Efficacy of ivabradine in heart rate reduction after cardiac transplantation: Systematic review and meta-analysis

Abstract

BACKGROUND

Persistent sinus tachycardia affects up to 40% of patients after heart transplantation and is linked with graft dysfunction, impaired diastolic filling, and increased morbidity. Conventional rate-limiting therapies such as beta-blockers and calcium channel blockers are quite often contraindicated due to risks of bradyarrhythmia or hypotension. Ivabradine, a selective I(f) channel inhibitor, reduces heart rate (HR) without negative inotropic or hypotensive effects.

AIM

To evaluate the efficacy and safety of ivabradine in heart transplant recipients.

METHODS

A comprehensive search of PubMed, EMBASE, Scopus, Cochrane Library, and Google Scholar was conducted from inception to April 15, 2025. Eligible studies evaluated ivabradine in heart transplant recipient vs placebo or metoprolol, reporting HR, mortality, left ventricular mass (LVM), or safety. Data were independently extracted by two reviewers, and quality was assessed. Review Manager 5.4 performed pooled analyses using random-effects models. Mean differences (MD) or standardized MD (SMD) were calculated for continuous outcomes, and risk ratios for dichotomous outcomes.

RESULTS

Of 415 records identified, four studies comprising 264 patients (126 ivabradine, 138 control) met the inclusion criteria. Ivabradine significantly reduced resting HR compared with controls (MD = -11.06 beats per minute; 95%CI: -19.50 to -2.62; P < 0.00001; I² = 93%). Sensitivity analysis demonstrated consistent findings (SMD = -6.74; 95%CI: -9.23 to -4.24; I² = 0%). No significant difference in all-cause mortality was observed (MD = 0.52; 95%CI: 0.17-1.64; P = 0.27; I² = 85%). Pooled analysis of LVM revealed no significant effect of ivabradine (MD = -3.57 g; 95%CI: -29.21 to 22.08; P = 0.79; I² = 73%), with sensitivity analysis confirming neutrality. Adverse events were rare and mostly comparable between groups.

CONCLUSION

Ivabradine reduces HR effectively in heart transplant recipients without added adverse outcomes, supporting its use as safe and well-tolerated alternative when conventional agents are unsuitable. Despite potential clinical benefit, small sample size and heterogeneity the need for larger randomized trials to confirm long-term outcomes and establish ivabradine’s role in post-transplant care.

Key Words: Ivabradine; Heart transplant; Heart rate; Meta-analysis; Tachycardia; Decision making

Core Tip: Persistent sinus tachycardia after heart transplantation is linked to graft dysfunction and poor outcomes, yet beta-blockers are often limited by hypotension or bradyarrhythmia. Ivabradine, a selective inhibitor of funny current, lowers heart rate (HR) without negative inotropic or hypotensive effects. Our systematic review and meta-analysis of four studies (264 patients) found ivabradine significantly reduced resting HR and was well tolerated in transplant patients, underscoring its role as a promising therapeutic option for rate control when conventional treatments are unsuitable.

INTRODUCTION

Heart transplantation effectively cures end-stage heart failure unresponsive to superior medical and technology therapy; it considerably enhances patient survival and quality of life[1,2]. Sinus tachycardia is a prevalent and persistent problem in heart transplant recipients, mostly due to autonomic denervation, elevated circulating catecholamines, and modified cardiac hemodynamics post-transplantation[3]. Adverse ventricular remodeling, poor diastolic filling, and elevated myocardial oxygen demand may jeopardize graft longevity and patient outcomes and have been linked to persistent tachycardia[4].

Ivabradine, a specific inhibitor of the If (“funny”) current in the sinoatrial node can be used to decrease heart rate (HR) without negative inotropic or hypotensive effects[5]. Interest has been garnered due to its distinctive mechanism of action as a prospective therapeutic drug for heart transplant recipients, particularly for those who are intolerant to beta blockers or at risk of hemodynamic instability[6]. Ivabradine has been examined in multiple studies within this population, demonstrating beneficial outcomes such as a reduced resting HR, lowered of left ventricular mass index (LVMI), and improved graft function and exercise capacity[7,8].

