Rationale, design, and results from RENO-DEFEND 1: a randomized, dose-finding study of the selective A1 adenosine antagonist SLV320 in patients hospitalized with acute heart failure.

Abstract

BACKGROUND:

Baseline renal impairment as well as worsening renal function during hospitalization is associated with worse short- and long-term outcomes in patients hospitalized for acute heart failure (AHF). We hypothesized that selective A1 adenosine receptor blockade would induce natriuresis while preserving renal function in AHF patients with renal dysfunction.

METHODS:

A phase II, randomized, double-blind, placebo-controlled, parallel group, multicenter study to evaluate the efficacy and safety of 2.5, 7.5, 15, and 30 mg/d SLV320 (1 hour intravenous infusions of 1.25, 3.75, 7.5, and 15 mg SLV320, every 12 hours for 3 days [a total of 6 doses] in addition to standard therapy) in subjects hospitalized with AHF and renal impairment who meet all inclusion/exclusion criteria. The study planned to enroll 450 subjects, with 90 subjects allocated equally to each treatment arm.

RESULTS:

The study was terminated early. The decision, which was unrelated to the study conduct or results, with a total of 46 subjects randomized. Of those randomized, 6:8:8:8 and 6 patients, respectively, completed the study in each of the dosing subgroups, with placebo as the fifth group. For the 1.25-mg study group, the mean age was 73 years; mean (SD) systolic blood pressure (SBP), 128.5 (16.2); heart rate, 80.8 (25.0); brain natriuretic peptide, 969.7 (571.28); creatinine (μmol/L), 149.7 (41.0); cystatin C, 1.468 (0.2777); estimated glomerular filtration rate, 33.8 (7.913); and blood urea nitrogen, 12.1 (2.9), with roughly similar values in each treatment arm. No seizures were reported during the study. Eight patients died during the study, none of whom were associated with the study drug per an independent, blinded, data safety monitoring board.

CONCLUSION:

Because of the limited number of subjects and variability observed in the results, no definite conclusions can be made regarding the efficacy and safety of SLV320.

• Authors: Peter S Pang, Mandeep Mehra, Aldo P Maggioni, Gerasimos Filippatos, Jayne Middlebrooks, Prasad Turlapaty, Dmitri Kazei, Mihai Gheorghiade, RENO-DEFEND Investigators
• Journal: American heart journal (Am Heart J) Vol. 161 Issue 6 Pg. 1012-23.e3 (Jun 2011) ISSN: 1097-6744 [Electronic] United States
• PMID: 21641345 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: Copyright © 2011 Mosby, Inc. All rights reserved.

Chemical References

• Adenosine A1 Receptor Antagonists
• Cyclohexanes
• Heterocyclic Compounds, 2-Ring
• SLV320 compound
• Creatinine

Topics

• Adenosine A1 Receptor Antagonists (administration & dosage)
• Aged
• Creatinine (blood)
• Cyclohexanes (administration & dosage)
• Female
• Heart Failure (drug therapy, physiopathology)
• Heterocyclic Compounds, 2-Ring (administration & dosage)
• Humans
• Infusions, Intravenous
• Male
• Natriuresis (drug effects)
• Research Design