Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial.
BACKGROUND
Ischemia/reperfusion injury remains an important cause of morbidity and mortality after coronary artery bypass graft (CABG) surgery. In a meta-analysis of randomized controlled trials, perioperative and postoperative infusion of acadesine, a first-in-class adenosine-regulating agent, was associated with a reduction in early cardiac death, myocardial infarction, and combined adverse cardiac outcomes in participants undergoing on-pump CABG surgery.


OBJECTIVE
To assess the efficacy and safety of acadesine administered in the perioperative period in reducing all-cause mortality, nonfatal stroke, and severe left ventricular dysfunction (SLVD) through 28 days.


METHODS
The Reduction in Cardiovascular Events by Acadesine in Patients Undergoing CABG (RED-CABG) trial, a randomized, double-blind, placebo-controlled, parallel-group evaluation of intermediate- to high-risk patients (median age, 66 years) undergoing nonemergency, on-pump CABG surgery at 300 sites in 7 countries. Enrollment occurred from May 6, 2009, to July 30, 2010.


METHODS
Eligible participants were randomized 1:1 to receive acadesine (0.1 mg/kg per minute for 7 hours) or placebo (both also added to cardioplegic solutions) beginning just before anesthesia induction.


METHODS
Composite of all-cause mortality, nonfatal stroke, or need for mechanical support for SLVD during and following CABG surgery through postoperative day 28.


RESULTS
Because results of a prespecified futility analysis indicated a very low likelihood of a statistically significant efficacious outcome, the trial was stopped after 3080 of the originally projected 7500 study participants were randomized. The primary outcome occurred in 75 of 1493 participants (5.0%) in the placebo group and 76 of 1493 (5.1%) in the acadesine group (odds ratio, 1.01 [95% CI, 0.73-1.41]). There were no differences in key secondary end points measured.


CONCLUSIONS
In this population of intermediate- to high-risk patients undergoing CABG surgery, acadesine did not reduce the composite of all-cause mortality, nonfatal stroke, or SLVD.


BACKGROUND
clinicaltrials.gov Identifier: NCT00872001.
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27710, USA. newma005@mc.duke.edu
Mark F
MF
Newman
T Bruce
TB
Ferguson
Jennifer A
JA
White
Giuseppe
G
Ambrosio
Joerg
J
Koglin
Nancy A
NA
Nussmeier
Ronald G
RG
Pearl
Bertram
B
Pitt
Andrew S
AS
Wechsler
Richard D
RD
Weisel
Tammy L
TL
Reece
Armando
A
Lira
Robert A
RA
Harrington
D000241:Adenosine / Q000378:metabolism*; D000368:Aged; D000620:Aminoimidazole Carboxamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001026:Coronary Artery Bypass / Q000009:adverse effects* / Q000379:methods / Q000401:mortality*; D003324:Coronary Artery Disease / Q000601:surgery; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D059035:Perioperative Period; D015427:Reperfusion Injury / Q000517:prevention & control*; D012263:Ribonucleosides / Q000009:adverse effects / Q000627:therapeutic use*; D020521:Stroke; D018487:Ventricular Dysfunction, Left
D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D000241:Adenosine