Journal of Cardiology (2012) 59, 352—358 View metadata, citation and similar papers at core.ac.uk brought to you by CORE Available online at www.sciencedirect.com provided by Elsevier - Publisher Connector j ournal homepage: www.elsevier.com/locate/jjcc Original Article Comparative study of therapeutic effects of short- and long-acting loop diuretics in outpatients with chronic heart failure (COLD-CHF) Masaaki Miyata (MD, FJCC), Takeshi Sasaki (MD), Yoshiyuki Ikeda (MD), Takuro Shinsato (MD), Takuro Kubozono (MD), Yuko Furusho (MD), Atsushi Kusumoto (MD), Shuichi Hamasaki (MD, FJCC), ∗ Chuwa Tei (MD, FJCC) , COLD-CHF Investigators Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan Received 23 September 2011; received in revised form 7 December 2011; accepted 28 December 2011 Available online 24 February 2012 KEYWORDS Summary Background: Loop diuretics have two different classes with different duration of activity: short- Chronic heart failure; Diuretic; acting such as furosemide (duration of activity, 6 h) and long-acting such as azosemide (duration of activity, 10—12 h). We conducted a multicenter, randomized, controlled trial in order to Brain natriuretic peptide; compare the therapeutic effects of azosemide, a long-acting loop diuretic, and furosemide, a short-acting one, on neurohumoral factors and cardiac function in outpatients with chronic Atrial natriuretic peptide heart failure (CHF). Methods: We enrolled 98 patients with CHF who were receiving furosemide and an angiotensin- converting enzyme inhibitor, and they were randomly divided into furosemide (n = 49) and azosemide (n = 49) groups. The furosemide group continued furosemide at the same dosage, and the azosemide group switched from furosemide to azosemide. At baseline and after 3 months, we measured body weight, and levels of brain natriuretic peptide (BNP), atrial natri- uretic peptide (ANP), norepinephrine, active renin, creatinine, blood urea nitrogen, sodium, potassium, and hematocrit. Chest X-ray and echocardiography were also performed. Results: Body weight and plasma levels of BNP and ANP significantly decreased after 3 months in the azosemide group compared to the furosemide group. There were no significant differ- ences in changes of levels of creatinine, blood urea nitrogen, sodium, potassium, hematocrit, norepinephrine, and active renin after 3 months between the furosemide and azosemide groups. ∗ Corresponding author at: Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. Tel.: +81 99 275 5316; fax: +81 99 275 5322. E-mail address: [email protected] (C. Tei). 0914-5087/$ — see front matter © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jjcc.2011.12.007 Short- and long-acting diuretics in CHF 353 Echocardiography and chest X-ray did not demonstrate significant differences between the two groups. Conclusions: Long-acting azosemide is suggested to be useful for the improvement of neurohu- moral factors compared with short-acting furosemide in patients with CHF. © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. Introduction Study design Heart failure is a major and growing public health prob- This randomized multicenter clinical trial was conducted at lem, and the number of heart failure deaths has increased 16 hospitals in Japan from October, 2005 to January, 2008. steadily despite advances in treatment [1]. Diuretics have The patients were randomly divided into furosemide and been shown to improve cardiac function, symptoms, and azosemide groups by an envelope method. The furosemide exercise tolerance in patients with chronic heart failure group was assigned to continue receiving furosemide, and (CHF) [2—4]. Loop diuretics with strong diuretic effects are the azosemide group was assigned to switch from furosemide essential for the treatment of pulmonary congestion and to azosemide. Regarding the doses of both drugs, 20 and symptoms in heart failure patients [1]. The loop diuretics 40 mg furosemide was equivalent to approximately 30 and are categorized into short- and long-acting groups based on 60 mg azosemide, respectively, based on the results of a clin- their duration of action. Furosemide with rapid action is a ical pharmacology study [5]. Examinations were conducted potent diuretic representing the short-acting group, while 3 months after registration, and all clinical parameters were azosemide with a mild and long-lasting effect is representa- examined before and 3 months after assignment. Readers of tive of the long-acting group [5]. chest X-ray and echocardiography were blinded to the inves- Despite their hypotensive effects, short-acting calcium tigation in the treatment