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Original Investigation |

Kidney Function After Off-Pump or On-Pump Coronary Artery Bypass Graft Surgery:  A Randomized Clinical Trial FREE

Amit X. Garg, MD, PhD1,2,3; P. J. Devereaux, MD, PhD3,4; Salim Yusuf, DPhil3,4; Meaghan S. Cuerden, MSc1,5; Chirag R. Parikh, MD, PhD6; Steven G. Coca, DO, MS6; Michael Walsh, MD, MSc3,4; Richard Novick, MD7; Richard J. Cook, PhD5; Anil R. Jain, MBBS8; Xiangbin Pan, MD9; Nicolas Noiseux, MD10; Karel Vik, MD11; Noedir A. Stolf, MD, PhD12; Andrew Ritchie, MD, PhD13; Roberto R. Favaloro, MD14; Sirish Parvathaneni, MD15; Richard P. Whitlock, MD, MSc3,4,16; Yongning Ou, MD4; Mitzi Lawrence, RN4; Andre Lamy, MD, MHSc3,4,16; for the CORONARY Investigators
[+] Author Affiliations
1Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada
2Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
3Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
4Population Health Research Institute, Hamilton, Ontario, Canada
5Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, Ontario, Canada
6Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut
7Division of Cardiac Surgery, Western University, London, Ontario, Canada
8SAL Hospital and Medical Institute, Ahmadabad, India
9Department of Cardiovascular Surgery, Fuiwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
10Department of Cardiac Surgery, Centre Hospitalier de l’Université de Montréal CHUM, Montreal, Quebec, Canada
11University Hospital Motol, Praha, Czech Republic
12Instituto do Coracao do Hospital das Clinicas da, São Paulo, Brazil
13Essex Cardiothoracic Centre and Anglia Ruskin University, Essex, England
14Department of Cardiovascular Surgery, Hospital Universitario Fundacion Favaloro, Buenos Aires, Argentina
15Mercy Hospital, Springfield, Missouri
16Division of Cardiac Surgery, McMaster University, Hamilton, Ontario, Canada
JAMA. 2014;311(21):2191-2198. doi:10.1001/jama.2014.4952.
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Published online

Importance  Most acute kidney injury observed in the hospital is defined by sudden mild or moderate increases in the serum creatinine concentration, which may persist for several days. Such acute kidney injury is associated with lower long-term kidney function. However, it has not been demonstrated that an intervention that reduces the risk of such acute kidney injury better preserves long-term kidney function.

Objectives  To characterize the risk of acute kidney injury with an intervention in a randomized clinical trial and to determine if there is a difference between the 2 treatment groups in kidney function 1 year later.

Design, Setting, and Participants  The Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY) enrolled 4752 patients undergoing first isolated coronary artery bypass graft (CABG) surgery at 79 sites in 19 countries. Patients were randomized to receive CABG surgery either with a beating-heart technique (off-pump) or with cardiopulmonary bypass (on-pump). From January 2010 to November 2011, 2932 patients (from 63 sites in 16 countries) from CORONARY were enrolled into a kidney function substudy to record serum creatinine concentrations during the postoperative period and at 1 year. The last 1-year serum creatinine concentration was recorded on January 18, 2013.

Main Outcomes and Measures  Acute kidney injury within 30 days of surgery (≥50% increase in serum creatinine concentration from prerandomization concentration) and loss of kidney function at 1 year (≥20% loss in estimated glomerular filtration rate from prerandomization level).

Results  Off-pump (n = 1472) vs on-pump (n = 1460) CABG surgery reduced the risk of acute kidney injury (17.5% vs 20.8%, respectively; relative risk, 0.83 [95% CI, 0.72-0.97], P = .01); however, there was no significant difference between the 2 groups in the loss of kidney function at 1 year (17.1% vs 15.3%, respectively; relative risk, 1.10 [95% CI, 0.95-1.29], P = .23). Results were consistent with multiple alternate continuous and categorical definitions of acute kidney injury or kidney function loss, and in the subgroup with baseline chronic kidney disease.

Conclusions and Relevance  Use of off-pump compared with on-pump CABG surgery reduced the risk of postoperative acute kidney injury, without evidence of better preserved kidney function with off-pump CABG surgery at 1 year. In this setting, an intervention that reduced the risk of mild to moderate acute kidney injury did not alter longer-term kidney function.

Trial Registration  clinicaltrials.gov Identifier: NCT00463294

Acute kidney injury is a sudden loss of kidney function defined by an acute increase in serum creatinine concentration.1 Dialysis is used when acute kidney injury is severe, and this type of acute kidney injury contributes to poor long-term kidney function.2 It is more common for patients to develop less severe acute kidney injury in the hospital (ie, a ≥50% increase in serum creatinine concentration that may persist for several days before returning back to a concentration that predated the acute kidney injury). Up to 30% of patients develop less severe acute kidney injury after cardiac surgery, while 1% require acute dialysis.3 The effects of mild or moderate acute kidney injury on long-term kidney function are not clear. Animal studies suggest a causal link between acute kidney injury and long-term kidney function loss, mediated by microvascular damage, reduced capillary density, and chronic renal hypoxia.46 Several human observational studies demonstrate a robust association between mild or moderate acute kidney injury and kidney function loss as early as 3 months after the injury.79 However, it has not been proven in any trial that an intervention that reduces the risk of acute kidney injury better preserves longer-term kidney function.

