Prophylactic ACE inhibitors, β-blockers Attenuate Trastuzumab-Mediated LVEF Decline

Canadian researchers identify a role for the cardiac drugs perindopril and bisoprolol in the prevention of trastuzumab-mediated cardiotoxicity

medwireNews: In women with HER2-positive early breast cancer, prophylactic treatment with the angiotensin-converting enzyme (ACE) inhibitor perindopril or the β-blocker bisoprolol can reduce trastuzumab-related declines in left ventricular ejection fraction (LVEF), shows a placebo-controlled trial.

However, the pharmacotherapy agents did not prevent trastuzumab-mediated LV remodelling, the primary outcome of the trial. Indeed, recruitment was terminated prematurely on the recommendation of the data and safety monitoring committee as additional participants were unlikely to affect the primary outcome, the study authors report in the Journal of Clinical Oncology.

They explain that "LV remodeling and/or dysfunction typically precede the development of symptomatic heart failure, and, thus, measures of cardiac geometry and function are potentially attractive measures for the early detection of [cancer therapy-related cardiac dysfunction]."

In the double-blind MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research) 101–Breast trial, 33 newly diagnosed patients with stage I–IIIA breast cancer were randomly assigned to receive perindopril alongside trastuzumab for the duration of the adjuvant treatment. A further 31 patients received bisoprolol alongside trastuzumab and 30 were given placebo.

Treatment with 17 cycles of trastuzumab led to an increase in indexed LV end-diastolic volume – a measure of cardiac remodelling – from baseline regardless of whether patients received perindopril, bisoprolol or placebo, with average increases of 7, 8 and 4 mL/m2, respectively.

But the average absolute decrease in LVEF was lower in the perindopril and bisoprolol groups relative to placebo, at 3% and 1%, respectively, versus 5%.

Researcher D Ian Paterson, from the University of Alberta in Edmonton, Canada, and co-authors did not find a correlation between changes in indexed LV end-diastolic volume and LVEF, suggesting that the beneficial effects of ACE inhibitors and β-blockers on LVEF in this patient population "do not seem to be mediated via favorable effects on cardiac geometry."

Perindopril- and bisoprolol-treated patients were also less likely than their placebo-treated counterparts to require interruptions in trastuzumab therapy due to LV dysfunction, report the investigators. They add that cancer therapy-related cardiac dysfunction was less common in the perindopril and bisoprolol groups than in the placebo group after four cycles of trastuzumab, but not after 17 cycles.

The researchers say that "larger studies with longer follow-up are required to reaffirm the protective effects of [ACE inhibitors] and [β-blockers] on LV function and to determine the impact of such interventions on cardiovascular outcomes."

They add: “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.”

Reference

Pituskin E, Mackey JR, Koshman S, et al. Multidisciplinary approach to novel therapies in cardio-oncology research (MANTICORE 101–Breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity. J Clin Oncol; Advance online publication 28 November 2016. doi:10.1200/JCO.2016.68.7830

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