ACE Inhibitors, Beta-Blockers Could Mediate Trastuzumab Cardiac Toxicity

In patients with HER2-positive breast cancer undergoing trastuzumab therapy, the use of an ACE inhibitor or beta-blocker could protect against cancer therapy–related declines in left ventricular ejection fraction (LVEF), according to a new randomized trial. The therapy did not, however, prevent trastuzumab-mediated left ventricular remodeling.

“Addition of trastuzumab to adjuvant regimens for treatment of HER2-positive early breast cancer has significantly improved patient outcomes,” wrote study authors led by D. Ian Paterson, MD, of Walter C. Mackenzie Health Sciences Centre in Edmonton, Alberta, Canada. “However, dose-independent left ventricular dysfunction has been found in up to 18% of cases and overt heart failure in up to 4%.”

Because ACE inhibitors and beta-blockers are recommended therapies as initial treatment of heart failure and for established cancer therapy–related cardiac dysfunction (CTRCD), the authors conducted a randomized trial comparing perindopril, bisoprolol, or placebo in a 1:1:1 fashion. The trial included 94 patients with HER2-positive early breast cancer undergoing trastuzumab therapy. The results were published in the Journal of Clinical Oncology.

After 17 trastuzumab cycles, the primary outcome of indexed left ventricular end diastolic volume (LVEDVi; a measure of cardiac remodeling) was similar between the groups. The LVEDVi was +4 ± 11 mL/m² with placebo, +7 ± 14 mL/m² for perindopril, and +8 ± 9 mL/m² for bisoprolol (P = .36).

The change in LVEF from baseline, however, was better with bisoprolol (−1 ± 5%) than with placebo (−3 ± 4%) or with perindopril (−5 ± 5 %; P = .001). Indexed left ventricular mass and LVEDVi did not differ between the groups.

A multivariable analysis showed that only baseline LVEDVi was predictive of the change in that measure after treatment. However, baseline LVEF as well as the use of either perindopril (P = .016) or bisoprolol (P < .001) predicted decline in LVEF.

There were no significant study drug–related adverse events or serious adverse events in the trial.

“We have shown that prophylactic treatment with perindopril or bisoprolol prevents trastuzumab-mediated declines in LVEF,” the authors concluded. “Of further clinical relevance, these therapies also prevented CTRCD and associated interruptions in trastuzumab therapy.” They called for larger studies with longer follow-up to confirm the cardioprotective effects in this patient group. “Important considerations for future studies also include the identification of patient subgroups that are most likely to benefit from primary prophylaxis therapies as well as the optimal duration of treatment.”