allocation, although the grouping channel blockers were reported to increase mortality in was open to physicians and patients. patients with cardiovascular disease, while long-acting cal- Concomitant ACE inhibitors already being used at enroll- cium channel blockers were not associated with increased ment were continued as prescribed. Other drugs were mortality in hypertensive patients [6,7]. This hypothesis also allowed to continue without making further changes can also be applied theoretically to diuretics with differ- after registration. Cases requiring any changes in medica- ent durations of action in patients with CHF. Azosemide, tion, including other heart failure drugs, were defined as a long-acting loop diuretic, was associated with a better dropouts. outcome in Dahl rat heart-failure models compared with The study design complied with the Declaration of short-acting furosemide, partly through attenuation of the Helsinki and was unanimously approved by the Ethics Com- reflex increase in cardiac sympathetic neuronal activity mittee of Kagoshima University. Written informed consent caused by the development of heart failure [8]. Further- was obtained before enrolment from all of the patients who more, the comparative effects of long-acting azosemide and participated in the present study. short-acting furosemide on neurohumoral factors, and the usefulness of azosemide for improving quality of life were Physical examination and chest X-ray shown in a clinical study [9,10]. However, these studies were only performed in a small number of patients in a single hos- pital, and thus the usefulness of long-acting diuretics has not The NYHA functional class, body weight, systolic blood yet been validated. Therefore, we conducted a multicenter pressure (SBP), diastolic blood pressure (DBP), and cardio- randomized controlled trial, and compared the effects of thoracic ratio (CTR) on chest radiography were determined azosemide on neurohumoral factors and cardiac function to before and 3 months after commencing the study. those of furosemide in outpatients with CHF of New York Heart Association (NYHA) class I—III. Laboratory examinations Methods A fasting blood sample was taken in the morning. The plasma Patients levels of BNP, atrial natriuretic peptide (ANP), norepineph- rine (NE), and renin activity, the serum levels of creatinine, blood urea nitrogen, sodium, potassium, and chloride, and We enrolled 98 consecutive CHF outpatients with NYHA class hematocrit were measured before and 3 months after assign- I—III whose brain natriuretic peptide (BNP) level was greater ment. than 20 pg/ml, who had been receiving an angiotensin- converting enzyme (ACE) inhibitor and furosemide for at least 1 month and were in a stable condition. They were Echocardiography not administered any angiotensin II type 1 receptor blocker (ARB). The diagnosis of heart failure was defined by symp- Cardiac function was evaluated by echocardiography toms, clinical signs, and BNP levels more than 100 pg/ml before and 3 months after the start of the clinical trial. before medication [11]. Standard two-dimensional and Doppler echocardiographic 354 M. Miyata et al. a Tei index Mitral = (ICT + IRT) / ET (Tricuspid ) ICT ET inflow IRT = (a –b) / b Aortic (Pulmonary ) ICT: isovo lumic contraction time ejection flo w IRT: isovolumic relaxation time bbc ET : ejection time ECG c d IRT Figure 1 Scheme and principle of measurement of Tei index. examinations were performed in all subjects using 1- to Figure 2 Changes in body weight (A) and cardiothoracic 5-MHz phased array transducers and commercially available ratio (CTR) on chest X-ray (B) after 3 months. White bars are scanners [12]. Left ventricular systolic dimension (LVDs) and furosemide group; black bars are azosemide group. diastolic dimension (LVDd), and left atrial dimension (LAD) were determined. Left ventricular ejection fraction (LVEF) Results was obtained by modified biplane Simpson’s method from apical 2- and 4-chamber views. LV mass was calculated by the American Society of Echocardiography-recommended Patient characteristics × { formula [13]: LV mass (g) = 0.8 1.04[(LVDd + posterior wall thickness + interventricular septum Ninety-eight patients were enrolled and randomly divided 3 − 3 } thickness) (LVDd) ] + 0.6 g. LV mass was divided by into furosemide and azosemide groups. One patient in the body surface area to obtain LV mass index (LVMI). azosemide group was excluded from the trial, because she Doppler time intervals were measured from the left ven- complained of frequent urination and refused the continu- tricular (LV) inflow and outflow velocities, and Tei index