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Givertz et al. J Am Coll Cardiol 2007;50:1551-60

The Effects of KW-3902, an Adenosine A 1 -Receptor Antagonist, on Diuresis and Renal Function in Patients with Acute Decompensated Heart Failure and Renal Impairment or Diuretic Resistance. Givertz et al. J Am Coll Cardiol 2007;50:1551-60.

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Givertz et al. J Am Coll Cardiol 2007;50:1551-60

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  1. 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 Givertz et al. J Am Coll Cardiol 2007;50:1551-60 Michael M. Givertz, MD, FACC, Barry M. Massie, MD, FACC, Tara K. Fields, Leeanne L. Pearson, RN, BS, and Howard C. Dittrich, MD, FACC, on behalf of the CKI-201 and CKI-202 Investigators

  2. Background and Objectives • Intravenous loop diuretics are the mainstay of therapy for patients with acute decompensated heart failure (ADHF). Treatment, however, may be complicated by diuretic resistance and/or worsening renal function. • We sought to evaluate the dose-dependent effects of adenosine A1-receptor blockade on diuresis and renal function in patients with acute decompensated heart failure (ADHF) and renal impairment or diuretic resistance.

  3. Methods • We carried out a pair of randomized, double-blind, placebo controlled, proof-of-concept studies in two clinically challenging ADHF populations. • CKI-201: Hospitalized acute decompensated heart failure patients with renal impairment • CKI-202: Patients refractory to high doses of conventional diuretics

  4. CKI-201 Protocol • Double-blind, randomized Rx with placebo or one of 4 doses of KW-3902 (2.5 mg, 15 mg, 30 mg, 60 mg) • 146 subjects, morning 2 hr infusion for up to 3 days • First 6 hours (Day 1 only) KW-3902 or placebo given as monotherapy (diuretics held for 12 hours) • Primary endpoint: 6 hour urine volume • IV loop diuretics given as indicated after 6 hours • KW-3902 or placebo administered in assigned dose on Days 2 and 3, simultaneous with furosemide as needed • Final efficacy measures on day of discharge or Day 4, whichever came first

  5. CKI-201 Cumulative Urine Volume Cumulative urine volume (mean  SEM) 6 hours after initiation of placebo or KW-3902 in ADHF patients with renal impairment (*P = 0.02 vs. placebo).

  6. CKI-201 Furosemide Administration Daily dose of IV furosemide (mean  SEM) administered to the placebo and four KW-3902 groups over the first 3 days of the study (*P < 0.05 vs. placebo).

  7. CKI-202 Protocol • Randomized, double-blind, placebo controlled, dose escalation, exploratory study • 35 subjects: 23 active in three escalating dose groups (10 mg, 30 mg and 60 mg) and 12 placebo • 3-5 hour baseline period: diuretics withheld and baseline hourly urine volume and creatinine clearance established • 2-3 hour infusion of KW-3902 or placebo • Rescue IV furosemide allowed after study drug • Efficacy measures through 24 hours and safety measures through 48 hours • Primary endpoint: change in hourly urine volume

  8. CKI-202 Hourly Urine Volume Change in hourly urine volume (mean  SEM) through 24 hours post-dosing with placebo or KW-3902 in ADHF patients refractory/resistant to diuretics.

  9. CKI-202 Creatinine Clearance Change in measured creatinine clearance (mean  SEM) relative to baseline in ADHF patients refractory/resistant to diuretics (*P < 0.05 vs. baseline).

  10. Conclusion In patients with acute decompensated heart failure and volume overload, KW-3902, an adenosine A1-receptor antagonist, enhances the response to loop diuretics and may have a renal protective effect.

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