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Comment & Response
February 2017

Potential Benefit of Low-Dose Candesartan in Trastuzumab-Induced Cardiotoxic Effects—Reply

Author Affiliations
  • 1Division of Medical Oncology, Department of Clinical Pharmacology, NKI, Amsterdam, Netherlands
JAMA Oncol. 2017;3(2):279-280. doi:10.1001/jamaoncol.2016.3595

In Reply We thank Yun et al for their comments. Our trial tested the concept that upfront coadministration of the angiotensin II–receptor blocker (ARB) candesartan could prevent development of trastuzumab-induced cardiotoxic effects in the setting of early-stage human epidermal growth factor receptor 2 (HER2)–positive breast cancer treatment.1 When we designed the trial, there were no studies initiated that tested this hypothesis. According to the posology, in case of heart failure candesartan is often used at an initial dose of 4 mg/d and uptitrated to 32 mg/d to achieve maximal effect.2 However, in our study candesartan was prescribed to patients who a priori did not have clinically manifest heart failure; thus, starting with 4 mg/d and uptitration would be illogical because there was no clinical guidance for the uptitration. There is also no guidance for dose-selection in prevention of trastuzumab-induced heart failure, which mechanistically is fundamentally different from the cardiac toxic effects induced by anthracyclines. Furthermore, the studies referred to by Yun et al illustrate benefit of low dose candesartan on an angiotensin-converting enzyme inhibitor backbone,3 which does not apply to our clinical condition and trial. Therefore, we chose for the maximal optimal dose and reduced dose in case of intolerance. The baseline cardiac performance was relatively good since all patients had to have a left ventricular ejection fraction (LVEF) of 50% or higher, in line with the available safety information of trastuzumab. We cannot exclude the possibility that in high-risk patients with baseline value of LVEF below 50% the effect of ARB coadministration is different. Because the incidence of heart failure in the early studies with trastuzumab in low-risk patients was relatively high and limiting for optimal treatment we decided to select these patients for our trial. For a first trial testing, this concept for selection of high-risk patients was not considered appropriate.

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