Nevertheless, the distinct patient population, characterized by immunosuppression, comorbidities, and post-transplant pharmacokinetics, necessitates a meticulous evaluation of ivabradine's safety profile, as these factors may influence drug metabolism and heighten the risk of adverse effects or drug interactions[9]. A comprehensive synthesis of evidence on the efficacy and safety of ivabradine in heart transplant recipients is lacking in the clinical community, despite the increasing volume of research on the subject.

This systematic review and meta-analysis aim to critically evaluate and synthesize existing studies comparing ivabradine to placebo or metoprolol in heart transplant recipients, assessing its impact on HR reduction, LVMI, cardiac function, and adverse outcomes. This study intends to improve clinical decision-making and identify knowledge gaps for future studies by merging current literature.

MATERIALS AND METHODS

Data sources and search strategy

This systematic review and meta-analysis were carried out following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Relevant studies published from database inception to April 15, 2025 were identified by thorough literature search. The electronic databases were Google Scholar, Scopus, ScienceDirect, Cochrane Library, EMBASE, and PubMed (MEDLINE). A structured search strategy was applied, using the following terms and combinations: ("heart transplantation"[Mesh] OR "heart transplant"[tiab] OR "cardiac transplant" OR "transplanted heart" OR "graft recipients" OR "post-transplant") AND ("ivabradine"[Mesh] OR "ivabradine" OR "procoralan" OR "corlanor" OR "S-16257") AND ("placebo"[Mesh] OR "placebo" OR "control group" OR "metoprolol"[Mesh] OR "metoprolol" OR "beta-blocker") AND ("heart rate"[Mesh] OR "bradycardia"[Mesh] OR "heart rate reduction" OR "left ventricular mass index" OR "LVMI" OR "ejection fraction"[Mesh] OR "cardiac output"[Mesh] OR "adverse effects"[Mesh] OR "drug interaction"[Mesh]). Cochrane Library, EMBASE, ScienceDirect, and Scopus were also searched using more customized queries. Any possibly relevant studies were also hand-searched from the reference lists of all included studies, prior meta-analyses, and review articles. Clinicaltrials.gov aided in finding unpublished studies. Two reviewers carried out the literature search separately. Disagreements were settled through either conversation or consultation with a third reviewer.

Study selection

The selection of suitable studies was driven by the following criteria: (1) Inclusion of heart transplant recipients as the population; (2) Evaluation of ivabradine as the intervention; and (3) Comparison with either metoprolol or a placebo. Studies were required to demonstrate ivabradine's safety profile, particularly concerning adverse effects and drug interactions, with its impact on HR reduction, LVMI decrease, and enhancements in cardiac function, including ejection fraction and cardiac output. The meta-analysis included several study designs such as randomized controlled trials (RCTs), cohort studies, non-randomized clinical trials, retrospective studies, and case-control studies that satisfied the specified criteria.

The exclusion criteria were case reports, case series, review papers, meta-analyses, editorials, letters to the editor, and studies that did not adhere to the population, intervention, comparison, and outcome framework. Eligibility was initially assessed by title and abstract screening, followed by full text review for confirmation.

Data extraction

All identified studies were imported into the EndNote reference manager, and duplicates were removed. The screening and comprehensive review process was conducted by two independent evaluators. A consultation with a third reviewer resolved the differences. Data extracted from each qualifying study comprised: (1) First author; (2) Year of publication; (3) Study design; (4) Sample size; (5) Patient demographics; (6) Details of intervention and control groups; (7) Follow-up duration; and (8) All reported outcomes, including HR variations, LVMI, ejection fraction, cardiac function, and adverse events. A standardized Microsoft Excel spreadsheet was used to document and administer the data.

Statistical analysis

The meta-analysis was conducted using Review Manager version 5.4, developed by The Nordic Cochrane Centre, The Cochrane Collaboration, in 2014. The expected clinical and methodological variability among research necessitated the aggregation of results through a random-effects model. Dichotomous outcomes were utilized to calculate risk ratios with 95%CI; continuous variables were employed to determine mean differences (MD) or standardized MD (SMD). The χ² test assessed heterogeneity, while the I² statistic quantified it. Sensitivity analysis was conducted to assess the robustness of the data; and I² value exceeding 50% was considered indicative of substantial heterogeneity. Forest plots were generated to visually represent the effect sizes and confidence ranges.

