Published online Jul 26, 2026. doi: 10.4330/wjc.v18.i7.121472
Revised: April 20, 2026
Accepted: May 28, 2026
Published online: July 26, 2026
Processing time: 117 Days and 7.9 Hours
Anthracyclines by generating reactive oxygen species (ROS), causes a dose-dependent, irreversible myocardial injury, resulting in cardiomyopathy and con
To investigate the efficacy of Ivabradine in prevention of anthracycline-induced cardiotoxicity.
PubMed and Google Scholar were searched for randomized controlled trials (RCTs) comparing Ivabradine to placebo in patients receiving Anthracycline based chemotherapy. After careful screening 3 studies including 210 patients were analyzed using a random-effects model in RevMan 5.4.1 and results were generated in form of relative risk (RR) and mean difference (MD).
Ivabradine failed to show any statistical significant reduction in; troponin [SMD = 0.10; 95% confidence interval (95%CI): -2.14 to 2.33; P = 0.93], NT-proBNP (SMD = 0.26; 95%CI: -1.39 to 1.92; P = 0.76), systolic blood pressure (SMD = -0.13; 95%CI: -0.44 to 0.19; P = 0.43), diastolic blood pressure (SMD = -0.16; 95%CI: -047 to 0.16; P = 0.33), global longitudinal strain reduction (RR = 0.80; 95%CI: 0.28-2.32; P = 0.68), or left ventricular ejection fraction (SMD = –0.01; 95%CI: -0.28 to 0.26; P = 0.95).
Our analysis failed to show efficacy of ivabradine in mitigating anthracycline-induced cardiotoxicity. small sample size and heterogeneity limits definitive interpretation, warranting a large-scale RCT with longer follow-up period.
Core Tip: Anthracyclines-induced chemotherapy is associated with a risk of cardiotoxicity, often manifesting as reductions in left ventricular ejection fraction and subclinical myocardial injury. In this meta-analysis of randomized studies, ivabradine did not demonstrate a significant effect in preserving left ventricular ejection fraction or improving cardiac biomarkers, including troponin and NT-proBNP, nor did it significantly reduce global longitudinal strain deterioration. These findings suggest that while ivabradine is well tolerated and does not adversely affect blood pressure, current evidence does not support its routine use for the prevention of anthracycline-induced cardiotoxicity. Larger randomized trials are needed to clarify its potential cardioprotective role.
- Citation: Sohail R, Khattak R, Shah HH, Khan Z, Jawed S, Wasim AU, Akram B, Patel R, Patel S, Alam M, Chaudhry S, Mehdi S, Patel V, Singh M. Preventing anthracycline-induced cardiotoxicity with ivabradine: A systematic review and meta-analysis. World J Cardiol 2026; 18(7): 121472
- URL: https://www.wjgnet.com/1949-8462/full/v18/i7/121472.htm
- DOI: https://dx.doi.org/10.4330/wjc.v18.i7.121472
Anthracyclines remain a cornerstone of modern oncology and are widely used in the treatment of breast cancer, lymphomas, leukemias, sarcomas, and other solid tumors[1]. Agents such as doxorubicin and epirubicin are incorporated into standard-of-care regimens, contributing significantly to improved remission rates and long-term survival across multiple malignancies. It is estimated that anthracyclines are used in up to 50-60% of chemotherapy protocols for breast cancer and hematologic malignancies, underscoring their substantial role in cancer management[2]. Their potent antineoplastic efficacy stems from DNA intercalation, topoisomerase II inhibition, and free radical generation, mechanisms that induce tumor cell apoptosis and drive meaningful improvements in oncologic outcomes[3].
However, these same molecular pathways are not entirely tumor selective. Along with targeting malignant cells, anthracyclines expose cardiomyocytes to oxidative stress and mitochondrial injury[3]. The redox cycling process that contributes to cytotoxicity in cancer cells also generates excessive reactive oxygen species within myocardial tissue, promoting mitochondrial dysfunction, impaired calcium handling, and progressive myocyte apoptosis[4]. Because cardiomyocytes have limited regenerative capacity, cumulative injury translates into dose-dependent and often irreversible left ventricular dysfunction[3]. Clinically, this may manifest as asymptomatic decline in ejection fraction, arrhythmias, or overt heart failure, sometimes appearing years after treatment completion[5]. The development of anthracycline-induced cardiomyopathy has been associated with significantly reduced long-term survival, thereby influencing cumulative dose thresholds and, in some cases, limiting optimal chemotherapy delivery[6,7].
