Change In Myocardial T2 Research Articles

Pantoprazole reduces serum ferritin in patients with thalassemia major and intermedia: A randomized, controlled study

Complications due to iron overload exert a problematic situation in patients with thalassemia. Proton pump inhibitors (PPIs) like pantoprazole are effective agents to reduce acid gastric acid secretion and perhaps to interrupt iron absorption in conditions with increased iron absorption. Our purpose was to study effects of pantoprazole addition to chelators on iron levels in patients with thalassemia major and intermedia. This randomized, controlled, and single center trial was performed on 60 patients with thalassemia major and intermedia in Amir Kabir hospital, Iran. Patients were randomized 1:1 to pantoprazole group (iron chelator plus pantoprazole) or control group (iron chelator) for 6 months. Serum ferritin was measured by ELISA. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. After 6 months of treatment, a significant reduction was seen in serum ferritin levels in the pantoprazole group (1444±613μg/mL to 1197±956μg/mL; P<0.001). A further reduction was seen in patients with thalassmeia intermedia. There were no significant changes in myocardial T2* values in pantoprazole group compared to control group (23.6±7.3ms to 24.1±6.4ms). Compared to the control group, pantoprazole therapy had no effect on hepatic T2* value (9.7±2.3ms to 9.8±2.6ms). However, between-group difference was significant (P<0.05). Pantoprazole therapy for 6 months has benefits for reducing serum ferritin in patients with thalassemia major and intermedia. Pantoprazole addition to iron chelators seems safe.

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

AbstractRandomized 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 β-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.

Impact Of Liver Iron Overload On Myocardial T2* Response In Transfusion-Dependent Thalassemia Major Patients Treated With Deferasirox For Up To 3 Years

Background Patients with myocardial iron overload require effective cardiac iron removal to minimize the risk of cardiac complications. The 3 year EPIC cardiac sub-study showed that the oral iron chelator, deferasirox (DFX), effectively reduced cardiac iron overload. Previous reports demonstrate that cardiac iron removal is slow and suggest that liver iron concentration (LIC) may affect cardiac iron removal rate by chelators (Pennell et al., 2012; Blood). The objective of these analyses was to evaluate the impact of the severity of the liver iron overload on the change in myocardial T2* (mT2*) for patients receiving up to 3 years of DFX treatment in the EPIC sub-study. Methods Inclusion and exclusion criteria have been described previously (Pennell et al. , 2012; Haematologica). Patients were categorized into LIC ≤15 and >15 mg Fe/g dry weight (hereafter mg/g) at baseline (BL) and by LIC 15 mg/g at 12, 24, and 36 months to assess the impact of BL LIC and changes in LIC overtime on mT2*, respectively. During study, LIC and mT2* were measured every 6 months. Efficacy was assessed in per-protocol population that entered third year extension. Here, mT2* is presented as the geometric mean (Gmean) ± coefficient of variation (CV) unless otherwise specified. Statistical significance was established at α-level of 0.05 using a 2-sided paired t-test for within group comparisons and ANOVA for multiple group comparisons. All p -values were of exploratory nature for this post-hoc analysis. Results Of the 71 patients, who continued into study year 3, 68 patients considered evaluable were included in this analysis (per protocol population); 59 patients had LIC values available at end of study (EOS). Mean age was 20.5 ±7.35 years and 61.8 % of patients were female. Mean actual dose of DFX (mg/kg/day) was 32.1 ±5.5 and 35.1 ±4.9 in patients with BL LIC ≤15 and >15 mg/g, respectively. At EOS, mean actual doses were 32.9 ±5.4 (LIC 15 mg/g). Overall, patients had high BL LIC (Mean, 29.0 ±10.0 mg/g); 61 patients had LIC >15 (30.8 ±8.8) mg/g, only 7 patients had LIC ≤15 (12.7 ±1.1) mg/g, and no patients had LIC 15 mg/g, respectively. Notably, 51.9% of patients with BL LIC >15 mg/g achieved EOS LIC <7 mg/g. Overall, mean mT2* was 12.8 ±4.6 ms. The impact of BL LIC on mT2* and LIC response was as follows: in patients with LIC ≤15 mg/g (Mean BL mT2*, 14.2 ±3.6 ms) and >15 mg/g (BL mT2*, 12.7 ±4.7 ms), mT2* increased by 52% (Mean abs. change, 7.5 ±4.1 ms, p =0.0016) and 46% (7.3 ±7.3 ms, p 15 mg/g, (20.1 ±10.6 ms) displaying a lag of nearly 12 months. The relation between post-BL LIC on mT2* response at 12, 24 and 36 months is shown in the figure. At 12 months, there was no significant difference in mT2* that had occurred in patients with LIC 15 mg/g (13% increase; 1.9 ±3.2 ms). However, at 24 months, there was a statistically significant difference amongst the 3 subgroups in percent increase in the mT2* that had occurred; patients with LIC 15 mg/g had 54% (Mean abs. change, 8.3 ±7.3 ms), 33% (5.2 ±5.2 ms) and 10% (2.1 ±4.3 ms) increase ( p 15mg/g group. At all-time points, in patients who achieved an LIC <7 mg/g, a statistically significant increase in T2* from BL had occurred. Discussion Overall, DFX treatment resulted in a significant decrease in LIC and improved mT2*. A greater difference in mT2* improvement was shown to have occurred in patients who achieved lower end-of-year LIC after treated with DFX. This divergence was progressive with time, being maximal at 36 months. Thus, a therapeutic response in LIC with DFX is associated with a greater likelihood of improving mT2*. This may assist in monitoring liver and cardiac response to DFX. Prospective evaluation of this relationship is indicated. ![Graphic][1] Disclosures: Porter: Novartis Pharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Taher: Novartis Pharma: Honoraria, Research Funding. Aydinok: Novartis Oncology: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cappellini: Novartis Pharma: Honoraria, Speakers Bureau; Genzyme: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kattamis: Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. El-Ali: Novartis Pharma: Employment. Martin: Novartis Pharma: Employment. Pennell: Novartis: Consultancy, Honoraria, Research Funding; ApoPharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. [1]: /embed/inline-graphic-1.gif

