Amlodipine with chelation therapy reduces cardiac iron accumulation in thalassemia major

The addition of amlodipine to chelation therapy effectively reduced cardiac iron in patients with thalassemia major, according to a subgroup analysis of a randomized trial.

Up to 50% of patients with thalassemia major can experience myocardial iron overload. Iron cardiomyopathy accounts for a high proportion of deaths and hospitalizations due to arrhythmia and heart failure, especially among patients with high myocardial iron concentrations (MIC).

“Experiments in mice suggest the possibility of preventing iron uptake by cardiomyocytes through voltage-gated calcium channel blockade,” Juliano L. Fernandes, MD, PhD, of University of Campinas in Brazil, and colleagues wrote. “Amlodipine is an inexpensive, widely available calcium-channel blocker with a well-known safety profile in both adults and children and a first small, open-label study in humans showed its use reduced MIC as measured by MRI in patients with thalassemia major.”

Fernandes and colleagues sought to determine whether adding oral amlodipine to traditional iron chelation therapy could reduce MIC in this patient population after 1 year of treatment.

The researchers designed a double blind, randomized controlled trial, in which 62 patients received 5 mg daily oral amlodipine or placebo in addition to their current chelation regimen.

Researchers measured patients’ initial MIC values and determined whether their T2* was above or below the normal human threshold of 35 ms in order to stratify patients based on whether they needed to reduce their MIC or prevent MIC increases. Patients with an MIC greater than 0.59 mg/g dry weight or with a T2* less than 35 ms were stratified into the reduction group, whereas patients with an MIC of 0.59 mg/g dry weight or less with a T2* of 35 ms or higher were stratified into the prevention group.

In the reduction group, median MIC was comparable among those assigned amlodipine or placebo (1.31 mg/g vs. 0.77 mg/g).

The rate of MIC at 12 months defined by T2* levels served as the primary outcome measure.

The researchers observed similar iron intake during follow-up in the amlodipine and placebo arms (173 ± 57 mg/kg/year vs. 177 ± 56 mg/kg/year).

There were no significant differences in modifications to chelation therapy, with escalation of chelation occurring in 30% of the amlodipine arm and 24% of the placebo arm, and reduction of chelation occurring in 27% of the amlodipine arm and 14% of the placebo arm.

Overall, patients assigned amlodipine experienced a significant reduction in MIC, from 1.31 mg/g (range, 0.64-12.81) at baseline to 1.05 mg/g (range. 0.48-10.81) at 12 months (P = .02). Patients assigned placebo did not experience a significant decrease (0.77 mg/g vs. 0.75 mg/g).

A subgroup analysis showed that patients in the reduction group assigned amlodipine (n = 15) achieved a significant decrease in median MIC compared with patients assigned placebo (n = 15; –0.26 mg/g vs. 0.01 mg/g; P = .02).

The prevention group demonstrated no significant changes.

No patients died or were hospitalized due to cardiovascular complications. Four patients in the amlodipine arm and no patients in the placebo arm experienced mild adverse events. Three patients assigned amlodipine required dose reductions.

The researchers acknowledged study limitations, including the short observation period and the relatively small patient population.

“The use of oral amlodipine in addition to standard chelation therapy can reduce myocardial iron more effectively than iron chelation alone in patients with thalassemia major and myocardial siderosis, and may be useful in patients with a cardiac T2* below 35 ms,” Fernandes and colleagues wrote. – by Cameron Kelsall

Disclosure: Fernandes reports personal fees from Novartis and Sanofi Aventis and nonfinancial support from Siemens, all outside the submitted work. The other researchers report no relevant financial disclosures.