Currently, preventive strategies for anthracycline-induced cardiomyopathy remain limited[8,9]. Approaches primarily include cumulative dose restriction, liposomal formulations, use of dexrazoxane in selected high-risk patients, and initiation of guideline-directed heart failure therapies once dysfunction develops[4,8,10]. Nevertheless, no universally effective pharmacologic strategy has been established for primary prevention. Ivabradine, a selective inhibitor of the sinoatrial If current, has recently emerged as a potential cardioprotective agent[11]. Beyond heart rate reduction, preclinical studies suggest that ivabradine enhances mitochondrial function and restores calcium homeostasis, thereby attenuating myocardial injury[12]. Animal models have demonstrated structural and functional preservation, and early clinical trials, typically initiating therapy at 5 mg twice daily with up titration as tolerated, have shown trends toward preservation of left ventricular ejection fraction (LVEF), though statistical significance has not been consistently achieved[13-15].
Despite encouraging mechanistic rationale and preliminary clinical findings, important knowledge gaps remain. Existing trials are limited by small sample sizes, heterogeneous study designs, and short follow-up durations, with variable reporting of clinically relevant outcomes such as LVEF decline, troponin elevation, NT-proBNP levels, and blood pressure changes. The magnitude of benefit, optimal timing of initiation, and patient populations most likely to derive cardio protection are yet to be clearly defined. Therefore, we are conducting a meta-analysis of clinical trials to comprehensively evaluate the role of ivabradine in preventing anthracycline-induced cardiomyopathy. Our study aims to provide a more precise estimate of its effect on preservation of left ventricular function and cardiac biomarkers, thereby informing evidence-based cardioprotective strategies in patients receiving anthracycline chemotherapy.
This systematic review and meta-analysis were reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (Figure 1)[16]. The objective was to investigate and the compare the efficacy of Ivabradine as compared to placebo, for the prevention of anthracyclines-induced chemotherapy. The analysis integrated data from randomized controlled trials (RCTs) comparing Ivabradine to placebo. The protocol for this meta-analysis was registered and published with PROSPERO CRD420261290122.
A structured search strategy was applied across PubMed, the Cochrane Library, and Google Scholar to identify studies published up to October 2025. The search combined MeSH terms and keywords to formulate a search string: “(“Ivabradine”) AND (“Anthracyclines”) AND (“Cardiotoxicity” OR “heart failure” OR “left ventricular dysfunction”) AND (“Breast Neoplasms” OR “cancer” OR “lymphoma” OR “breast cancer” OR “breast carcinoma”)”. Only clinical trials comparing Cancer patients on anthracyclines receiving ivabradine or placebo were included. Clinical trials.gov was searched to screen for ongoing studies using the following words: Ivabradine, anthracyclines, cardiotoxicity, heart failure, left ventricular dysfunction, breast neoplasms, cancer, lymphoma, breast cancer, breast carcinoma.
Eligible studies enrolled adult patients (aged 18 years or older) with malignancy receiving anthracyclines who were treated with ivabradine or placebo. Only trials comparing the two groups were included. The outcomes included: Primary outcomes- Change in LVEF; and secondary outcomes - systolic blood pressure (SBP), diastolic blood pressure (DBP), proBNP, troponin, and change in global longitudinal strain (GLS). Studies were excluded if they lacked a comparator group, used drugs other than ivabradine, involved non-human subjects, or were not published in English. Title and abstract screening were conducted independently by two reviewers (Khattak R and Sohail R), followed by full-text assessment. Any disagreements were resolved through discussion or with input from a third reviewer (Khan Z).
