Combinatorial approach to treat iron overload cardiomyopathy in pediatric patients with thalassemia-major: A systematic review and meta-analysis

Abstract

BACKGROUND

Iron overload cardiomyopathy is a significant cause of morbidity and mortality in transfusion-dependent thalassemia patients. Standard iron chelation therapy is less efficient in alleviating iron accumulation in many organs, especially when iron enters the cells via specific calcium channels.

AIM

To validate our hypothesis that adding amlodipine to the iron chelation regimen is more efficient in alleviating myocardial iron overload.

METHODS

Five databases, including PubMed, Cochrane Library, Embase, ScienceDirect, and ClinicalTrials.gov, were systematically searched, and three randomized controlled trials involving 144 pediatric patients with transfusion-dependent thalassemia were included in our meta-analysis based on the predefined eligibility criteria. The quality of the included studies was assessed based on the Cochrane collaboration tool for bias assessment. The primary outcome assessed was myocardial-T2 and myocardial iron concentration, while the secondary results showed serum ferritin level, liver iron concentration, and treatment adverse outcomes. Weighted mean difference and odds ratio were calculated to measure the changes in the estimated treatment effects.

RESULTS

During the follow-up period, Amlodipine treatment significantly improved cardiac T2 by 2.79 ms compared to the control group [95% confidence interval (CI): 0.34-5.24, P = 0.03, I² = 0%]. Additionally, a significant reduction of 0.31 in myocardial iron concentration was observed with amlodipine treatment compared to the control group [95%CI: -0.38-(-0.25), P < 0.00001, I² = 0%]. Liver iron concentration was slightly lower in the amlodipine group by -0.04 mg/g, but this difference was not statistically significant (95%CI: -0.33-0.24, P = 0.77, I² = 0%). Amlodipine also showed a non-significant trend toward a reduction in serum ferritin levels (-328.86 ng/mL, 95%CI: -1212.34-554.62, P = 0.47, I² = 90%). Regarding safety, there were no significant differences between the groups in the incidence of gastrointestinal upset, hypotension, or lower limb edema.

CONCLUSION

Amlodipine with iron chelation therapy significantly improved cardiac parameters, including cardiac-T2 and myocardial iron, in patients with transfusion-dependent thalassemia without causing significant adverse events but enhancing the efficacy of iron chelation therapy.

Key Words: Amlodipine; Cardiomyopathy; Iron overload; Randomized controlled trials; Thalassemia

Core Tip: Thalassemia is the most common inherited blood disorder caused by genetic mutations that significantly reduce or abolish normal hemoglobin production altogether. Iron chelation therapy, which aims to maintain safe iron levels, eliminate deposited iron, and promptly reverse the failing heart condition, is the current treatment for iron overload in thalassemia. Our systematic review and meta-analysis attempts to establish evidence from the reported randomized controlled trials that amlodipine can effectively alleviate cardiotoxicity related to iron overload in thalassemia major patients, especially when combined with iron chelators.

INTRODUCTION

Thalassemia is the most common inherited blood disorder due to genetic mutations significantly reducing or completely abrogating normal hemoglobin production[1]. Among different types, β-thalassemia is one of the most prevalent inherited blood disorders among thalassemia births[2]. Based on their severity, two clinical forms of β-thalassemia include thalassemia major and intermedia, with thalassemia major as the typical presentation resulting from either homozygous or compound heterozygous defects[3,4]. The imbalance in alpha and beta chains leads to ineffective red blood cell production, resulting in life-threatening anemia by approximately one to two years of age[5,6]. Chronic hemolytic anemia thus necessitates lifelong transfusion therapy[7]. One of the complications observed in patients with transfusion-dependent thalassemia is accumulating excessive iron, which damages various organs, including the heart[8], which is especially susceptible to iron toxicity (cardiac siderosis) due to such iron homeostasis disruption[9]. Cardiac siderosis thus may lead to heart failure with poor prognosis, and hence, remains the most common cause of death in primary thalassemia patients[10].

