OBJECTIVES: Approximately 18-20% of non-valvular atrial fibrillation (NVAF) patients are unable or unwilling to tolerate oral anticoagulant therapy (OAT), leaving them at risk of stroke. Left atrial appendage closure (LAAC) device offers an alternative stroke risk reduction strategy that enables the majority of patients to discontinue long-term systematic OAT. Acknowledging both potential improvements in health outcomes and additional upfront implantation costs of a LAAC device, this study considers the lifetime costs and benefits of LAAC compared to aspirin plus clopidogrel (A+C) in high-risk NVAF patients ineligible or unwilling to take OAT from the Italian and Spanish public healthcare payer perspectives. METHODS: A Markov model was constructed to assess the cost-effectiveness of LAAC compared to A+C. Due to the lack of direct clinical trial data an indirect comparison was undertaken; having warfarin as the common comparator, PROTECT-AF (mean follow-up: 3.8 years) and ACTIVE-W (1.3 years) trials were used to indirectly compare LAAC against A+C. Clinical results were combined with cost and utility data to assess the relative cost-effectiveness of the device. Furthermore, to reflect the real-world patient population, patients were stratified according to the severity of stroke and bleeding using CHADS-VASc and HAS-BLED scores. RESULTS: The base-case results demonstrate the LAAC as the cost-effective strategy compared to A+C in both countries with ICERs of €5,116 per life-year gained (LYG) and €3,942 per quality-adjusted life year (QALY) gained for Italy, and €10,298 per LYG and €7,683 per QALY gained for Spain. The ICERs per QALY gained are significantly below the willingness-to-pay thresholds generally accepted by each country: €25,000 in Italy and €30,000 in Spain. Results also demonstrate that the clinical benefit of LAAC becomes greater when risk of stroke and bleeding increases. CONCLUSIONS: LAAC device should be prioritised in patients who require an alternative to OAT and at relatively higher risk of stroke or bleeding.