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Table 3 Summary of prospective randomised controlled trials on medical prevention of cardiac dysfunction during oncological treatment

From: Evidence-based prediction and prevention of cardiovascular morbidity in adults treated for cancer

Intervention (LOE) Population Study design Primary outcome Result
ACEI/ARB/beta-blockers Meta-analysis N = 2301 early breast cancer pts., HER2+/− [28] RCT’s ACEI, ARB and/or BB Change in LVEF Standardized mean difference LVEF baseline vs treatment completion for all groups: − 2.36 [95% CI: − 3.23 to − 1.49]
  Meta-analysis N = 633 pts. [29] RCT’s carvedilol vs placebo Occurrence of low LVEF Low LVEF carvedilol vs. placebo 3.2% vs. 5.8% (OR: 0.42; 95% confidence interval: 0.18–0.99; p = 0.05).
LVEF reduction carvedilol vs. placebo: mean difference 2.41% (95% CI: 0.01–4.81; p = 0.05).
  Meta-analysis N = 1984 pts. [30] RCT’s with neurohormonal therapy vs placebo (BB, ACEi, ARB, mineralocorticoid receptor antagonists) Change in LVEF Intervention arms had a higher LVEF on follow-up (standardized mean difference + 1.04% (95% CI 0.57–1.50) but significant heterogeneity (I2 96%)
  N = 69 pts. with malignancy treated with anthracycline [29] Prospective RCT, single-blind, enalapril vs. placebo Change in LVEF from baseline to 6 months Preserved LVEF in enalapril group (p = 0.58), decreased LVEF in control group (p < 0.001)
  N = 40 pts. with non-Hodgkin lymphoma, combination (CHOP) chemotherapy [31] Prospective RCT, open-label, valsartan (80 mg/day) vs. control Explorative; changes in neurohumoral, echocardiographic, electrocardiographic markers during therapy Compared to control, valsartan significantly inhibited the dilatation of LVDd (P = 0.01), elevation of BNP (P = 0.001), and prolongation of the QTc interval and QTc dispersion (P = 0.0009 and P = 0.02, respectively) after CHOP chemotherapy
  N = 49 pts., different malignancies treated with epirubicin [32] Prospective RCT, telmisartan vs. placebo Change in strain rate by echocardiography compared to baseline. Biomarkers. Decrease in strain rate in both arms, but recovery to baseline values in telmisartan group. Lower levels of inflammatory marker IL-6 in telmisartan group compared to control. No differences in (changes in) LVEF.
  N = 36 acute leukemia receiving intensive chemotherapy, N = 54 hematologic malignancies receiving stem cell transplantation. LVEF ≥50% at baseline [33]. Prospective RCT, carvedilol + enalapril vs. control group Change in LVEF by echocardiography Preserved LVEF in intervention arm (− 3.28 [− 5.49 to − 1.07] in control group, − 0.17 [− 2.24 to 1.90] intervention group, difference − 3.11%, p = 0.04)
In control group lower incidence death/heart failure (6.7% vs. 22%, p = 0.036) and of death, heart failure, or a final LVEF < 45% (6.7% vs. 24.4%, p = 0.02).
  N = 147 lymphoma pts., doxorubicin combination chemotherapy [34] Prospective randomised three-arm trial (metoprolol, enalapril or placebo) Clinical heart failure and subclinical cardiotoxicity No statistically significant differences in the study arms (up to 10 yr follow-up) [35]
  N = 468 early HER2+ breast cancer pts., treated with trastuzumab +/− anthracyclines [36] Prospective randomised three-arm trial (lisinopril, carvedilol or placebo) Cardiotoxic event Cardiotoxicity occurred in 32% patients on placebo, 29% on carvedilol, and 30% on lisinopril.
  N = 121 pts. with early breast cancer treated with adjuvant chemotherapy including anthracyclines [37] Prospective 2 × 2 factorial placebo-controlled double-blind RCT. Change in LVEF The overall decline in LVEF was 2.6% (95% CI 1.5, 3.8) 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.
  N = 94 pts. with early HER2+ breast cancer [38] Prospective randomised three-arm trial (perindopril, bisoprolol or placebo) Trastuzumab-mediated left ventricular remodeling on ultrasound No difference between groups
Statins N = 40 pts. with malignancy planned for anthracycline treatment [39] Prospective RCT 6 months of atorvastatin (40 mg/day) vs. control Rate LVEF < 50% No difference primary endpoint (p = 0.18), but mean change in LVEF in control group significantly larger than in statin group (− 7.9 ± 8.0 vs. 1.3 ± 3.8, p < 0.001)
Other Meta-analysis of 2177 breast cancer pts. treated with anthracyclines +/− trastuzumab [40] Dexrazoxane vs placebo Rate of CHF and cardiac events Reduction in CHF (RR: 0.19; 95% CI: 0.09 to 0.40, P < 0.001) and cardiac events (RR: 0.36; 95% CI: 0.27 to 0.49, p < 0.001)
  N = 27 pts. treated with doxorubicin [41] Prospective open label RCT, sildanefil (100 mg 3 times daily) vs. control Change in mean LVEF No difference. No difference in (changes in) serum troponin I.
  1. Abbreviations: HER2 Human Epidermal growth factor Receptor 2, pts patients,RCT randomised controlled trial, ACEI Angiotensin Enzyme Converse Inhibitors, ARB Angiotensin Receptor Blockers, BB beta-blockers, yr year, LVEF left ventricular ejection fraction, LVDd left ventricular diastolic diameter, BNP brain natriuretic peptide, IL-6 interleukin 6, TDI tissue Doppler imaging, OR odds ratios, CI confidence interval