The current treatment for iron overload in thalassemia is iron chelation therapy, which aims to maintain safe iron levels, eliminate deposited iron, and promptly reverse the failing heart condition[11]. Three iron chelators – deferoxamine, deferiprone, and deferasirox - are approved by most regulatory agencies for use in thalassemia[12]. Intensive chelation can be beneficial, but it often takes years to reduce cardiac iron levels, and the mortality rate is high if patients do not fully adhere to their treatment. Traditional iron chelation therapy may not prevent iron accumulation in many organs, especially when iron (Fe²⁺) enters cells through L-type voltage-dependent Ca²⁺ channels (LVDCC). Recent data suggests that treatment with LVDCC blockers like amlodipine, nifedipine, and verapamil can prevent calcium from entering cardiomyocytes, thereby reducing the amount of iron load in the heart and improving the iron load in the liver[13]. Among the calcium channel blockers available for clinical applications, as listed below, amlodipine, a third-generation dihydropyridine Ca²⁺ blocker, has antioxidant properties and an established safety profile for children and adults alike[14,15]. Amlodipine also has significant antioxidant activity in the heart and blood and improves lipid profile[15]. This non-calcium channel-dependent antioxidant activity of amlodipine has been attributed to its preferred affinity for the lipid constituents in the cell membrane of the vasculature[15]. Additionally, amlodipine is affordable, taken orally with excellent patient compliance, and has a long half-life of 35-50 hours (vs verapamil’s 3-7 hours and nitrendipine’s 2-5 hours), which necessitates longer dosing frequency and minimizing fluctuations between peak and trough plasma concentrations[16]. Our systematic review and meta-analysis attempt to establish evidence from the reported randomized controlled trials (RCTs) that amlodipine can effectively alleviate cardiotoxicity related to iron overload in children with thalassemia major. The primary outcomes of our analysis include changes in cardiac T2, myocardial iron concentration (MIC), liver iron concentration (LIC), and serum ferritin level. The secondary outcomes included the safety profile of amlodipine in this patient population.

MATERIALS AND METHODS

Protocol registration

The study protocol was registered within the prospective International of Systematic Reviews with a registration number CRD42024568279 (Supplementary material).

Search strategies

A systematic search was performed across several major medical databases, including PubMed, Cochrane Library, Embase, ScienceDirect, and ClinicalTrials.gov, to conduct a comprehensive systematic review. This search spanned the databases’ entire duration, from their inception until July 2024, ensuring no relevant studies were overlooked. The search strategy used a combination of common text words and medical subject heading terms, such as “calcium channel blockers”, “CCBs”, “amlodipine”, “nifedipine”, “verapamil”, “thalassemia”, “iron overload”, “iron chelation”, “hemochromatosis”, “cardiac siderosis”, “cardiomyopathy”, “cardiac iron overload”, and “cardiac dysfunction”. These key terms were systematically combined using appropriate Boolean operators, for example, searching for “amlodipine AND thalassemia AND cardiac siderosis”. Additionally, the reference lists of all selected articles were manually screened to identify any other potentially relevant studies that may have been missed in the database searches. No language restrictions were applied during the search, ensuring a comprehensive and inclusive approach. This search methodology was conducted according to the guidelines outlined in the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. This rigorous and transparent systematic review process ensures the reliability and trustworthiness of our findings.

Study selection

To be eligible for inclusion in the analysis, a study has to fulfill the following inclusion criteria: (1) Be an RCT; (2) Involve patients under 18 years of age and diagnosed with transfusion-dependent thalassemia; (3) Utilize amlodipine as the intervention; (4) Has a control group for comparison; (5) Reports data on one or more of the following outcomes: Cardiac T2, MIC, LIC, serum ferritin, and adverse events, and (6) Has a minimum follow-up duration of three months. Any study that did not meet these criteria or was unavailable in the full text would be excluded from the analysis.

Data extraction

The data extraction process from the included RCTs was conducted by two independent authors. A third independent author reviewed the data extraction and resolved disagreements. For each included study, the following information was extracted and recorded on a predefined Excel sheet: The name of the first author, publication year, and the country; study design and baseline characteristics of the study population; type of chelation agent used; follow-up duration; the radiological assessment modalities employed; and the study endpoints results, including cardiac T2, MIC, LIC, and serum ferritin. The extracted data for these endpoints were recorded as mean ± SD. The data extraction process was conducted transparently and systematically, ensuring the accuracy and reliability of the extracted information.

