A randomized trial of amlodipine in addition to standard chelation therapy in patients with thalassemia major

Abstract

Key Points• In thalassemia patients with cardiac siderosis, amlodipine combined with iron chelation resulted in more effective reduction of cardiac iron.• The combined treatment did not have any effect on serum ferritin and left ventricular ejection fraction.Cardiovascular disease resulting from iron accumulation is still a major cause of death in patients with thalassemia major (TM). Voltage-gated calcium-channel blockade prevents iron entry into cardiomyocytes and may provide an adjuvant treatment to chelation, reducing myocardial iron uptake. We evaluated whether addition of amlodipine to chelation strategies would reduce myocardial iron overload in TM patients compared with placebo. In a multicenter, double-blind, randomized, placebo-controlled trial, 62 patients were allocated to receive oral amlodipine 5 mg/day or placebo in addition to their current chelation regimen. The main outcome was change in myocardial iron concentration (MIC) determined by magnetic resonance imaging at 12 months, with patients stratified into reduction or prevention groups according to their initial T2* below or above the normal human threshold of 35 ms (MIC, 0.59 mg/g dry weight). At 12 months, patients in the reduction group receiving amlodipine (n 5 15) had a significant decrease in MIC compared with patients receiving placebo (n 5 15) with a median of 20.26 mg/g (95% confidence interval, 21.02 to 20.01) vs 0.01 mg/g (95% confidence interval, 20.13 to 0.23), P 5 .02. No significant changes were observed in the prevention group (treatment-effect interaction with P 5 .005). The same findings were observed in the subgroup of patients with T2* <20 ms. Amlodipine treatment did not cause any serious adverse events. Thus, in TM patients with cardiac siderosis, amlodipine combined with chelation therapy reduced cardiac iron more effectively than chelation therapy alone. Because this conclusion is based on subgroup analyses, it needs to be confirmed in ad hoc clinical trials. This trial was registered at www.clinicaltrials.gov identifier as #NCT01395199. (Blood. 2016;128(12):1555-1561

A randomized, controlled study evaluating effects of amlodipine addition to chelators to reduce iron loading in patients with thalassemia major

“…It consists of α 1, α 2, β, γ, and δ subunits . Till now, it has been shown by small number of studies that calcium channel blockers (CCBs) like amlodipine are able to reduce iron content of the heart and the blockade is associated with therapeutic improvement in patients with thalassemia major . The present work was designed to evaluate the efficacy and safety of amlodipine addition to iron chelators for reducing iron levels in patients with thalassemia.…”

“…Current data about efficacy of amlodipine as add‐on therapy are very limited and not conclusive. Notably, our results are in accordance with a very recent work by Fernandes et al which provided the first findings for the effects of amlodipine in thalassemia . In that study, the main outcome was myocardial iron concentration (MIC) which had a significant reduction after 1 year of treatment in 57 patients older than 6 years.…”

Keeping heart homeostasis in check through the balance of iron metabolism

“…Excess NTBI iron will enter in cardiomyocytes through calcium channels . Small randomized trials have shown that the use of calcium channel blockers such as amlodipine can attenuate the beneficial effects of iron chelation . A systematic review of these trials shows that these results should be taken with caution because of the small number of patients included, differences in subgroups analysis and lack of data concerning the type of chelation therapy .…”

Current Perspective of Beta Thalassemia and Its Treatment Strategies

“…Non-transferrin-bound iron enters into tissues through numerous cellular channels that are capable for destruction of cells rather than using the transferrin receptors [27]. Thalassemia patients have the potential to diminish the non-transferrin-bound iron by administrations of chelators [25,28]. Administration of chelators through intravenously is more effective than subcutaneous administration at reducing NTBI.…”