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).
| Ref. | Type of study | Location | Total study population | Ivabradine | Placebo | Duration of study |
| Čiburienė et al[13], 2023 | Randomized open label trial | Lithuania | 48 | 21 | 27 | 6 months |
| Rizk et al[14], 2025 | Tripple blind randomized controlled trial | Spain | 107 | 51 | 56 | 12 months |
| Vasyuk et al[15], 2017 | Open labelled randomized controlled trial | Russia | 55 | 23 | 32 | 12 months |
| Characteristics | Čiburienė et al[13], 2023 | Rizk et al[14], 2025 | Vasyuk et al[15], 2017 | ||||
| Ivabradine | Placebo | Ivabradine | Placebo | Ivabradine | Placebo | ||
| Age (years) | 47.8 ± 9.9 | 48 ± 10.2 | 49 (32-59) | 39 (26-60) | 49.8 ± 9.4 | 48.7 ± 9.5 | |
| Female | 21 (100) | 27 (100) | 24 (41) | 18 (35.3) | 28 (50.0) | 4 (16.7) | |
| Cancer type | Breast | 21 (100) | 25 (92.6) | 0 | 0 | 23 (100) | 32 (100) |
| NHL | 0 | 0 | 30 (58.8) | 29 (51.8) | 0 | 0 | |
| HL | 0 | 0 | 18 (35.3) | 26 (46.4) | 0 | 0 | |
| Sarcoma | 0 | 2 (7.4) | 3 (5.9) | 1 (1.8) | 0 | 0 | |
| Anthracyclines commutative dose (mg/m2) | Doxorubicin | 236 ± 70 | 246 ± 69 | 300 (250-300) | 300 (250-300) | 441.4 ± 84.5 | 391.7 +/- 103.8 |
| Epirubicin | 360 ± 70 | 360 ± 70 | - | - | - | - | |
| Risk factors | HTN | 3 (15) | 2 (7.4) | 13 (25.5) | 9 (16.4) | 5 (21.0) | 9 (28.3) |
| DM | 0 | 0 | 4 (7.8) | 5 (8.9) | 1 (4.3) | 1 (3.1) | |
| HLD | 13 (65) | 21 (77.8) | 4 (8.0) | 3 (5.4) | - | - | |
| Smoking | 1 (5) | 6 (22.2) | 7 (13.7) | 9 (16.4) | - | - | |
| CKD | 0 | 0 | - | - | 1 (4.3) | 3 (9.4) | |
The risk of bias was evaluated using the ROB-2 for RCTs (Figure 2)[17-19]. Discrepancies in bias assessment were discussed among the authors until consensus was achieved.
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 interval (95%CI). The I2 statistic was used to quantify heterogeneity, with a threshold of > 50% indicating considerable heterogeneity[20]. 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.
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)[21,22].
| Certainty assessment | No. of patients | Effect | Certainty | Importance | ||||||||
| No. of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | LVEF | Placebo | Relative (95%CI) | Absolute (95%CI) | ||
| LVEF | ||||||||||||
| 3 | Randomised trials | Serious1 | Not serious | Not serious | Serious2 | None | 95 | 115 | - | SMD 0.01 lower (0.28 lower to 0.26 higher) | ⊕⊕◯◯, low1,2 | CRITICAL |
| GLS reduction | ||||||||||||
| 2 | Randomised trials | Serious1 | Not serious | Serious2 | Serious2 | None | 31/72 (43.1%) | 35/83 (42.2%) | RR = 0.80 (0.28-2.32) | 84 fewer per 1000 (from 304 fewer to 557 more) | ⊕◯◯◯, very low1,2,3 | CRITICAL |
| NT-proBNP | ||||||||||||
| 2 | Randomised trials | Serious1 | Not serious | Not serious | Serious2 | None | 72 | 83 | - | SMD 0.26 higher (1.39 Lower to 1.92 higher) | ⊕⊕◯◯, low1,2 | CRITICAL |
| Troponin | ||||||||||||
| 2 | Randomised trials | Serious1 | Not serious1 | Not serious | Serious2 | None | 72 | 83 | - | SMD 0.1 higher (2.14 lower to 2.33 higher) | ⊕⊕◯◯, low1 | CRITICAL |
| SBP | ||||||||||||
| 2 | Randomised trials | Serious1 | Not serious | Not serious | Serious2 | None | 74 | 79 | - | SMD 0.13 lower (0.44 lower to 0.19 higher) | ⊕⊕◯◯, low1,2 | CRITICAL |
| DBP | ||||||||||||
| 2 | Randomised trials | Serious1 | Not serious | Not serious | Serious2 | None | 74 | 83 | - | SMD 0.16 lower (0.47 lower to 0.16 higher) | ⊕⊕◯◯, low1 | CRITICAL |
Change in LVEF: Three studies evaluated the effect of ivabradine on changes in LVEF following anthracycline therapy. Pooled analysis demonstrated no statistically significant difference between ivabradine and control groups (SMD =
Troponin levels: Two studies reported changes in troponin levels. Pooled analysis showed no significant difference between ivabradine and control groups (SMD = 0.10 ng/L; 95%CI: -2.14 to 2.33; P = 0.93; I2 = 97%). The generalizability of calculated results is limited as the analysis demonstrated substantial heterogeneity, likely reflecting variability in baseline cardiac risk profiles, cumulative anthracycline exposure, and troponin assay methods across the included studies (Figure 4A).