Continued Improvement and Normalization of Myocardial T2* In Patients with β-thalassemia Major Treated with Deferasirox (Exjade®) for up to 3 Years

Abstract 4276 Background: To date, the efficacy of various iron chelators in reducing cardiac iron, a leading cause of death in transfused patients with β-thalassemia major (TM), has been demonstrated in prospective controlled studies of up to 1-yr duration. Since removal of iron from the heart takes several years, it is important to assess longer-term effects of iron chelation therapy in terms of cardiac iron removal. We report here end-of-study (EOS) results from the EPIC cardiac substudy in TM patients treated with deferasirox for up to 3 yrs. Methods: Patients aged ≥10 yrs with myocardial T2* >5 to 2500 ng/mL, MR (R2) liver iron concentration (LIC) >10 mg Fe/g dry weight (dw) and ≥50 lifetime transfused blood units were included in the study. Deferasirox was initiated at 30 mg/kg/day and increased to 40 mg/kg/day by the start of yr 2. Dose decreases were allowed for safety reasons. Primary endpoint was change in myocardial T2* from baseline (BL) to 3 yrs. Results: Seventy-one patients completed 2 yrs of treatment and entered the 3 rd yr of the study. Mean age was 20.5 ± 7.4 yrs. BL cardiac T2* was >5 to st , 2 nd and 3 rd yr, respectively. Geometric mean T2* significantly increased from 11.9 ms ± 39.0% at BL to 13.9 ms ± 46.9% after 1 yr, 15.6 ms ± 57.7% after 2 yrs, and continued to increase to 17.1 ms ± 62.0% after 3 yrs, (increase from BL of 17% at 1 yr, 31% at 2 yrs and 44% at 3 yrs; P 5 to After 3 yrs, 68.1% of patients with BL T2* 10 to 5 to P P Of 71 patients, 66 (93.0%) completed the 3 rd yr. Reasons for discontinuation were unsatisfactory therapeutic effect (n=3) and consent withdrawal (n=2). There were no deaths during the 3-yr study. Drug-related AEs (≥5%) decreased year by year: increased blood creatinine (n=19 [26.8%] vs n=16 [22.5%] vs n=9 [12.7%]), rash (n=11 [15.5%] vs n=0 vs n=0), increased ALT (n=5 [7.0%] vs n=3 [4.2%] vs n=2 [2.8%]), increased AST (n=4 [5.6%] vs n=3 [4.2%] vs n=1 [1.4%]) and diarrhea (n=4 [5.6%] vs n=1 [1.4%] vs n=0). In yr 3, serious AEs included atrial fibrillation, chronic sinusitis, femur fracture, gastritis, muscle abscess and rheumatic fever (all n=1); none were considered deferasirox-related. Six patients (8.5%) had 2 consecutive increases in serum creatinine >33% above BL and upper limit of normal (ULN); 3 patients in the 1 st yr and 3 in the 3 rd yr. Two (2.8%) patients had 2 consecutive increases in ALT >10 × ULN; 1 patient in the 2 nd yr and 1 patient in both the 2 nd and 3 rd yr. Conclusion: This is the first prospective study to report 3-yr data on cardiac iron removal for an iron chelator. Once-daily deferasirox monotherapy at doses of 30–40 mg/kg/day effectively removed cardiac iron, allowing 68% of patients with moderate-to-mild cardiac iron loading to normalize and 50% of patients with severe myocardial iron loading at BL to reduce their cardiac iron levels to the moderate-to-mild range, associated with a much lower risk of heart failure. Importantly, there were no reports of death during the study. The long-term improvements in cardiac iron loading with deferasirox at doses of >30 mg/kg/day were associated with a manageable safety profile, maintenance of normal cardiac function and a concomitant significant decrease in hepatic and total body iron burden by nearly 50% over the 3 yrs. Disclosures: Pennell: Siemens: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apotex: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; CVIS: Equity Ownership. Porter: Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cappellini: Novartis: Speakers Bureau. Aydinok: Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim: Novartis: Honoraria. Li: Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Viprakasit: Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Kattamis: Novartis: Honoraria, Research Funding, Speakers Bureau. Smith: Novartis: Consultancy, Research Funding. Habr: Novartis: Employment. Domokos: Novartis: Employment. Roubert: Novartis: Employment. Taher: Novartis: Honoraria, Research Funding.

