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Superiority of Long-Acting to Short-Acting Loop Diuretics in The Advance Publication by J-STAGE Circulation Journal LATE BREAKING CLINICAL TRIAL (JCS 2012) Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Superiority of Long-Acting to Short-Acting Loop Diuretics in the Treatment of Congestive Heart Failure – The J-MELODIC Study – Tohru Masuyama, MD; Takeshi Tsujino, MD; Hideki Origasa, PhD; Kazuhiro Yamamoto, MD; Takashi Akasaka, MD; Yutaka Hirano, MD; Nobuyuki Ohte, MD; Takashi Daimon, PhD; Satoshi Nakatani, MD; Hiroshi Ito, MD Background: Diuretics are the most prescribed drug in heart failure (HF) patients. However, clinical evidence about their long-term effects is lacking. The purpose of this study was to compare the therapeutic effects of furosemide and azosemide, a short- and long-acting loop diuretic, respectively, in patients with chronic heart failure (CHF). Methods and Results: In this multicenter, prospective, randomized, open, blinded endpoint trial, we compared the effects of azosemide and furosemide in patients with CHF and New York Heart Association class II or III symptoms. 320 patients (160 patients in each group, mean age 71 years) were followed up for a minimum of 2 years. The pri- mary endpoint was a composite of cardiovascular death or unplanned admission to hospital for congestive HF. During a median follow-up of 35.2 months, the primary endpoint occurred in 23 patients in the azosemide group and in 34 patients in the furosemide group (hazard ratio [HR], 0.55, 95% confidence interval [CI] 0.32–0.95: P=0.03). Among the secondary endpoints, unplanned admission to hospital for congestive HF or a need for modification of the treatment for HF were also reduced in the azosemide group compared with the furosemide group (HR, 0.60, 95%CI 0.36–0.99: P=0.048). Conclusions: Azosemide, compared with furosemide, reduced the risk of cardiovascular death or unplanned admis- sion to hospital for congestive HF. Key Words: Azosemide; Chronic heart failure; Furosemide; Loop diuretics iuretics are the most frequently prescribed medicine in tion. However, there has been no randomized clinical trial at patients with chronic heart failure (CHF), not only in all that provides data showing the presence or absence of the D Japan but also in Western countries. Diuretics, par- benefits of long-term administration of loop diuretics. Most ticularly loop diuretics, are even more frequently prescribed recently, subanalyses of megatrials such as the Studies Of Left than renin-angiotensin system (RAS) inhibitors or β-blockers Ventricular Dysfunction and The Digitalis Investigation Group in any cohort study, although any guideline of CHF manage- trial study suggest that prognosis is poorer in CHF patients ment clearly recommends the use of RAS inhibitors and β- given larger doses of loop diuretics.7,8 Moreover, the Japanese blockers prior to diuretics.1–6 This is because any cardiologist Cardiac Registry of Heart Failure in Cardiology (JCARE- knows that persistent congestion is associated with a poor CARD) study revealed that diuretic use at discharge was an prognosis and loop diuretics are effective in lessening conges- independent predictor for all-cause death during long-term Received January 5, 2012; revised manuscript received February 26, 2012; accepted February 27, 2012; released online March 16, 2012 Time for primary review: 7 days Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya (T.M.); Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe (T.T.); Division of Biostatistics and Clinical Epidemiology, Univer- sity of Toyama Graduate School of Medicine, Toyama (H.O.); Division of Molecular Medicine and Therapeutics, Department of Mul- tidiscipinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago (K.Y.); Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama (T.A.); Division of Central Clinical Laboratory, Kinki University School of Medicine, Osakasayama (Y.H.); Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Nagoya (N.O.); Division of Biostatistics, Department of Mathematics, Hyogo College of Medicine, Nishinomiya (T.D.); De- partment of Health Sciences, Osaka University Graduate School of Medicine, Suita (S.N.); and Department of Cardiovascular Medicine, Akita University Graduate School of Medicine, Akita (H.I.), Japan This paper was presented at the 76th Annual Scientific Meeting of the Japanese Circulation Society, Late Breaking Clinical Trials 2-4. ClinicalTrials.gov number, NCT00355667; UMIN Clinical trial registry number, UMIN000000528. Mailing address: Tohru Masuyama, MD, PhD, FACC, Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-11-1500 