Potential role of angiotensin-converting enzyme inhibitors vs beta-blockers in preventing anticancer agents-induced cardiotoxicity: A systematic review and meta-analysis

Abstract

BACKGROUND

Anthracyclines cause dose-dependent, irreversible cardiac dysfunction, whereas trastuzumab leads to dose-independent, reversible cardiotoxicity. Both beta-blockers and angiotensin-converting enzyme inhibitor (ACEI) have shown protective effect against anti-cancer agents-induced cardiotoxicity, however to date there is no head-to head comparison. Our metanalysis focuses on bridging this gap.

AIM

To compare the efficacy of ACEI and beta-blockers in preventing cardiotoxicity and to evaluate whether either class offers superior cardio-protection.

METHODS

PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials comparing beta-blockers with ACEI in patients of chemotherapy. 4 studies including 680 patients were analyzed using Revman random-effects model, and results were generated in form of relative risk and mean difference (MD).

RESULTS

There was no difference in the two groups in regards to: Change in E/E’ [MD = -0.25; 95% confidence interval (CI): -0.50 to 0.01; P = 0.06], change of left ventricular (LV) ejection fraction (MD = 0.38%; 95%CI: -0.35 to 1.11; P = 0.31), cardiotoxicity (MD = 1.07; 95%CI: 0.66-1.75, P = 0.77), change in LV end diastolic diameter (MD = -0.41%; 95%CI: -0.98 to 0.16;P = 0.16), change in LV end systolic diameter (MD = -0.20%; 95%CI: -0.70 to 0.30; P = 0.43) and change in E/A (MD = -0.01; 95%CI: -0.25 to 0.23; P = 0.92). While risk of total adverse events and palpitation were same in two groups, hypotension (11% vs 3%, P = 0.004) and dizziness (13% vs 6%, P = 0.01) were more frequent with ACEI.

CONCLUSION

Our study demonstrates that both groups offer similar protection against cardiotoxicity, with ACEI associated with more side-effects. Therefore, choice of agent should be guided by individual tolerability and clinical context.

Key Words: Cardiotoxicity; Angiotensin converting enzyme inhibitors; Beta blockers; Anthracycline-induced cardiotoxicity; Transtuzumab-induced cardiotoxicity

Core Tip: This meta-analysis compared angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers for the prevention of anti-cancer agents-induced cardiotoxicity. Across randomized controlled trials, both drug classes showed similar effectiveness in preserving left ventricular ejection fraction and preventing overall, early, and late cardiotoxicity. Overall adverse event rates were similar between groups; however, hypotension and dizziness occurred more frequently with ACEI therapy. These findings suggest that ACEI and beta-blockers provide comparable cardioprotective benefit. Choice of therapy should therefore be individualized based on patient characteristics, blood pressure profile, and tolerability. Larger, adequately powered trials with longer follow-up are needed to determine whether meaningful differences between these strategies emerge over time.

INTRODUCTION

Advances in cancer therapy have markedly improved survival across a wide range of malignancies; however, chemotherapy-related cardiotoxicity has emerged as a major cause of long-term morbidity and mortality[1]. Among anticancer agents, anthracyclines and trastuzumab are the most frequently implicated in cardiotoxic injury[2,3]. Anthracyclines induce dose-dependent myocardial damage through mechanisms including oxidative stress, mitochondrial dysfunction, and topoisomerase-IIβ-mediated cardiomyocyte injury, leading to irreversible myocyte loss and progressive left ventricular (LV) dysfunction[4]. Clinically overt heart failure develops in approximately 5% of treated patients, while asymptomatic declines in LV ejection fraction (LVEF) are substantially more common and increase with cumulative exposure, affecting up to 65% of patients receiving doxorubicin doses above 500 mg/m²[5].

Trastuzumab, a human epidermal growth factor receptor-2, targeted monoclonal antibody, produces a distinct form of cardiotoxicity characterized by impaired cardiomyocyte signaling and contractile dysfunction rather than direct structural injury[3,6]. Unlike anthracyclines, trastuzumab-associated cardiotoxicity is generally not dose-dependent and is often reversible upon treatment interruption[6-8]. Nevertheless, its clinical burden remains significant, with LV dysfunction reported in 8%-17% of patients and symptomatic heart failure occurring in up to 5%[9,10]. The risk is substantially amplified when trastuzumab is administered sequentially or concurrently with anthracyclines, underscoring the cumulative epidemiologic burden of cardiotoxicity in contemporary oncologic practice[11].

