Author's summary There is a fundamental trade-off that exists between ischemic and bleeding risk that must be considered in deciding the optimal strategy of dual antiplatelet therapy. Prasugrel-based de-escalation decreased the risk of net adverse clinical event (NACE) due to a reduction in bleeding in the HOST-REDUCE-POLYTECH-ACS trial. In non-ST-segment elevation acute coronary syndromes patients, prasugrel-based dose de-escalation from one-month post-percutaneous coronary intervention reduced the risk of NACE. In ST-elevation myocardial infarction (STEMI), de-escalation showed no benefit for NACE and a statistically insignificant but numerically higher rate of ischemic events. Our data raises caution about prasugrel dose reduction in higher thrombotic conditions.