European Journal of Heart Failure (2013) 15, 119122

doi:10.1093/eurjhf/hfs152

Sildenafil in Heart Failure (SilHF). An

investigator-initiated multinational randomized
controlled clinical trial: rationale and design
Trond J. Cooper 1*, Marco Guazzi2, Abdallah Al-Mohammad 3, Offer Amir 4,
Tuvia Bengal 5, John G. Cleland 6, and Kenneth Dickstein 1
1
Stavanger University Hospital, 4011 Stavanger, Norway; 2San Donato Hospital, University of Milano, Italy; 3Sheffield Teaching Hospital, Sheffield, UK; 4Lady Davis Carmel Medical
Centre, Israel; 5Rabin Medical Center, Israel; and 6University of Hull, UK

Received 9 April 2012; revised 25 June 2012; accepted 31 August 2012; online publish-ahead-of-print 24 October 2012

Aims

Heart failure (HF) is a major clinical problem and, despite advances in both pharmacological and device therapy, the
mortality remains high and quality of life poor. Over the last decade there has been growing interest in using
phosphodiesterase-5 (PDE-5) inhibitors in HF associated with group 2 pulmonary hypertension (PH), with benefits
reported on pulmonary haemodynamic and functional status in single-centre trials
.....................................................................................................................................................................................
Methods
The Sildenafil in Heart Failure (SilHF) trial is a randomized, placebo-controlled multinational trial designed to assess
efficacy and tolerability of PDE-5 inhibition with sildenafil (target dose 40 mg three times per day) in 210 patients with
HF, New York Heart Association (NYHA) functional class II or III, and evidence of group 2 PH. The co-primary endpoints are patient global assessment and the 6 min walk test. Secondary endpoints include NYHA functional class and
the quality of life tools Euro QoL 5D and the Kansas City questionnaire. Patients will be followed up for 6 months.
.....................................................................................................................................................................................
Perspective
The authors hypothesize that PDE-5 inhibition can improve exercise capacity and symptoms with acceptable tolerability in patients with HF and group 2 PH

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Heart failure Pulmonary hypertension Sildenafil Symptoms Quality of life tools

Introduction
It is estimated that 23% of the adult population suffers from heart
failure (HF), and the condition is highly prevalent in the elderly. HF
is present in . 10% of the patients admitted to hospital and
accounts for 2% of national health expenditure. Approximately
50% of these costs are related to hospitalization.1
Despite optimal pharmacological and device therapy, the morbidity among HF patients is high, with symptoms such as dyspnoea
and exercise intolerance.1
During the last decade, inhibition of phosphodiesterase-5
(PDE-5), the cGMP breakdown isoenzyme, has attracted the interest of researchers as a potential treatment for HF2 7 based on the
rationale of targeting the nitric oxide pathway downstream. These
pilot investigations, although very promising, have been performed
in a small number of patients with possible selection bias. Trials
assessing the acute effects of PDE-5 inhibition in patients with

symptomatic HF due to systolic left ventricular (LV) dysfunction

have been performed mainly with sildenafil. Sildenafil has a short
half-life and should be administered three times daily when assessing its chronic effects.
Importantly, there is considerable off-label use of sildenafil with
anecdotal evidence in symptomatic HF patients in most European
countries.2

Evidence and potential indications for

phosphodiesterase-5 inhibition in heart
failure
The effects of sildenafil have been tested in both the acute and
chronic setting in both human and animal studies. Trials assessing
the acute effects have primarily focused on the pulmonary and systemic haemodynamics.

* Corresponding author. Tel: +47 94164191, Fax: +47 51519905, Email: trond.cooper@gmail.com
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.com.

