Sildenafil for Secondary Pulmonary Hypertension Due to Valvular Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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Sildenafil for Improving Outcomes After Valvular Correction

Conditions
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Pulmonary Hypertension, Valvular Heart Disease

Intervention / Treatment
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* Drug: Sildenafil Citrate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil Citrate<br>Sildenafil Citrate 40 mg t.i.d. oral | Drug: Sildenafil Citrate<br>* 40 mg t.i.d.<br>|
| Placebo Comparator: Placebo<br>Sildenafil-matched oral placebo 40 mg t.i.d | Drug: Placebo<br>* Placebo t.i.d.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | Six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to the sixth month in the in the six-minute walk test |  | 6 Months | 
| Change on WHO functional capacity |  | 3 & 6 Months | 
| All cause mortality |  | 6 Months | 
| Cardiovascular mortality |  | 6 months | 
| Number of hospital admissions caused by or related to heart failure in each patient |  | 6 months | 
| Rate of progression/regression of tricuspid regurgitation by Doppler-echocardiography |  | 3 & 6 Months | 
| Change on right ventricular (RV) dimensions and function assessed by Doppler echocardiography |  | 3 & 6 months | 
| Change on RV volumes and function assessed by cardiac magnetic resonance |  | 6 Months | 
| Change on the right catheterization hemodynamic parameters |  | 6 Months | 
| Identify patients who are more likely to respond to therapy by pharmacogenetics analysis |  | 6 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Secondary Pulmonary Hypertension, Valvular Heart Disease, Phosphodiesterase-Inhibitors, Sildenafil, Outcomes Research