ACEI/ARB and beta-blocker therapies for preventing cardiotoxicity of antineoplastic agents in breast cancer: a systematic review and meta-analysis

Anthracyclines and trastuzumab are widely used to treat breast cancer but increase the risk of cardiomyopathy and heart failure. With the use of trastuzumab and anthracycline-containing medications, this study intends to evaluate the effectiveness and security of current treatments against cardiotoxicity. We conducted a systematic review of randomized controlled trials (RCTs), which used at least one angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or beta-blocker (BB) to prevent cardiotoxicity of antineoplastic agents for breast cancer, in 4 databases (PubMed, Cochrane Library, EMBASE, Web of Science) from inception to 11 May 2022, without language restrictions. The outcome of interest was left ventricular ejection fraction (LVEF) and adverse events. Stata 15 and R software 4.2.1 were used to perform all statistical analyses. The Cochrane version 2 of the risk of bias tool was used to assess the risk of bias, and the grading of recommendations assessment, development, and evaluation (GRADE) assessment was used to appraise the quality of the evidence. Fifteen randomized clinical studies with a total of 1977 patients were included in the analysis. The included studies demonstrated statistically significant LVEF in the ACEI/ARB and BB treatment groups (χ2 = 184.75, I2 = 88.6%, p = 0.000; SMD 0.556, 95% CI 0.299 to 0.813). In an exploratory subgroup analysis, the benefit of experimental agents on LVEF, whether anthracyclines or trastuzumab, was prominent in patients treated with ACEIs, ARBs, and BBs. Compared to placebo, ACEI/ARB and BB treatments in breast cancer patients protect against cardiotoxicity after trastuzumab and anthracycline-containing medication treatment, indicating a benefit for both. Supplementary Information The online version contains supplementary material available at 10.1007/s10741-023-10328-z.


Introduction
Cancer is one major cause of morbidity and mortality worldwide, and in response, anticancer therapies are increasing to prolong the survival of patients [1].In comparison, the cardiotoxicity associated with anticancer therapy poses a challenge for oncologists and cardiologists [2].Of these, anthracyclines and trastuzumab are widely used to treat breast cancer, the leading cause of death from cancer in women, but are associated with several cardiovascular toxicities [3][4][5].The latest oncology cardiology guidelines recommend angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), beta-blocker (BB), and calcium channel blocker (CCB) classes as cardioprotective drugs [6].Although ACEIs, ARBs, and BBs have been investigated as primary prevention options, the strength of the available evidence does not support using these medications routinely for breast cancer patients receiving anthracyclines and/or trastuzumab [7,8].Currently, it is not clear which drug is the best choice as the primary option.Incorporating various recent studies into an updated meta-analysis can significantly improve the current body of evidence available.The purpose of this review is to thoroughly analyze studies that specifically focus on the heartprotective benefits of ACEI/ARBs and BBs in breast cancer patients who have undergone treatment with anthracycline or trastuzumab.

Methods
The PRISMA Checklist 2020 was used to perform this study (Supplemental Table 1) [9].

Search strategy
From their inception through May 11, 2022, we searched PubMed, EMBASE, Cochrane Library, and Web of Science without regard to language or abstract requirements.Two authors (YG and JJ) were the only ones for whom the search was allowed.In addition, we searched past systematic reviews for any references to RCTs that were not returned by our own search.Reviews, in vitro experiments, and animal research were not included.The intended studies were RCTs comparing the effects of anthracyclines, trastuzumab, and mono-or combination therapy with an ACEI, ARB, or BB on LVEF in comparison to placebo.

Eligibility criteria of articles
We incorporated published RCTs comparing ACEI, ARB, BB, or both with placebo.RCTs involving breast cancer patient enrollment qualified as studies for inclusion.We counted each intervention separately for trials that included more than two comparisons.Studies were to include data on adverse events and LVEF in percent (%) before and after breast cancer treatment.A multi-gated acquisition (MUGA) scan, magnetic resonance imaging (MRI), or echocardiography might have been used to determine the LVEF.Studies that were not randomized, looked at different tumor kinds, or in which the BC group's outcomes could not be examined separately were eliminated.
The titles and abstracts of the retrieved papers were examined independently by two reviewers (YG and RTW).The complete texts of trials that might be considered eligible were studied in order to make this determination.Discussion was used to settle any disputes, and a third reviewer (HL) was contacted if necessary.