For this reason, we studied acute kidney injury in the setting of a trial of coronary artery bypass graft (CABG) surgery performed with either a beating-heart technique (off-pump) or cardiopulmonary bypass (on-pump).10 Compared with on-pump, we expected off-pump CABG surgery to reduce the risk of postoperative acute kidney injury,11,12 and if correct, aimed to determine if there was a difference in kidney function between the 2 groups 1 year later.

Study Design and Setting

The randomized clinical Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY) compared patients undergoing their first isolated CABG surgery using the off-pump or on-pump technique.13 A central telephone randomization service was used to assign 4752 patients at a 1:1 ratio to 1 of the 2 surgical groups from November 2006 through November 2011 (randomization stratified by site). Results from CORONARY have been published.14,15 There was no significant difference between the 2 groups on the composite outcome of death, nonfatal myocardial infarction, stroke, or new dialysis for kidney failure within 30 days or 1 year postrandomization (30 days: 9.8% for off-pump vs 10.3% for on-pump CABG surgery; 1 year: 12.1% vs 13.3%, respectively).14,15 Similarly, none of the outcome components differed between the 2 groups, and there was not a significant difference in the rate of coronary revascularization within 1 year (1.4% for off-pump vs 0.8% for on-pump CABG surgery).

The prespecified protocol and analysis plan for this CORONARY kidney function substudy was published.10 After receipt of grant funding for this substudy, 63 of 79 study sites participated in the protocol, which required additional serum creatinine concentrations to be measured and recorded in new enrollees. Regional ethics boards approved additional kidney data collection in centers that agreed to study participation, and all patients provided informed consent. Each site randomized their first consecutive patients into the protocol between January 2010 and June 2011. Thus, 1777 of 4752 enrollees from CORONARY were not assessed for kidney function substudy eligibility (1336 from participating sites prior to substudy initiation, and 441 from nonparticipating sites).

Patients

The overall eligibility criteria for CORONARY have been published (eMethods in Supplement).14 As per the CORONARY kidney function substudy protocol, patients were not eligible for participation if they had end-stage renal disease prior to randomization because the assessment of acute kidney injury is no longer relevant (estimated glomerular filtration rate [GFR] <15 mL/min/1.73 m2 or receipt of chronic dialysis), or if they were missing a prerandomization serum creatinine concentration because this is needed to define acute kidney injury. Baseline characteristics were similar between all patients in the CORONARY trial and those in the kidney function substudy (minor differences appear in eTable 1 in Supplement).

Outcomes

The primary postoperative acute kidney injury outcome was evidence of a 50% or greater increase in the serum creatinine concentration from the prerandomization (preoperative) value within 30 days of CABG surgery. The prerandomization serum creatinine concentration was obtained in the 7 days prior to randomization. Postoperative serum creatinine measurements were collected while the patient was still in the hospital as per routine care at each participating site. In the primary analysis, the highest serum creatinine concentration collected within 30 days after surgery was used to determine whether acute kidney injury was present or not.

The primary outcome of loss of kidney function at 1 year was determined by a 20% or greater loss in estimated GFR from the prerandomization value, in which a serum creatinine concentration at 1 year was measured and recorded as part of the kidney function substudy protocol. The last 1-year serum creatinine concentration was recorded on January 18, 2013. We calculated estimated GFR using the Chronic Kidney Disease Epidemiology Collaboration equation, with knowledge of black race (<0.1% of patients).16

Statistical Analyses

The analysis was performed according to the prespecified protocol, with any deviations justified (eTable 2 in Supplement). We conducted all primary analyses according to the intention-to-treat principle and used SAS version 9.2 (SAS Institute Inc) for all statistical analyses.

We used mixed-effects logistic regression, considering center as a random effect (randomization stratum), and expressed the treatment effect as a relative risk (RR) derived from this model.17 We conducted a nonparametric analysis of covariance to report the continuous 30-day perioperative percentage change in serum creatinine concentration (residual variance was not constant),18,19 and a parametric analysis of covariance to report estimated GFR at 1 year, treating center (randomization strata) as a fixed effect. In adjusted analyses, all models were adjusted for the following prespecified covariates assessed prior to surgery: age (per year), sex, left ventricular function categories (≥50%, 35%-49%, 20%-34%, <20%), presence of diabetes, long-term use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, statin use, diuretic use, urgent vs elective surgery, and chronic kidney disease (defined by a prerandomization estimated GFR ≤60 mL/min/1.73 m2). Results were assessed in subgroups defined by prerandomization chronic kidney disease.20 A P value of .05 or less was interpreted as significant for both the test for interaction and the alternately defined kidney outcomes if concordant with the primary results.

With the enrollment of 2932 patients, there was more than 80% power to detect a 25% RR reduction in a 20% or greater loss in estimated GFR at 1 year (assumptions: 2-tailed α level of .05 and 10% loss to measurement). A sample of 1800 patients provided 80% power to detect a 4% or higher difference in the percentage change in 1-year estimated GFR between the 2 groups (details appear in protocol10).

