Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: a systematic review and meta-analysis.

Cardiotoxicity is a well-recognised complication of chemotherapy with anthracycline and/or trastuzumab, and its prevention remains an important challenge in cancer survivorship. Several successful preventative strategies have been identified in animal trials. We sought to assemble the clinical evidence that prophylactic pharmacological interventions could prevent left ventricular (LV) dysfunction and heart failure in patients undergoing chemotherapy. We undertook a systemic review of the evidence from randomised trials and observational studies where a prophylactic intervention was compared with a control arm in patients with a normal ejection fraction and no past history of heart failure. The primary outcome was development of heart failure (HF), a drop in ejection fraction (EF) or both. A random-effects model was used to combine relative risks (RR) and 95% confidence intervals (CIs), and a meta-regression was undertaken to assess the impact of potential covariates. Data were collated from 14 published articles (n=2015 paediatric and adult patients) comprising 12 randomised controlled trials and two observational studies. The most studied chemotherapeutic agents were anthracyclines, and prophylactic agents included dexrazoxane, statins, beta-blocker and angiotensin antagonists. There were 304 cardiac events in the control arm compared to 83 in the prophylaxis arm (RR=0.31 [95% CI: 0.25-0.39], p<0.00001). Cardiac events were reduced with dexrazoxane (RR=0.35 [95% CI 0.27-0.45], p<0.00001), beta-blockade (RR=0.31 [95% CI 0.16-0.63], p=0.001), statin (RR=0.31 [95% CI 0.13-0.77], p=0.01) and angiotensin antagonists (RR=0.11 [95% CI 0.04-0.29], p<0.0001). Prophylactic treatment with dexrazoxane, beta-blocker, statin or angiotensin antagonists appear to have similar efficacy for reducing cardiotoxicity.

Kalam K ，Marwick TH 《-》

Effect of prophylactic betablocker or ACE inhibitor on cardiac dysfunction & heart failure during anthracycline chemotherapy ± trastuzumab.

Administration of anthracycline chemotherapy ± trastuzumab is associated with cardiac dysfunction. We sought to identify whether prophylactic administration of angiotensin converting enzyme (ACE) inhibitor or beta-blocker attenuates subsequent left ventricular dysfunction and heart failure. Electronic databases were searched for studies examining the effect of beta-blockers or ACE inhibitors on left ventricular ejection fraction (LVEF) and heart failure in patients receiving anthracycline chemotherapy ± trastuzumab. The end-point was change in LVEF or development of heart failure. Eight studies (1048 patients) were identified. There was no difference in the change in LVEF (weighted mean difference (MWD) - 4.74 (95% confidence interval (CI): -12.6 to 3.1), p = 0.24) or risk of new heart failure diagnosis (Odds ratio (OR) 0.24 (95% CI: 0.03-1.73), p = 0.16) between patients receiving ACE inhibitor or control. Betablocker use was associated with a significant smaller drop in LVEF compared to control (MWD -3.28 (95% CI: -6.1 to -0.51), p = 0.02) but not in patients who received anthracycline chemotherapy alone (MWD - 3.05 (95% CI -7.22 to 1.12), p = 0.15). There was a significant reduction in new heart failure diagnosis in those receiving beta-blocker compared to those not (OR 0.33 (95% CI: 0.14-0.80), p = 0.01). Prophylactic ACE inhibitor does not attenuate development of LV dysfunction or heart failure in patients receiving anthracycline chemotherapy ± trastuzumab. Beta-blocker attenuated reduction in LVEF and new heart failure diagnosis. However, the effect in patients only receiving anthracycline is less certain. Studies examining the effect on mortality are required.

Gujral DM ，Lloyd G ，Bhattacharyya S 《-》

Cardioprotective role of β-blockers and angiotensin antagonists in early-onset anthracyclines-induced cardiotoxicity in adult patients: a systematic review and meta-analysis.