Data extraction
Using standardized forms, two reviewers (YG and JJ) independently retrieved data from accepted papers.A third reviewer (HL) settled any differences.Publication data were among the information that was extracted (e.g., publication year, authors), participant data (e.g., number, female sex, age, primary study drug), intervention data (e.g., drug, duration, duration of ACEI/ARB or BB), and outcome data (e.g., mean baseline EF, mean final EF, type of LVEF measurement).

Risk of bias assessment
Using version 2 of Cochrane's revised tool to assess the risk of bias in randomized trials (RoB 2), two reviewers (YG and JJ) independently evaluated the risk of bias [10] (see Supplementary Table 3).Any discrepancies were discussed with a third reviewer (RTW) before being decided.Based on the randomization method, variations from the intended intervention, missing outcome data, measurement of the outcome, and choice of the report result, we assessed the likelihood of bias.

Assessment of evidence quality
The quality of the evidence was evaluated using the GRADE (grading of recommendations assessment, development, and evaluation) assessment [11].Each key outcome's finding table was summarized and presented.

Statistics
The outcome data on the results are shown as mean difference (MD) with standard deviation (SD) or with associated 95% confidence intervals (95% CIs) of LVEF during the follow-up period.If MD ± SD was not presented, it was computed using the VassarStats calculator based on the median, range, and number of cases.Considering differences in the staging of breast cancer, treatment duration, and demographic characteristics in different studies, we performed meta-analyses of RCT data with a random effects model.Statistical analysis was performed using Stata 15 and R software 4.2.1.We used a frequentist meta-analysis to produce forest plots and estimate the I 2 statistic along with a 95% confidence interval, which indicates the percentage of the variability that is not due to random errors.This approach will provide a heterogeneity assessment.

Sensitivity analysis
Sensitivity analysis was conducted to investigate possible sources of heterogeneity by removing the data in sequence.The result indicated that the meta-analyses outcomes were stable, as shown in Supplementary Fig. 3.

Risk of bias
A total of 5 out of 15 studies were assessed to have a high risk of bias in overall bias.The overall trend in these assessments was the randomization process and the blinding of both participants and investigators (Supplementary Fig. 4).Five included studies were assessed as high risk in terms of deviations from intended interventions, for their open-label and placebo-controlled design.As noted by the authors, this can be partly explained by ethical considerations and informed consent to include late-phase breast cancer patients.

Overall quality of the evidence
Summary of the finding table was used to show the overall quality of the evidence for the primary outcome, LVEF.To present the results more intuitively, we summarize direct proof of all types of comparisons related to these outcomes in one table (Supplementary Table 4).The reasons to downgrade the quality of evidence are limitations of methodological quality of included trials according to the risk of bias assessment, statistical heterogeneity among included trials, and the small sample size.There were 13 (59.09%)moderate-quality evidence and 9 (40.91%)low-quality evidence.