Despite their well-established cardiovascular risks, anthracyclines and trastuzumab remain cornerstone therapies for breast cancer, lymphomas, leukemias, and other solid tumors[12]. However, the development of cardiotoxicity frequently necessitates dose reduction, treatment interruption, or permanent discontinuation, potentially compromising oncologic efficacy and long-term survival[13]. The need for intensive cardiac monitoring and the fear of irreversible LV dysfunction may also limit optimal dosing strategies, particularly in patients with pre-existing cardiovascular risk factors. Consequently, effective cardioprotective strategies are essential to allow safe continuation of life-saving cancer therapies.

Several pharmacologic strategies have been investigated to mitigate anti-cancer agents-induced cardiotoxicity, most notably β-blockers and angiotensin-converting enzyme inhibitors (ACEIs)[14]. Both classes have demonstrated potential benefit in preserving LVEF and reducing the incidence of treatment-related cardiac dysfunction in randomized controlled trials. β-blockers are thought to attenuate sympathetic overactivation and oxidative stress, while ACEIs counteract maladaptive renin-angiotensin system activation and ventricular remodeling[15]. Although multiple studies suggest these agents may reduce declines in LVEF during anthracycline and trastuzumab therapy, results have been variable, and the magnitude of benefit remains uncertain across different patient populations.

Despite increasing use of these cardioprotective strategies in clinical practice, direct comparative evidence between β-blockers and ACEIs remains limited. Most trials have evaluated each therapy independently against placebo rather than against one another, leaving uncertainty regarding relative efficacy and safety. Additionally, heterogeneity in cardiotoxicity definitions and follow-up duration has hindered definitive conclusions. Our study aims to address this gap by systematically comparing β-blockers and ACEI therapy for the prevention of anthracycline- and trastuzumab-associated cardiotoxicity, with the goal of providing clearer evidence to guide cardioprotective treatment selection.

MATERIALS AND METHODS

Study design and objectives

This systematic review and meta-analysis were reported in accordance with PRISMA statement (Figure 1)[16]. The objective was to investigate the comparative efficacy of beta-blockers (BB) vs ACEI, for the management of anti-cancer agents-induced cardiotoxicity. The analysis integrated data from randomized controlled trials (RCTs) comparing BB and ACEI. The protocol for this meta-analysis was registered and published with PROSPERO (ID: CRD420261309420).

Figure 1 PRISMA flow diagram representing breakdown of screened and included studies. ¹Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). ²If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools. This work is licensed under CC BY 4.0. To view a copy of this license, visit https://creativecommons.org/Licenses/by/4.0/. Citation: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021; 372: N71. Copyright ©The Author(s) 2021. Published by BMJ Publishing Group Ltd[35]. PICO: Population, intervention, control and outcome.

Literature search and data sources

A structured search strategy was applied across PubMed, the Cochrane Library, and Google Scholar to identify studies published up to February 2026. The search combined medical subject heading terms and keywords to formulate a search string: “(Beta blockers OR BB OR Angiotensin Converting Enzymes OR Angiotensin II Receptor Blockers, ACEI OR ACE Inhibitors) AND (Anthracyclines-Induced Chemotherapy OR Transtuzumab-induced Cardiotoxicity OR Anti-cancer agents-induced Cardiotoxicity OR Cardiotoxicity OR Heart Failure OR Cardiac Dilation) AND (Randomized controlled trials OR RCTs) AND (Leukemia OR Breast cancer OR Solid tumor OR Lymphoma OR malignancy)”. Only clinical trials comparing cancer patients on anthracyclines or transtuzumab receiving BB or ACEI were included. Clinical trials.gov was searched to screen for ongoing studies using the following words: Beta blockers, angiotensin receptor blockers, ACEI, BB, anthracycline-induced cardiotoxicity, transtuzumab-induced cardiotoxicity, breast cancer, solid tumors, leukemia, lymphoma, malignancy.