Myocardial T2* is not affected by ageing, myocardial fibrosis, or impaired left ventricular function

To evaluate the influence of alterations in myocardial structure and function from increasing age, myocardial fibrosis, or impaired left ventricular function on myocardial T2*. Myocardial T2* was measured in 126 subjects without cardiac iron loading, of whom 63 were normals of varying ages, 39 were patients with impaired left ventricular function from various nonsiderotic cardiac causes, and 24 were patients with chronic myocardial infarction affecting the interventricular septum (where myocardial T2* measurements are normally made). The median (Q1, Q3) of myocardial T2* in the normals was 36.3 ms (31.6, 45.4). There was no significant correlation between myocardial T2* and age (R(2) = 0.04; P = 0.11). In the patients with impaired left ventricular function, the median myocardial T2* was 35.5 ms (31, 42.2) (P = 0.34 versus normals). There was no significant correlation between ejection fraction and T2* in patients with left ventricular impairment (R(2) = 0.03; P = 0.33). In the patients with septal infarction, the median septal myocardial T2* was 35.4 ms (32.7, 43) (P = 0.81 vs normals). There was no significant change in myocardial T2* associated with any alterations of myocardial structure and function occurring with increasing age, impairment of left ventricular function or septal fibrosis from chronic myocardial infarction. These results indicate that myocardial T2* measurements are robust to these potential confounding parameters.

Efficacy of deferasirox in reducing and preventing cardiac iron overload in β-thalassemia

Cardiac iron overload causes most deaths in beta-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with beta-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n = 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n = 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean +/- coefficient of variation) improved from a baseline of 11.2 ms (+/- 40.5%) to 12.9 ms (+/- 49.5%) (+16%; P < .001). LVEF (mean +/- SD) was unchanged: 67.4 (+/- 5.7%) to 67.0 (+/- 6.0%) (-0.3%; P = .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (+/- 25.6%) to 32.5 ms (+/- 25.1%) (+2%; P = .57) and LVEF increased from baseline 67.7 (+/- 4.7%) to 69.6 (+/- 4.5%) (+1.8%; P < .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials.gov as NCT00171821.

Efficacy and Safety of Deferasirox (Exjade®) in β-Thalassemia Patients with Myocardial Siderosis: 2-Year Results From the EPIC Cardiac Sub-Study.

