A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension

Circulation

Volumn 125, Issue 2, 2012, Pages 324-334

  Barst, Robyn J ^a   Ivy, D Dunbar ^b   Gaitan, Guillermo ^c   Szatmari, Andras ^d   Rudzinski, Andrzej ^e   Garcia, Alberto E ^f   Sastry, B K S ^g   Pulido, Tomas ^h   Layton, Gary R ⁱ   Serdarevic Pehar, Marjana ⁱ   Wessel, David L ^j  

^a Och Spine at New York Presbyterian Hospitals   (United States)

^b Children's Hospital Colorado   (United States)

^c UNICAR   (Guatemala)

^d Hungarian Institute of Cardiology   (Hungary)

^e JAGIELLONIAN UNIVERSITY   (Poland)

^f FUNDACIÓN CARDIOINFANTIL INSTITUTO DE CARDIOLOGÍA   (Colombia)

^g CARE HOSPITAL   (India)

^h INSTITUTO NACIONAL DE CARDIOLOGÍA IGNACIO CHÁVEZ   (Mexico)

ⁱ PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

^j CHILDREN'S NATIONAL MEDICAL CENTER   (United States)

more..

Author keywords

cardiopulmonary exercise; clinical trials; pediatrics; pulmonary arterial hypertension; sildenafil

Indexed keywords

PLACEBO; SILDENAFIL;

ABDOMINAL PAIN; ADOLESCENT; ADVERSE OUTCOME; ARTICLE; BRONCHITIS; CHILD; CONTROLLED STUDY; COUGHING; DIARRHEA; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG MEGADOSE; DRUG SAFETY; EPISTAXIS; EXERCISE TEST; FEMALE; FEVER; HEADACHE; HUMAN; LOW DRUG DOSE; LUNG HEMODYNAMICS; MAJOR CLINICAL STUDY; MALE; MORTALITY; NAUSEA; OXYGEN CONSUMPTION; PENIS ERECTION; PHARYNGITIS; PRESCHOOL CHILD; PRIORITY JOURNAL; PULMONARY HYPERTENSION; RANDOMIZED CONTROLLED TRIAL; RHINOPHARYNGITIS; RHINORRHEA; SCHOOL CHILD; SIDE EFFECT; TREATMENT OUTCOME; UPPER RESPIRATORY TRACT INFECTION; VOMITING;

ADMINISTRATION, ORAL; ADOLESCENT; CHILD; CHILD, PRESCHOOL; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; EXERCISE TEST; HEMODYNAMICS; HUMANS; HYPERTENSION, PULMONARY; INFANT; OXYGEN CONSUMPTION; PIPERAZINES; PURINES; SULFONES;

EID: 84856106514     PISSN: 00097322     EISSN: 15244539     Source Type: Journal    
DOI: 10.1161/CIRCULATIONAHA.110.016667     Document Type: Article

References (43)

1. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:13S-24S. (Pubitemid 38759713)
2. Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA III, Soubrier F, Trembath RC, Chung WK. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S32-S42.
3. Humbert M, Trembath RC. Genetics of pulmonary hypertension: From bench to bedside. Eur Respir J. 2002;20:741-749.
4. Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial hypertension: A national cohort study. Heart. 2010;96:1401-1406.
5. van Loon RL, Roofthooft MT, van Osch-Gevers M, Delhaas T, Strengers JL, Blom NA, Backx A, Berger RM. Clinical characterization of pediatric pulmonary hypertension: Complex presentation and diagnosis. J Pediatr. 2009;155:176 -182, e171.
6. van Loon RL, Hoendermis ES, Duffels MG, Vonk-Noordegraaf A, Mulder BJ, Hillege HL, Berger RM. Long-term effect of bosentan in adults versus children with pulmonary arterial hypertension associated with systemic-to-pulmonary shunt: Does the beneficial effect persist? Am Heart J. 2007;154:776-782. (Pubitemid 47429578)
7. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart. 2000;84:E4.
8. Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: Twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation. 2005;111:3274-3280. (Pubitemid 40875000)
9. Kothari SS, Duggal B. Chronic oral sildenafil therapy in severe pulmonary artery hypertension. Indian Heart J. 2002;54:404-409. (Pubitemid 35447129)
10. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med. 2000;343:1342.
11. Sastry BK, Narasimhan C, Reddy NK, Anand B, Prakash GS, Raju PR, Kumar DN. A study of clinical efficacy of sildenafil in patients with primary pulmonary hypertension. Indian Heart J. 2002;54:410-414. (Pubitemid 35447130)
12. Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: A randomized, placebocontrolled, double-blind, crossover study. J Am Coll Cardiol. 2004;43: 1149-1153. (Pubitemid 38452588)
13. Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: From angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov. 2006;5:689-702. (Pubitemid 44151606)
14. Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM. Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol. 1998;159:2164-2171. (Pubitemid 29190800)
15. Anderson BJ, Meakin GH. Scaling for size: Some implications for paediatric anaesthesia dosing. Paediatr Anaesth. 2002;12:205-219. (Pubitemid 34264439)
16. Holford NH. A size standard for pharmacokinetics. Clin Pharmacokinet. 1996;30:329-332. (Pubitemid 26177179)
17. West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science. 1997;276:122-126. (Pubitemid 27161259)
18. LaFarge CG, Miettinen OS. The estimation of oxygen consumption. Cardiovasc Res. 1970;4:23-30.
19. Kieser M, Friede T. Simple procedures for blinded sample size adjustment that do not affect the type I error rate. Stat Med. 2003;22: 3571-3581. (Pubitemid 37483535)
20. Lammers AE, Hislop AA, Flynn Y, Haworth SG. The 6-minute walk test: Normal values for children of 4-11 years of age. Arch Dis Child. 2008; 93:464-468. (Pubitemid 352025761)
21. Smith G, Reyes JT, Russell JL, Humpl T. Safety of maximal cardiopulmonary exercise testing in pediatric patients with pulmonary hypertension. Chest. 2009;135:1209-1214.
22. Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161:487-492. (Pubitemid 30129457)
23. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S55-S66.
24. McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126: 78S-92S. (Pubitemid 38932344)
25. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary arterial hypertension: Insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164-172.
26. Ivy DD, Rosenzweig EB, Lemarie JC, Brand M, Rosenberg D, Barst RJ. Long-term outcomes in children with pulmonary arterial hypertension treated with bosentan in real-world clinical settings. Am J Cardiol. 2010; 106:1332-1338.
27. Hayashi N, Harnisch L. Population PK of sildenafil and PK/PD assessment of exercise tolerability in children with pulmonary arterial hypertension (PAH). Paper presented at: European Respiratory Society Annual Congress; September 12-16, 2009; Vienna, Austria.
28. Watt S, Hayashi N, Harnish L, Gao X. Population pharmacokinetics (PK) of sildenafil in paediatric and adult patients with pulmonary arterial hypertension (PAH). Paper presented at: European Society of Cardiology Annual Meeting; August 28-September 1, 2010; Stockholm, Sweden.
29. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148-2157. (Pubitemid 41653106)
30. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC; Multisite Stimulation in Cardiomyopathies Study I. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344: 873-880. (Pubitemid 32224395)
31. Auricchio A, Stellbrink C, Butter C, Sack S, Vogt J, Misier AR, Bocker D, Block M, Kirkels JH; on behalf of the Pacing Therapies in Congestive Heart Failure II Study Group; Kramer A, Huvelle E; on behalf of the Guidant Heart Failure Research Group. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol. 2003;42:2109-2116. (Pubitemid 37549894)
32. Brar S, Jadhav P, Stockbridge N, Gobburu J, Madabushi R. Hemodynamic determinants of clinical endpoints in pulmonary arterial hypertension trials. Paper presented at: American Conference on Pharmacometrics; October4 -7, 2009; Mashantucket, CT.
33. Beghetti M, Haworth SG, Bonnet D, Barst RJ, Acar P, Fraisse A, Ivy DD, Jais X, Schulze-Neick I, Galie N, Morganti A, Dingemanse J, Kusic-Pajic A, Berger RM. Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: The FUTURE-1 study. Br J Clin Pharmacol. 2009;68:948-955.
34. Fasnacht MS, Tolsa JF, Beghetti M. The Swiss registry for pulmonary arterial hypertension: The paediatric experience. Swiss Med Wkly. 2007; 137:510-513. (Pubitemid 47441802)
35. Fraisse A, Jais X, Schleich JM, di Filippo S, Maragnes P, Beghetti M, Gressin V, Voisin M, Dauphin C, Clerson P, Godart F, Bonnet D. Characteristics and prospective 2-year follow-up of children with pulmonary arterial hypertension in France. Arch Cardiovasc Dis. 2010;103: 66-74.
36. Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, Abman SH, Morganti A, Nguyen N, Barst RJ. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:697-704. (Pubitemid 41132700)
37. Haworth SG, Beghetti M. Assessment of endpoints in the pediatric population: Congenital heart disease and idiopathic pulmonary arterial hypertension. Curr Opin Pulm Med. 2010;16(suppl 1):S35-S41.
38. Barst RJ. Sitaxsentan: A selective endothelin-A receptor antagonist, for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2007;8:95-109. (Pubitemid 46070832)
39. Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, Frost AE, Zwicke D, Naeije R, Shapiro S, Olschewski H, Rubin LJ. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:529-535. (Pubitemid 41040298)
40. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, Sitbon O, Torbicki A, Delcroix M, Naeije R, Hoeper M, Chaouat A, Morand S, Besse B, Simonneau G. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: A randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496-1502. (Pubitemid 34439066)
41. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197-1208.
42. Houde C, Bohn DJ, Freedom RM, Rabinovitch M. Profile of paediatric patients with pulmonary hypertension judged by responsiveness to vasodilators. Br Heart J. 1993;70:461-468. (Pubitemid 23342808)
43. Simpson CM, Penny DJ, Cochrane AD, Davis AM, Rose ML, Wilson SE, Weintraub RG. Preliminary experience with bosentan as initial therapy in childhood idiopathic pulmonary arterial hypertension. J Heart Lung Transplant. 2006;25:469-473.