For our primary method of imputing missing serum creatinine values, we carried forward the prerandomization serum creatinine concentration for missing 30-day or 1-year values (eTable 3 in Supplement lists deaths and other reasons for missing measurements). We imputed an estimated GFR value of 5 mL/min/1.73 m2 at 1 year for any patient who developed end-stage renal disease (≥3 months of continuous dialysis), or who died shortly after receipt of acute dialysis for severe acute kidney injury (eTable 3 in Supplement). All other baseline and follow-up data were complete.

Patients

Among the 2975 consecutive patients enrolled in CORONARY and assessed for kidney function substudy participation, 43 were ineligible due to prerandomization end-stage renal disease (1.3% patients; n = 18 in off-pump and n = 21 in on-pump CABG surgery group) or a missing serum creatinine value prior to surgery (0.13% patients; n = 1 in off-pump and n = 3 in on-pump CABG surgery group). Thus, 2932 patients (from 63 sites in 16 countries) participated in the kidney function substudy. Of these, 1472 patients were randomly assigned to off-pump and 1460 to on-pump CABG surgery. All randomized patients received CABG surgery and the median time from randomization to surgery was 1 day (interquartile range [IQR], 1-2 days). Baseline characteristics are presented in Table 1. With respect to crossovers between the groups, 102 of 1472 patients (6.9%) assigned to off-pump CABG surgery actually underwent on-pump CABG surgery, and 105 of 1460 patients (7.2%) assigned to on-pump underwent off-pump CABG surgery. The timing of and reasons for the crossovers in all CORONARY participants are reported elsewhere.14 Even though the characteristics of patients differed based on who did and who did not provide a 1-year creatinine measurement (eTable 4 in Supplement), there was no evidence of differential ascertainment of the primary outcomes between the 2 groups (eTable 3 in Supplement).

Table Graphic Jump LocationTable 1.  Baseline Characteristics of Patients in the CORONARY Kidney Function Substudy

More than 90% of eligible patients had their 1-year serum creatinine concentration recorded as per protocol. In both groups, the median time postsurgery to the date of the 1-year serum creatinine measurement was 1.0 year (IQR, 1.0-1.1 years), the hospital length of stay was 7 days (IQR, 6-9 days), and the number of postoperative serum creatinine measurements was 5 (IQR, 3-7). Similarly, the 2 groups did not differ during follow-up in their use of medications that affect kidney function or its measurement (eTable 5 in Supplement). The median time was 2 days (IQR, 1-4 days) after surgery for the highest serum creatinine value used to define acute kidney injury within 30 days after surgery, and 90% of the 561 acute kidney injury events occurred within 7 days after surgery.

Postoperative Acute Kidney Injury

There was less acute kidney injury with off-pump (257/1472 [17.5%]) vs on-pump (304/1460 [20.8%]) CABG surgery (adjusted RR, 0.83 [95% CI, 0.72 to 0.97], P = .01; Table 2). Observed RRs were consistent when the data were reanalyzed using multiple alternate definitions of acute kidney injury, and a composite outcome of acute kidney injury or death (Table 2). The mean highest postoperative serum creatinine concentration was 114 (SD, 61) μmol/L (median, 97 [IQR, 80 to 124] μmol/L) with off-pump vs 120 (SD, 66) μmol/L (median, 102 [IQR, 86 to 133] μmol/L) with on-pump CABG surgery. The mean percentage increase in serum creatinine concentration was 28% (SD, 59%) with off-pump vs 33% (SD, 63%) with on-pump CABG surgery (mean difference between the groups, −5% [95% CI, −10% to −1%], P = .02; eFigure 1 in Supplement). The median percentage increase in serum creatinine concentration was 14% (IQR, 0% to 37%) with off-pump vs 19% (IQR, 3% to 43%) with on-pump CABG surgery. The mean absolute increase in serum creatinine was 24 (SD, 50) μmol/L with off-pump vs 29 (SD, 56) μmol/L with on-pump CABG surgery (mean difference in the absolute change, −6 μmol/L [95% CI, −9 to −2 μmol/L], P = .005). The median absolute increase in serum creatinine concentration was 11 μmol/L (IQR, 0 to 31 μmol/L) with off-pump vs 18 μmol/L (IQR, 2 to 35 μmol/L) with on-pump CABG surgery. In survivors, using the most recent available serum creatinine value prior to hospital discharge, most patients with acute kidney injury no longer met the definition (ie, serum creatinine concentration at discharge <150% preoperative value: 169/236 [72%] with off-pump vs 180/280 [64%] with on-pump CABG surgery; χ2P = .08).