Quality assessment

The methodological quality of the included studies was assessed using the Cochrane Collaboration risk of the bias assessment tool. This tool evaluates studies based on the following criteria: Random sequence generation, allocation concealment, blinding of participants, blinding of outcome assessors, incomplete outcome data, selective reporting, and other biases. Each criterion was categorized as having a high risk, unclear risk, or low risk of bias. The overall assessment of the studies’ risk of bias was presented in a risk of bias summary graph.

Statistical analysis

All statistical analyses were conducted using RevMan software version 5.4. The longest-reported follow-up period results were extracted from the included studies for continuous outcomes, including cardiac T2, LIC, MIC, and serum ferritin. Mean and SD differences from baseline to follow-up were calculated for each study. Weighted mean difference (WMD) was then estimated and presented with a 95% confidence interval (CI). For the dichotomous outcomes, namely adverse events, the total number of events observed in the included trials for each adverse event (including gastrointestinal upset, hypotension, lower limb edema, and others) were combined into one intervention group and one control group. These numbers were pooled to determine the odds ratio (OR) for each adverse event, which was reported with a 95%CI. Results were considered significant if the CI did not include the null hypothesis value (i.e., zero) and the P-value was less than 0.05. Between-study heterogeneity was assessed using the I² statistic, with interpretation as follows: 0%-40% indicates unimportant heterogeneity, 30%-60% indicates moderate heterogeneity, and 75%-100% indicates high heterogeneity.

RESULTS

Literature search

Figure 1 summarizes the study retrieval process for this meta-analysis. In summary, initially, we identified 668 records through database searches, including PubMed, Cochrane, EMBASE, ScienceDirect, and ClinicalTrials.gov. After duplicate removal, 541 records remained for abstract screening. Subsequently, we selected 18 records for full-text screening, and ultimately, the three RCTs met the eligibility criteria for inclusion in the systematic review and meta-analysis. The reasons for excluding other records are provided in Figure 1.

Figure 1  Study selection flow diagram (PRISMA chart).

Characteristics of the included studies

The baseline characteristics of the included studies have been summarized in Table 1. The RCTs were conducted between 2018 and 2021, with one study conducted in India[17] and the other in Egypt[18,19]. The total sample size across the studies was 144, with 72 participants in the intervention group and 72 in the control group. In the intervention group, the percentage of males ranged from 40% to 78%, while in the control group, it ranged from 45% to 78%. The mean age of the participants ranged from 10 to 14 years. Among the intervention group, 38% had undergone splenectomy, compared to 33% in the control group. Additionally, 23% of the intervention group and 25% of the control group participants were diagnosed with hepatitis C. All included RCTs provided details on the type of chelator used. Deferasirox was the most commonly used agent, followed by deferoxamine, and the least used was deferoxamine combined with deferiprone (Table 2). The included studies were evaluated for selection, performance, detection, attrition, and reporting biases using the Cochrane collaboration risk of the bias assessment tool. Figure 2 summarizes the authors’ judgment on each domain for each RCT included in the analysis.

Figure 2 Risk of bias assessment graph. The symbols used represent as follows: “+”: Low risk of bias; “-”: High risk of bias; “?”: Unclear risk of bias.

Table 1 Summary of the baseline characteristics of the included studies, n (%).

