Sildenafil Therapy In Thalassemia Patients With Doppler-Defined Risk Of Pulmonary Hypertension

• Type of Material: Article
• Authors: Claudia R. Morris, Emory University; Hae-Young Kim, New England Research Institutes; John Wood, Children’s Hospital of Los Angeles; John B. Porter, University College London; Elizabeth S. Klings, Boston University School of Medicine; Felicia L. Trachtenberg, New England Research Institutes; Nancy Sweeters, Children’s Hospital & Research Center Oakland; Nancy F. Olivieri, Toronto General Hospital; Janet L. Kwiatkowski, Children’s Hospital of Philadelphia; Lisa Virzi, New England Research Institutes; Sylvia T. Singer, Children’s Hospital & Research Center Oakland; Ali Taher, American University of Beirut; Ellis J. Neufeld, Children’s Hospital Boston; Alexis A. Thompson, Children’s Memorial Hospital, Chicago; Vandana Sachdev, Lung and Blood Institute; Sandra Larkin, Children’s Hospital Oakland Research Institute; Jung H. Suh, Children’s Hospital Oakland Research Institute; Frans A. Kuypers, Children’s Hospital Oakland Research Institute; Elliott P. Vichinsky, Children’s Hospital & Research Center Oakland
• Language: English
• Date: 2013-09
• Publisher: Ferrata Storti Foundation
• Publication Version: Final Published Version
• Copyright Statement: © Ferrata Storti Foundation
• Final Published Version (URL): http://www.haematologica.org/content/98/9/1359
• Title of Journal or Parent Work: Haematologica
• ISSN: 0390-6078
• Volume: 98
• Issue: 9
• Start Page: 1359
• End Page: 1367
• Grant/Funding Information: Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NHLBI.; This work was supported by the NIH-NHLBI cooperative agreement U01 HL065238NIH grant.; This research was also supported in part by FDA grant 1R01FD003531-03 (to CRM), the Intramural Research Program of the NIH, NHLBI and by the following NIH-NHLBI cooperative agreements: U01-HL65232 and NIH/NCRR UL1-RR-024134 to the Children’s Hospital of Philadelphia, U01-HL72291 and by Harvard Catalyst CTSC U-01RR025758 to the Children’s Hospital, Boston, U01-HL65233 to the University Health Network Toronto General Hospital, UL1RR024131-01 to the Children’s Hospital & Research Center Oakland, U01-HL65244 and CTSC UL1-RR024996 to Weill Medical College of Cornell University, and U01-HL65238 to New England Research Institutes.
• Research Categories: Health Sciences, Human Development; Health Sciences, Oncology

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.