Table Graphic Jump LocationTable 2.  Acute Kidney Injury (AKI) After Coronary Artery Bypass Graft (CABG) Surgery Within 30 Days Postsurgery
Kidney Function Loss at 1 Year

The mean estimated GFR at 1 year was 72 (SD, 19) mL/min/1.73 m2 with off-pump and 73 (SD, 19) mL/min/1.73 m2 with on-pump CABG surgery. There was no significant difference in a 20% or greater loss of estimated GFR from the prerandomization value at 1 year between off-pump (252/1472 [17.1%]) vs on-pump (224/1460 [15.3%]) CABG surgery (adjusted RR, 1.10 [95% CI, 0.95 to 1.29], P = .23; Table 3). A nonsignificant result was consistent when the data were reanalyzed using multiple alternate definitions of kidney function loss, a composite outcome of kidney function loss or death, or an outcome that required a patient to have both postoperative acute kidney injury and kidney function loss at 1 year (Table 3). A nonsignificant result was also observed with multiple imputation for any missing 1-year serum creatinine value (RR, 1.05 [95% CI, 0.93 to 1.19]; eTable 6 in Supplement). The mean percentage change in estimated GFR was −2% (SD, 24%) with off-pump and 0% (SD, 26%) with on-pump CABG surgery, and the mean difference in the percentage change in estimated GFR between the 2 groups was −2% (95% CI, −4% to 0%, P = .04) in favor of better estimated GFR with on-pump CABG surgery (eFigure 2 in Supplement). Similarly, the mean absolute change in estimated GFR was −3 (SD, 16) mL/min/1.73 m2 with off-pump and −2 (SD, 16) mL/min/1.73 m2 with on-pump CABG surgery (mean difference in the absolute change, −1 [95% CI, −2 to 0] mL/min/1.73 m2; P = .04).

Table Graphic Jump LocationTable 3.  Loss in Estimated Glomerular Filtration Rate (GFR) at 1 Year From the Estimated GFR Prior to Randomization
Subgroup Analysis of Preoperative Chronic Kidney Disease

The RR of acute kidney injury with off-pump vs on-pump CABG surgery was lower in those with preoperative chronic kidney disease than in those without chronic kidney disease (P = .01 for interaction; Table 4). The absolute risk reduction of acute kidney injury with off-pump vs on-pump CABG surgery was greater in those with chronic kidney disease (−11.0% [95% CI, −17.4% to −4.6%]) compared with those without chronic kidney disease (−1.1% [95% CI, −4.2% to 2.1%]). The RR for off-pump vs on-pump CABG surgery and kidney function loss at 1 year remained nonsignificant in those with and without chronic kidney disease (P = .58 for interaction; Table 4). Results were consistent when the data were reanalyzed using multiple alternate definitions of acute kidney injury and kidney function loss (eTable 7 in Supplement).

Table Graphic Jump LocationTable 4.  Off-Pump and On-Pump Coronary Artery Bypass Graft (CABG) Surgery Outcomes Assessed in Those With and Without Baseline Chronic Kidney Disease
Complete Case As-Treated Analysis

The results from a complete case as-treated analysis (restricted to patients with complete serum creatinine measurements and who received their allocated type of CABG surgery) were consistent with the intention-to-treat results (eTable 6 in Supplement).

Observational Cohort Analysis

When CORONARY was analyzed as a prospective cohort, acute kidney injury (180/561 [32.1%]) vs no acute kidney injury (296/2371 [12.5%]) was independently associated with a greater risk of kidney function loss at 1 year (adjusted odds ratio, 3.37 [95% CI, 2.65-4.28], P < .001; eTable 8 and eTable 9 in Supplement).

In this study of almost 3000 patients, off-pump relative to on-pump CABG surgery reduced the risk of postoperative acute kidney injury by 17% (95% CI, 5%-28%). In a recent meta-analysis of 22 prior randomized controlled trials (total of 4819 patients), off-pump vs on-pump CABG surgery reduced the RR of postoperative acute kidney injury by 40% (95% CI, 16%-57%).12 Therefore, convincing evidence now exists that off-pump CABG surgery reduces the risk of mild to moderate acute kidney injury. The relative and absolute risk reduction appears greatest in patients with preoperative chronic kidney disease.

However, it remains unproven in a randomized clinical trial that an intervention that prevents such acute kidney injury better preserves long-term kidney function. In CORONARY, a group of patients randomly assigned to off-pump vs on-pump CABG surgery did not have better kidney function 1 year later despite having less mild to moderate acute kidney injury. Results were consistent across multiple definitions of kidney function, and in the subgroup with preoperative chronic kidney disease. We offer several possible reasons for this observed result.

First, a follow-up duration of 1 year may be too short. However, the association is robust at 1 year in prior observational studies.21,22 A between-group difference during longer follow-up may be unlikely if a benefit was not evident at 1 year. In CORONARY, there was slightly more (and not less) estimated GFR loss at 1 year with off-pump vs on-pump CABG.

Second, errors with serum creatinine concentration as a measure of kidney function, particularly when collected once at baseline and at 1 year, may mean a true signal went undetected. A 20% loss of estimated GFR at 1 year is no substitute for the highly relevant outcome of end-stage renal disease (the latter was an infrequent event in CORONARY). Worldwide efforts to better standardize the serum creatinine assay have been ongoing during the last decade.23 It remains likely that intra- or interlaboratory variability contributed to measurement error in the difference between 1 year and baseline serum creatinine concentration in certain patients at some CORONARY sites. The baseline serum creatinine concentration in some patients in CORONARY could also be unstable from poor renal perfusion or recent contrast. Despite this, a reduction in acute kidney injury risk remained evident with off-pump vs on-pump CABG surgery, and 30-day and 1 year results were no different after adjusting for urgent surgery.