Eligibility criteria and study selection

Eligible studies enrolled adult patients (aged 18 years or older) with any form of malignancy receiving anthracycline or transtuzumab based chemotherapy were included. The outcomes included: Primary outcomes- change in LVEF and total cardiotoxicity events; and secondary outcomes- early cardiotoxicity events, late cardiotoxicity events, change in LV end diastolic diameter (LVEDD), change in E/E’, change in E/A, total adverse events, dizziness, hypotension, and palpitation. Studies were excluded if they lacked a comparator group, used drugs other than BB or ACEI, involved non-human subjects, or were not published in English. Title and abstract screening were conducted independently by two reviewers (Rohab Sohail and Ridda Khattak), followed by full-text assessment. Any disagreements were resolved through discussion or with input from a third reviewer (Zaraq Khan).

Data collection and quality evaluation

Study characteristics and relevant outcome data were extracted using a predefined data collection form. Extracted variables included study design, population demographics duration of follow-up, and reported endpoints (Tables 1 and 2)[17-20].

Table 1 Tabulated representation of baseline characteristics of included randomized controlled trials.

Ref.	Type of study	Type of malignancy	Anti-cancer agent used	Beta blocker used	ACEI used	Location	Total study population (n)	Beta blocker (n)	ACEI/ARBs (n)	Duration of study
Pituskin et al[17], 2017	Randomized control trial	Breast	Transtuzumab	Bisoprolol	Perindopril	Canada	64	31	33	3 years
Guglin et al[18], 2019	Randomized control trial	Breast cancer	Transtuzumab	Carvedilol	Lisinopril	United States	314	156	158	12 months
Barletta et al[19], 2023	Phase 3 Randomized control trial	Breast cancer	Anthracycline	Bisoprolol	Ramipril	Italy	132	66	66	2 years
Georgakopoulos et al[20], 2010	Randomized control trial	Lymphoma	Anthracycline	Metoprolol	Enalapril	Greece	85	42	43	36 months

ACEI: Angiotensin-converting enzymes inhibitors; ARB: Angiotensin II receptor blockers.

Table 2 Tabulated representation of baseline characteristic of included, n (%)/mean ± SD.

Characteristics		Pituskin et al[17], 2017		Guglin et al[18], 2019		Barletta et al[19], 2023		Georgakopoulos et al[20], 2010
Subgroups		BB	ACEI/ARB	BB	ACEI/ARB	BB	ACEI/ARB	BB	ACEI/ARB
Age (years)		53 ± 10	50 ± 8	51.58 ± 10.93	20.58 ± 10.91	47 (31-71)	48.5 (23-68)	51.0 ± 18.0	47.4 ± 16.2
Female		31 (100)	33 (100)	156 (100)	156 (100)	66 (100)	66 (100)	20 (48)	21 (49)
Comorbidities	DM	3 (10)	1 (3)	4 (2.56)	5 (3.23)	-	-	10 (24)	3 (7)
	HTN	3 (5)	0	2 (6)	6 (3.79)	-	-	10 (24)	14 (33)
	Smoking	3 (10)	2 (6)	-	-	12 (18.2)	6 (9.1)	9 (21)	8 (19)
BMI (IQR)		30.5 ± 6.2	29.4 ± 6.5	28.26 ± 6.17	28.01 ± 6.86	-	-	25.7 ± 4.7	25.6 ± 5.1
Baseline parameters	SBP (mmHg)	121 ± 12	126 ± 13	124.57 ± 17.7	125.76 ± 17.63	128.8	123.0	-	-
	DBP (mmHg)	74 ± 6	78 ± 11	73.82 ± 10.38	75.73 ± 10.39	74.8	75.0	-	-
	Heart rate (bpm)	72 ± 9	82 ± 14	76.8 ± 20.8	60.2 ± 27.2	74	74	-	-
	LVEF (%)	62 ± 4	62 ± 5	62.55 ± 6.61	62.97 ± 6.18	-	-	67.7 ± 5.0	65.2 ± 7.1

BB: Beta-blockers; ACEI: Angiotensin-converting enzyme inhibitors; DM: Diabetes mellitus; HTN: Hypertension; BMI: Body mass index; IQR: Interquartile range; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; LVEF: Left ventricular ejection fraction.

Risk of bias

The risk of bias was evaluated using the revised Cochrane risk of bias toll for randomized trials for RCTs (Figure 2)[21-23]. Discrepancies in bias assessment were discussed among the authors until consensus was achieved.

Figure 2 Risk of bias assessment of included randomized controlled trials.

