Phosphodiesterase-5 (PDE5) Inhibition and Pulmonary Hypertension in Diastolic Heart Failure

Pulmonary Hypertension Clinical Trial

Official title:

Pulmonary Hypertension Secondary to Heart Failure With Preserved Systolic Function: a Target of Phosphodiesterase - 5 Inhibition in a 1- Year Duration Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01156636
• Other study ID #: 444-10
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: July 2, 2010
• Last updated: June 14, 2012
• Start date: January 2006
• Est. completion date: December 2009

Study information

• Verified date: June 2009
• Source: University of Milan
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

Prevalence of heart failure (HF) with left ventricular (LV) diastolic dysfunction and preserved ejection fraction (EF) (HFpEF) is increasing. Prognosis worsens with development of pulmonary vasoconstriction and hypertension (PH) and right ventricular (RV) failure. The investigators aimed at modulating pulmonary vascular tone and RV burden in HFpEF due to high blood pressure (HBP), by using the phosphodiesterase-5 (PDE5) inhibitor sildenafil.

Description:

Heart failure (HF) with preserved left ventricular (LV) ejection fraction (EF) (HFpEF) is a public health problem and a major topic in clinical cardiology. Its prevalence, in fact, is increasing and the outcome seems to be similar to that of HF with LV systolic dysfunction (LVSD). Pulmonary hypertension (PH) in HFpEF is highly prevalent and often severe and, like in LVSD (3), is a predictor of morbidity and mortality (4). Because of the thin wall and the distensibility, the right ventricle (RV) is much more vulnerable by an excessive afterload than by preload. The pulmonary circulation is a central determinant of RV afterload, and an increase in impendance to RV ejection, like occurring in LV dysfunction, can easily result in RV failure, tricuspid regurgitation, central venous pressure (CVP) rise. Development of RV failure is unanimously viewed as a predictor of poor prognosis but the underlying mechanisms have not been extensively investigated.

Because of the prevalence and clinical significance of PH secondary to HF, attenuation of the pulmonary vascular tone and of the RV hemodynamic burden has been suggested as a goal to be achieved with HF therapy. Attempts with endothelin receptor antagonists, or prostacyclin analogues, were basically unsuccessful. Experimental models and human studies, showing that in HF nitric oxide (NO) - dependent pulmonary vasodilatation is impaired and pulmonary vascular resistance elevation is at least in part due to pulmonary endothelial dysfunction, have suggested therapeutic strategies with agents that increase NO activity, like nitrates or phosphodiesterase - 5 (PDE5) inhibitors (12-14). The latter agents offer the double advantage of selectively dilating the pulmonary vessels and not producing tachyphylaxis.

In this 1-year duration study, the primary end-point was to probe whether pulmonary hemodynamics and RV performance in HFpEF with PH may be targets of PDE5 inhibition with sildenafil.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: December 2009
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• LVEF >50%

• sinus rhythm and stable clinical condition defined as no changes in therapeutic regimen, or hospitalization in the 6 months preceding recruitment.

• pulmonary artery systolic pressure > 40 mm Hg,

Exclusion Criteria:

• Patients receiving nitrates

• A history of pulmonary disease

• Alternative causes of PH other than cardiac-related

• Renal failure (creatinine > 2mg/dL)

• Anemia

• Pericardial disease

• Cardiac amyloidosis

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diastolic Heart Failure
• Heart Failure
• Heart Failure, Diastolic
• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Drug:
• Sildenafil
50 mg 3 times/day for 1 year
• Placebo

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of Milan

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pulmonary hemodynamics		1 year	Yes