Effects of Sildenafil on pulmonary artery pressure in patients with heart failure with preserved ejection fraction and pulmonary hypertension

Isolated diastolic left heart failure, also called heart failure with preserved
ejection fraction (HFpEF) is a clinical syndrome with severe symptoms and high
mortality. It counts for 40-60% of all patients with left heart failure.
Nevertheless the level of evidence for medical treatment regiments is low
compared to systolic left heart failure. Systolic left heart failure and also
HFpEF can be associated with pulmonary hypertension (PH), and then belong to
group 3 ( PH due to left heart disease) of the current clinical classification
of pulmonary hypertension from Dana point 2008. More recent studies suggest
that PH is even more common in HFpEF than in systolic heart failure. The
presence of PH in both conditions is associated with increased mortality .
The PDE/5 inhibitor Sildenafil , on the market as specific PAH medication
targeting the pulmonary vascular tone is promising as new treatment option for
this specific condition of HFpEF and PH . Next to dilation and
antiproliferative impact on de pulmonary vascular system in PAH it also has
potential favorable effects on the myocardium that may block adrenergic
hypertrophic and proapoptotic signaling. For that reason Sildenfil might have
an ideal profile for treatment of HFpEF and PH.
With the presented study we want to investigate the hemodynamic and clinical
impact of Sildenafil in patients with HFpEF as an important step to possibly
establishing the first medical therapy for HFpEF and PH ( see also page 4/5 of
the protocol)

Primary objective
To investigate wether Sildenafil treatment results in a reduction of pulmonary
artery pressure without decrease of cardiac output in HFpEF patients with PH

Secondary objectives
To investigate wether Sildenafil treatment results in a reduction of wedge
pressure in HFpEF patients with PH.
To investigate wether Sildenafil treatment results in improvement of exercise
capacity in these patients ( defined as change in VO2max ).

multicenter, prospective, randomized, placebo controled study.
Recruitment in 2010 and inclusion continues until 52 patients have been
randomized.

Oral treatment with Sildenafil at initial dose of 20 mg 3 times daily, after 2
weeks increase dose to 60 mg 3 times daily. Administration period: 12 weeks.
Changes of co-medication in this period only if heavily indicated ( for
instance cardial decompensation) and must be documented.

Study entry at the moment of right heart catheterisation evaluating the reason
of pulmonary hypertension. When right heart catheterisation documents PH
secondary th left heart failure and echocardiography or MUGA a systolic LV
function with a left ventricular ejection fraction (LVEF) more than 45% patient
can be asked for inclusion.

First burden of the study is that the patients will get oral treatment with
Sildenafil at a maximum dosis of 3 times 60 mg. Sildenafil is already
registered for two indications ( PAH and erectile dysfunction) and it could be
documented that the drug can be used safely. Side effects are scarce and mostly
mild. Most important side effect is possible reduction of the artery pressure .
Therefore the dose is increased gradually in the study and patients with
hypotension are excluded. Also described interaction with other medication
(for instance nitrates) is taken into consideration in de exclusion criteria.
Second burden of the study is one extra right heart catheterisation after 12
weeks of treatment with Sildenafil of placebo. Furthermore the patient has to
fill in two quality of life questionnaires. All other examinations are part of
standard diagnostics for this condition.
A right heart catheterisation is a invasive examinanation with a puncture of
the femoral vein. An arterial punctur is not neccessary. The right heart
catheterisation has a low risk ( 1%) of bleeding in the groin where the vena
femoralis has been punctured, a very low risk of infection and a very low risk
of damage of cardiovascular structures by leading the swan ganz catheter to
the pulmonay artery( <0.1%) For the right heart catheterisation the patient has
to be admitted on the short stay ward for about 6 hours.
As the study population suffers from a disease with high mortality and mobidity
with up to now no evidence based treatment options the possible benefit of th
investigated treatment will strongly overweight the small risks of a right
heart catheterisation and the time the patient would have to spend to come for
a short stay in the hospital (6 hours).