Sildenafil therapy in thalassemia patients with Doppler-defined risk of pulmonary hypertension
Claudia R. Morris,
Hae-Young Kim,
John Wood,
John B. Porter,
Elizabeth S. Klings,
Felicia L. Trachtenberg,
Nancy Sweeters,
Nancy F. Olivieri,
Janet L. Kwiatkowski,
Lisa Virzi,
Sylvia T. Singer,
Ali Taher,
Ellis J. Neufeld,
Alexis A. Thompson,
Vandana Sachdev,
Sandra Larkin,
Jung H. Suh,
Frans A. Kuypers,
Elliott P. Vichinsky
Affiliations
Claudia R. Morris
Department of Pediatrics, Division of Emergency Medicine, Emory-Children’s Center for Developmental Lung Biology, Emory University School of Medicine, Atlanta, GA, USA
Hae-Young Kim
New England Research Institutes Watertown, MA, USA
John Wood
Children’s Hospital of Los Angeles, Los Angeles, CA, USA
John B. Porter
University College London, London, UK
Elizabeth S. Klings
The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
Felicia L. Trachtenberg
New England Research Institutes Watertown, MA, USA
Nancy Sweeters
Hematology/Oncology, Children’s Hospital & Research Center Oakland, Oakland, CA, USA
Nancy F. Olivieri
Toronto General Hospital, Toronto, ON, Canada
Janet L. Kwiatkowski
Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Lisa Virzi
New England Research Institutes Watertown, MA, USA
Sylvia T. Singer
Hematology/Oncology, Children’s Hospital & Research Center Oakland, Oakland, CA, USA
Ali Taher
American University of Beirut, Beirut, Lebanon
Ellis J. Neufeld
Children’s Hospital Boston, Boston, MA, USA
Alexis A. Thompson
Hematology, Oncology & Stem Cell Transplant, Children’s Memorial Hospital, Chicago, IL, USA
Vandana Sachdev
Cardiovascular and Pulmonary Medicine Branch, National Heart, Lung and Blood Institute, Bethesda, MD, USA
Sandra Larkin
Children’s Hospital Oakland Research Institute, Oakland, CA, USA.
Jung H. Suh
Children’s Hospital Oakland Research Institute, Oakland, CA, USA.
Frans A. Kuypers
Children’s Hospital Oakland Research Institute, Oakland, CA, USA.
Elliott P. Vichinsky
Hematology/Oncology, Children’s Hospital & Research Center Oakland, Oakland, CA, USA
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)
