PROJECT SUMMARY/ABSTRACT Only half of the >60 million US adults for whom statin therapy is indicated receive statins, and adherence and persistence is low. The most common reason of statin discontinuation is statin-associated muscle symptoms (SAMS), a spectrum of muscle symptoms the patient perceives as intolerable enough to impair daily activities and quality of life. A major driver of SAMS includes patient beliefs that statins are unsafe, further propagated by misconceptions, conspiracy theories, and negative lay media coverage. Over 90% of patients who experience SAMS can tolerate continued statin therapy after simple regimen modifications such as dose reductions, switching to a different statin, or alternate-day dosing. The most effective interventions to improve statin use, dose intensity, and outcomes in patients with SAMS include careful follow-up and management with team-based care models. However, reimbursement models, patient and provider acceptance, and other factors are significant barriers to the widespread implementation of team-based care. Even when team-based care is available, time constraints and the unique psychology associated with SAMS management have resulted in only 50% of those who experience SAMS ever re-challenging statin therapy. Systems-based practice—which uses ancillary personnel, mid-level providers, provider-facing health information technology, and patient self- management—combined with insights from clinical psychology and novel technology can help address these challenges to effectively managing SAMS. We propose to develop and test virtual SAMS management (VSM): a self-guided, web-based tool that incorporates (1) collection of self-reported patient beliefs, medication use behavior, and symptoms; (2) assessment of the likelihood that statin use is causing the self-reported symptoms; (3) provision of individualized cardiovascular risk, statin benefit, and SAMS treatment options, with delivery informed by cognitive debiasing literature; and (4) as appropriate, patients’ ability to self-manage their SAMS by modifying their statin regimen according to set protocols. First, we will use user iterative design and usability testing to develop the VSM software (Aim 1). Then, we propose a hybrid type II effectiveness- implementation randomized trial to determine whether VSM can improve the efficiency and effectiveness of team-based care at managing SAMS (Aim 2), and to identify facilitators and barriers that affect the uptake, adoption, and impact of the VSM strategy in team-based care settings (Aim 3). Results from our analysis of this innovative approach will answer important and timely questions concerning strategies for improving how patients view statins and encouraging statin re-challenge with evidence-based statin regimen modifications after SAMS occur. This will address an urgent public health need and open new avenues for research by optimizing SAMS management leading to increased statin adherence and persistence ...