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Obstructive sleep apnea (OSA) significantly impacts cardiovascular health, demonstrated by observational investigations showing an independently increased risk of ischemic heart disease, diabetes, hypertension, congestive heart failure, acute coronary syndrome, stroke, cardiovascular mortality, and all-cause mortality. Positive airway pressure (PAP), a medical therapy for sleep apnea, reverses airway obstruction and may help reduce cardiovascular risk. Prior to planning large Phase III randomized controlled trials to test the impact of PAP on cardiovascular outcomes, several gaps in knowledge need to be addressed. This paper describes two independent studies that worked collaboratively to fill these gaps. The populations, design features, and relative benefits/challenges of the two studies (SleepTight and BestAIR) are described. Both studies were encouraged to have multidisciplinary teams with expertise in behavioral interventions to improve PAP compliance. Both studies provide key information that will be useful to the research community in future large-scale, event-driven, randomized trials to evaluate the efficacy and/or effectiveness of strategies to identify and treat significant obstructive sleep apnea for decreasing risk of major adverse cardiovascular events in high-risk patients.