ULTIMATE-SHF trial (UdenafiL Therapy to Improve symptoMAtology, exercise Tolerance and hEmodynamics in patients with chronic systolic heart failure): study protocol for a randomized, placebo-controlled, double-blind trial
Trials
ULTIMATE-SHF trial (UdenafiL Therapy to Improve symptoMAtology, exercise Tolerance and hEmodynamics in patients with chronic systolic heart failure): study protocol for a randomized, placebo-controlled, double-blind trial
Kyung-Hee Kim 0 1
Hyung-Kwan Kim 0 1
In-Chang Hwang 0 1
Seung-Pyo Lee 0 1
Hyun-Jai Cho 0 1
Hyun-Jae Kang 0 1
Yong-Jin Kim 0 1
Dae-Won Sohn 0 1
0 Cardiovascular Center, Seoul National University Hospital , Seoul 110-744 , Korea
1 Department of Internal Medicine, Seoul National University College of Medicine , Seoul 110-744 , Korea
Background: Over the last few years, the use of phosphodiesterase type 5 (PDE5) inhibitors has been expanded to management of various cardiovascular disorders beyond pulmonary arterial hypertension. This study is designed to investigate the ability of udenafil, a newly developed long-acting PDE5 inhibitor, to improve functional capacity and hemodynamic status in a cohort of chronic systolic heart failure (SHF) patients. Methods/design: Stable, chronic SHF patients will be randomly assigned to placebo (26 patients) or udenafil at a dose of 50 mg twice per day (26 patients) for the first 4 weeks followed by 100 mg twice daily for the next 8 weeks. Eligibility criteria will be age ≥18 years, clinical diagnosis of chronic SHF with current New York Heart Association class II to IV symptoms, left ventricular ejection fraction ≤ 40%, and experience of at least one of following during the 12 months prior to study entry: hospitalization for decompensated heart failure, acute treatment with intravenous loop diuretics or hemofiltration, or pulmonary artery systolic pressure ≥40mmHg on transthoracic echocardiography. Pharmacological therapy for SHF will be optimized in all patients at least 30 days before study entry. The primary outcome will be the change of maximal oxygen uptake, assessed by cardiopulmonary exercise testing. Secondary outcomes will include changes in ventilatory efficiency (minute ventilation/carbon dioxide production slope), left ventricular systolic and diastolic parameters, pulmonary artery systolic pressure, plasma concentration of brain natriuretic peptide, occurrence of mortality or hospitalization for heart failure, and the occurrence of any adverse event. Clinical trial registration: Unique identifier: NCT01646515
Phosphodiesterase type 5 inhibitor; Udenafil; Chronic heart failure; Exercise capacity
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Background
Heart failure is a leading cause of death that continues
to cause a significant socioeconomic burden worldwide
[1]. The prevalence of chronic heart failure (HF) in
relation to left ventricular (LV) systolic dysfunction is
estimated to be as high as 2 to 11% [2]. Despite the aggressive
use of medications, such as angiotensin-converting
enzyme inhibitors, β-blockers and spironolactone, proven
to improve the survival of chronic HF patients with a
reduced LV ejection fraction, mortality and morbidity
remain high, and one of the potential reasons for this
might be the development of pulmonary hypertension.
According to a number of earlier works, up to 60% of
patients with severe LV systolic dysfunction develop
pulmonary hypertension [3,4]. Hence, it is conceivable
that the development of pulmonary venous or mixed
pulmonary venous/arterial hypertension, which results
in HF symptoms such as dyspnea and limitation of
exercise capacity, and consequently adversely affects
quality of life and prognosis, is an important milestone in
the progression of uncomplicated LV systolic
dysfunction to clinically manifested HF. In this respect,
development of a new therapeutic option that deals with the
issue of pulmonary hypertension in association with LV
systolic failure is both attractive and clinically relevant.
Phosphodiesterase type 5 (PDE5) is a key enzyme in the
catabolism of cyclic guanine monophosphate (cGMP) and
is predominantly abundant in the vascular smooth muscle
cells of the pulmonary vasculature [5]. Given the
important role of cGMP in the regulation of nitric oxide and
that defective nitric oxide release is a major factor of
vasoconstriction in chronic HF [6], the addition of PDE5
inhibitors to established medications for chronic HF
could be a theoretically appealing treatment strategy.
PDE5 inhibitors were initially introduced as a treatment
option for erectile dysfunction, and even in the late 20th
century this type of drug was believed to have little to
contribute in the cardiology field. However, since PDE5
inhibitors were found to have beneficial effects on
pulmonary arterial hypertension in man [7], and the
confirmation of this finding in clinical trials [8,9], PDE5
inhibition is now considered a viable therapeutic option
for the treatment of pulmonary arterial hypertension. In
addition to their favorable therapeutic impacts on
pulmonary arterial hypertension, PDE5 inhibitors have
recently been shown to be effective therapeutics in patients
with chronic systolic heart failure (SHF) [8,10].
Udenafil (Zydena®; Dong-A Pharmaceut (...truncated)