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A recent animal study by Borgdoff and colleagues8 showed that
sildenafil was beneficial in the pressure-loaded right ventricle, with
improvements in right ventricular function, wall stress, and exercise tolerance. However, the same effects were not seen in the
volume-loaded right ventricle.
Guazzi and co-workers5 assessed chronic HF patients 60 min
after administration of 50 mg of sildenafil. It was found that
PDE-5 inhibition attenuated pulmonary hypertension (PH) due
to LV impairment by lowering pulmonary arteriolar resistance.
Further, it facilitated alveolar gas exchange, and improved overall
exercise performance, with a beneficial activity on VO2 kinetics
and ventilation efficacy. In addition, sildenafil was noted to
improve endothelial function by improving the brachial artery flowmediated dilatation (FMD). These effects were not observed in the
placebo group and have been similarly reproduced in other
trials.3,9
Interestingly, the reported modulatory activity on endothelial
function is not accompanied by any significant systemic hypotensive effect, in agreement with the concept that the drug exerts a
preferential selective haemodynamic effect on the pulmonary circulation due to the high PDE-5 expression in the lung
microvessels.10
In a placebo-controlled trial including 20 patients with chronic
HF with left ventricular ejection fraction (LVEF) ,35%, 50 mg of
sildenafil was noted to increase the cardiac performance significantly as a result of an LV unloading effect.11
A number of trials are now available testing the chronic effects
of sildenafil in chronic HF patients. In a study3 reporting the 6
months effects of sildenafil therapy (50 mg of sildenafil three
times daily), a significant improvement in FMD and quality of lofe
(QoL) was observed, along with a modulatory effect on muscle
ergoreflex overactivation, increased maximal oxygen uptake, and
decreased sensation of dyspnoea. Lewis and co-workers7 performed a placebo-controlled trial with 50 mg of sildenafil three
times daily for 3 months. They found a significant decrease in
resting and exercise pulmonary arterial resistance, improvement
in exercise cardiac output, improvement in 6 min walk test
(6MWT), and maximal oxygen uptake. The QoL score improved
and the number of hospitalizations was lower than in the
placebo group. Behling and co-workers12 conducted a 4 week
study in chronic HF outpatients with LVEF 28 + 6%, receiving
50 mg of sildenafil three times daily. Sildenafil was found to
improve functional capacity, ventilatory efficiency, oxygen uptake
kinetics, and PH. In all these studies, PDE-5 inhibition was well tolerated and no patients discontinued the therapy. A good tolerability has been confirmed in a recent trial of 1 year duration reporting
a clear improvement in LV diastolic dysfunction, cardiac geometry,
and clinical status in patients with stable systolic HF.6
A recent study by Guazzi and colleagues assessed the effect of
sildenafil on exercise oscillatory breathing (EOB) in patients with
chronic HF. EOB is a complex pathological ventilation pattern
during exercise and is prevalent in the HF population. It is associated with a poor prognosis. The authors demonstrated that sildenafil reversed EOB in 87% of patients at 6 months and in 93% at 1
year during cardiopulmonary exercise testing. No change was seen
with placebo. Further, the authors also demonstrated significant
reductions in pulmonary arterial and wedge pressures.13

T.J. Cooper et al.

An ongoing National Institutes of Health (NIH)-funded placebocontrolled trial run in the USA and Canada, the RELAX trial
(PDE5-Inhibition to Improve Clinical Status and Exercise Capacity
in Diastolic Heart Failure), is enrolling HF patients with preserved
LVEF (patients with diastolic HF), randomized to receive either
sildenafil three times daily (increasing doses) or placebo for
24 weeks. This is a phase III trial aimed at assessing as the primary
endpoint changes in LV mass, exercise capacity, peak oxygen
uptake, and clinical status. The trial is anticipated to recruit 190
patients altogether from September 2008 to January 2013.

The SilHF trial

Sildenafil (Revatio) is currently licensed for group 1 pulmonary arterial hypertension. The recommended dosing regimen is 20 mg
three times daily, although higher dose are frequently used. In
most of the current literature, investigators have used higher
doses of sildenafil. Based on this evidence, we consider sildenafil
40 mg three times daily to be a suitable dose to achieve clinical
benefit with good tolerability.
The SilHF trial is an investigator-initiated multinational randomized controlled clinical trial planned to widen the spectrum of information on drug effectiveness and safety by including a large
number of patients with systolic HF and mild to moderate group
2 PH. The primary endpoints of the study will be symptoms and
functional capacity. Additional secondary endpoints include
New York Heart Association (NYHA) functional class, and the
QoL tools Euro QoL 5D and the Kansas City questionnaire.