		El-Haggar et al[18], 2018, Egypt	Gupta et al[17], 2021, India	Khaled et al[19], 2019, Egypt
Design		RCT	RCT	RCT
Sample size	Total	40	64	40
	Intervention, male	20 (60)	32 (78)	20 (40)
	Control, male	20 (50)	32 (78)	20 (45)
Age, years	Intervention	10.1 ± 1.4	10.66 ± 3.54	12.50 ± 1.02
	Control	10.7 ± 2.3	10.62 ± 3.99	13.40 ± 1.01
BMI, kg/m2	Intervention	NA	16.15 ± 1.69	19.48 ± 0.72
	Control	NA	16.18 ± 1.49	19.17 ± 0.61
Baseline hemoglobin	Intervention	NA	NA	7.24 ± 0.27
	Control	NA	NA	7.47 ± 0.37
Baseline serum ferritin, ng/mL	Intervention	4067.1 ± 733.2	2527.00 ± 1558.97	2949.85 ± 420.90
	Control	4089.8 ± 1029.9	2307.00 ± 1209.23	2752.20 ± 342.47
Splenectomy	Intervention	13 (65)	12 (38)	3 (15)
	Control	16 (80)	6 (19)	2 (10)
Hepatitis C	Intervention	16 (80)	1 (3.1)	NA
	Control	18 (90)	0	NA
Comparison		Standard iron chelation therapy plus spirulina	Standard iron chelation therapy plus placebo	Standard iron chelation therapy plus placebo
Follow-up duration		3 months	12 months	6 months
Assessment modality	Echocardiography	No	Yes	No
	MRI	Yes	Yes	Yes

RCT: Randomized controlled trial; BMI: Body mass index; NA: Not available; MRI: Magnetic resonance imaging.

Table 2 Summary of the iron chelators used in the studies included in the analysis, n (%).

		El-Haggar et al[18], 2018, Egypt	Gupta et al[17], 2021, India	Khaled et al[19], 2019, Egypt
DFO	Intervention	5 (25)	0	0
	Control	7 (35)	0	0
DFX	Intervention	15 (75)	31 (97)	20 (100)
	Control	13 (65)	31 (97)	20 (100)
DFO and DFP	Intervention	0	1 (3.1)	0
	Control	0	1 (3.1)	0

DFO: Deferoxamine; DFX: Deferasirox; DFP: Deferiprone.

Primary outcome - efficacy

Cardiac outcomes (cardiac T2 and MIC): Assessment of cardiac T2 using magnetic resonance imaging (MRI) to detect myocardial iron accumulation was reported in all three RCTs[17-19] involving 144 patients (intervention and control groups n = 72 each) during the follow-up period. The pooled analysis revealed a statistically significant improvement of 2.79 ms in cardiac T2 in the amlodipine group compared to the control group (WMD: 2.79, 95%CI: 0.34-5.24, P = 0.03, I² = 0%) (Figure 3A). Two RCTs[17,19] measured MIC in 104 patients (intervention group = 52, control group = 52). The analysis showed a statistically significant reduction of 0.31 in MIC after follow-up in the amlodipine group compared to the control group [WMD: -0.31, 95%CI: -0.38-(-0.25), P < 0.00001, I² = 0%] (Figure 3B).

Figure 3 Forest plot showing changes in cardiac T2, myocardial iron concentration, and liver iron concentration. A: Forest plot showing changes in cardiac T2 with adding amlodipine to chelation therapy compared to chelation therapy alone, from baseline to follow-up. The analysis revealed a significant improvement in cardiac T2 in the amlodipine group, with a mean difference of 2.79 ms and a 95% confidence interval (CI) of 0.34 to 5.24 ms. The heterogeneity between the studies, assessed using the I² statistic, was 0%, indicating no variability in the outcome across the included studies; B: The forest plot illustrates changes in myocardial iron concentration between the amlodipine group and the control from baseline to follow-up. The analysis demonstrated a significant decrease in myocardial iron concentration within the amlodipine group, with a mean reduction of 0.31 and a 95%CI ranging from -0.38 to -0.25. Additionally, the heterogeneity among the studies, evaluated through the I² statistic, was 0%, indicating no variability in outcomes across the included studies; C: The forest plot illustrates the changes in liver iron concentration observed in the amlodipine group compared to the control group from baseline to follow-up. The analysis revealed a non-significant reduction in liver iron concentration within the amlodipine group, with a mean decrease of 0.04 and a 95%CI ranging from -0.33 to 0.24. Furthermore, the heterogeneity among the studies, assessed using the I² statistic, was determined to be 0%, indicating no variability in the outcomes across the studies included. CI: Confidence interval.