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Advance Publication by J-STAGE MASUYAMA T et al. Figure 1. Trial profile. follow-up among elderly patients hospitalized with HF.9 Some uncontrolled hypertension; current symptomatic hypotension; experimental studies have demonstrated the adverse effects of serum creatinine >2.5 mg/dl; acute coronary syndrome; im- furosemide in HF models.10,11 This may be explained by the plantable cardiac defibrillator; hemodynamically significant fact that loop diuretics activate the RAS and sympathetic left ventricular outflow tract obstruction; acute myocardial in- nerve system, resulting in the poor prognosis in patients given farction within the past 3 months; percutaneous coronary inter- loop diuretics.10–12 Diuretics are certainly essential in most vention or open heart surgery within the past 3 months; any patients with CHF to minimize symptoms related to conges- change in cardiovascular drug therapy within the month prior tion and therefore should not be withdrawn. However, the use to randomization; requirement for intravenous inotropes; and of a long-acting rather than a short-acting loop diuretic may any serious non-cardiovascular disease including malignancy. well provide a better prognosis in patients with CHF. Yoshida et al reported that the administration of azosemide, a long-act- Study Procedure ing loop diuretic, improved the mortality rate in a hypertensive The study used a multicenter, prospective, randomized, open, HF model.13 However, there has been no randomized clinical blinded endpoint (PROBE) design. After screening for eligibil- trial of loop diuretics in patients with CHF. Thus, we designed ity and obtaining written informed consent, patients were ran- a multicenter prospective study, J-MELODIC (Japanese Mul- domized to either azosemide or furosemide treatment in a 1:1 ticenter Evaluation of LOng- versus short-acting Diuretics In ratio. In any arm, patients were treated with standard therapy Congestive heart failure) to obtain clinical evidence of the including digitalis, mineralocorticoid receptor blockers, angio- effects of diuretics in HF patients.14 This is the first prospec- tensin-converting enzyme inhibitors, angiotensin II type 1 re- tive randomized study of the effect of long-term administra- ceptor blockers, β-blockers, and calcium-channel blockers. tion of a long-acting vs. a short-acting diuretics on the prog- Patients discontinued taking any previous loop diuretic(s) nosis in patients with CHF. and were directly rolled over to one of the 2 arms with either azosemide 30–60 mg/day or furosemide 20–40 mg/day, with- out a placebo run-in period. We considered 40 mg furosemide Methods to be equivalent to approximately 60 mg azosemide, based on Patients the result of a previous clinical pharmacology study.17 The The design of the J-MELODIC study has been published in dose of each diuretic was appropriately adjusted within 8 weeks detail.14 The trial was approved by each center’s ethics com- according to the symptoms of each patient, and patients were mittee and all patients provided written informed consent. maintained for the rest of the study. When it was difficult Eligibility criteria were as follows: 20 years or older; clinical to stabilize symptoms of HF, azosemide was increased up to diagnosis of HF based on a slight modification of the Framing- 120 mg/day, and furosemide was increased up to 80 mg/day. ham criteria15 as previously described16 within 6 months before Diuretics other than furosemide, azosemide, thiazides and min- study entry; New York Heart Association (NYHA) functional eralocorticoid inhibitors were not allowed to be taken. class II or III symptoms; loop diuretic(s) user; and no change in Thereafter, patients were reviewed every 2–8 weeks. The baseline therapy or symptoms of HF within 1 month. planned minimum follow-up period for each patient was 2 Key exclusion criteria were: uncontrolled diabetes mellitus; years, and electrocardiography, echocardiography, chest X-ray Advance Publication by J-STAGE Long-Acting Loop Diuretic in Congestive HF Table 1. Baseline Characteristics of the Patients According to Study Group Furosemide group Azosemide group P value (n=160) (n=160) Age (years) 71±11 71±11 0.45 Female 65 (41) 59 (37) 0.49 Smoking 25 (16) 22 (14) 0.75 NYHA class III 19 (12) 16 (10) 0.76 SAS questionnaire score (Mets) 4.7±1.5 4.6±1.7 0.30 Weight (kg) 59.0±12.8 59.8±13.3 0.56 CTR (%) 55.7±7.3 55.3±7.4 0.61 BMI (kg/m2) 23.2±4.2 23.6±4.5 0.40 SBP (mmHg) 125±17 126±18 0.58 DBP (mmHg) 71±11 71±11 0.74 Heart rate (beats/min) 71±14 72±13 0.54 LVEF
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