NT-proBNP: Two studies assessed changes in NT-proBNP levels. Meta-analysis revealed no statistically significant difference between ivabradine and control groups (SMD = 0.26 pg/mL; 95%CI: -1.39 to 1.92; P = 0.76; I2 = 95%) (Figure 4B). Pooled analysis demonstrated substantial heterogeneity making the results unreliable. It can be due to variability in baseline cardiac risk profiles, cumulative anthracycline exposure, and troponin assay methods across the included studies.
GLS reduction: Two studies evaluated the incidence of GLS reduction during follow-up. Pooled analysis demonstrated no statistically significant difference between ivabradine and control groups (RR = 0.80; 95%CI: 0.28-2.32; P = 0.68; I2 = 57%). The wide confidence interval indicates limited precision and heterogeneity across studies (Figure 4C).
SBP: Two studies reported SBP outcomes. Pooled analysis demonstrated no significant difference between ivabradine and control groups (SMD = -0.13 mmHg; 95%CI: -0.44 to 0.19; P = 0.43; I2 = 0%) (Figure 4D).
DBP: Two studies assessed changes in DBP. Meta-analysis demonstrated no statistically significant difference between ivabradine and control groups (SMD = -0.16 mmHg; 95%CI: -0.47 to 0.16; P = 0.33; I2 = 0%) (Figure 4E).
Our meta-analysis of three randomized controlled trials including 210 patients showed that use of ivabradine in patients receiving anthracycline-based chemotherapy as a preventive agent did not have any demonstrable benefits. The intervention group did not show any significant improvement in troponin levels, NT-proBNP levels, systolic and DBP, or global longitudinal strain. Neither did it have any effect on preserving LVEF. So, no beneficial effect of ivabradine was evident in preventing cardiotoxicity in patients on anthracycline-based regimen.
The initial promise of ivabradine being cardioprotective for these patients stemmed from its selective decrease in heart rate by inhibiting If without causing a drop in blood pressure or affecting contractility[11]. Hence oxygen consumption would be reduced, making the myocardium less susceptible to damage from anthracycline-generated free radicals[23]. At a cellular level, that translates to improved mitochondrial function, enhanced calcium homeostasis, and better regulation of apoptosis[24]. It was manifested in a preclinical study where co-treatment with ivabradine increased cell viability and reduced oxidative stress[25].
However, these benefits did not translate into clinically significant effects in our pooled analysis. We can attempt to understand this by taking into account that anthracycline-induced cardiotoxicity is a multifactorial process and in addition to free radical mediated injury, it also includes topoisomerase-2β-mediated DNA damage, and maladaptive myocardial apoptosis and fibrosis[6,26]. Heart rate reduction alone does not directly affect these pathogenic pathway. Unlike agents such as dexrazoxane, which targets iron-mediated free radical formation, ivabradine exerts no direct molecular interference with these core mechanisms driving anthracycline toxicity[27,28]. Another factor to consider is the dosing; In the clinical trial, ivabradine did not significantly reduce heart rate more than placebo, because it was given at a fixed dose without titration tailored to individual heart rates and insufficient heart rate lowering likely blunt its downstream protective effects[29-31].