LIC: Data on LIC from two of the three included RCTs involving 104 patients (intervention group = 52, control group = 52) were available for analysis[17,19]. The amlodipine group exhibited a trend towards a reduction in LIC, but this reduction was not statistically significant compared to the control group (WMD: -0.04, 95%CI: -0.33-0.24, P = 0.77, I² = 0%) (Figure 3C).

Serum ferritin: All included studies provided data on serum ferritin after follow-up, involving 144 patients (intervention group = 72 and control group = 72). The pooled analysis revealed a reduction of serum ferritin in the intervention group by 328.86 ng/mL compared to the control group. However, the observed reduction was not statistically significant (WMD: -328.86, 95%CI: -1212.34-554.62, P = 0.47, I² = 90%) (Figure 4A).

Figure 4 The forest plot of serum ferritin levels and reported adverse events. A: The forest plot illustrates the non-significant changes in serum ferritin levels observed in the amlodipine group compared to the control group from baseline to follow-up. The analysis indicated that amlodipine resulted in a non-significant reduction in serum ferritin, with a mean decrease of 328.86 and a 95% confidence interval ranging from -1212.34 to 554.62. The heterogeneity among the studies, evaluated using the I² statistic, was found to be 90%, which suggests a high level of variability in the outcomes across the included studies; B: The forest plot illustrates the odds ratio for reported adverse events, including gastrointestinal upset, hypotension, and lower limb edema, in the amlodipine group compared to the control group. The analysis demonstrated a statistically non-significant increased risk of adverse events in the amlodipine group, with an odds ratio of 2.17 and a 95% confidence interval ranging from 0.34 to 13.79. The heterogeneity among the studies, evaluated using the I² statistic, was found to be 58%, indicating moderate variability in outcomes across the included studies. CI: Confidence interval; GI: Gastrointestinal.

Secondary outcome - safety

Gastrointestinal upset was observed in 9.7% of patients (7 out of 72) in the amlodipine group and 23.6% (14 out of 72) in the control group. The OR comparing the incidence of gastrointestinal upset in the amlodipine group to the control group was estimated to be 0.45 (95%CI: 0.17-1.18), indicating a lower risk in the amlodipine group. One patient (1.3%) in the amlodipine group experienced hypotension compared to none in the control group, resulting in an OR of 3.04 (95%CI: 0.12-75.92), suggesting a higher risk, however, without statistical significance. Lower limb edema occurred in three patients (4.2%) in the amlodipine group and none in the control group, with an OR of 9.53 (95%CI: 0.50-180.25), indicating a higher risk, which is also not statistically significant. The pooled OR of all the mentioned adverse events in the amlodipine group did not show a statistically significant difference compared to the control arm (OR: 2.17, 95%CI: 0.34-13.79, P = 0.41, I² = 58%) (Figure 4B).

DISCUSSION

We assess the safety and efficacy endpoints, including MIC and cardiac T2 measured by MRI, LIC, and serum ferritin level changes in pediatric thalassemia patients receiving amlodipine treatment. Our key findings include: (1) Amlodipine treatment significantly improves the cardiac parameters, including cardiac T2 and MIC, compared to the control group; (2) There is no statistically significant difference observed in LIC and serum ferritin levels between the amlodipine group and the control group; and (3) Adverse events, i.e., gastrointestinal upset, hypotension, and lower limb edema, show no statistical difference between the amlodipine group and the standard chelation therapy.

Frequent blood transfusions in thalassemia patients carry a significant risk of iron buildup in various body tissues, including the heart, liver, and endocrine glands[20]. Among these, cardiac siderosis, which may be present at the age of 10 and manifests as clinical heart failure or fatal arrhythmias (most commonly atrial fibrillation), remains the leading cause of mortality in this patient population[10,21]. A study of 100 pediatric patients (age 13.9 ± 2.4 years) with thalassemia major reported cardiac iron overload in approximately 32% of patients[22]. Similarly, after a decade-long follow-up on Egyptian children with thalassemia on deferoxamine therapy, it was reported that approximately 44% of the patients developed mild to severe cardiac siderosis[23]. Although treatment with iron chelators is beneficial, it necessitates prolonged therapy to lower myocardial iron levels besides the toxicity risk, thus compromising patient compliance.

