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Original Contribution |

Effect of Adenosine-Regulating Agent Acadesine on Morbidity and Mortality Associated With Coronary Artery Bypass Grafting:  The RED-CABG Randomized Controlled Trial FREE

Mark F. Newman, MD; T. Bruce Ferguson, MD; Jennifer A. White, MS; Giuseppe Ambrosio, MD; Joerg Koglin, MD; Nancy A. Nussmeier, MD; Ronald G. Pearl, MD, PhD; Bertram Pitt, MD; Andrew S. Wechsler, MD; Richard D. Weisel, MD; Tammy L. Reece, MS; Armando Lira, MD; Robert A. Harrington, MD; for the RED-CABG Steering Committee and Investigators
[+] Author Affiliations

Author Affiliations: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina (Drs Newman and Harrington and Mss White and Reece); Department of Cardiovascular Sciences, East Carolina Heart Institute, Greenville, North Carolina (Dr Ferguson); University of Perugia School of Medicine, Perugia, Italy (Dr Ambrosio); Merck Sharp & Dohme Corp, Whitehouse Station, New Jersey (Drs Koglin and Lira); SUNY Upstate Medical University, Syracuse, New York (Dr Nussmeier); Stanford University School of Medicine, Palo Alto, California (Dr Pearl); University of Michigan School of Medicine, Ann Arbor (Dr Pitt); Drexel University College of Medicine, Philadelphia, Pennsylvania (Dr Wechsler); and the University Health Network, Toronto, Ontario, Canada (Dr Weisel).


JAMA. 2012;308(2):157-164. doi:10.1001/jama.2012.7633.
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Published online

Context 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.

Design, Setting, and Participants 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.

Interventions 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.

Main Outcome Measure 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.

Conclusion 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.

Trial Registration clinicaltrials.gov Identifier: NCT00872001

Figures in this Article

Despite improvements in myocardial protection and perioperative care, the risk of death is still substantial in the first month after coronary artery bypass graft (CABG) surgery, averaging 3.0% to 6.0%,112 and can be even higher in patients with poor left ventricular function. Up to 50% of these deaths have been attributed to a cardiac cause, and this percentage has remained fairly constant over time.13,14 This suggests that there are still cases in which the ischemia/reperfusion injury to the myocardium during the cross-clamp period may not be fully addressed by current techniques of myocardial protection. Several drugs with purported cardioprotective effects, particularly a sodium-proton exchange inhibitor,15 a purinergic receptor antagonist,16 and a complement activation inhibitor,17 have been tested in large-scale randomized controlled trials in patients undergoing CABG surgery but failed to yield better postoperative outcomes.

One cardioprotective approach is based on the pharmacological duplication of one of the most powerful physiologic means of reducing ischemia/reperfusion injury, ischemic preconditioning.18 This endogenous protective process involves the release of several mediators, among which adenosine plays a key role. The administration of adenosine during CABG surgery is difficult to regulate and was not demonstrated to be beneficial.19 These issues led to the development of adenosine-regulating agents, of which acadesine is the first to be tested in large-scale clinical trials. By competing with adenosine for the nucleoside transporter, acadesine increases extracellular adenosine levels by inhibiting adenosine deaminase and increases intracellular adenosine levels.2022 Additionally, acadesine activates AMP-activated protein kinase, the central regulator of a host of intracellular enzymes involved in regulation of cellular energy and production of intracellular adenosine triphosphate.2326

To date, 5 studies of acadesine in participants undergoing CABG surgery have been conducted. Outcomes of these studies, which included a total of 4043 participants, were examined in a 1997 meta-analysis.27 In that meta-analysis, the use of acadesine was correlated with significant reductions in the occurrence of 3 end points: a 27% reduction in perioperative myocardial infarction (odds ratio [OR], 0.69 [95% CI, 0.51-0.95]; P = .02), a 50% reduction in cardiac death through postoperative day 4 (OR, 0.52 [95% CI, 0.27-0.98]; P = .04), and a 26% reduction in a composite of cardiac death, stroke, and myocardial infarction (OR, 0.73 [95% CI, 0.57-0.93]; P = .01). These significant associations persisted when examined in a random-effects model.27 The meta-analysis results prompted implementation of the current trial, designed to more definitely test whether acadesine could reduce the composite of all-cause mortality, nonfatal stroke, or need for mechanical support for severe left ventricular dysfunction (SLVD) occurring during and after CABG surgery through postoperative day 28.

Study Design and Population

The Reduction in Cardiovascular Events by Acadesine in Patients Undergoing CABG (RED-CABG) trial was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the ability of acadesine to reduce the incidence of ischemia/reperfusion injury in high-risk participants undergoing nonemergency CABG surgery. Study participants were patients undergoing CABG surgery with cardiopulmonary bypass who were at high risk of postoperative adverse events and who met all of the inclusion criteria and none of the exclusion criteria (eTable 1). The study was open to both sexes, and race/ethnicity was self-reported by participants. Enrollment was projected for 7500 patients at 300 sites in 7 countries (see “Statistical Analysis”). Enrollment occurred from May 6, 2009, to July 30, 2010. Each investigative site received institutional review board or ethics committee approval of the protocol, and all participants provided written informed consent.

Standard local procedures for CABG surgery or associated preoperative and postoperative care were followed. The study intervention was intravenous infusion of study drug or placebo before, during, and immediately after CABG surgery, which exposed the myocardium to a sufficient amount of study drug. The cardioplegic solution and cardiopulmonary bypass priming solution were also supplemented with either blinded study drug or placebo.

