Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol

Geeta Gulati, Siri Lagethon Heck, Anne Hansen Ree, Pavel Hoffmann, Jeanette Schulz-Menger, Morten W Fagerland, Berit Gravdehaug, Florian von Knobelsdorff-Brenkenhoff, Åse Bratland, Tryggve H Storås, Tor-Arne Hagve, Helge Røsjø, Kjetil Steine, Jürgen Geisler, Torbjørn Omland, Geeta Gulati, Siri Lagethon Heck, Anne Hansen Ree, Pavel Hoffmann, Jeanette Schulz-Menger, Morten W Fagerland, Berit Gravdehaug, Florian von Knobelsdorff-Brenkenhoff, Åse Bratland, Tryggve H Storås, Tor-Arne Hagve, Helge Røsjø, Kjetil Steine, Jürgen Geisler, Torbjørn Omland

Abstract

Aims: Contemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the β-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation.

Methods and results: In a 2 × 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the β-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI -0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed.

Conclusion: In patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function.

Keywords: Angiotensin antagonist; Biomarkers; Breast cancer; Cardiomyopathy; Imaging; β-Blocker.

© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1
Figure 1
Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): screening and randomization. *Excluded from all analysis. The intention-to-treat population included all patients who had a valid measurement for the primary outcome, received chemotherapy, and had no pre-randomization cardiac complications. HER, human epidermal growth factor receptor; MRI, magnetic resonance imaging.
Figure 2
Figure 2
Effect of candesartan and metoprolol on left ventricular ejection fraction during adjuvant therapy for early breast cancer. Shown are the changes in left ventricular ejection fraction expressed in percentage points with 95% confidence intervals. Concomitant therapy with candesartan alleviated the decline in left ventricular ejection fraction observed in the placebo group. This effect was consistent across subgroups with no formal interaction observed when patients were stratified according to age, current smoking, history of hypertension, body mass index, trastuzumab, or radiation (A). No effect of metoprolol on the mean left ventricular ejection fraction was observed (B). Median age at baseline was 49 years, and median body mass index at baseline was 25.6 kg/m². EOS, end-of-study; LVEF, left ventricular ejection fraction by magnetic resonance imaging; BMI, body mass index.

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