KW-3902 in Patients With Acute Decompensated Heart Failure - KW-3902 in Patients With Acute Decompensated Heart Failure
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).
Patients Enrolled: 146
Mean Follow Up: 30 days
Mean Patient Age: Mean age 67 years
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.
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.
Total urine output during the 6 h after the first dose study drug.
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defined as an increase from baseline in SCr ≥0.3 mg/dl; mean cumulative dose of IV furosemide; and number of subjects withdrawn from the study because of treatment failure.
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.
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.
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.
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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