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Heck SL, Mecinaj A, Ree AH, et al. Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol. Circulation. 2021;143(25):2431-2440doi: 10.1161/CIRCULATIONAHA.121.054698.
Heck, S. L., Mecinaj, A., Ree, A. H., Hoffmann, P., Schulz-Menger, J., Fagerland, M. W., Gravdehaug, B., Røsjø, H., Steine, K., Geisler, J., Gulati, G., & Omland, T. (2021). Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol. Circulation, 143(25), 2431-2440. https://doi.org/10.1161/CIRCULATIONAHA.121.054698
Heck, Siri Lagethon, et al. "Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol." Circulation vol. 143,25 (2021): 2431-2440. doi: https://doi.org/10.1161/CIRCULATIONAHA.121.054698
Heck SL, Mecinaj A, Ree AH, Hoffmann P, Schulz-Menger J, Fagerland MW, Gravdehaug B, Røsjø H, Steine K, Geisler J, Gulati G, Omland T. Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol. Circulation. 2021 Jun 22;143(25):2431-2440. doi: 10.1161/CIRCULATIONAHA.121.054698. Epub 2021 May 16. PMID: 33993702; PMCID: PMC8212877.
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Circulation. 2021 Jun 22;143(25):2431-2440. doi: 10.1161/CIRCULATIONAHA.121.054698. Epub 2021 May 16.

Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol.

Circulation

Siri Lagethon Heck, Albulena Mecinaj, Anne Hansen Ree, Pavel Hoffmann, Jeanette Schulz-Menger, Morten Wang Fagerland, Berit Gravdehaug, Helge Røsjø, Kjetil Steine, Jürgen Geisler, Geeta Gulati, Torbjørn Omland

Affiliations

  1. Department of Diagnostic Imaging (S.L.H.), Akershus University Hospital, Lørenskog, Norway.
  2. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway (S.L.H., A.M., A.H.R., H.R., K.S., J.G., G.G., T.O.).
  3. Department of Cardiology (A.M., K.S., G.G., T.O.), Akershus University Hospital, Lørenskog, Norway.
  4. Department of Oncology (A.H.R., J.G.), Akershus University Hospital, Lørenskog, Norway.
  5. Section for Interventional Cardiology, Department of Cardiology, Division of Cardiovascular and Pulmonary Diseases (P.H.), Oslo University Hospital, Ullevål, Norway.
  6. Department of Cardiology, Charité Campus Buch, Universitätsmedizin Berlin, Germany (J.S.-M.).
  7. HELIOS Clinics, Berlin, Germany (J.S.-M.).
  8. Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Norway (M.W.F.).
  9. Department of Breast and Endocrine Surgery, (B.G.), Akershus University Hospital, Lørenskog, Norway.
  10. Division of Research and Innovation (H.R.), Akershus University Hospital, Lørenskog, Norway.
  11. Department of Cardiology, Division of Medicine (G.G.), Oslo University Hospital, Ullevål, Norway.

PMID: 33993702 PMCID: PMC8212877 DOI: 10.1161/CIRCULATIONAHA.121.054698

Abstract

BACKGROUND: Adjuvant breast cancer therapy containing anthracyclines with or without anti-human epidermal growth factor receptor-2 antibodies and radiotherapy is associated with cancer treatment-related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the β-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury.

METHODS: In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations.

RESULTS: A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (

CONCLUSIONS: Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.

Keywords: adrenergic beta-antagonists; angiotensin receptor antagonists; biomarkers; breast neoplasms; cardiomyopathies; magnetic resonance imaging

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