Prevalence and risk factors for pulmonary arterial hypertension in a large group of ß-thalassemia patients using right heart catheterization: a Webthal study.

BACKGROUND: Pulmonary arterial hypertension (PAH) remains a concern in patients with ß-thalassemia major (TM) and intermedia (TI); however, studies evaluating its prevalence and risk factors using systematic confirmation on right heart catheterization are lacking. METHODS AND RESULTS: This was a multicenter cross-sectional study of 1309 Italian ß-thalassemia patients (mean age 36.4±9.3 years; 46% men; 74.6% TM, 25.4% TI). Patients with a tricuspid-valve regurgitant jet velocity ≥3.2 m/s (3.6%) on transthoracic echocardiography further underwent right heart catheterization to confirm the diagnosis of PAH (mean pulmonary arterial pressure ≥25 mm Hg and pulmonary capillary wedge pressure ≤15mm Hg). The confirmed PAH prevalence on right heart catheterization was 2.1% (95% confidence interval [CI], 1.4-3.0) and was higher in TI (4.8%; 95% CI, 3.0-7.7) than TM (1.1%; 95% CI, 0.6-2.0). The positive predictive value for the tricuspid-valve regurgitant jet velocity ≥3.2 m/s threshold for the diagnosis of pulmonary hypertension was 93.9%. Considerable functional limitation and decrease in the 6-minute walk distance were noted in patients with confirmed PAH. On multivariate logistic regression analysis, independent risk factors for confirmed PAH were age (odds ratio, 1.102 per 1-year increase; 95% CI, 1.06-1.15) and splenectomy (odds ratio, 9.31; 95% CI, 2.57-33.7). CONCLUSIONS: The prevalence of PAH in ß-thalassemia patients as confirmed on right heart catheterization was 2.1%, with an ≈5-fold higher prevalence in TI than TM. Advanced age and splenectomy are risk factors for PAH in this patient population. CLINICAL TRIAL REGISTRATION URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01496963.

Thalassemia major between liver and heart: Where we are now.

The aim of the study was to assess the current state in terms of liver and heart iron overload as well as of liver and heart related morbidity and mortality in a large cohort of thalassemia patients. Myocardial iron loading was present in 28.9% patients, which was severe in 3.2%. Liver iron was normal in 9.3% and severe in 15%. The rate of cardiac deaths started to decrease between 2000 and 2003 and dropped significantly afterwards. The prescription of combination therapy soon after the hospital admission for decompensated heart failure was associated with a decrease in the short-term mortality. In 111 adult patients who underwent liver elastometry, 14 HCVRNA positive subjects and 2 HCVRNA negative, had stiffness values suggestive of cirrhosis. No cases of hepatocarcinoma were reported. Liver "iron free foci" occurred in a HCV negative patient and the occurrence of a malignant epithelioid hemangioendothelioma led to liver transplantation in another. The study suggests that a subset of patients continues to develop progressive hemosiderosis that may lead to cardiac disease and death. Beyond its key role in preventing myocardial iron overload, liver iron chelation is essential for hampering the onset of hepatic tumors, which may not be limited to hepatocarcinoma.

Impact of heart magnetic resonance imaging on chelation choices, compliance with treatment and risk of heart disease in patients with thalassaemia major.

This study aimed to verify the impact of heart magnetic resonance imaging on chelation choices and patient compliance in a single-institution cohort as well as its predictive value for heart failure and arrhythmias. Abnormal cardiac T2* values determined changes in treatment in most subjects. Heart T2* was confirmed to be highly predictive over 1 year for heart failure and arrhythmias. The choice of chelation regimens known to remove heart iron efficiently was not sufficient by itself to influence the risk. Compliance with treatment had a more remarkable role.

Clinical management of cardiovascular complications in patients with thalassaemia major: a large observational multicenter study.