Design and treatment

Eligible patients will be randomly allocated to either sildenafil
40 mg three times daily or placebo.
The study will have two arms with a 2:1 distribution of
treatment and placebo.
Active arm (140 patients): Sildenafil 40 mg 3
Placebo arm (70 patients): Matched tablets 3
The duration of study drug exposure will be 6 months.
The study population consists of outpatients with stable chronic
systolic HF (NYHA functional class II III and LVEF 40%) and a
systolic pulmonary pressure 40 mmHg on optimal medical
therapy, which includes the use of diuretics, angiotensin-converting
enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs),
beta-blockers, and aldosterone antagonists. PH will be documented using conventional echo/Doppler recording by standard technique. As the systolic pulmonary arterial pressure (SPAP) may be
affected by the systemic arterial pressure, supine systolic/diastolic
systemic blood pressure will be recorded during the echocardiographic assessment.

Sample size considerations

The SilHF trial represents a pilot study designed to assess tolerability, safety, and clinical efficacy using soft endpoints such as
patient global assessment (PGA), QoL tools, and 6MWT. It is
not adequately powered to assess clinical outcomes with a
sample size of 210 patients. Patients will be randomized in a 2:1
fashion in order to maximize the number of patients in the
active treatment arm.

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The SilHF trial

Objectives and endpoints

Significant improvements in these two parameters would constitute a positive result. Secondary endpoints include the Euro QoL
5D and Kansas City Cardiomyopathy questionnaire, and NYHA
class. The two primary and three secondary endpoints have all
been validated and are sensitive to improvements in patients
with HF.14 The authors also intend to perform an exploratory analysis by prospective subgroup evaluation in patients with an estimated SPAP above and below 60 mmHg.
Table 1 summarizes the study endpoints. Additional information
will be acquired by monitoring safety, renal function, and SPAP.

Study intervention
Study medication will be either sildenafil 40 mg three times daily or
placebo three times daily. An initial dose of 10 mg of sildenafil or
placebo will be issued with a 2 h observation period and, if tolerated, the subject will be given a dose of 20 mg of sildenafil or
placebo three times daily. Up-titration will be performed from
1 week to 1 month (according to tolerance) after the randomization visit.
At the randomization and the up-titration visits, patients will be
observed for 2 h after the study drug has been given, to capture
any potential acute side effects and to ensure first dose tolerability.
Patients will continue all other medications. There will be a screening visit, a randomization visit, an up-titration visit at 1 week and
1 month, plus a 2-month and a 4-month follow-up visit. The final
visit is at 6 months. After study termination, a single visit/phone
call at 9 months is planned.

Timelines
All eligible patients will be screened for potential participation in
the study. The inclusion and exclusion criteria are listed below.
The primary, secondary, and exploratory endpoints will be
recorded at inclusion and at Weeks 8 and 24. Additionally,
NYHA functional class and a physical examination will be recorded
after 16 weeks. Blood tests for safety will be taken at inclusion and
after 24 weeks. Cardiorespiratory exercise testing as an optional

Table 1 Study endpoints

Primary endpoints

................................................................................
(1) Patient global assessment (PGA)
(2) 6 minute walk distance
Secondary endpoints
(1)
(2)
(3)
(4)

Quality of life (QoL) evaluation by Euro QoL 5D

Kansas City cardiomyopathy questionnaire
New York Heart Association (NYHA) functional class
Safety and tolerability

Exploratory endpoints
(1) Renal function, serum creatinine, and estimated glomerular
filtration rate
(2) Systolic pulmonary arterial pressure

endpoint will be undertaken at inclusion and at 24 weeks.

Adverse events will be recorded at all visits and by telephone consultation at 36 weeks.

