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

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension; Diastolic Heart Failure
• Intervention / Treatment: Drug: Placebo; Drug: Sildenafil

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo
Active Comparator: Sildenafil	Drug: Sildenafil; 50 mg 3 times/day for 1 year

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pulmonary hemodynamics	1 year

Collaborators and Investigators

• Sponsor: University of Milan

Publications and helpful links

General Publications

• Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation. 2011 Jul 12;124(2):164-74. doi: 10.1161/CIRCULATIONAHA.110.983866. Epub 2011 Jun 27.

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): December 1, 2009

Study Registration Dates

• First Submitted: July 2, 2010
• First Submitted That Met QC Criteria: July 2, 2010
• First Posted (Estimate): July 5, 2010

Study Record Updates

• Last Update Posted (Estimate): June 15, 2012
• Last Update Submitted That Met QC Criteria: June 14, 2012
• Last Verified: June 1, 2009

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Diastolic Heart Failure
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Hypertension; Hypertension, Pulmonary; Heart Failure, Diastolic; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: 444-10