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

Abstract

AimsContemporary 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 resultsIn 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.ConclusionIn 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.

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

“…The PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial tested whether angiotensin receptor blockers and/or beta‐blockers would be effective in preventing cardiotoxicity in patients diagnosed with breast cancer receiving anthracycline‐based chemotherapy with and without trastuzumab. The study showed modest benefit of candesartan, but not metoprolol, in preventing LVEF reduction assessed by magnetic resonance imaging94; however, neither medication was effective in preventing increases in high‐sensitivity troponin, a marker of subclinical myocardinal injury. A more‐recent randomized controlled trial failed to reproduce such beneficial effects of candesartan in patients treated with trastuzumab 95.…”

2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines

“…Kwestia, czy pacjenci z małym początkowym ryzykiem leczeni antracyklinami również odnoszą korzyści z profilaktycznego stosowania inhibitorów ACE, ARB lub beta-adrenolityków, pozostaje kontrowersyjna i obecnie nie można sformułować zalecenia na ten temat. W niedawno przeprowadzonej prospektywnej próbie klinicznej kontrolowanej placebo u chorych z wczesnym rakiem piersi leczonych antracyklinami stosowanie kandesartanu ograniczyło zmniejszenie LVEF w porównaniu z placebo lub beta-adrenolitykiem, natomiast nie miało wpływu na GLS ani biomarkery sercowe [227]. W tej próbie klinicznej metoprolol nie zapobiegł spadkowi LVEF związanemu z chemioterapią.…”

Possibilities of Ivabradine, a Selective Inhibitor of Ion F-Channels of Sinus Node, in Prevention of Anthracycline Cardiotoxicity in Patients With Breast Cancer

“…Также есть сведения о при-менении в качестве кардиопротективных препаратов на фоне терапии антрацаклинами сартанов, статинов, антагонистов минералокортикоидных рецепторов, метформина [21]. В недавно завершившемся иссле-довании PRADA был продемонстрирован хороший кардиопротективный эффект кандесартана при его назначении онкологическим пациентам на фоне хи-миотерапевтического лечения [22]. Относительно ин-тервенционных методик имеются данные о том, что трансплантация сердца и ресинхронизирующая тера-пия при антрациклиновой кардиомиопатии не менее эффективны, чем при других неишемических кар-диомиопатиях [23,24].…”