Sildenafil in HFpEF (Heart Failure With Preserved Ejection Fraction) and PH

NCT ID: NCT01726049

Last Updated: 2016-03-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-10-31
• Study Completion Date: 2014-12-31

Brief Summary

Aim of the study is to investigate whether Sildenafil treatment results in a reduction of pulmonary artery pressure without decrease of cardiac output (CO) and in improvement of exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) with pulmonary hypertension ( PH).

Detailed Description

Rationale: Treatment of diastolic left heart failure is a challenging task. Compared to systolic left heart failure the level of evidence for known medical treatment regiments is low. Sildenafil, a phosphodiesterase 5 (PDE 5) inhibitor and effective therapy for pulmonary arterial hypertension acts as a selective pulmonary vasodilator by inhibiting the impaired nitric oxide (NO) pathway. Reducing the pulmonary vascular resistance would be the primary target by treatment of diastolic left heart failure with PH. But clinical and hemodynamical studies to evaluate the role of Sildenafil in diastolic heart failure, also called heart failure with preserved ejection fraction (HFpEF) with secondary pulmonary hypertension are lacking. Our hypothesis is that Sildenafil decreases pulmonary artery pressure in patients with HFpEF and pulmonary hypertension.

Objective: To investigate whether Sildenafil treatment results in a hemodynamic improvement and in an improvement of exercise capacity in these patients.

Study design: single-center, prospective, randomized, placebo controlled study. Study population: 52 patients with HFpEF and PH Intervention : One group receives three times daily 20 mg Sildenafil for 2 weeks followed by three times daily 60 mg Sildenafil for 10 weeks. The other group receives three times daily 20 mg of Placebo, followed by 3 times daily 60 mg placebo.

Main study parameters/endpoints:

Primary objectives

1. To investigate whether Sildenafil treatment results in a reduction of pulmonary artery pressure (PAP) in HFpEF patients with PH (investigated invasively by right heart catheterization) .

Secondary objectives

1. To investigate whether Sildenafil treatment results in an reduction of wedge pressure in HFpEF patients.

2. To investigate whether Sildenafil treatment results in an improvenemt of cardiac output (CO) in HFpEF patients.

3. To investigate whether Sildenafil treatment results in improvement of exercise capacity in these patients ( defined as change in VO2max)

Conditions

Heart Failure, Diastolic; Pulmonary Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Sildenafil

Sildenafil orally 3 times 20mg for 2 weeks , followed by 3 times 60 mg for 10 weeks

Group Type: ACTIVE_COMPARATOR

Sildenafil

Intervention Type: DRUG

Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks

Placebo

placebo orally 3 times 20mg tablets, followed by 3 times 60 mg for 10 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks

Interventions

Sildenafil

Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks

Intervention Type: DRUG

Placebo

Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• >18 years
• Written inform consent
• PH secondary to diastolic left heart failure defined as
• PAP mean >25 mmHg
• Wedge mean >15 mmHg
• Normal systolic left ventricular (LV) function on echo/nuclear imaging (left ventricular ejection fraction (LVEF) > or =45%)
• New York Heart Association class (NYHA) II-IV despite heart failure therapy

Exclusion Criteria

• Severe noncardiac limitation to exercise (as severe chronic obstructive pulmonary disease)
• Other cause of PH besides diastolic heart failure
• Coronary ischemia or recent myocardial infarction (<6 months)
• Hypotension ( <90/50 mmHg)
• Ongoing nitrate therapy
• Ongoing therapy with citochrome P450 3A4 ( CYP3A4) inhibitors (ketoconazole, erythromycin, cimetidine, clarithromycin, itraconazole, voriconazole and protease inhibitors) or CYP3A4 inductors(carbamacepine, phenytoin, phenobarbital, rifampicin, Sint Janskruid ). Furthermore patients will be informed not to drink grapefruit juice while on study medication because of the known impact of grape fruit on pharmacokinetics of Sildenafil.
• Ongoing therapy with alpha -inhibitors
• Significant mitral or aortic valve dysfunction
• Severe liver dysfunction
• Pregnancy
• Unable to read and comprehend Dutch language

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

University Medical Center Groningen

OTHER

Sponsor Role: lead

Responsible Party

E.S. Hoendermis

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

E S Hoendermis, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University Medical Center Groningen

Locations

University Medical Center Groningen

Groningen, , Netherlands

Countries

Netherlands

References

Liu LC, Hummel YM, van der Meer P, Berger RM, Damman K, van Veldhuisen DJ, Voors AA, Hoendermis ES. Effects of sildenafil on cardiac structure and function, cardiopulmonary exercise testing and health-related quality of life measures in heart failure patients with preserved ejection fraction and pulmonary hypertension. Eur J Heart Fail. 2017 Jan;19(1):116-125. doi: 10.1002/ejhf.662. Epub 2016 Nov 21.

Reference Type: DERIVED

PMID: 27873388 (View on PubMed)

Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, van Veldhuisen DJ, Voors AA. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J. 2015 Oct 7;36(38):2565-73. doi: 10.1093/eurheartj/ehv336. Epub 2015 Jul 17.

Reference Type: DERIVED

PMID: 26188003 (View on PubMed)

Other Identifiers

Sildenafil Groningen Study

Identifier Type: -

Identifier Source: org_study_id