AIMS: To determine the clinical management of cardiovascular complications, and the extent of cardiac left ventricular (LV) involvement, in a large cohort of homogenously treated patients with thalassaemia major. METHODS AND RESULTS: Participants were ≥ 16 years of age and diagnosed with thalassaemia major requiring regular blood transfusions since the age of 2. Patient characteristics, clinical and echocardiography data for 524 patients were extracted from Webthal®, an Internet-shared database. Patients were considered to have evidence of cardiovascular disease if at least one cardiovascular drug was recorded in their file. The majority of patients (422 of 524; 80.5%) had not taken any cardiovascular drug. Among those who had angiotensin-converting enzyme-inhibitors were the most commonly used (81 patients) and these were used by significantly more males than females (P < 0.01). Patients in whom cardiovascular drugs were prescribed showed evidence of cardiac structural and/or functional abnormalities, inasmuch as fractional shortening and ejection fraction were significantly lower (31.3 vs. 35% and 54.4 vs. 60.6; both P < 0.001) and LV end-diastolic diameter index was significantly higher (32.9 vs. 31.8; P = 0.004). Interestingly, when compared with patients in whom cardiovascular drug therapy was not deemed necessary, transfusion period was longer in treated patients (26.2 vs. 24.5 years; P= 0.002). CONCLUSION: Approximately 19% of regularly transfused and chelated thalassaemia major patients need cardiovascular drug therapy. This subgroup is characterized by a dilated and mildly hypokinetic left ventricle when compared with the majority of thalassaemia major patients, who do not need any cardioactive drug. These data underscore the importance of careful evaluation of cardiac functional status in patients with thalassaemia major. Moreover, this database may serve as a clinically useful reference grid for echocardiograph values in this patient population.

Increased survival and reversion of iron-induced cardiac disease in patients with thalassemia major receiving intensive combined chelation therapy as compared to desferoxamine alone.

Myocardial iron overload is the leading cause of death in patients with beta-thalassemia major. An intensification monotherapy with deferoxamine (DFO) as well as a combination therapy with DFO and deferiprone (DFP) reduces myocardial iron and improves cardiac function. However, the prognosis for thalassemia major patients with established cardiac disease switched from DFO monotherapy to combined DFP/DFO chelation is unknown. Twenty-eight thalassemia major patients with cardiac disease were enrolled in a prospective study lasting 42+/-6 months. Fifteen (9 high-ferritin and 6 low-ferritin) were placed on DFP/DFO (DFP, 75 mg/kg t.i.d.; DFO, 40-50mg/kg over 8-12h at night 5-7 days/week), while 13 (5 high- and 8 low-ferritin) received DFO alone. No cardiac events were observed among high-ferritin patients on combination therapy, whereas 4 cardiac events (p=0.0049), including three deaths, occurred in high-ferritin patients on DFO monotherapy. These findings demonstrate that in thalassemia major patients with well-established cardiac disease combined iron-chelation therapy with DFP/DFO is superior to DFO monotherapy.

Risk factors for heart disease in transfusion-dependent thalassemia: serum ferritin revisited.

Heart disease remains a leading cause of morbidity and mortality in transfusion-dependent thalassemia (TDT), which can be attributed to several factors but primarily develops in the setting of iron overload. This was a retrospective cohort study utilizing Webthal® patient data from five major centers across Italy. Patients without heart disease were followed-up for 10 years (2000-2010) and data were collected for demographics, splenectomy status, serum ferritin and hemoglobin levels, and comorbidities associated with heart disease. Among 379 patients analyzed (mean age 22.9 ± 5.1 years, 47.8% men), 44 (cumulative incidence: 11.6%) developed heart disease during the period of observation. Splenectomy (p = 0.002) and serum ferritin level (p < 0.001) were the only risk factors with significant association with heart disease. A serum ferritin threshold of ≥ 3000 ng/mL was the best predictor for the development of heart disease (86.4% sensitivity and 92.8% specificity, AUC: 0.912, 95% CI 0.852-0.971, p < 0.001). On multivariate analysis, only a serum ferritin level ≥ 3000 ng/mL remained significantly and independently associated with increased risk of heart disease (HR: 44.85, 95% CI 18.85-106.74), with a 5- and 10-year heart disease-free survival of 58 and 39%. The association between iron overload and heart disease in patients with TDT is confirmed, yet a new serum ferritin level of 3000 ng/mL to flag increased risk is suggested.

Combined therapy with deferiprone and desferrioxamine in thalassemia major.