Statistical analysis

Meta-analytic pooling was performed using a random-effects model to address potential heterogeneity among included studies. Risk estimates were presented as relative risks (RRs) with 95% confidence intervals (CIs). The I² statistic was used to quantify heterogeneity, with a threshold of > 50% indicating considerable heterogeneity[24]. Due to the limited number of included studies, funnel plot analysis for publication bias and meta-regression could not be performed. Statistical significance was defined as P < 0.05.

Certainty of evidence assessment

For evaluation of the certainty of the evidence, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used, and the quality of evidence of the pooled estimates was judged as high, moderate, low, or very low according to the GRADE Working Group (Table 3)[25,26].

Table 3 Certainty of evidence assessment using grading of recommendations assessments, development, and evaluation.

Certainty assessment							No. of patients		Effect		Certainty	Importance
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Change in LVEF	Placebo	Relative (95%CI)	Absolute (95%CI)
Change in LVEF
4	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	345	335	-	SMD 0.46 higher (0.14 lower to 1.06 higher)	⊕⊕⊕⊕ high	CRITICAL
Cardiotoxicity
3	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	68/279 (24.4%)	63/272 (23.2%)	RR 1.07 (0.66 to 1.75)	16 more per 1000 (from 79 fewer to 174 more)	⊕⊕⊕⊕ high	CRITICAL
Early cardiotoxicity
2	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	14/123 (11.4%)	16/114 (14.0%)	RR 0.79 (0.23 to 2.69)	29 fewer per 1000 (from 108 fewer to 237 more)	⊕⊕⊕⊕ high	CRITICAL
Late cardiotoxicity
2	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	9/123 (7.3%)	4/114 (3.5%)	RR 2.09 (0.66 to 6.68)	38 more per 1000 (from 12 fewer to 199 more)	⊕⊕⊕⊕ high	CRITICAL
Change in LVEDD
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	123	112	-	SMD 0.41 lower (0.98 lower to 0.16 higher)	⊕⊕⊕◯ moderate1	CRITICAL
Change in E/E’
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	156	146	-	SMD 0.31 lower (0.54 lower to 0.08 lower)	⊕⊕⊕◯ moderate1	CRITICAL
Change in E/A
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	156	192	-	SMD 0.04 lower (0.26 lower to 0.17 higher)	⊕⊕⊕◯ moderate1	CRITICAL
Total AEs
2	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	20/170 (11.8%)	15/153 (9.8%)	RR 1.23 (0.64 to 2.35)	23 more per 1000 (from 35 fewer to 132 more)	⊕⊕⊕⊕ high	CRITICAL
Dizziness
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	33/250 (13.2%)	16/237 (6.8%)	RR 2.04 (1.18 to 3.53)	70 more per 1000 (from 12 more to 171 more)	⊕⊕⊕◯ moderate1	CRITICAL
Hypotension
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	22/199 (11.1%)	6/200 (3.0%)	RR 3.50 (1.50 to 8.16)	75 more per 1000 (from 15 more to 215 more)	⊕⊕⊕◯ moderate1	CRITICAL
Palpatation
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	11/137 (8.0%)	6/121 (5.0%)	RR 1.54 (0.60 to 3.98)	27 more per 1000 (from 20 fewer to 148 more)	⊕⊕⊕◯ moderate1	CRITICAL
Change in LVESD
2	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	123	114	-	SMD 0.2 lower (0.7 lower to 0.3 higher)	⊕⊕⊕⊕ high	CRITICAL

¹Imprecision associated with indirect measure of the outcome in some of the included studies.

LVEF: Left ventricular ejection fraction; CI: Confidence interval; SMD: Standardized mean difference; RR: Risk ratio; ⊕⊕⊕⊕: High level of certainty; ⊕⊕⊕◯: Moderate level of certainty; CRITICAL: Importance of outcome; AEs: Adverse events; LVESD: Left ventricular end systolic diameter; LVEDD: Left ventricular end diastolic diameter.

RESULTS

Primary outcomes

Change in LVEF: There was no statistically significant difference in change in LVEF between the ACEI and BB groups [mean difference (MD) = 0.38%; 95%CI: -0.35 to 1.11; P = 0.31; I² = 94%]. The high heterogeneity associated, in the setting of variation in study groups, limits the ability to draw definitive conclusion. The associated forest plot is depicted in Figure 3A.

