Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone

Abstract

Background: Established heart failure in thalassaemia major has a poor prognosis and optimal management remains unclear.

Methods: A 1 year prospective study comparing deferoxamine (DFO) monotherapy or when combined with deferiprone (DFP) for patients with left ventricular ejection fraction (LVEF) <56% was conducted by the Thalassemia Clinical Research Network (TCRN). All patients received DFO at 50-60 mg/kg 12-24 hr/day sc or iv 7 times weekly, combined with either DFP 75 at mg/kg/day (combination arm) or placebo (DFO monotherapy arm). The primary endpoint was the change in LVEF by CMR.

Results: Improvement in LVEF was significant in both study arms at 6 and 12 months (p = 0.04), normalizing ventricular function in 9/16 evaluable patients. With combination therapy, the LVEF increased from 49.9% to 55.2% (+5.3% p = 0.04; n = 10) at 6 months and to 58.3% at 12 months (+8.4% p = 0.04; n = 7). With DFO monotherapy, the LVEF increased from 52.8% to 55.7% (+2.9% p = 0.04; n = 6) at 6 months and to 56.9% at 12 months (+4.1% p = 0.04; n = 4). The LVEF trend did not reach statistical difference between study arms (p = 0.89). In 2 patients on DFO monotherapy during the study and in 1 patient on combined therapy during follow up, heart failure deteriorated fatally. The study was originally powered for 86 participants to determine a 5% difference in LVEF improvement between treatments. The study was prematurely terminated due to slow recruitment and with the achieved sample size of 20 patients there was 80% power to detect an 8.6% difference in EF, which was not demonstrated. Myocardial T2* improved in both arms (combination +1.9 ± 1.6 ms p = 0.04; and DFO monotherapy +1.9 ± 1.4 ms p = 0.04), but with no significant difference between treatments (p = 0.65). Liver iron (p = 0.03) and ferritin (p < 0.001) both decreased significantly in only the combination group.

Conclusions: Both treatments significantly improved LVEF and myocardial T2*. Although this is the largest and only randomized study in patients with LV decompensation, further prospective evaluation is needed to identify optimal chelation management in these high-risk patients.

Figure 1

Baseline, 6 month and 12 month LVEF for each patient in DFO monotherapy and DFP combination arms. With DFP combination, mean LVEF increased from 49.9% to 55.2% at 6 months (n = 10) and to 58.3% at 12 months (n = 7): with monotherapy LVEF increased from 52.8% to 55.7% at 6 months (n = 6) and to 56.9% at 12 months (n = 4). The improvements are significant over time in both arms (p = 0.04) but without significant difference between arms (p = 0.86 for treatment; p = 0.89 for the interaction).

Figure 2

Baseline, 6 and 12 month myocardial T2* values with DFO monotherapy and DFP combination are shown. Myocardial T2* improved in both arms (p = 0.04), with no significant difference between treatments (p = 0.65 for treatment; p = 0.48 for the interaction): improvement with DFP was by 1.5 ms at 6 months and by 1.9 ms at 12 months: with DFP monotherapy this was by 1.1 ms and 1.9 ms respectively.

Figure 3

LIC values at baseline, 6 months and 12 months. There is a significant decrease in LIC with DFP combination (p = 0.03 for the interaction). At 6 months, there is reduction with DFP combination (from 13.91 ± 3.87 to 9.19 ± 3.91 (n = 9) and a slight increase with DFO monotherapy (from 6.27 ± 1.96 to 7.43 ± 2.44 mg/g dry wt. (n = 6). At 12 months, there is a reduction of 4.29 mg/g dry wt in DFP combination (from 16.1 ± 4.67 to 9.27 ± 3.61 mg/g dry wt, n = 7) and a slight reduction with DFO monotherapy from 5.62 ± 2.2 to 5.08 ± 3.18 mg/g dry wt (n = 4).

Figure 4

Baseline and 4 weekly ferritin values in DFP combination and DFO monotherapy arms for individual patients and mean (bold). With DFP combination, there is a significant downward trend from a baseline of 3308 ± 678 μg/L to 2371 ± 701 μg/L at 6 months (n = 9). Between baseline and 10–12 months, serum ferritin declined from 3601 ± 838 to 2132 ± 646 μg/L (n = 7). In the DFO monotherapy arm, there is a small downward trend from a baseline of 1880 ± 691 μg/L to 1603 ± 636 μg/L at 6 months (n = 6). In 4 samples at baseline and at 12 months, serum ferritin increased from 1613 ± 537 μg/L to 2018 ± 898 μg/L.