A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta-thalassemia major (CORDELIA)

Royal Brompton Hospital, London, United Kingdom;

Blood. 2014;123((10):):1447-54.

Clinical Commentary

Prof David Roberts, NHS Blood & Transplant, Oxford, UK

What is known?

Patients with transfusion- dependent thalassaemia accumulate considerable amounts of iron in their tissues, which causes oxidative stress, cell damage and significant functional impairment in the liver, heart and endocrine organs. Chelating agents such as the standard treatment of subcutaneous deferoxamine or the newer oral drug deferasirox can remove iron. The efficacy of iron removal for any given tissue Is different for each iron chelators. The relative effectiveness of each chelator over many months or years will inform the choice of chelation regime for individual patients with different absolute and relative levels of tissue iron loading.

What did this paper set out to examine?

The authors set out to compare efficacy and safety of deferasirox for myocardial iron removal as part of a randomised control trial of and deferasirox and subcutaneous deferoxamine in nearly 200 patients with beta-thalassemia major patients with significant myocardial iron loading as measured by magnetic resonance imaging where the T2* parameter is < 20 milliseconds (T2* 6-20 milliseconds) but with no signs of cardiac dysfunction. In particular, they wanted to show that deferasirox was no worse than deferoxamine in removing iron from the heart.

What did they show?

They showed that both oral deferasirox and subcutaneous deferoxamine removed iron from the heart and so the T2* parameter increased. There was no significant difference between the groups, although there was trend for greater removal of iron from the heart with deferasirox. The precise degree of iron removal depends on the dose of iron chelator that is given. The important finding is that both drugs can remove iron from the heart in transfusion- dependent thalassaemia. There was a high but similar frequency of overall adverse events in both groups.

What are the implications for practice and for future work?

It is now clear that the widely available iron chelator drugs all remove iron from the liver, heart and endocrine organs in a dose-dependent manner but efficacy and side effect profile differs between patients. The key for optimal treatment of patients is to decide a regime that suits each patient and to monitor tissue specific iron loading carefully and to adjust doses and/or treatment according to individual response. Within this framework, future RCTs that define the efficacy of individual iron chelators are very valuable, even essential to understand what iron chelators can be used, to define differences in side-effect profiles and in long term outcomes.
Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 beta-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.
Study details
Language : English
Additional Material : Comment in: Blood. 2014 Mar 6;123(10):1434-6; PMID: 24627546.
Credits : Bibliographic data from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine