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

Eur Heart J. 2016 Jun 1;37(21):1671-80. doi: 10.1093/eurheartj/ehw022. Epub 2016 Feb 21.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / therapeutic use*
  • Angiotensin Receptor Antagonists / therapeutic use*
  • Anthracyclines / adverse effects
  • Antineoplastic Agents / adverse effects
  • Benzimidazoles / therapeutic use*
  • Biphenyl Compounds / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Chemotherapy, Adjuvant
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Heart Failure / prevention & control*
  • Humans
  • Metoprolol / therapeutic use*
  • Middle Aged
  • Tetrazoles / therapeutic use*
  • Trastuzumab / adverse effects
  • Treatment Outcome


  • Adrenergic beta-Antagonists
  • Angiotensin Receptor Antagonists
  • Anthracyclines
  • Antineoplastic Agents
  • Benzimidazoles
  • Biphenyl Compounds
  • Tetrazoles
  • Metoprolol
  • Trastuzumab
  • candesartan cilexetil