Figure 3 Forest plot comparing angiotensin-converting enzymes inhibitors and beta-blockers for left ventricular ejection fraction change and total cardiotoxicity events. A: Change in left ventricular ejection fraction; B: Total cardiotoxicity events. ACE: Angiotesin converting enzymes; BB: Beta blockers; ACEI: Angiotensin-converting enzymes inhibitors; CI: Confidence interval.

Cardiotoxicity: Overall cardiotoxicity rates were comparable between groups (RR = 1.07; 95%CI: 0.66-1.75; P = 0.77; I² = 47%). The moderate heterogeneity related to the results, limits the ability to draw definitive conclusion. The forest plot is depicted in Figure 3B.

Secondary outcomes - diastolic function parameters

Change in E/E’: ACEI therapy was associated with a statistically significant improvement in diastolic function, as evidenced by a lower E/E’ ratio compared with the BB group (MD = -0.25; 95%CI: -0.50 to 0.01; P = 0.006; I² = 0%). The related forest plot is depicted in Figure 4A.

Figure 4 Forest plot of echocardiographic parameters comparing angiotensin-converting enzymes inhibitors and beta-blockers. A: Change in E/E’; B: Change in E/A; C: Change in left ventricular end diastolic diameter; D: Change in left ventricular end systolic diameter. ACE: Angiotesin converting enzymes; BB: Beta blockers; ACEI: Angiotensin-converting enzymes inhibitors; CI: Confidence interval.

Change in E/A: In contrast, there was no significant difference between groups in change in E/A ratio (MD = -0.01; 95%CI: -0.25 to 0.23; P = 0.92; I² = 0%). The related forest plot is depicted in Figure 4B.

Change in LV end systolic diameter and LVEDD: However, no significant differences were observed in structural remodeling parameters, including change in LVEDD (MD = -0.41%; 95%CI: -0.98 to 0.16; P = 0.16; I² = 77%), and change in LV end systolic diameter (MD = -0.20%; 95%CI -0.70 to 0.30; P = 0.43; I² = 71%). The high heterogeneity, limit the ability to draw definitive conclusion. The associated forest plots are depicted in Figure 4C and D.

Early and late cardiotoxicity

Subgroup analysis evaluating early and late cardiotoxicity did not demonstrate a statistically significant reduction with ACEI therapy. Event rates were similar between intervention and control groups across both time points [early cardiotoxicity (RR = 0.79; 95%CI: 0.23-2.69; P = 0.71; I² = 66%) and late cardiotoxicity (RR = 2.09; 95%CI: 0.66-6.68; P = 0.21; I² = 0%)], indicating no temporal benefit in preventing either early treatment-related dysfunction or late-onset cardiotoxicity. The associated forest plots are shown in Figure 5.

Figure 5 Forest plot comparing angiotensin-converting enzymes inhibitors and beta-blockers for early and late cardiotoxicity events. A: Early cardiotoxicity events; B: Late cardiotoxicity events. ACE: Angiotesin converting enzymes; BB: Beta blockers; ACEI: Angiotensin-converting enzymes inhibitors; CI: Confidence interval.

Adverse events

The overall risk of total adverse events (RR = 1.46; 95%CI: 0.72-2.97; P = 0.29; I² = 0%) and palpitations (RR = 1.54; 95%CI: 0.60-3.98; P = 0.37) was similar between groups. However, hypotension (RR = 3.50; 95%CI: 1.50-8.10; P = 0.004; I² = 0%) and dizziness (RR = 2.04; 95%CI: 1.18-3.53; P = 0.01; I² = 0%) were significantly more frequent in the ACEI group (Figure 6).

Figure 6 Forest plot comparing angiotensin-converting enzymes inhibitors and beta-blockers for total adverse events, palpitations, hypotension, and dizziness. A: Total adverse events; B: Palpitations; C: Hypotension; D: Dizziness. BB: Beta blockers; ACEI: Angiotensin-converting enzymes inhibitors; CI: Confidence interval.