Anthracyclines are commonly used chemotherapeutic agents with proven efficacy in such malignancies as breast cancer, Hodgkin and non-Hodgkin lymphomas. These agents are associated with irreversible accumulative dose-related cardiomyopathy. Many agents have been examined to reduce cardiotoxicity risk. We performed a systematic review and meta-analysis to determine the efficacy of β-blockers and angiotensin antagonists to prevent early-onset anthracyclines-induced left ventricular dysfunction and cardiac events. Relevant articles were searched in PubMed, EMBASE and Cochrane database of systematic reviews up to July 2015. Eligible studies were limited to randomised controlled trials comparing the efficacy of cardioprotective agents (β-blocker and angiotensin antagonist) with control (either no treatment or placebo) in adult patients (age >18 years) treated with anthracyclines-based regimens. Pooled analysis showed an association of β-blockers and/or angiotensin antagonists treatment with higher post-chemotherapy left ventricular ejection fraction (LVEF) of 64.03% compared with 57.48% for control treatment. The mean difference estimate (95% CI) was 6.06% (0.54 to 11.58), p=0.03, with significant heterogeneity, I(2) (95% CI)=96% (82.7 to 109.3). Though the point estimate for the relative rate of cardiac events was lower in the experimental arm, the difference was not statistically significant. In an exploratory subgroup analysis, the benefit of experimental agents on LVEF preservation was prominent in patients treated with higher accumulative dose of anthracyclines, but not in the lower dose group. β-Blockers and angiotensin antagonists treatments were associated with better LVEF preservation, and the benefit was prominent in patients treated with higher anthracyclines accumulative dose. Unexplained heterogeneity remains, indicating the need for more controlled studies. This analysis provides some support for the routine use of β-blockers or angiotensin antagonists in patients undergoing anthracyclines treatment, especially when higher accumulative dose is expected.

Yun S ，Vincelette ND ，Abraham I 《-》

Cardioprotective effect of renin-angiotensin inhibitors and β-blockers in trastuzumab-related cardiotoxicity.

Ohtani K ，Ide T ，Hiasa KI ，Sakamoto I ，Yamashita N ，Kubo M ，Tsutsui H ... -  《-》

Interventions for preventing cardiomyopathy due to anthracyclines: a Bayesian network meta-analysis.

The relative efficacy of interventions for primary prevention of anthracycline-associated cardiotoxicity is unknown. We conducted a systematic review of randomized controlled trials for primary prevention of anthracycline-associated cardiotoxicity in adult cancer patients. We used hierarchal outcome definitions in the following order of priority: (1) composite of heart failure or decline in left ventricular ejection fraction, (2) decline in ejection fraction, or (3) heart failure. Data were analyzed using a Bayesian network meta-analysis with random effects. A total of 16 trials reported cardiotoxicity as a dichotomous outcome among 1918 patients, evaluating dexrazoxane, angiotensin antagonists, beta-blockers, combination angiotensin antagonists and beta-blockers, statins, Co-enzyme Q-10, prenylamine, and N-acetylcysteine. Compared with control, dexrazoxane reduced cardiotoxicity with a pooled odds ratio (OR) of 0.26 (95% credible interval [CrI] 0.11-0.74) and had the highest probability (33%) of being most effective. No other agent was demonstrably better than placebo. Angiotensin antagonists had an 84% probability of being most effective in a sensitivity analysis excluding one outlying study (OR 0.06 [95% CrI 0.01- 0.24]). When the outcome was restricted to heart failure, dexrazoxane was associated with an OR of 0.12 (95% CrI 0.06-0.23) relative to control and had 58% probability of being most effective, while angiotensin antagonists had an OR of 0.18 (95% CrI 0.05-0.55). Available data suggested that dexrazoxane and angiotensin antagonists did not affect malignancy response rate or risk of death. Moderate quality data suggest that dexrazoxane, and low quality data suggest angiotensin antagonists, are likely to be effective for cardiotoxicity prevention.

Abdel-Qadir H ，Ong G ，Fazelzad R ，Amir E ，Lee DS ，Thavendiranathan P ，Tomlinson G ... -  《-》