After the screening phase and within 14 days before surgery, participants were randomized by a central randomization service via an interactive voice/web response system in a 1:1 fashion to receive either acadesine or placebo. Randomization was stratified by sex. The dose of acadesine, consistent with previous trials, was 42 mg/kg diluted in 500 mL of normal saline, delivered as an intravenous infusion over approximately 7 hours commencing within approximately 30 minutes before induction of anesthesia, at a rate of 0.1 mg/kg per minute (1.2 mL/min for a 500-mL solution).

In addition, either saline (placebo) or acadesine solution was added to the cardioplegia solution for patients randomized to receive placebo or acadesine (5 μg/mL cardioplegia solution of acadesine), respectively. The choice and technique of preparation and delivery of standard cardioplegia and priming solutions and the volume required were determined by the attending physician.

Primary End Point

The primary efficacy end point was a composite of the occurrence of any of the following during surgery or through postoperative day 28: all-cause mortality, nonfatal stroke, or need for mechanical support for SLVD (defined as new use of mechanical circulatory assist devices, such as intra-aortic balloon pump or ventricular assist device, during or after CABG surgery for 1 hour or longer for treatment of low cardiac output). Indications for using circulatory assist devices were determined by the attending physician based on clinical judgment and included cardiogenic shock, difficulty in weaning from cardiopulmonary bypass, refractory left ventricular failure, refractory ventricular arrhythmias, and other indications that the investigators deemed necessary for treatment of low cardiac output. All efficacy end points (except all-cause mortality) were adjudicated by an independent, blinded clinical events committee (CEC). Cardiovascular mortality was also adjudicated by the CEC.

Secondary End Points

The key secondary efficacy end point was the first occurrence of any component of the composite of cardiovascular mortality, nonfatal stroke, or need for mechanical support for SLVD occurring during and after CABG surgery through postoperative day 28.

Exploratory End Points

Potential mechanisms of protective effects and other associated measurable clinical benefits of improved myocardial function by attenuation of ischemia/reperfusion injury were evaluated by creatine kinase MB (CK-MB) or troponin I and T levels and the incidence of myocardial infarction within 24 hours after surgery. The duration of mechanical ventilation (time from intubation to extubation); length of intensive care unit stay; length of hospitalization; prevalence of new, clinically significant atrial fibrillation within 96 hours after surgery; and estimated health state using the EuroQol 5-dimension instrument28 were also assessed. Perioperative myocardial infarction and clinically significant atrial fibrillation were adjudicated by the CEC.

Statistical Analysis

The population for the efficacy analyses was the intention-to-treat (ITT) population, which included all randomized participants who had completed primary outcome follow-up, regardless of whether they received the assigned treatment or underwent CABG surgery. The as-treated population included all randomized participants who received any amount of study drug (acadesine or placebo). Safety analyses were performed in this as-treated population. General and CABG-specific safety end points were monitored, with attention given to renal function and risk of hyperuricemia and gout. All statistical tests were 2-sided.

The CEC adjudicated each suspected end point event except all-cause mortality. An independent data and safety monitoring board (DSMB) monitored aggregated and blinded efficacy end points and other safety data to ensure the safety of participants in the trial.

Using the event estimation worksheet from the American College of Cardiology/American Heart Association guidelines29 for high-risk individuals undergoing CABG surgery who fulfilled the enrollment criteria of this study, the estimated incidence of the primary composite efficacy end point was 10%. Based on data from previous acadesine trials,27 a relative reduction of approximately 25% in this end point was projected. Thus, the projected sample size of 7500 participants (3750 participants per treatment group) would have approximately 85% power to detect a 20% reduction in the primary efficacy end point among participants receiving acadesine vs placebo, assuming a primary end point event rate of 10% in participants receiving placebo and a 2-sided P value of .05. A staged futility analysis with increasing futility thresholds was planned once 30% and 40% of planned participants completed postoperative day 28.

The statistical methodology used to assess futility was based on a Bayesian posterior probability approach at the interim assessment to determine the probability of observing a statistically significant result at the end of the trial. For the first futility analysis, the decision was that the trial would continue if the interim results indicated at least a 20% probability to reject the null hypothesis at the end of the study. For the second futility analysis, the trial would continue if the interim results indicated that there was at least a 65% chance to reject the null hypothesis at the end of the study. The DSMB could recommend termination of the trial for a stipulated futility.

The primary hypothesis was that in patients undergoing CABG surgery with the use of cardiopulmonary bypass, the incidence of the primary composite end point would be significantly lower with acadesine compared with placebo. This hypothesis was evaluated using Cochran-Mantel-Haenszel testing that adjusted for the stratification factor (sex). Point estimates and associated 95% CIs for treatment differences are provided. Each participant contributed only 1 efficacy end point in the composite (ie, participants with multiple component events of a composite end point were counted only once for that composite). The key secondary hypothesis (administration of acadesine compared with placebo will reduce the incidence of the key secondary composite end point) was evaluated using methods similar to those specified for the primary efficacy end point.

To account for missing data, Kaplan-Meier estimates for the primary and key secondary end points were calculated and log-rank testing performed. In these analyses, participants were treated as censored as of the point when the data became unavailable. Other analyses included evaluating the clinical benefits of acadesine with respect to the secondary and exploratory end points previously described. The key secondary end point was not to be tested unless the primary end point was significant at the .05 level (2-sided test). The other secondary end points and the exploratory efficacy end points were supportive only, and no adjustment for multiplicity to these end points was applied. All statistical analyses were performed using SAS version 9 (SAS Institute Inc).

To evaluate the drug effects at different levels of mortality risk, the Society of Thoracic Surgeons (STS) risk stratification score was calculated. In the RED-CABG trial, 2934 of the 3080 randomized participants received CABG surgery. Of these, 55 had mitral valve repair and were excluded from this analysis. Thus, 2879 patients were eligible for application of the STS risk score for isolated CABG. The model coefficients were applied to their corresponding covariates in the data, and a predicted probability of 30-day mortality was calculated for each participant.

