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

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 ( P =0.021) and attenuated decline in global longitudinal strain ( P =0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. 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.

Primary prevention of chronic anthracycline cardiotoxicity with ACE inhibitor is temporarily effective in rabbits, but benefits wane in post-treatment follow-up

“…Furthermore, the present study highlights the importance of a longer post-chemotherapy FU period to properly evaluate the benefits of ACEis (and possibly other HF drugs providing neurohormonal blockade) in the primary prevention of chronic ANT-induced cardiotoxicity. This finding might be particularly relevant for studies investigating subjects with a lower cardiotoxic burden associated with currently prescribed maximal cumulative doses of ANT, as was recently highlighted by the results of the extension of the PRADA trial [59].…”

“…However, no significant benefit was recognizable after assessing the levels of cardiac biomarkers (NT-proBNP or cardiac troponins). Very recently, an extension of this trial has been published [59], where the patients were followed after candesartan withdrawal (up to approximately 2 years from randomization). Notably, no difference in LVEF was observed between candesartan-treated and non-treated patients (p=0.91).…”

Heart Failure Therapies for the Prevention of HER2-Monoclonal Antibody-Mediated Cardiotoxicity: A Systematic Review and Meta-Analysis of Randomized Trials

“…For example, Elkhateeb et al randomized 126 breast cancer patients treated with anthracycline chemotherapy, with or without trastuzumab, to either a combination of enalapril and carvedilol or placebo, and although the intervention group was associated with statistically fewer participants experiencing a reduction in LVEF ≥10% as assessed by cardiac MRI (1.9% vs. 12.5%, p = 0.04), only 24% of patients received trastuzumab and pre-specified subgroup analyses were not performed [ 45 ]. Additionally, the recently published Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) trial [ 46 ], which assessed the use of ARB’s or beta-blockade to attenuate the decline in LVEF in patients receiving adjuvant anthracycline-containing regimens, only included 27 patients treated with adjuvant trastuzumab. Neither the use of candesartan nor metoprolol was associated with prevention of cardiotoxicity at 2 years.…”

The Research Progress of Trastuzumab-Induced Cardiotoxicity in HER-2-Positive Breast Cancer Treatment

“…This may provide some theoretical basis for the use of ACEI or β-receptor inhibitors in the prevention of TIC. Several small randomized trials and single-center studies have also reported that ACEI and β-blockers ameliorate chemotherapy-induced cardiotoxicity, but these studies all emphasized high-dose anthracycline-induced cardiotoxicity and have limited clinical applicability in TIC ( 71 , 72 ). In 2016, the MANTICORE 101-Breast randomized clinical trial specifically investigated the pharmacological prevention of TIC and found that Perindopril and Bisoprolol were well-tolerated in the prevention of TIC and attenuated the decrease in LVEF, but trastuzumab-induced left ventricular remodeling was not reversed ( 73 ).…”