Randomized Trial of Lisinopril Versus Carvedilol to Prevent Trastuzumab Cardiotoxicity in Patients With Breast Cancer

Background Trastuzumab is highly effective for HER2-positive breast cancer but is associated with a decline in left ventricular ejection fraction. Objective To determine whether angiotensin converting enzyme (ACE) inhibitors or beta blockers (BB) reduce the rate of trastuzumab-induced cardiotoxicity (LVEF decrease >10%, or >5% if less than 50%) and limit treatment interruptions. Methods In this double-blind, multicenter, placebo-controlled trial, cardiotoxicity and treatment interruptions in patients with HER2-positive breast cancer treated with trastuzumab for 12 months were evaluated over a 2-year period. Patients were stratified by anthracycline use and then randomized to receive lisinopril, carvedilol, or placebo. Results The study included 468 women, 51±10.7 years old. For the entire cohort, cardiotoxicity was comparable in the three arms and occurred in 32% patients on placebo, 29% on carvedilol, and 30% on lisinopril. For patients receiving anthracyclines, the event rates were higher in the placebo group (47%) than in the lisinopril (37%) and the carvedilol (31%) groups. Cardiotoxicity-free survival was longer on both carvedilol (HR 0.49, 95% confidence intervals 0.27, 0.89, p=0.009) or lisinopril (HR 0.53, CI 0.30, 0.94, p=0.015) than on placebo. In the whole cohort, as well as in the anthracycline arm, patients on active therapy with either ACE inhibitor or BB experienced fewer interruptions in trastuzumab than those on placebo. Conclusions In patients with HER2-positive breast cancer treated with trastuzumab, both lisinopril and carvedilol prevented cardiotoxicity in patients receiving anthracyclines. For such patients, lisinopril or carvedilol should be considered to minimize interruptions of trastuzumab.