary and review literature were searched for articles published in peer-reviewed sources that were related to a putative connection between T2DM and AD. In addition, public sources of clinical trials were searched for the relevant information regarding the testing of antidiabetic drugs in AD patients. The evidence for a connection between T2DM and AD is based upon a variety of diverse studies, but definitive biochemical mechanisms remain unknown. Additional study is needed to prove the existence or the extent of a link between T2DM and AD, but sufficient evidence exists to warrant further study. Presently, AD patients might benefit from treatment with pharmacotherapy currently used to treat T2DM and clinical trials of such therapy are currently underway.