The trial was stopped early at the 30% futility analysis (after 3080 study participants were randomized), based on the recommendation of the DSMB. Figure 1 outlines the assignments and reasons for continuation in the study, resulting in a final sample size of 2986 patients in the ITT analysis. Figure 1 also outlines follow-up through postoperative day 28.

Place holder to copy figure label and caption
Figure 1. Study Flow
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aAs defined by protocol.
bParticipants without postoperative day 28 data were considered as not having completed follow-up.

Baseline characteristics (Table 1) are typical of an intermediate- to high-risk population of patients undergoing CABG surgery and reflect the inclusion and exclusion criteria of the trial (eTable 1). Median age was 66 years. The majority of participants were white men with a history of hyperlipidemia, diabetes, family history of cardiovascular disease, and previous percutaneous coronary intervention. eTable 2 lists the extent of coronary artery disease and the left ventricular ejection fraction by enrollment group.

Study Drug Therapy and Concomitant Therapies

Of the 1536 participants in the acadesine group, 1442 (93.9%) received study drug and 1493 completed the study. The ITT analysis included all randomized participants who completed follow-up, regardless of treatment received. Concomitant medical therapy before CABG surgery, during hospitalization, and at discharge is shown in eTable 3.

Study Outcomes

The primary efficacy outcome was observed in 5% of participants overall. There was no significant difference between the placebo and acadesine groups, with incidence rates of 5.0% and 5.1%, respectively (OR, 1.01 [95% CI, 0.73-1.41]; P = .94). Table 2 lists the primary and key secondary end points and individual components of the ITT population with complete follow-up and CEC-adjudicated end points. Figure 2, a Kaplan-Meier curve of the ITT analysis of the primary outcome, demonstrates the lack of effect of acadesine treatment on the composite end point. An exploratory post hoc analysis was performed to assess the effects of the patient risk profile on treatment efficacy. Using the STS risk stratification score,30 participants were categorized into quintiles. As shown in Figure 3 and eTable 4, a comparison of the primary end point across these quintiles did not show any statistical differences across the various risk groups.

Place holder to copy figure label and caption
Figure 2. Kaplan-Meier Curve of the Analysis of the Primary Composite End Point (All-Cause Mortality/Nonfatal Stroke/Severe Left Ventricular Dysfunction)—Intention-to-Treat Population
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Place holder to copy figure label and caption
Figure 3. Incidence of the Primary Composite End Point (All-Cause Mortality/Nonfatal Stroke/Severe Left Ventricular Dysfunction) by Postoperative Day 28 in Patients Undergoing CABG Surgery, by STS Quintiles of Risk
Graphic Jump Location

Odds ratios (ORs) with 95% CIs are for treatment effect. Risk levels for the 30-day mortality end point were produced using the Society of Thoracic Surgeons (STS) risk model for patients undergoing only coronary artery bypass graft (CABG) surgery. Using STS risk score for isolated CABG in this population, a predicted probability of 30-day mortality was computed for each participant. The probabilities were ranked from low to high and grouped into quintiles of increasing predicted 30-day mortality (see eTable 4).

Table Graphic Jump LocationTable 2. Primary and Key Secondary End Points, Intention-to-Treat Population

Of the secondary end points, none reached or approached statistical significance at 28 days, including all-cause mortality, nonfatal stroke, need for mechanical support for SLVD, and the other secondary composite end points (eTable 5). Cardiovascular mortality through postoperative day 4 was numerically lower in acadesine-treated participants, but this was not statistically significant and was not evident through postoperative day 28. Additional exploratory efficacy end points, including length of mechanical ventilation and intensive care unit and hospital stay, are listed in eTable 6 and eTable 7. None of these exploratory secondary end points, including peak cardiac enzyme level and quality of life (eTable 8 and eTable 9), reached statistical significance.

Consistent with previous trials, adverse events were not significantly different between the treatment and placebo groups, with the exception of an increased incidence of hyperuricemia and elevated uric acid levels in the treatment group. Safety end points of special interest are included in eTable 10 and eTable 11.

In this population of intermediate- to high-risk patients undergoing CABG surgery, acadesine had no effect on the composite end point of all-cause mortality, nonfatal stroke, and SLVD requiring mechanical support through postoperative day 28. The incidence of the primary composite end point in the overall study population (including the placebo group) was substantially below that projected from the previous studies and historical data. The lower-than-predicted incidence is consistent with results from recent perioperative CABG trials16,31 in which advances in clinical practice appeared to reduce morbidity and mortality. A large portion of the lower event rate was attributable to a lower-than-predicted incidence of SLVD requiring mechanical support, which also indicates an improved degree of myocardial protection in a high-risk population. There was no trend toward a benefit in the overall study, resulting in the recommendation by the DSMB that the study be terminated based on predefined stopping rules.

These findings illustrate inherent risks of using promising meta-analysis results to plan “confirmatory” clinical trials. There are several potential explanations for the negative results we observed. One consideration is the decision around study eligibility criteria and the overall primary end point of the trial. The eligibility criteria were based on previous studies of acadesine that showed a greater benefit in higher-risk patients, especially women. However, based on analysis of the risk profile of the patients enrolled, the overall mortality risk based on STS criteria was lower than originally projected, resulting in the study participants being at lower risk than anticipated. Although a comparison of the primary end point by treatment group across quintiles of STS risk stratification did not show any statistically significant differences, we cannot exclude the possibility that a more favorable result might have been obtained in patients deemed to be at higher risk of intraoperative ischemic events, such as those undergoing long and complex combined valve and coronary procedures (Figure 3). Moreover, where these robust national databases exist, the inclusion of major outcome-linked variables in the case report forms of major clinical trials enables this kind of risk profile comparison to be made.

