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 - 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)