RESULTS

Search strategy

A total of 415 relevant publications were identified using the search strategy, 11 full studies were reviewed and 4 studies (Dos Santos et al[10], Rivinius et al[11], Rivinius et al[12]; Doesch et al[13]) met the inclusion criteria. Baseline characteristics of the studies included are shown in Table 1[10-13]. Data of 264 participants were included in this meta-analysis (126 for ivabradine treatment and 138 for control).

Table 1 Table showing the characteristics of the studies included in the meta-analysis.

Number	Trial name	Type of study	Follow up duration	Left ventricular mass	Final heart rate	Intervention group (n)
1	Dos Santos et al[10], 2021	Prospective, randomized, open-label, single-center clinical trial	Minimum 1 year, maximum 3 years	IG: 174.2 ± 60.8 g, CG: 148.2 ± 52.9 g	IG: 74.6 ± 6.5 bpm, CG: 98.2 ± 6.5 bpm (at 36 months)	16
2	Rivinius et al[12], 2022	Observational cohort	5 years	IG: 154.8 ± 23.4 g, CG: 177.3 ± 28.4 g	IG: 73.3 ± 9.1, CG: 80.4 ± 10.1	50
3	Rivinius et al[11], 2018	Observational retrospective single-center study	2 years	Ivabradine: 151.3 ± 39.8 g, metoprolol: 178.3 ± 54.8 g	IG: 76.7 ± 10.2 bpm; CG: 82.0 ± 10.0 bpm	40
4	Doesch et al[13], 2007	Open-label, prospective, non-randomized crossover trial	8 weeks	NA	NA	NA

bpm: Beats per minute; CG: Control group; IG: Intervention group; NA: Not available.

Clinical results

The primary outcome of the study was the change in HR with the use of ivabradine. The rates of adverse events – including all-cause mortality, safety, left ventricular (LV) dysfunction, LVMI, diastolic dysfunction, and NT-proBNP levels – served as the secondary endpoints.

Baseline characteristics: Across the four included studies (n = 264), the majority of patients were male (71.4%). The mean age ranged from 46.0 ± 6.9 years to 57.9 ± 16.9 years, reflecting a predominantly middle-aged to older adult population. Baseline HR was elevated in most studies, with average values typically > 100 beats per minute (bpm) (range from 96.5 ± 7.0 bpm to 115.7 ± 13.3 bpm). LV mass (LVM) was increased where reported, indicating persistent hypertrophic remodeling after transplantation. NT-proBNP levels, available in two studies, were elevated at baseline (e.g., 536.32 ± 495.92 pg/mL), consistent with ongoing myocardial stress in this cohort.

Mortality outcomes

Two RCTs involving 119 patients reported mortality outcomes, with 56 receiving ivabradine and 63 in the control group. No statistically significant difference in mortality was observed between the groups (MD = 0.52; 95%CI: 0.17-1.64; P = 0.27). However, heterogeneity was substantial (I² = 85%, χ² = 6.70), indicating considerable variation between the included studies.

Changes in HR

Four RCTs involving 264 patients reported changes in HR, with 126 receiving ivabradine and 138 in the control group. A statistically significant reduction was observed in HR with ivabradine (MD = -11.06; 95%CI: -19.5 to -2.62; P < 0.00001), although heterogeneity was considerable (I² = 93%).

Sensitivity analysis in HR

The SMD for HR across these studies was -6.74 (95%CI: -9.23 to -4.24), indicating a significant reduction in HR following the intervention. This effect was highly statistically significant (P < 0.00001). The I² value was 0%, indicating no observed heterogeneity among the included studies, suggesting consistent findings across studies.

Changes in LVM

Three RCTs involving 223 patients evaluated changes in LVM. Ivabradine did not significantly affect LVM compared to control (MD = -3.57; 95%CI = -29.21 to 22.08; P = 0.79; I² = 73%).

Sensitivity analysis in LVM

A sensitivity analysis was performed for LVM by including 3 out of the 4 available studies. The pooled mean difference was 7.16 (95%CI: -14.46 to 28.78; P = 0.52), indicating no statistically significant difference between groups. Heterogeneity was low to moderate (I² = 31%). Excluding one study did not materially change the effect size or the level of heterogeneity, suggesting that the overall findings are robust and not significantly influenced by any single study.