Third, the nonacute kidney injury effects of off-pump CABG surgery, or the differential care in follow-up between the off-pump and on-pump CABG surgery groups (such as nephrology visits, which were not assessed in CORONARY), may have counterbalanced the effect of acute kidney injury on long-term kidney function. However, there was no difference in primary trial outcomes (death, myocardial infarction, stroke) between off-pump and on-pump CABG surgery during 1 year. In addition, there were no differences between the 2 groups in secondary trial outcomes (eg, coronary revascularization, quality of life, or neurocognitive function).15 We also observed no significant differences between the 2 groups in the use of diuretics and other medications.

Fourth, the magnitude of acute kidney injury reduction with off-pump CABG may be too small and affect too few patients to have an effect on long-term kidney function for the entire group. Even though a larger risk reduction was desired, the effect observed in CORONARY (a 17% RR reduction) is similar in magnitude to proven interventions for acute conditions.24 Off-pump CABG surgery is substantially different than on-pump CABG surgery, avoiding cannulation and cross-clamping of the aorta, cardioplegic arrest, bypass circuit changes in blood concentration and pulsatility, and a blood circuit interface that stimulates inflammation.25

Fifth, mild to moderate acute kidney injury (as defined in modern classification systems1) may not cause substantial chronic kidney disease. Multiple observational cohort studies demonstrate a robust association between mild to moderate acute kidney injury and long-term decrements in kidney function, which was also evident in CORONARY when analyzed as a prospective cohort. However, patients who develop acute kidney injury (vs those who do not) in nearly every observational study are sicker and have more comorbidity, which also contributes to the development and progression of chronic kidney disease. These factors confound some of the observed associations between mild acute kidney injury and the loss of long-term kidney function.26,27

Regardless of the reasons attributed to the observed 1-year kidney results from the CORONARY trial, the findings emphasize proof is needed to claim an intervention that reduces the risk of mild acute kidney injury better preserves long-term kidney function for the group that received it. This has implications for the development, testing, and use of interventions designed solely to prevent the degrees of acute kidney injury observed in CORONARY, and in determining acceptable adverse effects and costs of such interventions. An acute, nonsustained mild increase in the serum creatinine concentration is a surrogate outcome that may not directly influence how patients feel, function, or survive. The CORONARY results support the position of regulatory agencies such as the US Food and Drug Administration, which indicates that it will not approve an intervention simply because it prevents modest acute kidney injury.28 Rather there must be proof that the intervention has an effect on long-term permanent kidney function (or other clinically meaningful events). This provides pause for interventions such as n-acetylcysteine and intravenous sodium bicarbonate, which have been broadly adopted because smaller trials29,30 demonstrated a reduced risk of modest acute kidney injury without proof of an effect on permanent kidney function. Our results also have implications for trials currently examining intervention effects on mild acute kidney injury without assessing long-term kidney function.31

The limitations of the CORONARY trial have been reported.14,15 With respect to this kidney function substudy, it remains to be seen if findings similar to ours will be observed with other interventions that prevent single or recurrent episodes of acute kidney injury. Future trials should consider multiple measures of kidney function over time, both before and long after acute kidney injury occurs, examine trajectories of kidney function loss, and use new markers of kidney function or injury. Even though this information was sought in CORONARY, there were insufficient resources to reliably collect such measures within the efficient data collection schedule used in this large international trial. Also, consideration should be given to enrolling a greater number of patients with baseline chronic kidney disease, in which a causal relationship between acute kidney injury and longer-term kidney function may be most likely to be observed if it in truth exists.

Strengths of the kidney function substudy and the overall CORONARY trial are generalizable estimates derived from patients recruited from 63 centers in 16 countries, fidelity to the prespecified protocol, and use of a rigorous randomized trial method (eg, concealed allocation, blinded central adjudication of outcomes). There was no evidence of differential ascertainment of kidney outcomes in the 2 surgical groups, and more than 90% of eligible patients had their 1-year serum creatinine measurement recorded as per protocol.

The use of off-pump vs on-pump CABG surgery reduced the risk of postoperative acute kidney injury; however, we failed to observe better kidney function with off-pump vs on-pump CABG surgery 1 year later. In this setting, an intervention that reduced the risk of mild to moderate acute kidney injury did not alter longer-term kidney function.

Corresponding Author: Amit X. Garg, MD, PhD, London Health Sciences Centre, 800 Commissioners Rd E, London, ON N6A 4G5, Canada (amit.garg@lhsc.on.ca).

Published Online: June 2, 2014. doi:10.1001/jama.2014.4952.

Author Contributions: Dr Garg 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: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Garg.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Garg, Cuerden, Cook.

Obtained funding: All authors.

Administrative, technical, or material support: All authors.