Abstract 4062Poster Board III-997 BackgroundOver 70% of deaths in regularly transfused patients with β-thalassemia major (TM) are related to iron-induced cardiomyopathy. Deferasirox (Exjade®), in a sub-study of the 1-year multicenter prospective EPIC trial, demonstrated efficacy in reducing myocardial iron in TM patients with mild, moderate and severe cardiac siderosis, as evidenced by a statistically significant improvement in myocardial T2*. We herein report the extension phase results from the same study in patients who have received up to 2 years of deferasirox therapy. MethodsPatients aged ≥10 years with myocardial T2* >5–<20 ms (indicating cardiac siderosis) by cardiovascular magnetic resonance (CMR), left ventricular ejection fraction (LVEF) ≥56%, serum ferritin >2500 ng/mL, MR (R2) LIC >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units were included in the cardiac sub-study. Deferasirox was initiated at 30 mg/kg/day and increased to 40 mg/kg/day by the time patients had entered the 1-year extension. Dose decreases were allowed for safety reasons. The primary endpoint was change in myocardial T2* from baseline to 2 years. ResultsOut of 100 patients who entered the 1-year extension phase, 85 completed (85%); 24-month CMR data are available for 81 patients. Mean age was 20.6 ±7.3 years. Baseline cardiac T2* was <10 ms (severe cardiac siderosis) in 39 patients (39%) and 10–20 ms (mild-to-moderate cardiac siderosis) in 61 (61%). 67.0% had received prior deferoxamine (DFO) and 33.0% prior DFO/deferiprone combination therapy. Mean actual deferasirox dose increased from 33.1 ±3.7 mg/kg/day in the core 1-year phase to 36.1 ±7.4 mg/kg/day during the extension. Continued improvement in myocardial T2* was observed in the extension phase so that after 2 years of deferasirox treatment, T2* had significantly increased from a baseline geometric mean of 11.2 to 15.3 ms (P<0.001). Significant increases from 7.3 to 9.3 ms (P<0.001) and from 14.6 to 19.9 ms (P<0.001) were respectively noted in patients with baseline T2* <10 and 10–20 ms (Figure). LVEF remained stable in both subgroups throughout the 2-year follow up period. Both mean LIC and median serum ferritin were significantly reduced from baseline by 10.7 ± 12.8 mg Fe/g dw and 2343 ng/mL (range –12795 to 25127), respectively (P<0.001; based on last-observation-carried-forward analysis). [Display omitted] Reasons for discontinuation were: unsatisfactory therapeutic effect (n=8), consent withdrawal (n=3), protocol violation (n=2), lost to follow up (n=1) and abnormal laboratory value (increased urinary protein/creatinine ratio) leading to consent withdrawal (n=1); no deaths were reported. Incidence of investigator-assessed drug-related AEs (≥5%) decreased overall from the core phase to the extension: increased blood creatinine (n=21 [21.0%] vs n=18 [18.0%]), rash (n=15 [15.0%] vs n=0), increased alanine aminotransferase (ALT) (n=6 [6.0%] vs n=4 [4.0%]) and increased aspartate aminotransferase (n=4 [4.0%] vs n=3 [3.0%]). There were no drug-related serious AEs over 2 years. In total, 4 patients (4.0%) had increased serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; 3 patients (3.0%) during the core and 1 (1.0%) during the extension. 4 (4.0%) patients had increased ALT >10xULN on two consecutive visits; 2 patients (2.0%) during the core and 2 (2.0%) during the extension; levels were already >ULN at baseline in these patients. ConclusionsThis is the first large prospective study to report 2-year data on cardiac iron removal for any iron chelator. Results show that continued therapy with deferasirox for up to 2 years at doses 30–40 mg/kg/day was effective in removing iron from the heart in TM patients with mild, moderate and severe cardiac siderosis. Myocardial T2* continued to improve in year 2 and the statistically significant improvement from baseline was associated with maintenance of normal cardiac function and a concomitant decrease in hepatic and total body iron burden. Overall, deferasirox was well tolerated. Disclosures:Pennell:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Li:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government : Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Smith:Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

Efficacy and Safety of Deferasirox (Exjade®) in Reducing Cardiac Iron in Patients with β-Thalassemia Major: Results from the Cardiac Substudy of the EPIC Trial

