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KW-3902 in Patients With Acute Decompensated Heart Failure - KW-3902 in Patients With Acute Decompensated Heart Failure
Description:
The goal of the trial was to evaluate the effects of KW-3902 (rolofylline), an adenosine A1-receptor antagonist, on diuresis and renal function compared with placebo in patients with acute decompensated heart failure (ADHF).
Study Design
Study Design:
Patients Enrolled: 146
Mean Follow Up: 30 days
Mean Patient Age: Mean age 67 years
Female: 31
Patient Populations:
Age & ge;18 years; New York Heart Association (NYHA) functional class II to IV heart failure and renal impairment, defined as an estimated creatinine clearance (CrCl) of 20 to 80 ml/min; hospitalized with ≥2 of the following signs or symptoms of fluid overload: jugular venous distension, pitting sacral or pedal edema, dyspnea, or documented weight gain.
Exclusions:
Acute MI within 30 days; clinical evidence of ongoing ischemia causing worsening heart failure; uncorrected primary valvular, restrictive, or hypertrophic cardiomyopathy or pericardial disease; implantation of a cardioverter-defibrillator or cardiac resynchronization device within 7 days; need for mechanical ventilation, dialysis or ultrafiltration; active pulmonary, vascular, renal, hepatic, cerebrovascular or systemic disease; a recent surgical or diagnostic procedure that would confound heart failure management or interpretation of study results; serum potassium level <3.0 mEq/l or systolic blood pressure (SBP) <85 mm Hg.
Primary Endpoints:
Total urine output during the 6 h after the first dose study drug.
Secondary Endpoints:
Change in urine flow rate over the first 6 h; change in SCr level at day 4/early termination; proportion of patients with worsening renal function at day 4/early termination, defined as an increase from baseline in SCr ≥0.3 mg/dl; mean cumulative dose of IV furosemide; and number of subjects withdrawn from the study because of treatment failure.
Drug/Procedures Used:
Patients were randomized in a double-blind manner to placebo (n = 27) or one of 4 doses of KW-3902 (rolofylline) (2.5 mg, n= 29; 15 mg, n = 31; 30 mg, n = 30; or 60 mg, n = 29). Study drug was infused over 2 h daily for up to 3 days. All patients had received 40 mg IV furosemide 12 hours prior to the first dose of study drug.
Principal Findings:
While there was no ejection fraction enrollment criteria, ejection fraction was low, averaging from 26-37%. At baseline, mean serum creatinine was 1.8 mg/dl and creatinine clearance was 48 ml/min. NYHA class III was present in half of patients.
The primary endpoint of total urine output during the 6 hours after the first dose of study drug was directionally higher in all KW-3902 dose groups compared with placebo (445, 531, 631, and 570 ml, for 2.5-, 15-, 30-, and 60-mg groups, respectively vs 374 ml for placebo) with a significantly higher level in the 30-mg group vs placebo (p = 0.02). However, by 24 hours, total urine output was similar between the groups. At 1 to 2 hours, urine flow was increased compared to baseline in the KW-3902 30 mg and 60 mg groups (from 123 to 139 ml/h, p = 0.02 for 30 mg; and from 124 to 133 ml/h, p = 0.03 for 60 mg). Serum creatinine on day 2 decreased in all KW-3902 groups (-0.08, -0.03, -0.06, and -0.03 mg/dl for the 2.5-, 15-, 30-, and 60-mg groups, respectively) and increased in the placebo group (+0.04 mg/dl, p = 0.04 for 30 mg KW-3902 vs. placebo). There was no difference in the percentage of subjects with worsening renal function (serum creatinine ≥0.3 mg/dl) (7%, 3%, 7%, and 17%, respectively, vs. 19% for placebo). Intravenous furosemide use by day 4 or discharge if earlier trended lower in the KW-3902 groups compared with placebo (p = 0.10). Adverse events did not differ between placebo and KW-3902 groups. A large portion of patients discontinued treatment prior to day 3 (44%), primarily due to adequate dieresis.
Interpretation:
Among patients with acute decompensated heart failure, treatment with KW-3902 (rolofylline), a novel adenosine A1-receptor antagonist, was associated with an increase in urine output by 6 hours compared with placebo, although by 24 hours total urine output did not differ between the KW-3902 groups and placebo.
Loop diuretics, the current primary therapy to reduce volume overload in patients presenting with ADHF, can cause worsening renal function, which is already often a problem for this cohort of patients. While patients in the placebo arm of the present study reached similar levels urine output by 24 hours, those in the KW-3902 had higher levels earlier (at 6 hours), without an adverse effect on renal function. There was no difference in the percentage of subjects with worsening renal function between the groups, and serum creatinine on day 2 had decreased in all KW-3902 groups but had increased in the placebo group. Additional larger clinical trials are underway, the PROTECT 1 and 2 studies, to more fully evaluate the dose, safety and efficacy of KW-3902 on clinical outcomes in patients with ADHF and accompanying renal dysfunction.
References:
Givertz MM, et al. The Effects of KW-3902, an Adenosine A1-Receptor Antagonist, on Diuresis and Renal Function in Patients With Acute Decompensated Heart Failure and Renal Impairment or Diuretic Resistance. J Am Coll Cardiol 2007;50:1551-60.
Keywords: Diuretics, Heart Failure, Diuresis, Edema, Xanthines, Creatinine, Dyspnea, Sodium Potassium Chloride Symporter Inhibitors, Weight Gain, Furosemide
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