title: 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: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors.forename: Geeta
authors.initials: G
authors.lastname: Gulati
authors.affiliation: Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors.forename: Siri Lagethon
authors.initials: SL
authors.lastname: Heck
authors.affiliation: Department of Oncology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne Hansen
authors.initials: AH
authors.lastname: Ree
authors.affiliation: Department of Cardiology, Division of Cardiovascular and Pulmonary Diseases, Oslo University Hospital, Ullevål, Oslo, Norway.
authors.forename: Pavel
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Department of Cardiology, Charité Campus Buch, University Medicine Berlin, Berlin, Germany HELIOS Clinics Berlin-Buch, Berlin, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Schulz-Menger
authors.affiliation: Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway.
authors.forename: Morten W
authors.initials: MW
authors.lastname: Fagerland
authors.affiliation: Department of Breast and Endocrine Surgery, Division of Surgery, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Berit
authors.initials: B
authors.lastname: Gravdehaug
authors.affiliation: Department of Cardiology, Charité Campus Buch, University Medicine Berlin, Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: von Knobelsdorff-Brenkenhoff
authors.affiliation: Department of Oncology, Division of Cancer Medicine, Surgery & Transplantation, Oslo University Hospital-Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Åse
authors.initials: Å
authors.lastname: Bratland
authors.affiliation: Intervention Centre, Oslo University Hospital, Oslo, Norway.
authors.forename: Tryggve H
authors.initials: TH
authors.lastname: Storås
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway Section for Medical Biochemistry, Division for Diagnostics and Technology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Tor-Arne
authors.initials: TA
authors.lastname: Hagve
authors.affiliation: Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors.forename: Helge
authors.initials: H
authors.lastname: Røsjø
authors.affiliation: Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Steine
authors.affiliation: Department of Oncology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Geisler
authors.affiliation: Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway torbjorn.omland@medisin.uio.no.
authors.forename: Torbjørn
authors.initials: T
authors.lastname: Omland
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D018943:Anthracyclines / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure / Q000517:prevention & control*; D006801:Humans; D008790:Metoprolol / Q000627:therapeutic use*; D008875:Middle Aged; D013777:Tetrazoles / Q000627:therapeutic use*; D000068878:Trastuzumab / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D057911:Angiotensin Receptor Antagonists; D018943:Anthracyclines; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D008790:Metoprolol; D000068878:Trastuzumab; C077793:candesartan cilexetil
keywords: Angiotensin antagonist; Biomarkers; Breast cancer; Cardiomyopathy; Imaging; β-Blocker