In the clinical trials, ivabradine did not significantly reduce heart rate more than placebo, because it was given at a fixed dose without titration tailored to individual heart rates and insufficient heart rate lowering likely blunt its downstream protective effects[29-31]. Only Čiburienė et al[13] reported the heart rates for both groups at follow-up and although there was significant difference in heart rate among both groups, the mean heart rate was not sufficiently lowered (intervention group = 82.09, control group = 88.48). As decrease in heart rate was expected to be the major driver of cardioprotective effects of ivabradine, failure to achieve it sufficiently may be the reason for lack of any demonstrable benefit.
Chemotherapy induced cardiotoxicity remains a major cause of morbidity and mortality in cancer survivors. Subclinical and overt cardiotoxicity were reported at a staggering 17.9% and 6.3% respectively over 9 years of follow up by Cappetta et al[2]. Currently, dexrazoxane is the only Food and Drug Administration-approved agent for anthracycline-induced cardiotoxicity (AIC) but it comes with a trade-off of secondary malignancy. Preventive strategies are hence very im
Initial trials done on ivabradine like Čiburienė et al[13] and Rizk et al[14] showed a trend towards improved biomarkers in treatment groups, putting ivabradine forward as a promising cardioprotective agent in this population[15]. A case report also highlighted that multidrug treatment with add-on ivabradine can potentially treat worsening heart failure in young adult cancer survivors with anthracycline-induced cardiotoxicity[32].
But our pooled results show that there is no protective value in giving ivabradine to patients at risk of AIC. Our findings align with larger evidence syntheses, including a network meta-analysis of 128 RCTs, which concluded that current data are insufficient to support routine use of ivabradine in this setting[4].
Thus, while biologically plausible, the accumulated clinical evidence does not currently support ivabradine as an effective cardioprotective agent in anthracycline-treated patients.
Our study has some important limitations that warrant consideration. First, the relatively small, pooled sample size (n = 210) limits statistical power and may have precluded the detection of smaller yet clinically meaningful differences, underscoring that these findings should be interpreted with caution. Second, the included studies demonstrated a moderate to high risk of bias, which may have influenced the overall estimates. Notably, two of the three trials were open-label, introducing the potential for observer bias in outcome assessment. Third, several outcomes exhibited substantial heterogeneity, likely reflecting variations in study design, patient populations, and outcome measurement methods. Additionally, the follow-up duration ranged from six to twelve months, which may be insufficient to capture delayed cardiotoxic effects or long-term cardioprotective benefits. Importantly, the effect of ivabradine on heart rate reduction was not consistently reported across studies, and the impact of accelerated or up titrated dosing strategies was not evaluated, limiting mechanistic and dose-response interpretation.
Given the small overall sample size and these gaps in reporting, further investigation is necessary. Future studies should prioritize larger, adequately powered randomized controlled trials with longer follow-up durations and standardized outcome measures. In addition, dedicated evaluation of ivabradine’s heart rate-modulating effects and dosing strategies, as well as exploration of combination cardioprotective regimens, may provide more robust insights into optimizing preventive strategies in cardio-oncology.
In this meta-analysis of randomized trials, ivabradine did not demonstrate a significant improvement in LVEF or cardiac biomarkers for the prevention of anthracycline-induced cardiotoxicity. While preclinical data suggest potential cardioprotective effects, these findings were not clearly reflected in the available clinical evidence. However, given the small, pooled sample size, heterogeneity across studies, and methodological limitations, these results should be interpreted with caution. At present, routine prophylactic use of ivabradine cannot be supported, but its potential role remains uncertain and warrants further evaluation in larger, well-designed randomized trials with standardized endpoints and longer follow-up. Importantly, clinical decision-making should be individualized and guided by patient-specific cardiovascular risk factors and overall clinical context, rather than relying solely on this limited evidence base.
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