Discussion
Based on the analysis of key outcome indicators, this study conducted a meta-analysis of 15 RCTs and found that prophylactic treatment with BBs and/or ACEI/ARB greatly enhances LVEF in comparison to anthracyclines or trastuzumab.The reduction of ventricular remodeling and anti-oxidative stress by these two medicines may be connected to the protective mechanism [29].The lack of a substantial increase in LVEF in four studies using ACEI/ARB alone suggests that the favorable findings may be attributable to this early study [14].The subgroup analysis's findings also suggested that ACEI/ARB/ BBs might offer protection against cardiotoxicity brought on by both anthracyclines and trastuzumab.
In recent years, more and more studies have focused on the cardiotoxicity of trastuzumab in combination with anthracyclines and have attempted to reduce it [30].Doxorubicin liposomal has proven effective in reducing the harmful effects that doxorubicin can have on the heart, and new   studies are still ongoing and gaining ground [31].In many previous studies, the cardiotoxicity associated with trastuzumab was assumed to be transient and reversible with drug interruption or discontinuation.Recent data has partially revised this assumption, reporting a non-negligible incidence of long-term cardiotoxicity [32].
The recommended initial medications for treating heart failure are ACEI/ARB and BB.Research has indicated that ACEI/ARB and BB may have a positive impact on reducing the long-term health risks associated with anthracyclineinduced cardiac dysfunction [12,16].Previous clinical studies have examined the treatment of doxorubicin-induced cardiotoxicity, but the patients involved had tumors other than breast cancer [33,34].Lewinter et al. [7], Elghazawy et al. [8], and Jeyaprakash et al. [35] published a similar metaanalysis.Elghazawy et al. not only focused on randomized controlled trials, but also included observational studies.However, they did not extract the breast cancer subgroup indicators from the original study.According to Lewinter et al., the use of ACEI/ARB therapy, regardless of whether it is combined with anthracycline or trastuzumab therapy, resulted in a slightly higher LVEF compared to a placebo, although the difference was not statistically significant.Jeyaprakash et al.'s study found that cardioprotective agents did not differ in their effect on LVEF according to Bayesian analysis.However, frequentist analysis suggested that ACEI/ ARB and BB may offer significant cardio-protection.The inconsistency with the results of previous studies may be the different types and stages of the tumor and low-quality articles.The results still need to be further validated by highquality RCT.
In clinical practice, it is crucial to establish multidisciplinary teams where cardiologists and oncologists work together to give the best possible care to oncology patients undergoing treatment with cardiotoxic agents.Based on our findings, there is no evidence to suggest that ACEI/ARBs are more effective than BBs in preventing a decrease in LVEF among patients undergoing breast cancer treatment.
This study also has some limitations.More substantial, highquality, randomized, double-blind controlled trials are required to assess the clinical efficacy of beta-blockers and angiotensin receptor antagonists in the prevention of anthracyclineinduced early cardiotoxicity, as the majority of the included studies only evaluated a small number of patients, and the heterogeneity of the unknown cause remains unexplained.Meanwhile, total heterogeneity ranged from moderate to high.The causes of the variations between the RCTs were not identified.Meanwhile, the results may be impacted by the method used to measure LVEF.However, the lack of sufficient studies makes it difficult to conduct a subgroup analysis on this topic.
Future research will also investigate the efficacy and safety of new medications as well as complementary therapies.For example, sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, outperforms standard therapy in the treatment of heart failure with reduced ejection fraction, but further research is required to determine its cardioprotective effects in the context of cardio-oncology.There is a randomized, placebo-controlled, double-blind, multicenter clinical trial [36] to see if sacubitril/valsartan given concurrently with early breast cancer therapy regimens comprising anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction.Wang et al. [37], among others, have found that several herbal monomers have cardioprotective benefits in animal experiments.

Fig. 1 Fig. 2
Fig. 1 The PRISMA search strategy flow chart Fig. 2 Primary outcome.Meta-analysis of the impact of concomitant treatment with ACEIs, ARBs, and BBs compared with placebo on left ventricular ejection fraction in patients treated with anthracyclines or trastuzumab.SMD, standardized mean difference; CI, confidence interval

Fig. 3
Fig. 3 Meta-analysis of the impact of concomitant treatment with ACEIs or ARBs alone compared with placebo on left ventricular ejection fraction in patients treated with anthracyclines or trastuzumab.SMD, standardized mean difference; CI, confidence interval

Fig. 4
Fig. 4 Meta-analysis of the impact of concomitant treatment with BBs alone compared with placebo on left ventricular ejection fraction in patients treated with anthracyclines or trastuzumab.SMD, standardized mean difference; CI, confidence interval

Fig. 5
Fig. 5 Meta-analysis of the impact of concomitant treatment with ACEIs or ARB combined with BB compared with placebo on left ventricular ejection fraction in patients treated with anthracyclines or trastuzumab.SMD, standardized mean difference; CI, confidence interval The search terms were anthracycline*/Doxorubicin*/Adriamycin*/Daunorubicin*/Epirubicin*/Trastuzumab/beta blocker/ACEI/ARB et al.Supplemental Table 2 contains the PubMed search methodology.

Table 1
Baseline characteristics of the selected randomized controlled trial