DISCUSSION

This meta-analysis provides a direct comparison between ACEI and beta-blockers in the prevention of anti-cancer agents-induced cardiotoxicity. There was no significant difference in change in LVEF, overall cardiotoxicity, early or late cardiotoxicity, change in LVEDD, change in LV end systolic diameter, change in E/E’ or change in E/A. With respect to adverse events, total adverse events were similar between groups. However, hypotension and dizziness occurred more frequently in patients treated with angiotensin-converting enzymes inhibitors (ACEI)/angiotensin II receptor blockers (ARBs) compared to beta-blockers. Overall, based on the available randomized controlled trials, ACEI and beta-blockers appear to provide a comparable level of protection against anti-cancer agents-induced cardiotoxicity.

Clinical rationale

Although both ACEI and beta-blockers are considered cardioprotective in the setting of chemotherapy, their pharmacologic profiles differ substantially, which may explain potential differences in clinical effects.

ACEI primarily act through inhibition of the renin-angiotensin-aldosterone system (RAAS), leading to afterload reduction, attenuation of maladaptive ventricular remodeling, and suppression of neurohormonal activation[27]. These effects may be particularly relevant in patients experiencing subclinical increases in filling pressures or early diastolic dysfunction. By reducing systemic vascular resistance and ventricular wall stress, ACEI may preferentially influence diastolic parameters before measurable systolic decline occurs[28]. In contrast, beta-blockers exert their cardioprotective effect largely through reduction in heart rate, myocardial oxygen demand, and sympathetic overactivation[29]. Certain agents such as carvedilol may also confer antioxidant properties, but beta-blockers overall may have a more pronounced impact on chronotropic control and myocardial workload rather than ventricular loading conditions[30].

Despite these mechanistic differences, our analysis did not demonstrate any significant difference between ACEIs and beta-blockers in preventing anti-cancer agents-induced cardiotoxicity or in improving echocardiographic parameters. This suggests that the theoretical advantages of RAAS inhibition in modulating ventricular loading conditions and diastolic function do not translate into measurable clinical superiority. It is possible that both drug classes ultimately converge on shared downstream cardioprotective pathways, resulting in comparable efficacy in mitigating cardiotoxicity, despite differences in their primary mechanisms of action.

Adverse events

While total adverse events, and palpitations were not significantly different between the two groups, hypotension and dizziness were more frequently observed in patients receiving ACEI.

This finding is pharmacologically plausible. ACEI exert a more direct vasodilatory effect through RAAS inhibition, resulting in greater reductions in systemic vascular resistance and blood pressure[31]. Beta-blockers, particularly non-vasodilating agents, may have a comparatively milder effect on resting blood pressure. Therefore, the higher incidence of hypotension in the ACEI group is expected. The increased incidence of dizziness in the ACEI group likely reflects this greater blood pressure reduction. Although beta-blockers have been associated with orthostatic symptoms, the overall hemodynamic impact appears less pronounced in this setting compared to RAAS inhibition[15].

Agent selection, comparative limitation, and dose consideration in cardioprotection

Current cardio-oncology guidance, including recommendations from the European Society of Cardiology[12] and American College of Cardiology[32], does not differentiate between individual agents within the beta-blocker or ACE inhibitor classes, but acknowledges that commonly used drugs may have distinct pharmacologic profiles that can guide selection. Among beta-blockers, agents such as carvedilol, metoprolol, and bisoprolol are most frequently studied; carvedilol, a non-selective beta- and alpha-blocker, may provide additional antioxidant and afterload-reducing effects, whereas metoprolol and bisoprolol, as β1-selective agents, primarily exert chronotropic and anti-ischemic benefits with potentially better tolerability in certain patients. Within the ACE inhibitor class, agents such as enalapril, lisinopril, and ramipril differ in pharmacokinetics, tissue penetration, and blood pressure-lowering effects; however, these differences have not translated into clear evidence of superiority in preventing anti-cancer agents-induced cardiotoxicity.

However, there are currently insufficient adequately powered trials to allow for robust head-to-head comparisons between different beta-blockers or between different ACE inhibitors. This limitation in the existing literature precludes meaningful subgroup or agent-specific comparative analysis within our study. As such, our analysis was restricted to class-level comparisons, and conclusions regarding superiority of individual agents cannot be drawn[12,32,33].

Additionally, the impact of dosing strategies remains an important but underexplored area. Available studies use variable dosing regimens, ranging from low prophylactic doses to guideline-directed target doses, without consistent reporting of dose-response relationships. As a result, there is insufficient evidence to determine whether higher or optimized dosing confers incremental cardioprotective benefit. This gap in the literature limited our ability to assess dose-dependent effects in our analysis and highlights the need for future trials specifically designed to evaluate optimal dosing strategies for cardio protection in cardio-oncology patients[34].

