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

• ClinicalTrials.gov Identifier: NCT01156636
• Recruitment Status: Completed
• First Posted: July 5, 2010
• Last Update Posted: June 15, 2012
• Sponsor: University of Milan
• Information provided by: University of Milan

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Pulmonary Hypertension; Diastolic Heart Failure	Drug: Sildenafil; Drug: Placebo	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Pulmonary Hypertension Secondary to Heart Failure With Preserved Systolic Function: a Target of Phosphodiesterase - 5 Inhibition in a 1- Year Duration Study
• Study Start Date: January 2006
• Actual Primary Completion Date: September 2009
• Actual Study Completion Date: December 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Pulmonary hemodynamics [ Time Frame: 1 year ]

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

No Contacts or Locations Provided

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University of Milano, Cardiology (Marco Guazzi PI), University of Milano
• ClinicalTrials.gov Identifier: NCT01156636
• Other Study ID Numbers: 444-10
• First Posted: July 5, 2010
• Last Update Posted: June 15, 2012
• Last Verified: June 2009

Keywords provided by University of Milan:

Diastolic Heart Failure; Pulmonary Hypertension

Additional relevant MeSH terms:

Hypertension, Pulmonary; Hypertension; Heart Failure; Heart Failure, Diastolic; Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Lung Diseases; Respiratory Tract Diseases; Sildenafil Citrate; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Urological Agents