Lack of benefit of acadesine may be related to the dosing regimen used. Previous studies have indicated that sufficient concentrations of the drug in the ischemic myocardium are needed before application of the aortic cross clamp to prevent ischemic injury. In addition, the agent needs to be present during reperfusion to ensure adequate recovery of the myocardium. The delivery technique may not have provided sufficient concentrations of the agent in the myocardium to alter the recovery from ischemia. However, dosing in our study was identical to that used in previous studies included in the meta-analysis that showed benefit for this drug.27

Recent large analyses of cardiac surgery databases have demonstrated a correlation between enzyme elevations occurring after cardiac surgery and later mortality. In the current study, there was no difference in peak enzyme elevations or the incidence of enzyme elevations 5 times greater than the upper limit of normal between acadesine and placebo. This contrasts with previous trials of acadesine that indicated differences in early mortality and perioperative myocardial infarction within the first 4 postoperative days. The incidence of perioperative myocardial infarction was defined in this trial as an elevation of CK-MB, troponin I, or troponin T level greater than 5 times the upper limit of normal and the presence of new Q-wave myocardial infarction on electrocardiogram. Because of this stricter definition, the overall rate of perioperative myocardial infarction was much lower than that reported in earlier studies (0.6% with placebo and 1.0% with acadesine), and the overall incidence of perioperative myocardial infarction was not significantly different between the 2 groups. Myocardial infarction was an exploratory outcome of the trial, and enzyme levels were only collected through 24 hours. Because of the strict criteria and shorter period of surveillance, the lower incidence is not surprising. In each of the different enzymes assessed (CK-MB, troponin I, or troponin T), there was no significant difference in peak level or the incidence of patients with enzyme level elevations greater than 5 times the upper limit of normal by treatment group (eTable 8).

The results of CABG surgery have continued to improve, as reflected in the excellent outcomes found in this trial. Recent trends in the treatment of coronary artery disease have increased the risks of patients presenting for CABG surgery, without substantial associated increase in morbidity or mortality.32 Observed causes for improvement in postoperative morbidity and mortality are likely multifactorial and may include better preoperative selection and preparation, intraoperative treatment, and postoperative recovery. However, the period of cardioplegic arrest is an opportunity to condition the heart and prevent or reverse ischemic/reperfusion injury. Current methods of myocardial protection have markedly improved, but pharmacological additives have not been demonstrated to be beneficial.

Despite the lack of effect of acadesine in this population, the study allowed the evaluation of quality of life after CABG surgery in a large population across many geographical regions. A consistent finding was a preservation of quality of life measured by the EuroQol 5-dimension instrument at 28 days. There was also substantial improvement in several domains of quality of life (eTable 9). These findings, despite documented complications and the earlier-than-normal period of assessment, suggest that quality of life improves after cardiac surgery—results consistent with previous smaller studies.33,34

The RED-CABG study demonstrates that among intermediate- to high-risk patients undergoing CABG surgery, acadesine did not reduce all-cause mortality, nonfatal stroke, or need for mechanical support for SLVD through postoperative day 28. The incidence of the primary composite end point was 5%, indicating the need for continued investigation into therapies to reduce perioperative morbidity and mortality. However, effective therapies remain elusive.

Corresponding Author: Mark F. Newman, MD, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710 (newman005@mc.duke.edu).

Author Contributions: Dr Newman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Newman, Ferguson, Ambrosio, Nussmeier, Pearl, Pitt, Wechsler, Weisel, Reece, Lira, Harrington.

Acquisition of data: Newman, Harrington.

Analysis and interpretation of data: Newman, Ferguson, White, Ambrosio, Koglin, Nussmeier, Weisel, Harrington.

Drafting of the manuscript: Newman, Ferguson, Pearl.

Critical revision of the manuscript for important intellectual content: Newman, White, Ambrosio, Koglin, Nussmeier, Pearl, Pitt, Wechsler, Weisel, Reece, Lira, Harrington.

Statistical analysis: White.

Obtained funding: Koglin, Harrington.

Administrative, technical, or material support: Newman, Ferguson, Koglin, Reece, Lira, Harrington.

Study supervision: Newman, Ferguson, Ambrosio, Koglin, Pearl, Harrington.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Newman reported receiving grant support and honoraria from Schering-Plough/Merck for activities related to the RED-CABG study and this article (all funds paid to the Duke Clinical Research Institute). Dr Ferguson reported receiving honoraria for study committee activities and support for travel to study meetings from Schering-Plough/Merck and receiving a pending grant from Novadaq Technologies (paid to his institution). Dr Ambrosio reported receiving payments from Schering-Plough/Merck for travel to study meetings. Dr Koglin reported holding stock in Merck. Dr Nussmeier reported receiving consulting fees/honoraria from Schering-Plough/Merck (disbursed through the Duke Clinical Research Institute) and receiving support from Schering-Plough/Merck for travel to study-related meetings. Dr Pearl reported receiving consulting fees and honoraria from Schering-Plough/Merck (disbursed through the Duke Clinical Research Institute) for participating on the RED-CABG executive committee. Dr Pitt reported receiving honoraria for study committee activities and support for travel to study meetings from Schering-Plough/Merck; receiving payment for consultancies from Novartis, Bayer, Takeda, AstraZeneca, Lily, BMS, Relypsa, BG Medicine, Amorcyte, Aurascence, Ardelyx, and Cytopherx; receiving grants from Novartis, Medtronic, and Forrest Laboratories; and holding stock in Relypsa, BG Medicine, and Aurascence. Dr Weschler reported receiving consulting fees or honoraria from Schering-Plough/Merck (disbursed through the Duke Clinical Research Institute) and receiving support from Schering-Plough/Merck for travel to study-related meetings. Dr Weisel reported receiving financial support for board membership (executive committee) from Schering-Plough/Merck. Dr Harrington reported receiving grant support and honoraria from Schering-Plough/Merck for activities related to the RED-CABG study and this article; serving on a Merck advisory board and receiving grant funding for several other clinical trials supported by Merck (all such funds paid to the Duke Clinical Research Institute); and receiving direct payments from Merck for consulting activities; a full listing of disclosure information for Dr Harrington is available at https://dcri.org/about-us/conflict-of-interest. No other authors reported disclosures.