Background: Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients (pts) with β-thalassemia, hence the importance of using a chelator that can reduce cardiac iron. Deferasirox (Exjade®), a once-daily, oral iron chelator, has demonstrated removal of cardiac iron in preclinical and small clinical studies. The EPIC trial is a 1-yr, multicenter prospective longitudinal study, and is the largest of its kind for any chelation therapy. Here we report the EPIC cardiac sub-study, which evaluates the cardiac efficacy of deferasirox in β-thalassemia pts with myocardial siderosis.Methods: The sub-study of EPIC included pts with β-thalassemia aged ≥10 yrs who were eligible for enrollment in the core trial and who had magnetic resonance (MR) myocardial T2* >5–<20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) ≥56%, serum ferritin (SF) >2500 ng/mL, MR (R2) liver iron concentration (LIC) >10 mg Fe/g dw, and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/d and subsequent dose adjustments of 5–10 mg/kg/d were based on changes in SF, month-6 cardiac T2* and safety parameters. The primary endpoint was the change in myocardial T2* from baseline to 1 yr. Secondary endpoints included change in LVEF, SF and LIC at 1 yr.Results: Enrolled into this sub-study were 114 pts (54 M, 60 F; mean 20.9±7.3 yrs), of whom the baseline myocardial T2* was <10 ms in 47 (41%), and 10–20 ms in 67 (59%). Mean baseline LIC was 28.2±10.0 mg Fe/g dw, median SF 5235 ng/mL, and the mean amount of transfused blood in the previous yr 185 mL/kg. 68% of pts had received prior deferoxamine (DFO) and 32% DFO/deferiprone combination therapy. Mean actual deferasirox dose over 1 yr was 32.6 mg/kg/d. At 1 yr, the myocardial T2* improved significantly from a (geometric mean ± coefficient of variation) baseline of 11.2 ms ±40.5% to 12.9 ms ±49.5% (P<0.0001), representing an increase by a factor of 1.16 from baseline. Significant increases from 7.4 ms ±19.4% to 8.2 ms ±25.6% (P=0.0002) and from 14.6 ms ±20.9% to 17.4 ms ±31.2% (P<0.0001) were also noted in pts with baseline T2* <10 and 10–20 ms, respectively. Improvement in T2* (>4% increase) was seen in 69.5%; no change in 14.3%; and worsening (>4% decrease) in 16.2%. LVEF remained stable throughout the study: 67.4±5.7% to 67.1±6.0% (P=ns). Overall both mean LIC and median SF were reduced significantly from baseline by −6.6±9.9 mg Fe/g dw and −1257 ng/mL (P<0.0001 for both). Treatment was completed in 105 pts (92.1%) with 4 discontinuations due to AEs (3.5%) and 5 for other reasons (4.4%). No pts died during the study. Most investigator-assessed drug-related AEs (78.6%) were mild-to-moderate in severity; rash was the most common (n=15; 13.2%). Two drug-related serious AEs (one nephritis leading to acute renal failure and one renal tubular disorder) were reported which eventually resolved following drug discontinuation. In total, 5 pts (4.4%) had an increase in serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Two (1.8%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in these pts.Conclusions: In β-thalassemia pts with myocardial siderosis, deferasirox at a mean dose of 32.6 mg/kg/d over 1 yr removes iron from the heart. The statistically significant improvement in myocardial T2* was associated with maintained ejection fraction. Concomitantly, a significant decrease in hepatic and total body iron burden was also seen. Deferasirox treatment was generally well tolerated. Ongoing one-yr extension of this sub-study will elucidate further the cardiac efficacy of deferasirox.

A Randomized, Placebo-Controlled, Double-Blind Trial of the Effect of Combined Therapy With Deferoxamine and Deferiprone on Myocardial Iron in Thalassemia Major Using Cardiovascular Magnetic Resonance

Cardiac complications secondary to iron overload are the leading cause of death in beta-thalassemia major. Approximately two thirds of patients maintained on the parenteral iron chelator deferoxamine have myocardial iron loading. The oral iron chelator deferiprone has been demonstrated to remove myocardial iron, and it has been proposed that in combination with deferoxamine it may have additional effect. Myocardial iron loading was assessed with the use of myocardial T2* cardiovascular magnetic resonance in 167 patients with thalassemia major receiving standard maintenance chelation monotherapy with subcutaneous deferoxamine. Of these patients, 65 with mild to moderate myocardial iron loading (T2* 8 to 20 ms) entered the trial with continuation of subcutaneous deferoxamine and were randomized to receive additional oral placebo (deferoxamine group) or oral deferiprone 75 mg/kg per day (combined group). The primary end point was the change in myocardial T2* over 12 months. Secondary end points of endothelial function (flow-mediated dilatation of the brachial artery) and cardiac function were also measured with cardiovascular magnetic resonance. There were significant improvements in the combined treatment group compared with the deferoxamine group in myocardial T2* (ratio of change in geometric means 1.50 versus 1.24; P=0.02), absolute left ventricular ejection fraction (2.6% versus 0.6%; P=0.05), and absolute endothelial function (8.8% versus 3.3%; P=0.02). There was also a significantly greater improvement in serum ferritin in the combined group (-976 versus -233 microg/L; P<0.001). In comparison to the standard chelation monotherapy of deferoxamine, combination treatment with additional deferiprone reduced myocardial iron and improved the ejection fraction and endothelial function in thalassemia major patients with mild to moderate cardiac iron loading.

