BackgroundThe European Society of Cardiology (ESC) guideline on non-ST-elevation acute coronary syndrome (N-STE ACS) proposed a new ACS rule-out protocol. ObjectivesTo evaluate this new tool, which uses diagnostic levels of high-sensitivity troponin T (hs-TnT; > 14 ng/L) in a slightly modified version and compare this to a recently proposed approach using undetectable levels of hs-TnT to rule out patients. MethodsThere were 534 consecutive patients with suspected ACS included. Protocol 1: symptom duration, hs-TnT at 0 and 6–9 h, Global Registry of Acute Coronary Events (GRACE) score, and symptom status at 6–9 h. Protocol 2: a single blood sample of hs-TnT. The primary endpoint was a discharge diagnosis of ACS by blinded adjudication. Secondary endpoints were ACS re-admission < 30 days and 1-year mortality. ResultsProtocol 1 classified 434/534 (81%) patients, with 27.9% being ruled out. All myocardial infarctions were correctly ruled in, but 15 cases of unstable angina were missed, resulting in a sensitivity and negative predictive value of 87.3% (79.6–92.5%) and 87.6% (80.4–92.9%), respectively. Protocol 2 ruled out 17.5% of the population, yielding a sensitivity and negative predictive value of 94.1% (88.2–97.6%) and 90.8% (81.9–96.2%), respectively. Both protocols correctly ruled in 2/3 patients with ACS re-admission < 30 days and 55/56 1-year fatalities. ConclusionThe present study confirms the diagnostic value of a modified version of the ESC rule-out protocol (Protocol 1) in N-STE ACS patients, but also suggests that a simpler protocol using undetectable levels of hs-TnT (Protocol 2) could provide a similar or even superior sensitivity.