Funding/Support: The RED-CABG study was funded by Schering-Plough (subsequently Merck Sharp & Dohme Corp, Whitehouse Station, New Jersey).

Role of the Sponsor:The executive and steering committees, composed of members from academia and the study sponsor, were responsible for the overall design, conduct, and supervision of the study. Schering-Plough (subsequently Merck Sharp & Dohme Corp), funded the research. Two authors employed by the study sponsor participated in the design and conduct of the study (Dr Lira); analysis and interpretation of data (Dr Koglin); and critical revision of the manuscript (Drs Koglin and Lira). Statistical analysis was conducted by Ms White at the Duke Clinical Research Institute.

RED-CABG Steering Committee and Investigators A complete list of the RED-CABG site investigators is provided in the eAppendix. Executive Committee: Giuseppe Ambrosio, M:D, University of Perugia School of Medicine, Perugia, Italy; T. Bruce Ferguson Jr, MD, East Carolina Heart Institute, Greenville, North Carolina; Robert A. Harrington, MD, Duke Clinical Research Institute, Durham, North Carolina; Joerg Koglin, MD, Merck Research Laboratories, Rahway, New Jersey; Mark F. Newman, MD, Duke University Medical Center, Durham, North Carolina; Nancy Nussmeier, MD, SUNY Upstate Medical University, Syracuse, New York; Ronald G. Pearl, MD, PhD, Stanford University School of Medicine, Palo Alto, California; Bertram Pitt, MD, University of Michigan School of Medicine, Ann Arbor; Andrew S. Wechsler, MD, Drexel University College of Medicine, Philadelphia, Pennsylvania; Richard D. Weisel, MD, University Health Network, Toronto, Ontario, Canada. Steering Committee: Stephen Fremes, MD, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Philippe Menasché, Prof, Département de Chirurgie Cardiovasculaire Hôpital Européen Georges Pompidou, Paris, France; Friedrich Wilhelm Mohr, Dr Prof, Herzzentrum Leipzig GmbH; Klinik für Herzchirurgie, Leipzig, Germany; Ardawan J. Rastan, PD Dr med, Oberarzt Herzchirugie Herzzentrum der Universitat Leipzig, Leipzig, Germany; Axel Haverich, Prof Dr med Dr hc, Medizinische Hochschule Hannover Klinik für Herz-, Thorax-, Transplantations- und Gefässchirurgie, Hannover, Germany; Ugolino Livi, Prof, Dipartimento di Scienze Cardio-Polmonari Ospedale S. Maria della Misericordia, Udine, Italy; Pieter Kappetein, Dr, Afdeling Thoraxchirurgie, Erasmus MC, Rotterdam, the Netherlands; Gonzalo Pradas, Dr, Hospital do Meixoeiro Servicio de Cirugia Cardiaca, Vigo, Spain; Robert A. Harrington, MD, Duke Clinical Research Institute, Durham, North Carolina; Mark F. Newman, MD, Duke University Medical Center, Durham, North Carolina; Elliott Bennett-Guerrero, MD, Duke Clinical Research Institute, Durham, North Carolina; T. Bruce Ferguson, MD, East Carolina University Heart Institute, Greenville, North Carolina; Linda Mongero, CCP, New York Presbyterian MC-Columbia, New York, New York; and Xing Li Wang, MD, PhD. Data and Safety Monitoring Board: John H. Alexander, MD, MHS, Duke Clinical Research Institute, Durham, North Carolina; Davy Cheng, MD, MSc, London Health Sciences Centre & St Joseph Health Care, University of Western Ontario, London, Ontario, Canada; Frederick L. Grover, MD, University of Colorado Health Sciences Center, Aurora; Yuliya Lokhnygina, PhD, Duke Clinical Research Institute, Durham, North Carolina; Hans-Christoph Diener, MD, University Duisburg-Essen, Essen, Germany.

Additional Contributions: We gratefully acknowledge and thank Elizabeth Cook, BA, and Jonathan McCall, MS (Duke Clinical Research Institute, Durham, North Carolina), for editorial assistance with the manuscript. Neither received compensation for their contributions apart from their salaries.