Existing guidelines and alignment with current literature

The 2022 European Society of Cardiology Cardio-Oncology Guidelines[12] recommend consideration of ACEI and beta-blockers for primary prevention of anti-cancer agents-induced cardiotoxicity (class 2b) and management of already established cardiotoxicity (class 2a). Similarly, American College of Cardiology[32] expert consensus documents and recent JACC Cardio Oncology expert panel statements acknowledge the potential role of both RAAS inhibitors and beta-blockers in patients undergoing anthracycline or human epidermal growth factor receptor-2-targeted therapy who are at elevated cardiovascular risk.

Importantly, current guidelines do not favor one class over the other for primary prophylaxis or even treatment. Recommendations are generally based on overall risk stratification rather than superiority of a specific agent. The European Society of Cardiology guidelines[12] emphasize individualized therapy based on baseline cardiovascular risk, blood pressure profile, and comorbidities, rather than mandating ACEI or beta-blocker use preferentially.

Recent meta-analyses evaluating ACEI or beta-blockers separately have demonstrated preservation of LVEF compared with placebo; however, direct head-to-head comparisons remain limited[13-15]. Our findings align with existing guideline positions by demonstrating comparable efficacy between the two classes in preventing clinically meaningful cardiotoxicity.

Subgroup analyses in recent literature have suggested potential benefit of RAAS inhibition in patients receiving combined anthracycline and trastuzumab therapy, which remains an area of ongoing investigation. However, current evidence remains insufficient to support routine preferential use of one class over the other.

Clinical implications

While current guidelines already support the use of both ACEIs and beta-blockers for the prevention and management of anti-cancer agents-induced cardiotoxicity, they do not provide clear direction regarding the optimal choice between these agents. Our study adds clinically meaningful evidence by directly comparing these two commonly used strategies and demonstrating no significant difference in their efficacy. This reinforces a class-equivalent approach and reduces uncertainty in agent selection.

From a practical standpoint, our findings support tailoring therapy based on individual patient characteristics rather than perceived superiority of one drug class. Clinicians can prioritize factors such as baseline blood pressure, heart rate, comorbidities (e.g., hypertension, arrhythmias), drug tolerance, and potential adverse effects when choosing between ACEIs and beta-blockers. This is particularly relevant in cardio-oncology practice, where patients often have competing risks and complex clinical profiles.

Additionally, by confirming comparable outcomes between the two classes, our study helps streamline clinical decision-making and may improve adherence to cardioprotective strategies, as clinicians can confidently select either class without concern for compromising efficacy. Ultimately, these findings support a more individualized, patient-centered approach while aligning with and strengthening existing guideline recommendations. Moreover, further studies addressing the comparison of difference beta blockers or ACEI and at the same time different doses of these drugs can help bridge the existing gap.

Limitations

This meta-analysis has some limitations. The overall sample size was modest, with relatively low event rates, limiting power to detect small but clinically meaningful differences between ACEI/ARBs and beta-blockers and increasing the possibility of type II error. Clinical heterogeneity existed across trials, including differences in chemotherapy regimens, timing of cardioprotective therapy, follow-up duration, and definitions of cardiotoxicity, as well as variability in echocardiographic assessment methods, which may have influenced pooled estimates despite generally low to moderate statistical heterogeneity. Follow-up was relatively short in most studies, limiting assessment of long-term and late cardiotoxicity outcomes. Additionally, different agents within each drug class were pooled under the assumption of a class effect, which may not fully account for pharmacologic differences between individual medications. Finally, the small number of included trials limits formal assessment of publication.

CONCLUSION

In this meta-analysis of randomized controlled trials, ACEI/ARBs and beta-blockers demonstrated comparable efficacy in preventing anti-cancer agents-induced cardiotoxicity, with no significant differences observed in change in LVEF, overall cardiotoxicity, or early and late cardiotoxicity. Adverse event profiles were largely similar between groups, though hypotension and dizziness occurred more frequently with ACEI/ARBs. Overall, these findings support a risk-adapted, individualized approach to cardio protection consistent with current guidelines, while highlighting the need for larger, adequately powered head-to-head trials with longer follow-up to determine whether meaningful differences emerge over time.