title: Sildenafil therapy in thalassemia patients with Doppler-defined risk of pulmonary hypertension.
abstract: Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We, therefore, designed a 12-week, open-label, phase 1/2, pilot-scale, proof-of-principle trial of sildenafil therapy in 10 patients with β-thalassemia and at increased risk of pulmonary hypertension based on an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables compared at baseline and after 12 weeks of sildenafil treatment included Doppler-echocardiographic parameters, 6-minute walked distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function, and laboratory parameters. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0±0.7 versus 2.6±0.5 m/s, P=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in 6-minute walked distance was noted. Sildenafil was well tolerated, although minor expected adverse events were commonly reported. The total dose of sildenafil (mg) was strongly correlated with percent change in nitric oxide metabolite concentration in the plasma (ρ=0.80, P=0.01). There were also significant increases in plasma and erythrocyte arginine concentrations. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk of pulmonary hypertension; however, it was not demonstrated to improve the distance walked in 6 minutes. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in patients with β-thalassemia. (clinicaltrials.gov identifier: NCT00872170).
authors.affiliation: Department of Pediatrics, Division of Emergency Medicine, Emory-Children’s Center for Developmental Lung Biology,Emory University School of Medicine, Atlanta, GA, USA. claudiamorris@comcast.net
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Morris
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: John
authors.initials: J
authors.lastname: Wood
authors.forename: John B
authors.initials: JB
authors.lastname: Porter
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Klings
authors.forename: Felicia L
authors.initials: FL
authors.lastname: Trachtenberg
authors.forename: Nancy
authors.initials: N
authors.lastname: Sweeters
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Olivieri
authors.forename: Janet L
authors.initials: JL
authors.lastname: Kwiatkowski
authors.forename: Lisa
authors.initials: L
authors.lastname: Virzi
authors.forename: Sylvia T
authors.initials: ST
authors.lastname: Singer
authors.forename: Ali
authors.initials: A
authors.lastname: Taher
authors.forename: Ellis J
authors.initials: EJ
authors.lastname: Neufeld
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Thompson
authors.forename: Vandana
authors.initials: V
authors.lastname: Sachdev
authors.forename: Sandra
authors.initials: S
authors.lastname: Larkin
authors.forename: Jung H
authors.initials: JH
authors.lastname: Suh
authors.forename: Frans A
authors.initials: FA
authors.lastname: Kuypers
authors.forename: Elliott P
authors.initials: EP
authors.lastname: Vichinsky
mesh_terms: D000328:Adult; D015150:Echocardiography, Doppler / Q000379:methods; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D012307:Risk Factors; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D013789:Thalassemia / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000453:epidemiology; D014665:Vasodilator Agents / Q000627:therapeutic use*
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate