TABLE 2.

Design Considerations for a Future Intervention Trial to Reduce the Cardiovascular Effects of PM_2.5

Trial Characteristic	Design Considerations
Population	Most germane population High-risk patients with ischemic cardiovascular disease (coronary artery disease, stroke, PAD) Other potential populations (as separate trials or as subpopulations of above cohort) Heart failure with preserved or reduced ejection fraction Patients enriched with risk enhancers such as diabetes mellitus/metabolic syndrome Patients with COPD
Sample size	Feasibility of a large trial (n >10,000) ofair filtration on CVD outcomes needs further assessment. Performing smaller (n ≈ 800 to 1,000) trials assessing surrogate endpoints to inform the design of an outcome trial may be helpful.
Exposure levels	Conducted in regions of United States with higher levels of PM2.5 exposures (domestic focus) Focus on U.S. areas of high-exposure enriched for socioeconomic disparities in participants Exposure-response curve indicates health benefits with reductions from moderate to lower exposure levels Trials in heavily-polluted regions (e.g., China, India) could be considered at a later time or be the focus of other agencies
Duration	Determined by population and outcomes (above). Cardiovascular outcome trial would require long period of intervention and follow-up to determine effect of intervention on outcomes Trial of intermediate outcomes (e.g., relevant biomarkers, risk factors) feasible in more limited time frame; ideal duration dependent on intermediate outcomes selected.
Outcomes	Assessing “hard” clinical CVD outcomes (e.g., composite endpoint) would be the ultimate goal Possible initial or vanguard trials could focus on surrogate endpoints or biomarkers including: Cardiometabolic biomarkers in high-risk population (e.g., hs-CRP, hs-troponin, HbA1c%) Cardiovascular risk factors (e.g., blood pressure, LDL-C, eGFR) Patient-centered outcomes (adherence, usability, feasibility, health status)
Other design issues	Adaptive design with planned evaluation and revision of enrollment and biomarker parameters Pragmatic design for use of air filtration Necessity of patient-centered endpoints in trial design (adherence, usability, feasibility)

COPD = chronic obstructive pulmonary disease; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; HbA1c% = HemoglobinA1c; hs-CRP = high-sensitivity c-reactive protein; hs-troponin = high-sensitivity troponin; LDL-C = low-density lipoprotein-cholesterol; PAD = peripheral artery disease; PM_2.5 = fine particulate matter.