title: A randomized trial of amlodipine in addition to standard chelation therapy in patients with thalassemia major.
abstract: Cardiovascular disease resulting from iron accumulation is still a major cause of death in patients with thalassemia major (TM). Voltage-gated calcium-channel blockade prevents iron entry into cardiomyocytes and may provide an adjuvant treatment to chelation, reducing myocardial iron uptake. We evaluated whether addition of amlodipine to chelation strategies would reduce myocardial iron overload in TM patients compared with placebo. In a multicenter, double-blind, randomized, placebo-controlled trial, 62 patients were allocated to receive oral amlodipine 5 mg/day or placebo in addition to their current chelation regimen. The main outcome was change in myocardial iron concentration (MIC) determined by magnetic resonance imaging at 12 months, with patients stratified into reduction or prevention groups according to their initial T2* below or above the normal human threshold of 35 ms (MIC, 0.59 mg/g dry weight). At 12 months, patients in the reduction group receiving amlodipine (n = 15) had a significant decrease in MIC compared with patients receiving placebo (n = 15) with a median of -0.26 mg/g (95% confidence interval, -1.02 to -0.01) vs 0.01 mg/g (95% confidence interval, -0.13 to 0.23), P = .02. No significant changes were observed in the prevention group (treatment-effect interaction with P = .005). The same findings were observed in the subgroup of patients with T2* <20 ms. Amlodipine treatment did not cause any serious adverse events. Thus, in TM patients with cardiac siderosis, amlodipine combined with chelation therapy reduced cardiac iron more effectively than chelation therapy alone. Because this conclusion is based on subgroup analyses, it needs to be confirmed in ad hoc clinical trials. This trial was registered at www.clinicaltrials.gov identifier as #NCT01395199.
authors.affiliation: Jose Michel Kalaf Research Institute, Campinas, Brazil;
authors.forename: Juliano L
authors.initials: JL
authors.lastname: Fernandes
authors.affiliation: Centro de Hematologia de São Paulo, São Paulo, Brazil;
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Loggetto
authors.affiliation: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini, Campinas, Brazil;
authors.forename: Monica P A
authors.initials: MP
authors.lastname: Veríssimo
authors.affiliation: University of Campinas, Campinas, Brazil;
authors.forename: Kleber Y
authors.initials: KY
authors.lastname: Fertrin
authors.affiliation: Centro de Hematologia e Hemoterapia do Paraná, Curitiba, Brazil;
authors.forename: Giorgio R
authors.initials: GR
authors.lastname: Baldanzi
authors.affiliation: Jose Michel Kalaf Research Institute, Campinas, Brazil;
authors.forename: Luciana A B
authors.initials: LA
authors.lastname: Fioravante
authors.affiliation: Marilia Medical School, Marilia, Brazil;
authors.forename: Doralice M
authors.initials: DM
authors.lastname: Tan
authors.affiliation: Maringa State University, Maringa, Brazil;
authors.forename: Tatiana
authors.initials: T
authors.lastname: Higa
authors.affiliation: Londrina State University, Londrina, Brazil; and.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Mashima
authors.affiliation: University of Torino, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Piga
authors.affiliation: University of Campinas, Campinas, Brazil;
authors.forename: Otavio R
authors.initials: OR
authors.lastname: Coelho
authors.affiliation: University of Campinas, Campinas, Brazil;
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Costa
authors.affiliation: University of Campinas, Campinas, Brazil;
authors.forename: Sara T
authors.initials: ST
authors.lastname: Saad
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D017311:Amlodipine / Q000627:therapeutic use*; D015913:Chelation Therapy; D002648:Child; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D011379:Prognosis; D014665:Vasodilator Agents / Q000627:therapeutic use*; D055815:Young Adult; D017086:beta-Thalassemia / Q000188:drug therapy*
chemical_list: D014665:Vasodilator Agents; D017311:Amlodipine; D007501:Iron