Adverse events
Patients drug tolerability will be assessed throughout the study
period. To capture all potential side effects of sildenafil, the
patient will regularly fill in an appropriate form for patientreported side effects. All hospitalizations and MACEs (major
adverse cardiac events) will be recorded. All observed adverse
events will be reported to the regulatory authorities according
to national regulations and international guidelines.
Furthermore, an electronic case report form (CRF) has been
generated to capture patient characteristics and clinical events.
One electronic CRF will be used by all participating sites. The electronic CRF will provide the data safety and monitoring board with
unblinded data.

Inclusion criteria
(1) Men and women.
(2) 1880 years of age.
(3) Outpatients with chronic HF. NYHA class IIIII on optimal
treatment in sinus rhythm or atrial fibrillation.
(4) LVEF ,40% measured during the past 12 months.
(5) SPAP .40 mmHg using echocardiography.
(6) 6MWT distance ,400 m.
(7) N-terminal pro brain natriuretic hormone (NT-pro BNP)
.400 pg/mL or BNP .100 pg/mL measured during the past
12 months.
(8) Receiving optimal therapy, including a diuretic, an ACE inhibitor or receptor blocker, a beta-blocker, and an aldosterone
antagonist. Doses of all medication should be unchanged
during the last 30 days before inclusion.
(9) Implantable cardioverter defibrillators (ICDs) and cardiac
resynchronization therapies (CRT-P and CRT-D) are permitted. Implantation should have been performed . 3 months
before inclusion in 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) Any other known cause of PH, such as advanced lung disease
[including chronic obstructive pulmonary disease (COPD),
obstructive sleep apnoeas, and other severe pulmonary
parenchymal disease], congenital heart defects and shunts,
connective tissue disease, thrombo-embolic disease.
(4) Planned coronary angiography or planned device implantation.
(5) Moderate to severe obstructive valve disease.
(6) Documented episodes of sustained ventricular tachycardia.
(7) Oral nitrate therapy or frequent use of sublingual nitrate.
(8) Concomitant disease which interfere with assessment of dyspnoea, severe COPD, asthma, restrictive lung disease, severe
obesity.

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T.J. Cooper et al.

(9) Anaemia (haemoglobin ,10 g/dL)

(10) Uncontrolled hypertension (systolic blood pressure
.160 mmHg and/or diastolic blood pressure .90 mmHg).
(11) Symptomatic or orthostatic hypotension or systolic blood
pressure ,90 mmHg.
(12) Clinically important renal dysfunction ( glomerular filtration
rate ,40 mL/min).
(13) Women with child-bearing potential.
(14) Use of

(15)

(16)

(17)
(18)
(19)
(20)
(21)

(i) alpha-1 antagonist: doxazosin

(ii) CYP3A4 inhibitors: erythromycin, ritonavir, sakinovir,
itrakonazole, ketokonazole
(iii) CYP3A4 inducers: rifampicin
(iv) any calcium channel blockers.
Retinitis pigmentosa, previous diagnosis of NAION (nonarteritic ischaemic optic neuropathy), unexplained visual
disturbance.
Sickle cell anaemia, multiple myeloma, leukaemia, or penile
anatomic deformities (angulation, cavernosal fibrosis,
Peyronies disease) that increase 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.
Unexplained syncope.
Patients who have a clear ICD indication but have refused
ICD implantation.

Conclusions
The rationale for testing PDE-5 inhibitors has progressively
emerged over the last decade. Current evidence is primarily
based on experimental studies and small randomized controlled
trials. Our hypothesis is that PDE-5 inhibition with sildenafil may
improve symptoms, functional capacity, and QoL in patients with
symptomatic HF due to systolic LV dysfunction. Importantly,
there is considerable off-label use of sildenafil in symptomatic HF
patients in many European countries.2 Consequently, it is important to make firm assertions on the safety and therapeutic effectiveness of sildenafil in HF associated with PH due to left heart failure.
Our aim from this proposed multicentre randomized controlled
pilot study is to pave the way for further large-scale outcome trials.

Conflict of interest: none declared.

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