Mechanistic pre-clinical experimental data has shown that iron enters the myocardium via specialized L-type voltage-gated Ca²⁺ channels[24]. Body cells maintain an adequate iron supply by regulating iron uptake through transferrin receptor 1 and divalent metal transporter 1. These channels are tightly controlled by hepcidin, a liver-released hormone, and iron regulatory proteins. These regulatory mechanisms primarily respond to serum iron levels and intracellular iron concentrations to maintain iron homeostasis[25,26]. Unlike other tissues, myocardial tissue expresses specialized LVDCC on its membranes to facilitate iron uptake into the myocardium. Iron regulatory proteins, serum iron levels, or intracellular iron concentrations do not regulate these channels. Elevated cardiac iron levels can produce reactive oxygen species, which damage intracellular lipids and proteins[27]. This damage interferes with the excitation-contraction coupling process, ultimately contributing to the development of cardiac dysfunction. These observations highlight the importance of targeting calcium channels in the myocardium alongside chelation therapy. Combining iron chelation therapy with calcium channel blockers, such as amlodipine and nifedipine, is expected to reduce the risk of cardiomyopathy and improve patient prognosis. In this regard, amlodipine is an excellent option for younger patients due to its long duration of action, allowing for convenient once-daily oral dosing, thus enhancing patient compliance. Furthermore, it is also available in liquid dosage forms to facilitate patients with difficulty swallowing tablets[28]. The prolonged duration of action is due to its 30-to-50-hour elimination half-life, ensuring minimal fluctuations in peak-to-trough plasma concentrations during the dosing interval[16]. Our findings are consistent with preclinical data that concomitant treatment with amlodipine and iron chelation improves cardiac parameters more effectively than chelation monotherapy. Interestingly, no significant difference in LIC was observed between the amlodipine treatment and control groups. This may be due to iron accumulation in hepatocytes via specialized transport channels other than LVDCC, making them less effective in reducing liver iron levels[29].

Though the ferritin serum levels do not directly correlate with the tissue iron contents, they are valuable predictors of disease burden and prognostic biomarkers[21,30]. Our data show a statistically non-significant trend towards reduced serum ferritin levels in the amlodipine treatment group compared to the control group with chelation monotherapy. These data can be attributed to amlodipine’s role in blocking iron entry into the myocardium, thus raising the serum ferritin available for removal by the iron chelators. The cardiac T2 measurements using MRI provide a non-invasive, fast, reliable, and sensitive method for the early detection of cardiac iron load that disrupts the myocardial microenvironment’s magnetic homogeneity[31]. Recent evidence suggests that lower cardiac T2 values correlate with higher iron deposition levels, and the risk of morbidity escalates as T2 values decline. Research indicates that a T2 measurement of less than 20 ms is significantly associated with reduced left ventricular ejection fraction and an elevated risk of arrhythmias. On the same note, cardiac T2 levels below 10 ms demonstrate high sensitivity and specificity for predicting heart failure within one year[32]. A multicenter study with 652 thalassemia patients reported that 98% of the patients included in the study who developed heart failure had cardiac T2 values less than 10ms. The relative risk of heart failure in patients with T2 values under 10 ms, compared to those with values above 10 ms, was 160, representing a 60% increased risk[33]. This signifies cardiac T2 as a powerful predictor of heart failure development in thalassemia patients.

Our data suggest that concomitant amlodipine and chelation therapy significantly improve cardiac T2 values. It is pertinent to mention that the clearance of myocardial iron deposits is considerably slower than in other tissues. Therefore, normalizing the cardiac T2 can take years. Pennell et al[34] followed up on 105 thalassemia patients treated with deferasirox for two years and reported improved cardiac T2 (from 7.3 ms to 8.7 ms) in patients with baseline cardiac T2 values less than 10 ms. These data underscore the need for a cardiac T2-guided prolonged treatment using amlodipine to obtain meaningful clinical outcomes.