The Effect of Combined Chelation Therapy in the Treatment of Severe Myocardial Iron Loading in Beta Thalassaemia Major.

Introduction: Thalassaemia major ™ is an inherited haemoglobinopathy resulting from mutations of the β-globin gene. Survival is dependent upon lifelong blood transfusions and results in progressive total body iron overload. Cardiac failure secondary to myocardial iron loading is by far the commonest cause of death with only 50% of patients in the UK in recent cohorts surviving beyond the age of 35 years. Conventional treatment with the parenteral iron chelator deferoxamine improves morbidity and mortality but fails to clear the heart of iron in approximately two-thirds of patients. More recently, the oral iron chelator deferiprone has been demonstrated to remove myocardial iron and it has been proposed that in combination with deferoxamine it may have an additive effect. Through the T2* multi-echo cardiac magnetic resonance (CMR) technique, myocardial iron can now be non-invasively and reproducibly quantified, thereby providing a means to assess myocardial iron loading in response to chelation treatment.Purpose: To report the changes in myocardial T2* and cardiac function in patients with severe myocardial iron loading (myocardial T2* <8ms) following treatment with the un-blinded addition of deferiprone to continued deferoxamine chelation therapy.Methods: A mobile CMR scanner (1.5T Siemens Sonata) was transported to Cagliari, Italy. The myocardial T2* was assessed in 167 patients with TM aged 18v42 (30 +/− 5.3years). Of these, 22 patients were identified as having severe myocardial iron loading (T2* <8ms), 15 of whom (at their clinician's discretion) were subsequently given deferiprone in addition to continued deferoxamine therapy. Patients underwent further CMR assessment at baseline, 6 and 12 months.Results: Over a period of 12 months myocardial T2* improved significantly (6.1+/− 1.0ms to 8.2ms +/−2.5ms, p=0.007) in association with an improvement in cardiac function (LV ejection fraction 52 +/−12% to 65% +/−6.6%, p<0.0001). See Figures 1 and 2.Conclusion: This prospective study shows that patients with severe myocardial iron loading show significant improvement in iron loading and myocardial function with the addition of deferiprone to continued parenteral deferoxamine. [Display omitted] [Display omitted]

Vasodilator response assessment in porcine myocardium with magnetic resonance relaxometry.

This research describes an early preclinical study of the biophysical mechanisms governing changes in myocardial T2 during vasodilation in normal myocardium. Theoretical modeling and experimental studies in an instrumented pig model (n=7) provided measures of changes in myocardial T2, relative blood volume (BV), and microcirculation oxygen levels (%O2) during intracoronary adenosine infusion. Intracoronary adenosine increases perfusion without increasing blood volume or cardiac metabolic rate; thus, T2 elevations should reflect elevated microcirculation oxygen levels. Robust strategies were used for magnetic resonance imaging (MRI) data collection. Measures of myocardial and vascular T1 before and after Clariscan (Amersham Health) injection provided blood volume assessment. Changes in microcirculation oxygen levels were estimated via direct blood sampling from the left anterior descending (LAD) coronary vein. Perfusion changes were monitored using a Doppler flow wire within the left main coronary artery. Myocardial T2 elevations (DeltaT2=17+/-8%) within the LAD arterial perfusion bed were related to elevations in perfusion (coronary velocity reserve=3.2+/-0.4) and coronary venous %O2 [Delta(LAD CV%O2) =56+/-11%], whereas blood volume (DeltaBV=0 +/-2%) and cardiac metabolic rate [Delta(heart rate x blood pressure) = -4+/-11%] remained constant. Myocardial T2 elevation during intracoronary adenosine infusion was significant and repeatable, caused by increases in microcirculation oxygen levels. Changes in microcirculation oxygen levels of approximately 40%O2 should be detectable by this technique. This sensitivity should suffice for differentiating normal from abnormal myocardium via measurement of myocardial perfusion reserve.