Background: Trastuzumab (T) increases the incidence of cardiac events (CEs) in patients (pts) with early breast cancer (BC). Dual blockade with P+T improves BC outcomes and is the standard of care for high-risk HER2-positive BC pts following the phase 3 APHINITY trial that evaluated the addition of P or placebo (Pla) to T and chemotherapy (CT). We analyzed the cardiac safety of P+T in APHINITY. Methods: APHINITY eligibility required a left ventricular ejection fraction (LVEF) ≥55% at study entry. LVEF assessment was performed every 3 months (mos) during treatment, every 6 mos up to month 36, and yearly thereafter. Primary CE was defined as heart failure (HF) class III/IV and a significant decrease in LVEF of at least 10 percentage points from baseline and to <50%, or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF or CEs confirmed by the cardiac advisory board. Results: The safety analysis population consists of 4,769 pts. With 74 mos median follow-up (FU), CEs were observed in 159 pts (3.3%): 83 (3.5%) in the P+T and 76 (3.2%) in Pla+T arms, respectively. Most CEs occurred during anti-HER2 therapy: 123/159 (77.4%) and were asymptomatic or mildly symptomatic LVEF decrease (133/159; 83.6%) (Table 1). There were 2 cardiac deaths in each arm (0.1%). More CEs occurred in pts receiving an anthracycline-based CT compared to those receiving non-anthracycline CT (139 vs. 20 CEs, respectively). Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 pts (81.9%). Conclusions: Dual blockade with P+T does not increase the risk of CE compared to Pla+T alone. The use of anthracycline-based CT increases the risk of a CE; hence non-anthracycline CT may be considered particularly in pts with other cardiovascular risk factors. Clinical trial information: NCT01358877