Study supervision: All authors.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Garg reported receiving grant funding from Astellas, Roche, and Pfizer outside the submitted work. Dr Devereaux reported receiving grants from Abbott Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Roche Diagnostics, and Stryker outside the submitted work. Dr Parikh reported participating on a data monitoring committee for a phase 2 trial sponsored by Abbvie. Drs Yusuf, Coca, Walsh, Novick, Cook, Jain, Pan, Noiseux, Vik, Stolf, Ritchie, Favaloro, Parvathaneni, Whitlock, Ou, and Lamy and Mss Cuerden and Lawrence reported no disclosures.

Funding/Support: The Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY) and this kidney function substudy were financially supported by grants from the Canadian Institutes of Health Research.

Role of the Sponsors: The Canadian Institutes of Health Research had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: Investigators from the kidney function substudy of CORONARY at the coordinating center: S. Chrolavicius (project manager), Y. Ou (coordinator), M. Lawrence (events adjudication coordinator), J. Pogue (statistician), and A. X. Garg (kidney events adjudication), L. Robinson, A. Lamy, P. J. Devereaux, R. Whitlock, and S. Yusuf. Recruiting center principal investigators: H. Cacheda, R. R. Favaloro, W. D. Ferrara, and P. A. Olavegogeascoechea (Argentina); M. P. Vallely (Australia); D. M. Braile, E. Buffolo, F. D. A. Costa, J. B. P. de Oliveira, L. C. B. de Sousa, N. A. Groppo Stolf, F. A. Lucchese, A. C. Penna, A. C. Pires, and L. A. Rivetti (Brazil); R. Cartier, S. E. Fremes, D. M. Greentree, T. M. Kieser, A. Lamy, N. Noiseux, and R. J. Novick (Canada); X. Chen, C. Gao, T. Gu, S. Hu, Y. Kong, X. Meng, P. Su, L. Tao, C. Wang, S. Xue, D. Yi, and Q. Zhao (China); V. R. Castillo (Colombia); R. Brat, J. Harrer, V. Mikulenka, Z. Straka, and K. Vik (Czech Republic ); T. A. Sulling (Estonia); S. Chocron (France); S. K. Agarwal, B. Airan, D. R. Ayapati, A. G. Gokhale, A. R. Jain, U. Kaul, C. Padmanabhan, S. K. Reddy, P. Vaijyanath, and M. P. Vettath (India); M. Bentala (the Netherlands); D. R. De Souza (Sweden); A. R. Akar, S. Aykut Aka, K. Kaya, and E. Sener (Turkey); O. Gogayeva (Ukraine); A. J. Ritchie, D. P. Taggart, and V. Zamvar (United Kingdom); and S. V. Parvathaneni (United States).

Correction: This article was corrected online June 3, 2014, for changes to Table 1.