STS National Database.  Society of Thoracic Surgeons website. http://www.sts.org/national-database. Accessed June 24, 2011
Clark RE.Ad Hoc Committee on Cardiac Surgery Credentialing of the Society of Thoracic Surgeons.  Outcome as a function of annual coronary artery bypass graft volume.  Ann Thorac Surg. 1996;61(1):21-26
PubMed   |  Link to Article
Del Rizzo DF, Fremes SE, Christakis GT, Sever J, Goldman BS. The current status of myocardial revascularization: changing trends and risk factor analysis.  J Card Surg. 1996;11(1):18-29
PubMed   |  Link to Article
Edwards FH, Clark RE, Schwartz M. Coronary artery bypass grafting: the Society of Thoracic Surgeons National Database experience.  Ann Thorac Surg. 1994;57(1):12-19
PubMed   |  Link to Article
Edwards FH, Clark RE, Schwartz M. Impact of internal mammary artery conduits on operative mortality in coronary revascularization.  Ann Thorac Surg. 1994;57(1):27-32
PubMed   |  Link to Article
He GW, Acuff TE, Ryan WH, Bowman RT, Douthit MB, Mack MJ. Determinants of operative mortality in elderly patients undergoing coronary artery bypass grafting: emphasis on the influence of internal mammary artery grafting on mortality and morbidity.  J Thorac Cardiovasc Surg. 1994;108(1):73-81
PubMed
Jones RH, Hannan EL, Hammermeister KE,  et al; Working Group Panel on the Cooperative CABG Database Project.  Identification of preoperative variables needed for risk adjustment of short-term mortality after coronary artery bypass graft surgery.  J Am Coll Cardiol. 1996;28(6):1478-1487
PubMed   |  Link to Article
Magovern JA, Sakert T, Magovern GJ,  et al.  A model that predicts morbidity and mortality after coronary artery bypass graft surgery.  J Am Coll Cardiol. 1996;28(5):1147-1153
PubMed   |  Link to Article
Mangano DT.Multicenter Study of Perioperative Ischemia Research Group.  Aspirin and mortality from coronary bypass surgery.  N Engl J Med. 2002;347(17):1309-1317
PubMed   |  Link to Article
O’Connor GT, Plume SK, Olmstead EM,  et al;  Northern New England Cardiovascular Disease Study Group.  A regional intervention to improve the hospital mortality associated with coronary artery bypass graft surgery.  JAMA. 1996;275(11):841-846
PubMed   |  Link to Article
Tu JV, Jaglal SB, Naylor CD.Steering Committee of the Provincial Adult Cardiac Care Network of Ontario.  Multicenter validation of a risk index for mortality, intensive care unit stay, and overall hospital length of stay after cardiac surgery.  Circulation. 1995;91(3):677-684
PubMed   |  Link to Article
Ferguson TB Jr, Hammill BG, Peterson ED, DeLong ER, Grover FL.STS National Database Committee; Society of Thoracic Surgeons.  A decade of change—risk profiles and outcomes for isolated coronary artery bypass grafting procedures, 1990-1999: a report from the STS National Database Committee and the Duke Clinical Research Institute.  Ann Thorac Surg. 2002;73(2):480-490
PubMed   |  Link to Article
Guru V, Tu JV, Etchells E,  et al.  Relationship between preventability of death after coronary artery bypass graft surgery and all-cause risk-adjusted mortality rates.  Circulation. 2008;117(23):2969-2976
PubMed   |  Link to Article
O’Connor GT, Birkmeyer JD, Dacey LJ,  et al; Northern New England Cardiovascular Disease Study Group.  Results of a regional study of modes of death associated with coronary artery bypass grafting.  Ann Thorac Surg. 1998;66(4):1323-1328
PubMed   |  Link to Article
Mentzer RM Jr, Bartels C, Bolli R,  et al; EXPEDITION Study Investigators.  Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study.  Ann Thorac Surg. 2008;85(4):1261-1270
PubMed   |  Link to Article
Alexander JH, Emery RW Jr, Carrier M,  et al; MEND-CABG II Investigators.  Efficacy and safety of pyridoxal 5′-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery: the MEND-CABG II randomized clinical trial.  JAMA. 2008;299(15):1777-1787
PubMed   |  Link to Article
Verrier ED, Shernan SK, Taylor KM,  et al; PRIMO-CABG Investigators.  Terminal complement blockade with pexelizumab during coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial.  JAMA. 2004;291(19):2319-2327
PubMed   |  Link to Article
Ikonomidis JS, Shirai T, Weisel RD,  et al.  Preconditioning cultured human pediatric myocytes requires adenosine and protein kinase C.  Am J Physiol. 1997;272(3, pt 2):H1220-H1230
PubMed
Mentzer RM Jr, Birjiniuk V, Khuri S,  et al.  Adenosine myocardial protection: preliminary results of a phase II clinical trial.  Ann Surg. 1999;229(5):643-650
PubMed   |  Link to Article
Chan ES, Cronstein BN. Molecular action of methotrexate in inflammatory diseases.  Arthritis Res. 2002;4(4):266-273
PubMed   |  Link to Article
Gadalla AE, Pearson T, Currie AJ,  et al.  AICA riboside both activates AMP-activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus.  J Neurochem. 2004;88(5):1272-1282
PubMed   |  Link to Article
Gruber HE, Hoffer ME, McAllister DR,  et al.  Increased adenosine concentration in blood from ischemic myocardium by AICA riboside: effects on flow, granulocytes, and injury.  Circulation. 1989;80(5):1400-1411
PubMed   |  Link to Article
Guigas B, Sakamoto K, Taleux N,  et al.  Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators.  IUBMB Life. 2009;61(1):18-26
PubMed   |  Link to Article
Iglesias MA, Furler SM, Cooney GJ, Kraegen EW, Ye JM. AMP-activated protein kinase activation by AICAR increases both muscle fatty acid and glucose uptake in white muscle of insulin-resistant rats in vivo.  Diabetes. 2004;53(7):1649-1654
PubMed   |  Link to Article
Hardie DG. AMP-activated protein kinase as a drug target.  Annu Rev Pharmacol Toxicol. 2007;47:185-210
PubMed   |  Link to Article
Reznick RM, Zong H, Li J,  et al.   Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis.  Cell Metab. 2007;5(2):151-156
PubMed   |  Link to Article
Mangano DT.Multicenter Study of Perioperative Ischemia (McSPI) Research Group.  Effects of acadesine on myocardial infarction, stroke, and death following surgery: a meta-analysis of the 5 international randomized trials.  JAMA. 1997;277(4):325-332
PubMed   |  Link to Article
Schweikert B, Hahmann H, Leidl R. Validation of the EuroQol questionnaire in cardiac rehabilitation.  Heart. 2006;92(1):62-67
PubMed   |  Link to Article
Eagle KA, Guyton RA, Davidoff R,  et al; American College of Cardiology; American Heart Association.  ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery).  Circulation. 2004;110(14):e340-e437
PubMed
Shahian DM, O’Brien SM, Filardo G,  et al; Society of Thoracic Surgeons Quality Measurement Task Force.  The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 1—coronary artery bypass grafting surgery.  Ann Thorac Surg. 2009;88(1):(suppl)  S2-S22
PubMed   |  Link to Article
Tardif JC, Carrier M, Kandzari DE,  et al; MEND-CABG Investigators.  Effects of pyridoxal-5′-phosphate (MC-1) in patients undergoing high-risk coronary artery bypass surgery: results of the MEND-CABG randomized study.  J Thorac Cardiovasc Surg. 2007;133(6):1604-1611
PubMed   |  Link to Article
Davierwala PM, Maganti M, Yau TM. Decreasing significance of left ventricular dysfunction and reoperative surgery in predicting coronary artery bypass grafting–associated mortality: a twelve-year study.  J Thorac Cardiovasc Surg. 2003;126(5):1335-1344
PubMed   |  Link to Article
Cohen DJ, Van Hout B, Serruys PW,  et al; Synergy Between PCI With Taxus and Cardiac Surgery Investigators.  Quality of life after PCI with drug-eluting stents or coronary-artery bypass surgery.  N Engl J Med. 2011;364(11):1016-1026
PubMed   |  Link to Article
Grady KL, Lee R, Subačius H,  et al.  Improvements in health-related quality of life before and after isolated cardiac operations.  Ann Thorac Surg. 2011;91(3):777-783
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Study Flow
Graphic Jump Location