DISCUSSION

Ivabradine belongs to a class of drugs known as if current inhibitors also called funny channel inhibitors which selectively inhibit the If sodium-potassium current in the sinoatrial node targeting its pacemaker activity and this leads to slower HR by prolonging diastolic depolarization. It does not affect myocardial contractility or blood pressure[14]. This drug has been recommended for patients with heart failure with reduced ejection fraction who persistently remain in sinus rhythm with a resting HR ≥ 70 bpm despite maximally tolerated beta blocker therapy. In Europe, there is off-label use of ivabradine in sinus tachycardia or stable angina as well[15,16]. At times, its use is limited due to potential side effects which include excessive bradycardia, visual problems, atrial fibrillation and rarely hypertension[9]. Ivabradine has not been extensively studied in heart transplant patients who could potentially benefit from its reduced pacing activity as these patients have persistent sinus tachycardia due to transplant related denervation[11,17]. Our meta-analysis evaluated the comparative efficacy and safety of ivabradine vs control or standard therapy (including metoprolol where applicable) in heart transplant recipients, focusing on mortality, HR control, and LVMI. The findings, supported by recent literature, underscore the potential benefits of ivabradine in this patient population.

Differences in baseline characteristics

In our meta-analysis, four studies comprising 264 participants were quantitatively analyzed. To provide a broader perspective on baseline characteristics of heart transplant recipients treated with ivabradine, we additionally reviewed findings from other observational cohorts, bringing the total descriptive sample size to approximately 430 patients. Overall, 71.4% of the cohort was male which reflects the general male predominance in referral and listing patterns of heart transplant[18,19] The mean age of patients ranged widely, from 46.0 ± 6.9 years to 57.9 ± 16.9 years, with most studies including middle-aged to older adult populations, reflecting typical post-transplant demographics as well. The baseline HR was elevated across studies, with most reporting average values above 100 bpm, ranging from 96.5 ± 7.0 bpm to 115.7 ± 13.3 bpm. This trend is clinically relevant, as Ivabradine’s mechanism of action offers its greatest therapeutic benefit in patients with persistently elevated resting HR despite beta-blockade or as an alternative in beta-blocker intolerant individuals[20,21].

Regarding structural remodeling, some of the selected studies reported baseline LVM, which was notably increased in most cohorts indicating ongoing hypertrophic burden even in post-transplant patients[22]. NT-proBNP levels, a key biomarker of ventricular wall stress and neurohormonal activation, were inconsistently reported. In studies that did include this parameter, baseline values were elevated, around 500 pg/mL, again highlighting the persistent hemodynamic challenges faced by transplant recipients despite surgical correction of end-stage heart failure. Together, these baseline disparities, particularly in resting HR, cardiac structure, and neurohormonal profile, reinforce the need to account for patient-specific physiological load when evaluating Ivabradine’s effectiveness in post-transplant care. The heterogeneity in enrollment also underscores the need for standardized reporting of transplant cohort characteristics in future studies.

Outcomes

In our analysis, ivabradine showed a numerical trend toward lower all-cause mortality compared to metoprolol, with a pooled odds ratio of 0.52 (95%CI: 0.17-1.64; P = 0.27), although this difference did not reach statistical significance. This suggests a potential mortality benefit with ivabradine; however, the limited number of included studies and small event counts likely reduced the statistical power to detect a significant effect. Additionally, high heterogeneity was observed (I² = 85%, P = 0.01), likely driven by variability in study design, duration of follow-up, and patient selection criteria across the included studies. The study showing poor survival with Ivabradine was a single center randomized clinical trial, whereas the one reporting better survival was a retrospective study. Ivabradine may contribute to long-term survival benefits, potentially through more effective HR control, improved diastolic filling, and reduced myocardial oxygen demand[23,24].

Ivabradine demonstrated a statistically significant advantage over control or conventional management (including metoprolol in some studies) in reducing resting HR among heart transplant recipients, with a pooled mean difference of -11.06 bpm (95%CI: -19.50 to -2.62; P = 0.01). This degree of HR reduction is clinically meaningful in the post-transplant population, where persistent sinus tachycardia is common due to autonomic denervation and elevated circulating catecholamines. Given that elevated HR is associated with impaired diastolic filling, increased myocardial oxygen demand and adverse ventricular remodeling, effective rate control may translate into improved graft function and better long-term outcomes[25-27]. Although the initial analysis revealed substantial heterogeneity (I² = 90%, P < 0.00001), likely reflecting differences in baseline patient characteristics, time since transplantation and variability in comparative dosing strategies across studies, a sensitivity analysis was performed to explore the robustness of this finding by excluding a study that was contributing disproportionately to the heterogeneity. This analysis continued to show a statistically significant benefit with ivabradine, with a reduced mean difference of -6.74 bpm (95%CI: -13.24 to -4.24; P < 0.00001) and complete resolution of heterogeneity (I² = 0%). This consistency in effect size, even after sensitivity adjustment, supports the reproducibility of ivabradine’s HR-lowering benefit. Collectively, the evidence reinforces the rationale for ivabradine use in this population, particularly in patients who are intolerant to beta-blockers or fail to achieve adequate rate control with traditional agents.

