Clinical trial NCT01616381: Sildenafil Versus Placebo in Chronic Heart Failure
Official title: Sildenafil in Heart Failure (SilHF); An Investigator Initiated Multinational Randomized Controlled Clinical Trial.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Heart Failure
Pulmonary Hypertension
Lead sponsor: Helse Stavanger HF
Sponsor class: OTHER_GOV
Collaborators: name: Pfizer
First posted: 2012-06-11
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This protocol describes a 2-arm randomised 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 analysed 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. HF is present in over 10% of patients admitted to hospital and accounts for \~ 2% of national health expenses. Approximately 50% of these costs are related to hospitalisation.

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 rehospitalised 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 licenced 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 favourable with reduction in filling pressures, both systemic and pulmonary, vascular resistance accompanied by improvement in symptoms and submaximal 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.

Eligibility criteria: Inclusion Criteria:

1. Men and women
2. 18 - 80 years of age.
3. Outpatients with chronic HF. NYHA class II-III on optimal treatment in sinus rhythm or atrial fibrillation
4. LVEF \< 40% measured during the past 12 months
5. SPAP \> 40mmHg using echocardiography
6. 6MWTD \< 400 meters
7. NT-pro BNP \> 400 pg/ml or BNP \>100 pg/ml, measured during the past 12 months
8. 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.
9. ICDs and CRTs (CRT-P, CRT-D) are permitted. Implantation should have been performed at \> 3 months before inclusion to the trial.

Exclusion Criteria:

1. Acute Coronary Syndrome, including myocardial infarction, or coronary angiography, with or without intervention, within the last 3 months
2. Stroke within the last 3 months
3. Planned coronary angiography or planned device-implantation
4. Moderate to severe obstructive valve disease
5. Documented episodes of sustained ventricular tachycardia
6. Oral nitrate therapy or frequent use of sublingual nitrate
7. Concomitant disease which interfere with assessment of dyspnoea , severe COPD, asthma, restrictive lung disease, severe obesity
8. Anemia (hemoglobin \< 10g/dL)
9. Uncontrolled hypertension ( SBP \>160 mmHg and / or DBP \> 90 mmHg)
10. Symptomatic or orthostatic hypotension or systolic blood pressure \< 90 mmHg
11. Clinically important renal dysfunction (GFR \< 40m ml/min)
12. Women with child-bearing potential
13. Use of

    i) alpha-1 antagonist: doxazosin

    ii) CYP3A4 inhibitors: erytromycin, ritonavir, sakinovir, itraconazole, ketoconazole

    iii) CYP3A4-inducers: rifampicin

    iv) Any calcium channel blockers
14. Retinitis pigmentosa, previous diagnosis of NAION (non-arteritic ischemic optic-neuropathy), unexplained visual disturbance.
15. Sickle cell anemia, multiple myeloma, leukemia or penile anatomic deformities (angulation, cavernosal fibrosis, Peyronie's disease) that increases the risk of priapism.
16. Hepatic failure.
17. Drug and alcohol abuse which precludes compliance with the protocol.
18. Inability to understand or sign the written informed consent form of the study,

Primary outcomes:
measure: Patient Global Assessment
timeFrame: Baseline, 8 weeks, 24 weeks
measure: Six minute walk test
timeFrame: Baseline, 8 weeks, 24 weeks
Secondary outcomes:
measure: Quality of Life (QoL) evaluation by EuroQol5D
timeFrame: Baseline, 8 weeks and 24 weeks
measure: Kansas City Questionaire
timeFrame: Baseline, 8 weeks and 24 weeks
measure: New York Heart Association (NYHA) function class
timeFrame: Baseline, 8 weeks, 16 weeks and 24 weeks
Other outcomes:
Locations:
city: Haifa
country: Israel
facility: Lady Davis Carmel Medical CEnter
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
city: Milano
country: Italy
facility: San Donato Hospital
city: Stavanger
country: Norway
facility: Stavanger University Hospital
state: Rogaland
city: Hull
country: United Kingdom
facility: Castle Hill Hospital
city: Sheffield
country: United Kingdom
facility: Northern General Hospital
Study officials:
affiliation: Helse Stavanger HF
name: Kenneth Dickstein, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cooper TJ, Guazzi M, Al-Mohammad A, Amir O, Bengal T, Cleland JG, Dickstein K. Sildenafil in Heart failure (SilHF). An investigator-initiated multinational randomized controlled clinical trial: rationale and design. Eur J Heart Fail. 2013 Jan;15(1):119-22. doi: 10.1093/eurjhf/hfs152. Epub 2012 Oct 24.