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Basile  DP.  The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int. 2007;72(2):151-156.
PubMed   |  Link to Article
Ishani  A, Nelson  D, Clothier  B,  et al.  The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death. Arch Intern Med. 2011;171(3):226-233.
PubMed   |  Link to Article
Newsome  BB, Warnock  DG, McClellan  WM,  et al.  Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction. Arch Intern Med. 2008;168(6):609-616.
PubMed   |  Link to Article
Coca  SG, Singanamala  S, Parikh  CR.  Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2012;81(5):442-448.
PubMed   |  Link to Article
Garg  AX, Devereaux  PJ, Yusuf  S,  et al; CORONARY Investigators.  Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY): kidney substudy analytic protocol of an international randomised controlled trial. BMJ Open. 2012;2(2):e001080.
PubMed   |  Link to Article
Nigwekar  SU, Kandula  P, Hix  JK, Thakar  CV.  Off-pump coronary artery bypass surgery and acute kidney injury: a meta-analysis of randomized and observational studies. Am J Kidney Dis. 2009;54(3):413-423.
PubMed   |  Link to Article
Seabra  VF, Alobaidi  S, Balk  EM, Poon  AH, Jaber  BL.  Off-pump coronary artery bypass surgery and acute kidney injury: a meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2010;5(10):1734-1744.
PubMed   |  Link to Article
Lamy  A, Devereaux  PJ, Prabhakaran  D,  et al.  Rationale and design of the coronary artery bypass grafting surgery off or on pump revascularization study: a large international randomized trial in cardiac surgery. Am Heart J. 2012;163(1):1-6.
PubMed   |  Link to Article
Lamy  A, Devereaux  PJ, Prabhakaran  D,  et al; CORONARY Investigators.  Off-pump or on-pump coronary-artery bypass grafting at 30 days. N Engl J Med. 2012;366(16):1489-1497.
PubMed   |  Link to Article
Lamy  A, Devereaux  PJ, Prabhakaran  D,  et al; CORONARY Investigators.  Effects of off-pump and on-pump coronary-artery bypass grafting at 1 year. N Engl J Med. 2013;368(13):1179-1188.
PubMed   |  Link to Article
Levey  AS, Stevens  LA, Schmid  CH,  et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration).  A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612.
PubMed   |  Link to Article
Austin  PC.  Absolute risk reductions, relative risks, relative risk reductions, and numbers needed to treat can be obtained from a logistic regression model. J Clin Epidemiol. 2010;63(1):2-6.
PubMed   |  Link to Article
Koch  GG, Tangen  CM, Jung  JW, Amara  IA.  Issues for covariance analysis of dichotomous and ordered categorical data from randomized clinical trials and non-parametric strategies for addressing them. Stat Med. 1998;17(15-16):1863-1892.
PubMed   |  Link to Article
Zink  RC, Koch  GG. NParCov3: A SAS/IML macro for nonparametric randomization-based analysis of covariance.http://www.jstatsoft.org/v50/i03/paper. Accessibility verified May 16, 2014.
Chawla  LS, Kimmel  PL.  Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int. 2012;82(5):516-524.
PubMed   |  Link to Article
Siew  ED, Peterson  JF, Eden  SK,  et al.  Outpatient nephrology referral rates after acute kidney injury. J Am Soc Nephrol. 2012;23(2):305-312.
PubMed   |  Link to Article
James  MT, Ghali  WA, Tonelli  M,  et al.  Acute kidney injury following coronary angiography is associated with a long-term decline in kidney function. Kidney Int. 2010;78(8):803-809.
PubMed   |  Link to Article
Myers  GL, Miller  WG, Coresh  J,  et al; National Kidney Disease Education Program Laboratory Working Group.  Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program. Clin Chem. 2006;52(1):5-18.
PubMed   |  Link to Article
Cairns  JA, Yusuf  S, Cook  RJ,  et al; CANNeCTIN.  Canadian Network and Centre for Trials Internationally (CANNeCTIN): a national network for Canadian-led trials in cardiovascular diseases and diabetes mellitus. Can J Cardiol. 2010;26(7):353-358.
PubMed   |  Link to Article
Mariscalco  G, Lorusso  R, Dominici  C, Renzulli  A, Sala  A.  Acute kidney injury: a relevant complication after cardiac surgery. Ann Thorac Surg. 2011;92(4):1539-1547.
PubMed   |  Link to Article
Rifkin  DE, Coca  SG, Kalantar-Zadeh  K.  Does AKI truly lead to CKD? J Am Soc Nephrol. 2012;23(6):979-984.
PubMed   |  Link to Article
Liu  KD, Lo  L, Hsu  CY.  Some methodological issues in studying the long-term renal sequelae of acute kidney injury. Curr Opin Nephrol Hypertens. 2009;18(3):241-245.
PubMed   |  Link to Article
Palevsky  PM, Molitoris  BA, Okusa  MD,  et al.  Design of clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology. Clin J Am Soc Nephrol. 2012;7(5):844-850.
PubMed   |  Link to Article
Bagshaw  SM, McAlister  FA, Manns  BJ, Ghali  WA.  Acetylcysteine in the prevention of contrast-induced nephropathy: a case study of the pitfalls in the evolution of evidence. Arch Intern Med. 2006;166(2):161-166.
PubMed   |  Link to Article
Zoungas  S, Ninomiya  T, Huxley  R,  et al.  Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Intern Med. 2009;151(9):631-638.
PubMed   |  Link to Article
Faubel  S, Chawla  LS, Chertow  GM, Goldstein  SL, Jaber  BL, Liu  KD; Acute Kidney Injury Advisory Group of the American Society of Nephrology.  Ongoing clinical trials in AKI. Clin J Am Soc Nephrol. 2012;7(5):861-873.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Baseline Characteristics of Patients in the CORONARY Kidney Function Substudy
Table Graphic Jump LocationTable 2.  Acute Kidney Injury (AKI) After Coronary Artery Bypass Graft (CABG) Surgery Within 30 Days Postsurgery
Table Graphic Jump LocationTable 3.  Loss in Estimated Glomerular Filtration Rate (GFR) at 1 Year From the Estimated GFR Prior to Randomization
Table Graphic Jump LocationTable 4.  Off-Pump and On-Pump Coronary Artery Bypass Graft (CABG) Surgery Outcomes Assessed in Those With and Without Baseline Chronic Kidney Disease

