Synergistic Effects of PM2.5 and Use of Corticosteroids on Cardiovascular and Thromboembolic Events Among Older Adults: Evidence of Environment-Drug Interaction

Background: Numerous studies have reported associations between PM2.5 exposure and CTE. Meanwhile, other studies have demonstrated that systemic corticosteroid therapy is highly associated with increases to the risk of CTE. However, these previous studies have neglected to account for both PM2.5 and steroid use concomitantly, and thus never examined the potential synergy between these two risk factors.

Objectives: To assess the interaction between drug and fine particulate matter (PM2.5) exposure on cardiovascular and thromboembolic events (CTE) among older adults.

Methods: Using a 50% random sample from the Medicare Fee-for-Service population linked to neighborhood-level PM2.5 data derived from a well-validated, high-resolution model between 2008 and 2016, we identified a cohort of patients presenting with high-risk conditions for CTE. We followed patients until their first CTE event (atrial fibrillation [afib], heart failure [HF], stroke, acute coronary syndrome [ACS] or venous thromboembolism [VTE]) to evaluate whether PM2.5 and corticosteroid use are associated with these outcomes. Confounding is addressed by constructing inverse probability weights to fit time‐varying marginal structural proportional hazards models. Subsequently, we estimated the relative excess risk due to the interaction (RERI) to determine whether sufficient cause interactions exist between PM2.5 and corticosteroid use.

Results: Among 1,929,415 patients (mean age 76, 40% male, 87% white), mean PM2.5 exposure level was 8.34 μg/m3 and 35% used systemic steroid. During follow-up, 118,754 afib, 244,451 HF, 101,611 stroke, 93,191 ACS, and 41,635 VTE events were identified. After adjusting for confounding, both PM2.5 and corticosteroid were independently associated with increased risk in several outcomes. Increasing PM2.5 from 8 μg/m3 to 12 μg/m3 resulted in a significant excess risk increase for HF (RERI: 22.5% [11.8%-33.3%]) and death (RERI: 9.7% [2.4%, 16.9%]) attributable to the interaction between PM2.5 and corticosteroid use. Meanwhile, increasing PM2.5 from 5 μg/m3 to 10 μg/m3 resulted in excess risk increases due to interaction for HF (RERI: 42.3% [26.6%-58.2%]) as well as ACS (RERI: 31.2% [9.3%-53%])

Conclusions: In a large cohort of older adults at high risk for CTE, PM2.5 and systemic corticosteroid use were independently amd synergistically associated with increases in hospitalization for CTE. The results support the argument for the existence of potential drug-environment interactions which modify the risk of CTE events.