Background: Treatment of HER2-positive breast cancer patients with trastuzumab is highly effective. However, a trastuzumab-associated decline in the left ventricular ejection fraction (LVEF) and clinical heart failure often prompt interruption and discontinuation of treatment. We therefore evaluated the preventive impact of an ACE inhibitor or beta blockers on the left ventricular ejection fraction (LVEF) during treatment of trastuzumab and chemotherapy. Methods: In a prospective randomized study, women with early stage HER2 positive breast cancer undergoing (neo)adjuvant chemotherapy with trastuzumab were randomized to receive either once daily lisinopril (10mg), carvedilol (10mg) or placebo during treatment with trastuzumab and further stratified by anthracycline use (AC+T versus nonAC+T). In a follow up to the initially presented primary endpoint of overall cardiotoxicity, we measured the protective effects of lisinopril or carvedilol to prevent a trastuzumab induced LVEF decrease to less than 50% over the course of therapy as well as the impact on LVEF decrease by >10% within normal LVEF levels. Results: A total of 468 women (mean age was 51±10.7 years) with HER2 overexpressing early-stage breast cancer from 127 community-based oncology practices were enrolled, a prespecified minimum target of 189 (40%) patients were treated with AC+T and 279 (60%) with nonAC+T. Baseline cardiac risk factors of this study population included obesity and an elevated blood pressure. Patients in the anthracycline group were younger and without hypertension. A small, not clinically relevant decrease in LVEF was observed during trastuzumab therapy in all patients which was not significantly altered by any of the cardiac interventions. The rate of LVEF decline to <50% was much more frequent in patients treated with an anthracycline than those with a non-anthracycline containing regimen (21% vs 4.1%). Treatment with lisinopril averted the decline in LVEF in the AC+T group compared to placebo (10.8% vs 30.5%, p=0.045). A smaller but not significant effect was seen by carvedilol. The incidence of cardiotoxicity manifesting as LVEF decrease by ≥10% within the normal range was similar in both AC+T and the nonAC+T arms, and not affected by either lisinopril or carvedilol. Conclusions: In patients treated with trastuzumab without anthracyclines, the impact of trastuzumab on LVEF is small and infrequent. In contrast, patients treated with anthracyclines prior to trastuzumab, demonstrated a decrease in LVEF to below normal levels in a larger than previously reported number of women in this community based setting. The trastuzumab-anthracycline induced decline in LVEF could be prevented with concurrent treatment with lisinopril, which was tolerable even in patients without hypertension. Clinical trial information: NCT01009918