Table 1.
Primary Cardiotoxicity Prevention Trials in Patients With Breast Cancer
| Trial/First Author (Ref. #) | Sample | Intervention | Outcomes | Benefit (Yes/No) | Limitations | Path Forward |
|---|---|---|---|---|---|---|
| PRADA (34) | 130, all anthracycline, 22% trastuzumab | 1:1:1:1, metoprolol, candesartan, metoprolol and candesartan, or placebo | Changes in LVEF by CMR at 10 to 64 weeks | Yes Absolute LVEF change: 2.6% in placebo, 0.8% in candesartan (p = 0.026) |
Lack of follow-up beyond adjuvant therapy period Statistical power for subgroup analyses is limited |
PRADA II (NCT03760588): 300 patients with ESBC receiving anthracycline containing chemo randomized to Entresto or placebo |
| MANTICORE (34) | 94, all trastuzumab, 12–33% anthracycline | 1:1:1 bisoprolol, perindopril, or placebo | Changes in LVEDVI by CMR at 1 yr | Yes Small reduction in LVEF decline with bisoprolol compared with perindopril and placebo (–1% vs. –3% vs. –5%; p = 0.001) |
Limited follow-up period Patients younger and fewer cardiovascular risk factors than average in clinical practice |
Future trials involving subgroups with higher risk factors and that are most likely to benefit from primary prophylaxis therapies |
| Guglin et al. (32) | 468, all trastuzumab, 40% doxorubicin | 1:1:1 carvedilol, lisinopril, or placebo | LVEF >10% or LVEF decline >5% with absolute LVEF <50% | Yes >10% LVEF decline in subset with prior anthracycline exposure: 47% placebo, 31% carvedilol, 37% lisinopril (p = 0.009) |
Randomized to treatment groups post-anthracycline exposure Centers measured LVEF by their preferred method (echocardiography, MUGA) Not powered to compare efficacy of prevention between lisinopril and carvedilol |
Future trials comparing the efficacy of prevention with lisinopril vs. carvedilol and assessing optimum timing and dosing of cardioprotective medications alone and in combination |
| CECCY (35) | 200, all doxorubicin | 1:1 carvedilol or placebo | LVEF >10% decline from baseline to 6 months | No LVEF decline: 13.5% placebo,14.5% carvedilol (p = 1.00) |
Single center study Dose of carvedilol was optimized during chemotherapeutic treatment Interobserver variability may influence repeated LVEF measurements |
Future randomized controlled trials of preventive beta-blockade in larger populations and in patients with higher risk of severe left ventricular dysfunction and heart failure |
| Boekhout et al. (36) | 206, all epirubicin with trastuzumab | 1:1 candesartan or placebo | LVEF decline of >15% or a decrease below the absolute value of 45% | No LVEF decline: 19% in candesartan, 16% in placebo (p = 0.58) |
Small sample size Baseline LVEF values not available in 35.9% of patients |
Future trials exploring relationships between gene polymorphisms of ERBB2 and trastuzumab-related cardiotoxic effects |
CECCY = Carvedilol Effect in Preventing Chemotherapy-Induced Cardiotoxicity; CMR = cardiac magnetic resonance; ESBC = early stage breast cancer; LVEDI = left ventricular end-diastolic volume index; LVEF = left ventricular ejection fraction; MANTICORE = Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research; MUGA = multigated acquisition scan; PRADA = Prevention of Cardiac Dysfunction during Adjuvant Breast Cancer Therapy.