Sildenafil in US Heart Failure Patients (SilHF-US)

Study Overview
=================
Brief Summary
-----------------
This protocol describes a 2-arm randomized controlled pilot study assessing the tolerance, safety and efficacy of sildenafil compared to control. The hypothesis is that sildenafil will be well tolerated and efficacious in patients with chronic heart failure (NYHA class II and III) with evidence of systolic dysfunction (EF ≤40 %) and secondary pulmonary hypertension (SPAP >40mmHg). Patients that satisfy the inclusion criteria will be randomized to sildenafil (40mg x 3) or placebo therapy for 6 months in a 2:1 blinded fashion. The placebo group will be compared to the active therapy group and analyzed for differences in the main study end-points Patient Global Assessment and 6-Minute Walk Test. The study will also assess safety, tolerability, symptoms and quality of life.

Detailed Description
-----------------
It is estimated that 2-3 % of the adult population suffers from heart failure (HF) and the prevalence is increasing. The European Society of Cardiology (ESC) represents countries with a population > 1,1 billion, and it is estimated that approximately 30 million patients have HF in these 53 countries. Heart failure is particularly prevalent in the elderly population and represents a major burden for both patients and the health services. In United states (US) more than 5 million people, or almost 2% of population have HF (Go at al, 2013) Medicare data indicate that 12% to 27% of patients hospitalized for heart failure are readmitted within 30 days after their discharge, and all-cause mortality reaches 12% in the same period. (Jencks at al, 2009). Despite optimal non-pharmacological, pharmacological and device therapy, the morbidity among HF patients is high with symptoms such as dyspnoea and fatigue that reduce quality of life. Following diagnosis approximately 50% are dead after 4 years. Forty percent of patients admitted to hospital with HF are either dead or hospitalized within one year. During the last decade, PDE5-inhibitors have been evaluated as a potential treatment for heart failure (see scientific rationale and reference). However, these investigations have been small and there is still limited data. Trials assessing the acute effects of PDE5-inhibition in patients with symptomatic HF due to systolic dysfunction have been performed primarily with sildenafil. Due to the short half-life of sildenafil the drug is administered 3 times daily when studying its chronic effects. Previous studies have evaluated the 50 mg dose acutely and 50 mg 3 times daily during short-term chronic studies. Importantly, there is considerable off-label use of sildenafil in symptomatic heart failure patients in most European countries. Revatio is currently licensed for pulmonary hypertension group 1. The dosing scheme is 20mg x 3. However, we suggest targeting a higher dose to achieve optimal clinical benefit in patients with heart failure and moderate congestion. As mentioned above most of the clinical literature in patients with symptomatic heart failure has been done using the 50mg x 3 regimen. However, it is believed that in the proposed study using 40mg x 3 should be equally efficacious. There is already considerable experience using this dosage scheme in heart failure patients locally. The hemodynamic profile of PDE-5 inhibitors is favorable with reduction in filling pressures, both systemic and pulmonary, vascular resistance accompanied by improvement in symptoms and sub maximal and peak exercise performance. This pilot study will evaluate the use of the PDE5-inhibitor sildenafil in patients with heart failure, systolic dysfunction and documented secondary pulmonary hypertension.

Official Title
-----------------
Sildenafil in US Heart Failure Patients (SilHF-US)

Conditions
-----------------
Heart Failure, Pulmonary Hypertension

Intervention / Treatment
-----------------
* Drug: Sildenafil
* Drug: Placebo oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women 18 - 80 years of age. Outpatients with chronic HF. NYHA class II-III on optimal treatment in sinus rhythm or atrial fibrillation LVEF ≤ 40% measured during the past 12 months SPAP ≥ 40mmHg using echocardiography 6MWTD < 475 meters NT-pro BNP ≥ 400 pg/ml or BNP ≥100 pg/ml, measured during the past 12 months Receiving optimal therapy, including diuretic, ACE-inhibitor, ARB, beta-blocker and aldosterone antagonist. Doses of all medication should be unchanged during the last 30 days before inclusion. ICDs and CRTs (CRT-P, CRT-D) are permitted. Implantation should have been performed at > 3 months before inclusion to the trial. Exclusion Criteria: - Acute Coronary Syndrome, including myocardial infarction, or coronary angiography, with or without intervention, within the last 3 months Stroke within the last 3 months Planned coronary angiography or planned device-implantation Moderate to severe obstructive valve disease Documented episodes of sustained ventricular tachycardia Prior (past 30 days before the baseline visit) or ongoing use of oral nitrate therapy. Concomitant disease which interfere with assessment of dyspnea , severe COPD, asthma, restrictive lung disease, severe obesity Anemia (hemoglobin < 10g/dL) Uncontrolled hypertension ( SBP >160 mmHg and / or DBP > 90 mmHg) Symptomatic or orthostatic hypotension or systolic blood pressure < 90 mmHg Clinically important renal dysfunction (GFR < 40m ml/min) Women with child-bearing potential Prior (past 30 days before the baseline visit) or ongoing use of i) alpha-1 antagonist: doxazosin ii) CYP3A4 inhibitors: erytromycin, ritonavir, sakinovir, itrakonazole, ketokonazole iii) CYP3A4-inducers: rifampicin iv) Any calcium channel blockers V) Pulmonary vasodilators at the treatment dose level for Pulmonary hypertensionRetinitis pigmentosa, previous diagnosis of NAION (non-arteritic ischemic opticus-neuropathy), unexplained visual disturbance. Sickle cell anemia, multiple myeloma, leukemia or penile anatomic deformities (angulation, cavernosal fibrosis, Peyronie's disease) that increases the risk of priapism. Hepatic failure. Drug and alcohol abuse which precludes compliance with the protocol. Inability to understand or sign the written informed consent form of the study,

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sildenafil 40mgx3 daily<br>Sildenafil 40mgx3 daily for 6 months | Drug: Sildenafil<br>* PDE5 Inhibitor<br>|
| Placebo Comparator: Placebo tablet x3 daily<br>Placebo for Sildenafil 40mgx3 daily for 6 months | Drug: Placebo oral capsule<br>* Placebo for Sildenafil<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six minute walk test | Analysis of change from the baseline | Baseline, 8 weeks and 24 weeks | 
| Patient Global Assessment (PGA) | Analysis of change form the baseline | Baseline; 8 weeks and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1.Quality of Life (QoL) evaluation by EuroQol5D | Analysis of change from baseline | Baseline, 8 weeks and 24 weeks | 
| Kansas City Cardiomyopathy Questionnaire (KCCQ) | Analysis of change from baseline | Baseline, 8 weeks and 24 weeks | 
| New York Heart Association (NYHA) function class | Analysis of change from baseline | Baseline, 8 weeks and 24 weeks |