aAs defined by protocol.
bParticipants without postoperative day 28 data were considered as not having completed follow-up.

Place holder to copy figure label and caption
Figure 2. Kaplan-Meier Curve of the Analysis of the Primary Composite End Point (All-Cause Mortality/Nonfatal Stroke/Severe Left Ventricular Dysfunction)—Intention-to-Treat Population
Graphic Jump Location
Place holder to copy figure label and caption
Figure 3. Incidence of the Primary Composite End Point (All-Cause Mortality/Nonfatal Stroke/Severe Left Ventricular Dysfunction) by Postoperative Day 28 in Patients Undergoing CABG Surgery, by STS Quintiles of Risk
Graphic Jump Location

Odds ratios (ORs) with 95% CIs are for treatment effect. Risk levels for the 30-day mortality end point were produced using the Society of Thoracic Surgeons (STS) risk model for patients undergoing only coronary artery bypass graft (CABG) surgery. Using STS risk score for isolated CABG in this population, a predicted probability of 30-day mortality was computed for each participant. The probabilities were ranked from low to high and grouped into quintiles of increasing predicted 30-day mortality (see eTable 4).

Tables

Table Graphic Jump LocationTable 2. Primary and Key Secondary End Points, Intention-to-Treat Population

References

STS National Database.  Society of Thoracic Surgeons website. http://www.sts.org/national-database. Accessed June 24, 2011
Clark RE.Ad Hoc Committee on Cardiac Surgery Credentialing of the Society of Thoracic Surgeons.  Outcome as a function of annual coronary artery bypass graft volume.  Ann Thorac Surg. 1996;61(1):21-26
PubMed   |  Link to Article
Del Rizzo DF, Fremes SE, Christakis GT, Sever J, Goldman BS. The current status of myocardial revascularization: changing trends and risk factor analysis.  J Card Surg. 1996;11(1):18-29
PubMed   |  Link to Article
Edwards FH, Clark RE, Schwartz M. Coronary artery bypass grafting: the Society of Thoracic Surgeons National Database experience.  Ann Thorac Surg. 1994;57(1):12-19
PubMed   |  Link to Article
Edwards FH, Clark RE, Schwartz M. Impact of internal mammary artery conduits on operative mortality in coronary revascularization.  Ann Thorac Surg. 1994;57(1):27-32
PubMed   |  Link to Article
He GW, Acuff TE, Ryan WH, Bowman RT, Douthit MB, Mack MJ. Determinants of operative mortality in elderly patients undergoing coronary artery bypass grafting: emphasis on the influence of internal mammary artery grafting on mortality and morbidity.  J Thorac Cardiovasc Surg. 1994;108(1):73-81
PubMed
Jones RH, Hannan EL, Hammermeister KE,  et al; Working Group Panel on the Cooperative CABG Database Project.  Identification of preoperative variables needed for risk adjustment of short-term mortality after coronary artery bypass graft surgery.  J Am Coll Cardiol. 1996;28(6):1478-1487
PubMed   |  Link to Article
Magovern JA, Sakert T, Magovern GJ,  et al.  A model that predicts morbidity and mortality after coronary artery bypass graft surgery.  J Am Coll Cardiol. 1996;28(5):1147-1153
PubMed   |  Link to Article
Mangano DT.Multicenter Study of Perioperative Ischemia Research Group.  Aspirin and mortality from coronary bypass surgery.  N Engl J Med. 2002;347(17):1309-1317
PubMed   |  Link to Article
O’Connor GT, Plume SK, Olmstead EM,  et al;  Northern New England Cardiovascular Disease Study Group.  A regional intervention to improve the hospital mortality associated with coronary artery bypass graft surgery.  JAMA. 1996;275(11):841-846
PubMed   |  Link to Article
Tu JV, Jaglal SB, Naylor CD.Steering Committee of the Provincial Adult Cardiac Care Network of Ontario.  Multicenter validation of a risk index for mortality, intensive care unit stay, and overall hospital length of stay after cardiac surgery.  Circulation. 1995;91(3):677-684
PubMed   |  Link to Article
Ferguson TB Jr, Hammill BG, Peterson ED, DeLong ER, Grover FL.STS National Database Committee; Society of Thoracic Surgeons.  A decade of change—risk profiles and outcomes for isolated coronary artery bypass grafting procedures, 1990-1999: a report from the STS National Database Committee and the Duke Clinical Research Institute.  Ann Thorac Surg. 2002;73(2):480-490
PubMed   |  Link to Article
Guru V, Tu JV, Etchells E,  et al.  Relationship between preventability of death after coronary artery bypass graft surgery and all-cause risk-adjusted mortality rates.  Circulation. 2008;117(23):2969-2976
PubMed   |  Link to Article
