Sildenafil for Secondary Pulmonary Hypertension Due to Valvular Disease

Sildenafil for Improving Outcomes After Valvular Correction

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.

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.

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