The safety profile of amlodipine is of particular interest, especially in the young, non-hypertensive patient group[16]. Common side effects of amlodipine include hypotension, lower limb edema, dizziness, flushing, and gastrointestinal upset[35]. We observed that one patient in the included trials experienced hypotension, three developed lower limb edema, four experienced dizziness, and seven suffered from gastrointestinal disturbance from a total of 72 patients receiving combined amlodipine and chelation therapy. Conversely, in the control group (n = 72) receiving chelation therapy alone, although no cases of hypotension, lower limb edema, or dizziness were reported, 14 patients experienced gastrointestinal disturbances. Overall, the pooled analysis shows no statistically significant difference in the incidence of these adverse events in the two groups, thus indicating the clinical safety of the amlodipine-based combinatorial approach. Consistent with our findings, a prior review by Sahney et al[36] evaluated the safety of amlodipine in pediatric patients with hypertension. It indicated that data from RCTs show that amlodipine is generally better tolerated in children than nifedipine, and most adverse events associated with treatment, such as headache, edema, and dizziness, may be controlled by dose reduction.

Our systematic review and meta-analysis are the first to assess the safety and efficacy of amlodipine in children younger than 18. Our findings align with previous systematic reviews and meta-analyses by Soliman et al[37] evaluating the effectiveness of amlodipine in patients with thalassemia major. The study included 7 RCTs involving 233 patients diagnosed with transfusion-dependent thalassemia (mean age = 19.6) and found that treatment with amlodipine significantly improved cardiac T2 during twelve months of follow-up but not at six months. MIC was also considerably reduced at six and twelve months of follow-up. However, similar to our results, LIC and serum ferritin were not significantly reduced compared to the control group, thus revealing the cardiac specificity of amlodipine’s effects on iron loading. A meta-analysis published by Elfaituri et al[38] (including three RCTs with 130 patients with transfusion-dependent thalassemia) has concluded that combinatorial strategy based on amlodipine and iron chelation therapy may not result in a statistically significant difference in cardiac T2, LIC, or serum ferritin. The divergence in the data may be attributed to using different iron chelators used in the studies, which may affect their cardiac iron unloading potential in the presence of amlodipine. Hence, future studies must comprehensively evaluate the best combination of amlodipine with various iron chelators for optimum prognosis.

Despite encouraging data, our study is not without some limitations. First, the analysis included the small number of RCTs and the limited number of patients. Moreover, the included studies’ follow-up periods were divergent, rendering it challenging to compare the treatment effects over short and extended periods of observation. While changes in cardiac parameters have been reported at varying intervals, three months[18], six months[19], and twelve months[17], cardiac T2 often requires several years to show evident changes. This data signifies the need to design future RCTs with larger sample sizes and longer-term follow-ups to enhance our understanding of the combinatorial approach. Also, the geographic distribution of the included studies is limited to India[17] and Egypt[18,19]. Thalassemia is also prevalent in the Mediterranean, Middle East, and South Asian regions[39]. Additional RCTs conducted in these regions are needed to enhance the generalizability and ensure the applicability of our findings to diverse populations and clinical settings.

Future studies are warranted for pediatric thalassemia to further study the long-term effects of repeated exposure to iron chelators as monotherapy or combined with amlodipine as part of the combinatorial approach. More importantly, these studies should also investigate the impact of the combinatorial approach on the iron metabolism pathway and whether it leads to tolerance or adaptive changes over time. Additionally, it is crucial to study the long-term effects of this treatment on the growth, puberty, and endocrine health of children with thalassemia. We can ensure this combination therapy’s long-term safety and efficacy for the pediatric thalassemia population by addressing these key areas.

CONCLUSION

In conclusion, a combinatorial approach incorporating amlodipine into the routine iron chelation therapy protocol for children and young adults with transfusion-dependent thalassemia enhances cardiac T2. It decreases MIC without significantly increasing adverse events. However, future multi-center RCTs with larger sample sizes and extended follow-up periods using optimal amlodipine combination with iron chelator are warranted to optimize treatment outcomes.