Sildenafil Versus Placebo in Chronic Heart Failure
Sildenafil Versus Placebo in Chronic Heart Failure
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.
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.
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,