Cardiovascular Function and Treatment in β-Thalassemia Major

Abstract

This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in β-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non–cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision. Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes because of the unusual loading conditions in TM. The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus deferoxamine alone, and the equivalence of deferasirox versus deferoxamine.

Sustained improvements in myocardial T2* over 2 years in severely iron‐overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine

“…Importantly, 72.7% of patients treated with deferasirox and 54.5% of patients treated with DFO improved from severe (T2* <10 ms) to mild-to-moderate (T2* 10-20 ms) myocardial iron overload after 24 months-a clinically important increase since the relative risk of heart failure in patients with myocardial T2* <10 ms compared with T2* >10 ms has been shown to be significantly higher (relative risk 160 [95% CI 39-653]) [20]. This study did not evaluate chelation in patients with the most severe levels of myocardial iron overload (T2* <6 ms), where therapy based on a combination of DFO and deferiprone is advised [17].…”

“…The 1-year extension to the CORDELIA study generated long-term data on the efficacy and safety of deferasirox or DFO in patients with myocardial siderosis when treated for up to 2 years, adding to the body of evidence supporting a consensus statement on the use of these chelators in the treatment of myocardial siderosis in patients without cardiac decompensation [17]. Deferiprone monotherapy is also recommended in patients with myocardial siderosis; however, prospective data beyond 1 year of treatment are limited.…”

INCA (Peru) Study: Impact of Non‐Invasive Cardiac Magnetic Resonance Assessment in the Developing World

“…We had previously shown that CMR could be performed quickly in Thailand13 for a single indication, evaluation of cardiac iron, in a cohort where the clinical value for mortality and morbidity of this measurement is established 25. However, in this first pilot project, an approach was taken focusing on technology delivery with less investment in education and mentoring.…”

Acute cardiac decompensation in a patient with beta‐thalassemia and diabetes mellitus following cessation of chelation therapy

“…The 2013 American Heart Association (AHA) guidelines state that patients in acute heart failure should be immediately commenced on continuous (uninterrupted) intravenous iron chelation treatment with deferoxamine 50 mg/kg/day. Deferiprone should be introduced as soon as possible at a dose of 75 mg/kg/day (the total dose given in three divided doses) 2, 20, 21, 22. At the present time, data are lacking for the use of deferasirox in acute iron overload cardiomyopathy.…”

“…Management is based on regular blood transfusions to suppress ineffective erythropoiesis, with the goal to maintain pretransfusion hemoglobin concentration above 90 g/L 2. Repeated transfusions may lead to iron overload toxicity affecting the liver, spleen, heart, and endocrine system.…”