A 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 (PM 2.5 ) and corticosteroid use on hospitalization 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 PM 2.5 . Main Outcome Measures Incidences of myocardial infarction or acute coronary syndrome, ischemic stroke or transient ischemic attack, heart failure, venous thromboembolism, atrial fibrillation, and all-cause mortality. We assessed additive interactions between PM 2.5 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 PM 2.5 exposure level was 8.3 ± 2.4 μg/m 3 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 PM 2.5 exposure. PM 2.5 demonstrated a non-linear relationship with some outcomes. We also observed evidence of an interaction existing between corticosteroid use and PM 2.5 for some CTEs. For an increase in PM 2.5 from 8 μg/m 3 to 12 μg/m 3 (a policy-relevant change), the RERI of corticosteroid use and PM 2.5 was significant for heart failure (15.6%, 95% CI: 4.0%-27.3%). Increasing PM 2.5 from 5 μg/m 3 to 10 μg/m 3 yielded significant RERIs for incidences of heart failure (32.4; 95% CI: 14.9%-49.9%) and myocardial infarction/acute coronary syndromes (29.8%; 95% CI: 5.5%-54.0%). Conclusion PM 2.5 and systemic corticosteroid use were independently associated with increases in CTE hospitalizations. We also found evidence of significant additive interactions between the two exposures for heart failure and myocardial infarction/acute coronary syndromes suggesting synergy between these two exposures. Strengths and Limitations of this Study We conduct analyses using robust causal inference and machine learning techniques and incorporate a large set of individual-level factors that are typically absent in environmental health analyses with large claims data sets. We present statistics that evaluate the synergy between fine particulate matter and corticosteroid therapy on the additive scale, which is more relevant for assessing excess risks and informing policy. Patient medical history prior to receiving Medicare benefits is unknowable within a Fee-for-Service claims database, which may lead to exclusion of some high-risk individuals from the cohort. We censor participants after the earlier of the end of first corticosteroid regimen or the first incidence of the outcome of interest, which makes the analyses statistically tractable but sacrifices some information in the data.