O’Connor GT, Birkmeyer JD, Dacey LJ,  et al; Northern New England Cardiovascular Disease Study Group.  Results of a regional study of modes of death associated with coronary artery bypass grafting.  Ann Thorac Surg. 1998;66(4):1323-1328
PubMed   |  Link to Article
Mentzer RM Jr, Bartels C, Bolli R,  et al; EXPEDITION Study Investigators.  Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study.  Ann Thorac Surg. 2008;85(4):1261-1270
PubMed   |  Link to Article
Alexander JH, Emery RW Jr, Carrier M,  et al; MEND-CABG II Investigators.  Efficacy and safety of pyridoxal 5′-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery: the MEND-CABG II randomized clinical trial.  JAMA. 2008;299(15):1777-1787
PubMed   |  Link to Article
Verrier ED, Shernan SK, Taylor KM,  et al; PRIMO-CABG Investigators.  Terminal complement blockade with pexelizumab during coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial.  JAMA. 2004;291(19):2319-2327
PubMed   |  Link to Article
Ikonomidis JS, Shirai T, Weisel RD,  et al.  Preconditioning cultured human pediatric myocytes requires adenosine and protein kinase C.  Am J Physiol. 1997;272(3, pt 2):H1220-H1230
PubMed
Mentzer RM Jr, Birjiniuk V, Khuri S,  et al.  Adenosine myocardial protection: preliminary results of a phase II clinical trial.  Ann Surg. 1999;229(5):643-650
PubMed   |  Link to Article
Chan ES, Cronstein BN. Molecular action of methotrexate in inflammatory diseases.  Arthritis Res. 2002;4(4):266-273
PubMed   |  Link to Article
Gadalla AE, Pearson T, Currie AJ,  et al.  AICA riboside both activates AMP-activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus.  J Neurochem. 2004;88(5):1272-1282
PubMed   |  Link to Article
Gruber HE, Hoffer ME, McAllister DR,  et al.  Increased adenosine concentration in blood from ischemic myocardium by AICA riboside: effects on flow, granulocytes, and injury.  Circulation. 1989;80(5):1400-1411
PubMed   |  Link to Article
Guigas B, Sakamoto K, Taleux N,  et al.  Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators.  IUBMB Life. 2009;61(1):18-26
PubMed   |  Link to Article
Iglesias MA, Furler SM, Cooney GJ, Kraegen EW, Ye JM. AMP-activated protein kinase activation by AICAR increases both muscle fatty acid and glucose uptake in white muscle of insulin-resistant rats in vivo.  Diabetes. 2004;53(7):1649-1654
PubMed   |  Link to Article
Hardie DG. AMP-activated protein kinase as a drug target.  Annu Rev Pharmacol Toxicol. 2007;47:185-210
PubMed   |  Link to Article
Reznick RM, Zong H, Li J,  et al.   Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis.  Cell Metab. 2007;5(2):151-156
PubMed   |  Link to Article
Mangano DT.Multicenter Study of Perioperative Ischemia (McSPI) Research Group.  Effects of acadesine on myocardial infarction, stroke, and death following surgery: a meta-analysis of the 5 international randomized trials.  JAMA. 1997;277(4):325-332
PubMed   |  Link to Article
Schweikert B, Hahmann H, Leidl R. Validation of the EuroQol questionnaire in cardiac rehabilitation.  Heart. 2006;92(1):62-67
PubMed   |  Link to Article
Eagle KA, Guyton RA, Davidoff R,  et al; American College of Cardiology; American Heart Association.  ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery).  Circulation. 2004;110(14):e340-e437
PubMed
Shahian DM, O’Brien SM, Filardo G,  et al; Society of Thoracic Surgeons Quality Measurement Task Force.  The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 1—coronary artery bypass grafting surgery.  Ann Thorac Surg. 2009;88(1):(suppl)  S2-S22
PubMed   |  Link to Article
Tardif JC, Carrier M, Kandzari DE,  et al; MEND-CABG Investigators.  Effects of pyridoxal-5′-phosphate (MC-1) in patients undergoing high-risk coronary artery bypass surgery: results of the MEND-CABG randomized study.  J Thorac Cardiovasc Surg. 2007;133(6):1604-1611
PubMed   |  Link to Article
Davierwala PM, Maganti M, Yau TM. Decreasing significance of left ventricular dysfunction and reoperative surgery in predicting coronary artery bypass grafting–associated mortality: a twelve-year study.  J Thorac Cardiovasc Surg. 2003;126(5):1335-1344
PubMed   |  Link to Article
Cohen DJ, Van Hout B, Serruys PW,  et al; Synergy Between PCI With Taxus and Cardiac Surgery Investigators.  Quality of life after PCI with drug-eluting stents or coronary-artery bypass surgery.  N Engl J Med. 2011;364(11):1016-1026
PubMed   |  Link to Article
Grady KL, Lee R, Subačius H,  et al.  Improvements in health-related quality of life before and after isolated cardiac operations.  Ann Thorac Surg. 2011;91(3):777-783
PubMed   |  Link to Article
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