Growing evidence suggests that enteric-coated aspirin, the formulation currently dominating the market, is not providing the desired clinical performance thereby supporting the need for a better aspirin option. By 2035, medical costs of cardiovascular disease (CVD) in the U.S. are projected to skyrocket to $749 billion USD. Low-dose aspirin is effective in reducing the risk of cardiovascular events and it is estimated that approximately one-third of U.S. adults, aged ≥40 years use it daily. For a theoretical health plan of 1 million patients over a 5-year horizon, this results in $6 million USD in medication costs for aspirin. Gastrointestinal (GI) toxicity is the major limitation of aspirin therapy. In addition to ulcers and GI bleeds, less severe symptoms such as dyspepsia can still result in poor adherence or added costs from proton-pump inhibitors. Importantly, enteric-coated aspirin, designed to minimize GI toxicity and reduce GI complications, has been shown to carry the same risk for GI bleeding as regular aspirin in large observational meta-analyses. However, in addition to no safety advantage, enteric-coated aspirin appears to have efficacy limitations as well. Numerous pharmacokinetic and pharmacodynamic studies have shown that the coating impairs bioavailability and results in slower and less predictable antiplatelet activity compared with regular aspirin. The lack of definitive clinical trials demonstrating that the use of enteric-coated aspirin delivers the same efficacy as regular aspirin supplements the uncertainty. In fact, multiple recently published trials with enteric-coated aspirin failed to show benefit while showing increased GI bleeding. It therefore seems that adding a delayed-release coating to aspirin failed to deliver a safer next generation agent and may have jeopardized the ability to block platelets and prevent CV events. As such, a great unmet need remains for an alternative formulation with a safer GI profile and uncompromised antiplatelet activity.