The pooled analysis of three studies evaluating LVMI revealed no significant difference between ivabradine and metoprolol (mean difference: -3.57 g/m²; 95%CI: -29.21 to 22.08; P = 0.79), with moderate heterogeneity (I² = 73%). This suggests that, within the observed timeframes and study protocols, ivabradine may not confer a consistent advantage over metoprolol in modifying LV structural remodeling in heart transplant recipients. However, given the known pathophysiologic relationship between chronic sinus tachycardia and adverse ventricular remodeling, this outcome may be influenced by the short duration of follow-up or variability in imaging modalities used[28]. A sensitivity analysis that excluded the most heterogenous study still failed to demonstrate a significant difference (MD: 7.16 g/m²; 95%CI: -14.46 to 28.78; P = 0.52), further supporting the neutrality of this outcome. Nonetheless, observational data by Rivinius et al[12] have shown a statistically significant reduction in LVM among ivabradine-treated patients over time compared to those on beta-blockers. These discrepancies suggest that longer-term follow-up and uniform echocardiographic protocols may be necessary to detect subtle but clinically relevant changes in cardiac structure[29]. As such, while this meta-analysis does not confirm a structural benefit, it does not exclude the possibility either, which remains a target for future longitudinal investigation.

Strengths and limitations

Our findings provide insights that can be used in post-transplant management for this niche population that is clinically significant but is often not included in major clinical trials. Our analysis offered a comprehensive assessment of structural and functional outcomes including multiple variables: All-cause mortality, resting HR and LVMI. Sensitivity analyses were conducted for 2 outcomes to ensure the heterogeneity of results was accounted for.

Although the findings of our study were in accordance with previous studies for the effect on resting HR[30-32], the results for two of our outcomes were not statistically significant i.e. all-cause mortality and LVMI. The total sample size was relatively small, reducing the statistical power of the study. Additionally, substantial heterogeneity was observed in several outcome measures (I² = 85% for mortality and I² = 90% for HR), likely due to differences stated above. There was limited female representation in the study with male predominance which could restrict the generalizability of the study findings and hinder complete understanding of sex differences in the effects of the drug. The inconsistences observed in reporting clinical biomarkers such as NT-proBNP further add to the variance of the included trials. Prospective and retrospective studies were included which could potentially introduce bias and add to the heterogeneity of the results. The long-term effects caused by Ivabradine could have been missed due to the short duration of follow up in most studies.

Clinical implications

One of the major challenges faced by heart transplant recipients is increased resting HR which is associated with increased all-cause and cardiovascular mortality[33]. Therefore, one of the major goals of drugs prescribed for post-transplant management includes HR regulation. Ivabradine reduces resting HR but does not affect myocardial contraction, relaxation, or ventricular repolarization[14]. The results for all-cause mortality were not statistically significant in accordance with previous published studies[34]. The findings for LVMI were also neutral. These may provide statistically significant results if the follow up duration is prolonged or sensitive imagine techniques are employed. Overall, ivabradine is a safe and effective alternative for regulation of HR in this high-risk group when beta blockers are no longer useful. Further trials need to be conducted to confirm its long-term benefits and establish its role in post-transplant care.

CONCLUSION

In summary, ivabradine appears to offer superior HR control and a trend toward improved survival compared to metoprolol in heart transplant recipients. While our meta-analysis did not find a significant difference in LVMI, clinical studies suggest that ivabradine may contribute to favorable cardiac remodeling. These findings support the consideration of ivabradine as a viable alternative to beta-blockers in this patient population, particularly for those who are intolerant to beta-blockers or require enhanced HR control. Further large-scale, RCTs are warranted to confirm these benefits and to establish definitive clinical guidelines.