Key messages
1. Calcium channel blockers may reduce the amount of iron in the heart and improve liver iron load in people with transfusion-dependent beta thalassaemia after 12 months of treatment.
2. Larger and longer trials are needed to better understand the benefits and harms of calcium channel blockers in people with transfusion-dependent thalassaemia.
What is transfusion-dependent beta thalassaemia?
Beta thalassaemia is an inherited blood disorder. People with beta thalassaemia do not produce enough haemoglobin (a protein in the red blood cells that contains iron and carries oxygen around the body). As a result, these people can experience symptoms of anaemia: tiredness, weakness, dizziness, or shortness of breath. The most severe form of beta thalassaemia is called transfusion-dependent beta thalassaemia, because the people who have it need frequent blood transfusions. One serious disadvantage of this treatment is that it causes excess iron to accumulate in the heart and damage it. Heart complications are the most common cause of death and disability in people with beta thalassaemia who receive regular blood transfusions.
It is common practice to give people with transfusion-dependent beta thalassaemia medicines (known as chelators) to reduce iron in the body. In addition, studies have shown that iron enters the heart through pathways called calcium channels, and medicines that block these pathways (calcium channel blockers) may reduce iron entry into the heart. However, it is unclear if this treatment is effective and safe for people with beta thalassaemia.
What did we want to find out?
We wanted to find out if calcium channel blockers, given together with chelators, can prevent heart dysfunction due to excessive iron deposits in people with beta thalassaemia who receive regular blood transfusions.
What did we do?
We searched for studies that examined calcium channel blockers plus chelators compared with chelators alone or chelators plus placebo (dummy medicine). We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We included six studies that recruited a total of 253 people with transfusion-dependent beta thalassaemia. All the study participants had significant iron overload and were receiving standard chelation treatment. They were randomly assigned to one of two treatments: amlodipine (a calcium channel blocker) in addition to their chelators, or chelators (alone or with placebo). The studies lasted six to 12 months.
Main results
Amlodipine may decrease the amount of iron in the heart and improve liver iron load after 12 months of treatment. There was no difference between the groups in these outcomes after only six months or in other outcomes (such as iron levels in the blood, iron levels in the liver, and another measure of heart function) at six or 12 months, although the results at six months were very uncertain. The trials reported no serious unwanted effects, but there may be a higher risk of swollen ankles with amlodipine. No trials reported deaths, several measures of heart function (we only found data for one measure), the heart's electrical activity, quality of life, the percentage of people who followed the treatment, or cost.
Larger, long-term trials are needed to better understand the effectiveness and safety of calcium channel blockers in people with transfusion-dependent thalassaemia.
What are the limitations of the evidence?
The results at 12 months suggest that amlodipine may decrease the amount of iron in the heart and improve liver iron load, but we have little confidence in most of our results at 12 months, mainly because the studies were small and because the study participants may have been aware of which treatment they were getting
How up to date is the evidence?
This is an update of a review first published in 2018. The evidence is current to January 2022.
The available evidence suggests that calcium channel blockers may reduce MIC and may increase liver T2* values in people with transfusion-dependent beta thalassaemia. Longer-term multicentre RCTs are needed to assess the efficacy and safety of calcium channel blockers for myocardial iron overload, especially in younger children. Future trials should also investigate the role of baseline MIC in the response to calcium channel blockers, and include a cost-effectiveness analysis.
Beta-thalassaemia is an inherited blood disorder that reduces the production of haemoglobin. The most severe form requires recurrent blood transfusions, which can lead to iron overload. Cardiovascular dysfunction caused by iron overload is the leading cause of morbidity and mortality in people with transfusion-dependent beta-thalassaemia. Iron chelation therapy has reduced the severity of systemic iron overload, but removal of iron from the myocardium requires a very proactive preventive strategy. There is evidence that calcium channel blockers may reduce myocardial iron deposition.
This is an update of a Cochrane Review first published in 2018.
To assess the effects of calcium channel blockers plus standard iron chelation therapy, compared with standard iron chelation therapy (alone or with a placebo), on cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia.
We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books, to 13 January 2022. We also searched ongoing trials databases and the reference lists of relevant articles and reviews.
We included randomised controlled trials (RCTs) of calcium channel blockers combined with standard chelation therapy versus standard chelation therapy alone or combined with placebo in people with transfusion-dependent beta thalassaemia.
We used standard Cochrane methods. We used GRADE to assess certainty of evidence.
We included six RCTs (five parallel-group trials and one cross-over trial) with 253 participants; there were 126 participants in the amlodipine arms and 127 in the control arms. The certainty of the evidence was low for most outcomes at 12 months; the evidence for liver iron concentration was of moderate certainty, and the evidence for adverse events was of very low certainty.
Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may have little or no effect on cardiac T2* values at 12 months (mean difference (MD) 1.30 ms, 95% confidence interval (CI) −0.53 to 3.14; 4 trials, 191 participants; low-certainty evidence) and left ventricular ejection fraction (LVEF) at 12 months (MD 0.81%, 95% CI −0.92% to 2.54%; 3 trials, 136 participants; low-certainty evidence). Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may reduce myocardial iron concentration (MIC) after 12 months (MD −0.27 mg/g, 95% CI −0.46 to −0.08; 3 trials, 138 participants; low-certainty evidence). The results of our analysis suggest that amlodipine has little or no effect on heart T2*, MIC, or LVEF after six months, but the evidence is very uncertain.
Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may increase liver T2* values after 12 months (MD 1.48 ms, 95% CI 0.27 to 2.69; 3 trials, 127 participants; low-certainty evidence), but may have little or no effect on serum ferritin at 12 months (MD 0.07 μg/mL, 95% CI −0.20 to 0.35; 4 trials, 187 participants; low-certainty evidence), and probably has little or no effect on liver iron concentration (LIC) after 12 months (MD -0.86 mg/g, 95% CI −4.39 to 2.66; 2 trials, 123 participants; moderate-certainty evidence). The results of our analysis suggest that amlodipine has little or no effect on serum ferritin, liver T2* values, or LIC after six months, but the evidence is very uncertain.
The included trials did not report any serious adverse events at six or 12 months of intervention. The studies did report mild adverse effects such as oedema, dizziness, mild cutaneous allergy, joint swelling, and mild gastrointestinal symptoms. Amlodipine may be associated with a higher risk of oedema (risk ratio (RR) 5.54, 95% CI 1.24 to 24.76; 4 trials, 167 participants; very low-certainty evidence). We found no difference between the groups in the occurrence of other adverse events, but the evidence was very uncertain.
No trials reported mortality, cardiac function assessments other than echocardiographic estimation of LVEF, electrocardiographic abnormalities, quality of life, compliance with treatment, or cost of interventions.