Clinical trial NCT00862043: Sildenafil for Secondary Pulmonary Hypertension Due to Valvular Disease
Official title: Sildenafil for Improving Outcomes After Valvular Correction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Hypertension
Valvular Heart Disease
Keywords: Secondary Pulmonary Hypertension
Valvular Heart Disease
Phosphodiesterase-Inhibitors
Sildenafil
Outcomes Research
Lead sponsor: Hospital General Universitario Gregorio Marañon
Sponsor class: OTHER
Collaborators: name: Instituto de Salud Carlos III
name: Fundación de Investigación en Red en Enfermedades Cardiovasculares
First posted: 2009-03-16
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the clinical efficacy of the mid-term treatment with sildenafil in patients with persistent moderate or severe pulmonary hypertension (PH) after a heart valve intervention.

Detailed description: Phase IV, prospective, multicenter, randomized, double-blind, placebo-controlled, academically funded clinical trial, with 6 months follow-up. A total of 354 patients will be recruited. Inclusion criteria are: 1) successful surgical or percutaneous repair of a cardiac valve at least one year before screening and 2) persistent moderate or severe PH, and 3) absence of any residual significant valvular lesion. Patients will be randomized 1:1 to received sildenafil 40 mg t.i.d. or placebo. The primary endpoint is a clinical composite score combining: all-cause mortality, hospital admission for heart failure, World Health Organization (WHO) functional class, and the patient global assessment score. Additional clinical and mechanistic secondary end-points are defined.

Eligibility criteria: Inclusion Criteria:

* Age at the date of selection ≥ 18 years
* Mean pulmonary pressure ≥ 30 mmHg, measured by a Swan-Ganz catheter placed in the pulmonary artery
* Heart valve intervention: surgical or percutaneous replacement, repair or dilatation performed at least one year before inclusion
* Stable clinical condition for at least one month, without hospital admissions for heart failure, and on appropriate and stable doses of conventional cardiovascular medications

Exclusion Criteria:

* Requiring or likely to require the following medications: organic nitrates, alpha-blocker therapy, potent cytochrome P450 3A4 inhibitors (erythromycin, ketoconazole, cimetidine, HIV protease inhibitors such ritonavir and saquinavir) Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months.
* Patients with resting hypotension, with systolic blood pressure \< 90 mmHg
* Patients with retinitis pigmentosa
* Anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease) or patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia)
* Severe renal impairment with creatinine clearance \< 30 ml/min
* Significant hepatic dysfunction
* Prosthesis or valvular dysfunction with hemodynamic repercussion.
* Pregnant or breast-feeding women
* Patients unlikely to cooperate in the study or with inability or unwillingness to give informed consent
* Life expectancy less than 2 years due to non-cardiac disease

Primary outcomes:
measure: Combined Outcome End-Point: all-cause mortality or hospital admission for heart failure, worsening of World Health Organization (WHO) functional class, or of the patient global assessment score
timeFrame: Six months
Secondary outcomes:
measure: Change from baseline to the sixth month in the in the six-minute walk test
timeFrame: 6 Months
measure: Change on WHO functional capacity
timeFrame: 3 & 6 Months
measure: All cause mortality
timeFrame: 6 Months
measure: Cardiovascular mortality
timeFrame: 6 months
measure: Number of hospital admissions caused by or related to heart failure in each patient
timeFrame: 6 months
measure: Rate of progression/regression of tricuspid regurgitation by Doppler-echocardiography
timeFrame: 3 & 6 Months
measure: Change on right ventricular (RV) dimensions and function assessed by Doppler echocardiography
timeFrame: 3 & 6 months
measure: Change on RV volumes and function assessed by cardiac magnetic resonance
timeFrame: 6 Months
measure: Change on the right catheterization hemodynamic parameters
timeFrame: 6 Months
measure: Identify patients who are more likely to respond to therapy by pharmacogenetics analysis
timeFrame: 6 Months
Other outcomes:
Locations:
city: Santiago de Compostela
country: Spain
facility: Hospital Universitario Santiago de Compostela
state: A Coruña
city: Vitoria
country: Spain
facility: Hospital Universitario Alava
state: Alava
city: Badalona
country: Spain
facility: Hospital German Trias y Pujol
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu y San Pau
state: Barcelon
city: Alcorcón
country: Spain
facility: Hospital Fundación de Alcorcón
state: Madrid
city: Majadahonda
country: Spain
facility: Hospital Puerta de Hierro
state: Madrid
city: Galdakao
country: Spain
facility: Hospital de Galdakao
state: Vizcaya
city: Córdoba
country: Spain
facility: Hospital Reina Sofía
city: Granada
country: Spain
facility: Hospital Virgen de las Nieves
city: La Coruna
country: Spain
facility: Hospital Juan Canalejo
city: Leon
country: Spain
facility: Hospital de Leon
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Infanta Leonor
city: Malaga
country: Spain
facility: Hospital Virgen de la Victoria
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Tenerife
country: Spain
facility: Hospital Universitario de Canarias
city: Valladolid
country: Spain
facility: Hospital Clínico de Valladolid
Study officials:
affiliation: Hospital General Universitario Gregorio Maranon
name: Javier Bermejo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bermejo J, Gonzalez-Mansilla A, Mombiela T, Fernandez AI, Martinez-Legazpi P, Yotti R, Garcia-Orta R, Sanchez-Fernandez PL, Castano M, Segovia-Cubero J, Escribano-Subias P, Alberto San Roman J, Borras X, Alonso-Gomez A, Botas J, Crespo-Leiro MG, Velasco S, Bayes-Genis A, Lopez A, Munoz-Aguilera R, Jimenez-Navarro M, Gonzalez-Juanatey JR, Evangelista A, Elizaga J, Martin-Moreiras J, Gonzalez-Santos JM, Moreno-Escobar E, Fernandez-Aviles F; SIOVAC ("Sildenafil for Improving Outcomes after VAlvular Correction") Investigators. Persistent Pulmonary Hypertension in Corrected Valvular Heart Disease: Hemodynamic Insights and Long-Term Survival. J Am Heart Assoc. 2021 Jan 19;10(2):e019949. doi: 10.1161/JAHA.120.019949. Epub 2021 Jan 5.
citation: Bermejo J, Yotti R, Garcia-Orta R, Sanchez-Fernandez PL, Castano M, Segovia-Cubero J, Escribano-Subias P, San Roman JA, Borras X, Alonso-Gomez A, Botas J, Crespo-Leiro MG, Velasco S, Bayes-Genis A, Lopez A, Munoz-Aguilera R, de Teresa E, Gonzalez-Juanatey JR, Evangelista A, Mombiela T, Gonzalez-Mansilla A, Elizaga J, Martin-Moreiras J, Gonzalez-Santos JM, Moreno-Escobar E, Fernandez-Aviles F; Sildenafil for Improving Outcomes after VAlvular Correction (SIOVAC) investigators. Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: a multicenter, double-blind, randomized clinical trial. Eur Heart J. 2018 Apr 14;39(15):1255-1264. doi: 10.1093/eurheartj/ehx700.