Table 1.
Randomized controlled trials of RASi to protect against chemotherapy-induced cardiotoxicity
| Reference | CHT type, FU time |
Treatment (number of patients) |
Main findings | Outcome |
|---|---|---|---|---|
|
| ||||
| Primary prevention1 | ||||
|
| ||||
| Nakamae, 2005 (37) | CHOP, 7 days | Valsartan 80mg/d (20), Control (20) | Control: increased LVDd, BNP, ANP, QTc interval, QTc dispersion; Valsartan: prevented changes except of ANP elevation | Positive |
|
| ||||
| Georgakopoulos, 2010 (38) | Doxorubicin-based, 36 months | Enalapril (mean, 11mg/d) (43), Metoprolol (mean, 89mg/d) (42), Control (40) | No significant difference between the groups in echocardiographic parameters, and development of early/late cardiotoxicity or HF | Negative |
|
| ||||
| Cadeddu, 2010 (39) Dessì, 2011 (40) | Epirubicin-based, 18 months | Telmisartan 40mg/d (25), Placebo (24) | Diastolic impairment, reduced strain rate, and increased IL-6 and ROS in placebo group, but not in telmisartan group. Echocardiographic findings persisted till 12 months FU | Positive |
|
| ||||
| Liu, 2013 (41) | Anthracycline-based, 126 days | Candesartan 2.5mg/d + carvedilol 10mg/d (20), Placebo (20) | Attenuated decrease of LVEF in intervention group; increased LVEDD and LVESD in controls, not in intervention group; attenuated ECG changes and arrhythmias in intervention group; reduced troponin in intervention group | Positive |
|
| ||||
| Bosch, 2013 (42) | Intensive CHT for hematological malignancies, 6 months | Enalapril 20mg/d + carvedilol 50mg/d (45), Control (45) | Decreased LVEF only in control group; reduced incidence of combined event (death, HF, or final LVEF<45%) in intervention group | Positive |
|
| ||||
| Radulescu, 2013 (43) | Epirubicin-based, until 12 months after end of CHT | Perindopril 10mg/d (68), Control (68) | Significantly decreased LVEF only in controls; deterioration of LV diastolic function and prolongation of QTc in both groups | Inconclusive |
|
| ||||
| Janbabai, 2016 (44) | Anthracycline-based, 6 months | Enalapril 20mg/d (34), Placebo (35) | Systolic (including LVEF) and diastolic function only impaired in placebo group; troponin I and CK-MB higher in placebo group | Positive |
|
| ||||
| Gulati, 2016 (45) | Anthracycline-based +/− trastuzumab and radiation, 10–61 weeks | Candesartan 32mg/d + Metoprolol 100mg/d (30), Candesartan 32mg/d (32), Metoprolol 100mg/d (32), Placebo (32) | No interaction between candesartan and metoprolol; LVEF decline (primary outcome) was reduced by candesartan (but not by metoprolol) vs placebo; no effect of candesartan on secondary outcomes (RVEF, left ventricular global longitudinal strain, diastolic function, BNP, and troponin I) | Positive |
|
| ||||
| Boekhout, 2016 (46) | Trastuzumb (after anthracycline-based CHT), 92 weeks | Candesartan 32mg/d (103), Placebo (103) | No difference in LVEF and cardiac events between groups; NT-proBNP and hs-TNT not affected by candesartan | Negative |
|
| ||||
| Pituskin, 2017 (47) | Trastuzumab-based, 52 weeks | Perindopril 8mg/d (33), Bisoprolol 10mg/d (31), Placebo (30) | Primary outcome LV remodeling (LVEDVi) was not prevented by bisoprolol or perindopril; bisoprolol prevented reduction in LVEF; less trastuzumab interruptions due to LVEF drop in perindopril and bisoprolol; multivariate: perindopril and bisoprolol were independent predictors of maintained LVEF | Inconclusive |
|
| ||||
| Secondary prevention2 | ||||
|
| ||||
| Silber, 2004 (48) | Anthracycline-based, 34.6 months (mean) | Enalapril 0.15mg/kg/d (69), Placebo (66) | Enalapril had no effect on exercise performance (including MCI), but reduced LVESWS | Inconclusive |
|
| ||||
| Cardinale, 2006 (49) | High-dose CHT, 12 months | Enalapril 20mg/d (56), Control (58) | Reduction in LVEF and increase in end-systolic and diastolic volumes only in controls; incidence of cardiac events higher in controls; troponin I normalized within 3 months in enalapril (↑ troponin I at month 3: 0% vs 21%) | Positive |
Abbreviations: ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; CHT, chemotherapy; ECG, electrocardiogram; FU, follow-up; HF, heart failure; hs-TNT, high-sensitivity troponin T; LV, left ventricular; LVDd, LV end-diastolic diameter; LVEDVi, indexed LV end-diastolic volume; LVEF, LV ejection fraction; LVESWS, LV end-systolic wall stress; MCI, maximal cardiac index; NT-proBNP, N-terminal of prohormone BNP; RASi, renin-angiotensin system inhibitors; ROS, reactive oxygen species, RVEF, right ventricular ejection fraction.
1
Prophylactic setting
2
After detection of subclinical cardiotoxicity (e.g. ↑ troponin I, echocardiographic or ECG abnormalities)