BACKGROUND AND OBJECTIVES: Effective and convenient iron chelation remains one of the main targets of clinical management of thalassemia major. The combined treatment with desferrioxamine and deferiprone could have an increased chelation efficacy and sometimes allow drug doses and toxicity to be reduced and the number of days of desferrioxamine infusion to be decreased, improving compliance and quality of life. DESIGN AND METHODS: We used combined therapy with desferrioxamine and deferiprone to treat 79 patients with severe iron overload (serum ferritin higher than 3000 ng/mL) who had low compliance with subcutaneous desferrioxamine. RESULTS: Total therapy exposure was 201 patient-years. Three patients developed agranulocytosis and seven mild neutropenia. Other adverse effects were nausea, vomiting, abdominal pain, increased concentrations of liver transaminases and joint pain. The efficacy of combined therapy was evaluated in 64 patients treated for at least 12 months. Ferritin decreased from 5243+/-2345 to 3439+/-2446 ng/mL, p<0.001). Mean urinary iron excretion during combined therapy was double that with desferrioxamine or deferiprone monotherapy. In 20 patients receiving heart therapy at baseline, left ventricular ejection fraction increased from 48.6+/-9% to 57+/-6% (p=0.0001) over 12 to 57 months, without modifying the cardiac treatment. INTERPRETATION AND CONCLUSIONS: Continuous deferiprone treatment with intermittent administration of subcutaneous desferrioxamine is a practical and effective procedure to decrease severe iron overload in patients with thalassemia major. This study also shows that the combined therapy is associated with an improvement in heart function.

Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathies.

BACKGROUND AND OBJECTIVES: During the last decade new approaches to the treatment of pulmonary arterial hypertension (PH) have increased symptomatic relief and prolonged survival. PH is a common sequel of the hemoglobinopathies, thalassemia and sickle cell anemia, but the use of standard oral treatment options, such as calcium channel blockers, endothelin receptor antagonists, and long-term anticoagulation therapy, is limited because of toxicity and poor effectiveness. Sildenafil citrate is a selective and potent inhibitor of cGMP-specific phosphodiesterase-5 (PDE5) which promotes selective smooth muscle relaxation in lung vasculature and has been utilized successfully in the treatment of PH. The primary objective of this study was to evaluate the efficacy of sildenafil treatment in the control of PH in patients with hemoglobinopathies. DESIGN AND METHODS: In this study patients with hemoglobinopathies (thalassemia intermedia n=4; thalassemia major n=2; sickle thalassemia n=1) suffering from severe PH were treated with sildenafil citrate (50 mg b.i.d.) for periods ranging from 4 to 48 months. RESULTS: A significant decrease in pulmonary pressure and improvement in exercise capacity and functional class were observed in all patients. No significant adverse events were reported. INTERPRETATION AND CONCLUSIONS: These data, in a small group of patients, indicate that sildenafil citrate is effective in the treatment of PH in hemoglobinopathies that cannot be treated with alternative oral drugs and is well tolerated long-term at a daily dose of 100 mg, though studies including more patients may uncover toxicities and limitations of efficacy.

Guideline recommendations for heart complications in thalassemia major.

Thalassemia major is an inherited hemoglobin disorder resulting in a chronic hemolytic anemia. Transfusion therapy together with elevated gastrointestinal absorption of iron determines iron overload, which causes most of the mortality and morbidity associated with the disease. Heart complications represent the leading cause of mortality in this disease, although, because of an improvement in chelation treatment, an important and progressive increase of life expectancy mainly as a result of a reduction in mortality due to cardiac dysfunction has been demonstrated in recent years. Clinical pictures of heart damage range from the involvement of the ventricles to pulmonary hypertension or symptomatic ventricular or supra-ventricular arrhythmias. For this reason, the possibility of having specific recommendations is noteworthy. These recommendations outline the definition, the follow-up and the treatment of the main heart complications in this group of patients. The identification of topics and the nomination of the committee were made on behalf of the Society for the Study of Thalassemia and Hemoglobinopathies (SoSTE). The document obtained the auspices of ANMCO, SIC, SIRM and the Cardiovascular Magnetic Resonance Working Groups of the ANMCO, SIC and SIRM. All recommendations provided in this document have been performed according to the American Cardiology College (ACC) and American Heart Association (AHA) guidelines. Moreover, the recommendations were reviewed by two external referees before the definitive approval.