OBJECTIVES: To understand why dronedarone failed to unseat amiodarone as the primary antiarrhythmic treatment of choice for persistent AF, thus uncovering the clinical outcome requirements for a future AF therapy to achieve optimal market access. METHODS: Review published HTA reports and clinical trial outcomes for dronedarone to assess market access outcomes and associated Payer rationale for decision-making. Interview ten (10) managed care medical directors and AF key opinion leaders (KOLs) in US and thirteen (13) ex-Payers and AF KOLs in Europe (mix of stakeholders encompassing France, Germany, Italy, Spain, and UK) for validation and gap filling. RESULTS: Driven by benefits in all efficacy outcomes other than cardiovascular-related hospitalizations, Payers perceive amiodarone as more efficacious than dronedarone. The significant number of deaths during the high-risk PALLAS study crippled the safety image of dronedarone. Finally, a prohibitive price at launch contributed to a multiplicity of negative HTA assessments. In order to succeed where dronedarone failed and qualify as a step function increase over the standard-of-care amiodarone, Payers require at least:  40% reduction in AF recurrence; 30% relative risk reduction in hospitalizations compared to amiodarone; and fewer than 1% deaths as part of the clinical evidence package. Lower rates of bradyarrhythmia, liver toxicity, and no proarrhythmia will drive a favorable regulatory safety evaluation compared to amiodarone. CONCLUSIONS: The sub-optimal market access and relatively low utilization of dronedarone resulted primarily from a failure to demonstrate an improvement in recurrence as compared to amiodarone, as well as a significant number of deaths during pivotal trials. Manufacturers considering development of novel antiarrhythmics should strive for equivalent efficacy but superior safety to amiodarone if a 40% reduction in recurrence is not clinically feasible.