References

Kellum  JA, Lameire  N; for the KDIGO AKI Guideline Work Group.  Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013;17(1):204.
PubMed   |  Link to Article
Lo  LJ, Go  AS, Chertow  GM,  et al.  Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease. Kidney Int. 2009;76(8):893-899.
PubMed   |  Link to Article
Rosner  MH, Okusa  MD.  Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol. 2006;1(1):19-32.
PubMed   |  Link to Article
Basile  DP, Donohoe  D, Roethe  K, Osborn  JL.  Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol. 2001;281(5):F887-F899.
PubMed
Basile  DP.  Rarefaction of peritubular capillaries following ischemic acute renal failure: a potential factor predisposing to progressive nephropathy. Curr Opin Nephrol Hypertens. 2004;13(1):1-7.
PubMed   |  Link to Article
Basile  DP.  The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int. 2007;72(2):151-156.
PubMed   |  Link to Article
Ishani  A, Nelson  D, Clothier  B,  et al.  The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death. Arch Intern Med. 2011;171(3):226-233.
PubMed   |  Link to Article
Newsome  BB, Warnock  DG, McClellan  WM,  et al.  Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction. Arch Intern Med. 2008;168(6):609-616.
PubMed   |  Link to Article
Coca  SG, Singanamala  S, Parikh  CR.  Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2012;81(5):442-448.
PubMed   |  Link to Article
Garg  AX, Devereaux  PJ, Yusuf  S,  et al; CORONARY Investigators.  Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY): kidney substudy analytic protocol of an international randomised controlled trial. BMJ Open. 2012;2(2):e001080.
PubMed   |  Link to Article
Nigwekar  SU, Kandula  P, Hix  JK, Thakar  CV.  Off-pump coronary artery bypass surgery and acute kidney injury: a meta-analysis of randomized and observational studies. Am J Kidney Dis. 2009;54(3):413-423.
PubMed   |  Link to Article
Seabra  VF, Alobaidi  S, Balk  EM, Poon  AH, Jaber  BL.  Off-pump coronary artery bypass surgery and acute kidney injury: a meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2010;5(10):1734-1744.
PubMed   |  Link to Article
Lamy  A, Devereaux  PJ, Prabhakaran  D,  et al.  Rationale and design of the coronary artery bypass grafting surgery off or on pump revascularization study: a large international randomized trial in cardiac surgery. Am Heart J. 2012;163(1):1-6.
PubMed   |  Link to Article
Lamy  A, Devereaux  PJ, Prabhakaran  D,  et al; CORONARY Investigators.  Off-pump or on-pump coronary-artery bypass grafting at 30 days. N Engl J Med. 2012;366(16):1489-1497.
PubMed   |  Link to Article
Lamy  A, Devereaux  PJ, Prabhakaran  D,  et al; CORONARY Investigators.  Effects of off-pump and on-pump coronary-artery bypass grafting at 1 year. N Engl J Med. 2013;368(13):1179-1188.
PubMed   |  Link to Article
Levey  AS, Stevens  LA, Schmid  CH,  et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration).  A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612.
PubMed   |  Link to Article
Austin  PC.  Absolute risk reductions, relative risks, relative risk reductions, and numbers needed to treat can be obtained from a logistic regression model. J Clin Epidemiol. 2010;63(1):2-6.
PubMed   |  Link to Article
Koch  GG, Tangen  CM, Jung  JW, Amara  IA.  Issues for covariance analysis of dichotomous and ordered categorical data from randomized clinical trials and non-parametric strategies for addressing them. Stat Med. 1998;17(15-16):1863-1892.
PubMed   |  Link to Article
Zink  RC, Koch  GG. NParCov3: A SAS/IML macro for nonparametric randomization-based analysis of covariance.http://www.jstatsoft.org/v50/i03/paper. Accessibility verified May 16, 2014.
Chawla  LS, Kimmel  PL.  Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int. 2012;82(5):516-524.
PubMed   |  Link to Article
Siew  ED, Peterson  JF, Eden  SK,  et al.  Outpatient nephrology referral rates after acute kidney injury. J Am Soc Nephrol. 2012;23(2):305-312.
PubMed   |  Link to Article
James  MT, Ghali  WA, Tonelli  M,  et al.  Acute kidney injury following coronary angiography is associated with a long-term decline in kidney function. Kidney Int. 2010;78(8):803-809.
PubMed   |  Link to Article
Myers  GL, Miller  WG, Coresh  J,  et al; National Kidney Disease Education Program Laboratory Working Group.  Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program. Clin Chem. 2006;52(1):5-18.
PubMed   |  Link to Article
Cairns  JA, Yusuf  S, Cook  RJ,  et al; CANNeCTIN.  Canadian Network and Centre for Trials Internationally (CANNeCTIN): a national network for Canadian-led trials in cardiovascular diseases and diabetes mellitus. Can J Cardiol. 2010;26(7):353-358.
PubMed   |  Link to Article
Mariscalco  G, Lorusso  R, Dominici  C, Renzulli  A, Sala  A.  Acute kidney injury: a relevant complication after cardiac surgery. Ann Thorac Surg. 2011;92(4):1539-1547.
PubMed   |  Link to Article
Rifkin  DE, Coca  SG, Kalantar-Zadeh  K.  Does AKI truly lead to CKD? J Am Soc Nephrol. 2012;23(6):979-984.
PubMed   |  Link to Article
Liu  KD, Lo  L, Hsu  CY.  Some methodological issues in studying the long-term renal sequelae of acute kidney injury. Curr Opin Nephrol Hypertens. 2009;18(3):241-245.
PubMed   |  Link to Article
Palevsky  PM, Molitoris  BA, Okusa  MD,  et al.  Design of clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology. Clin J Am Soc Nephrol. 2012;7(5):844-850.
PubMed   |  Link to Article
Bagshaw  SM, McAlister  FA, Manns  BJ, Ghali  WA.  Acetylcysteine in the prevention of contrast-induced nephropathy: a case study of the pitfalls in the evolution of evidence. Arch Intern Med. 2006;166(2):161-166.
PubMed   |  Link to Article
Zoungas  S, Ninomiya  T, Huxley  R,  et al.  Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Intern Med. 2009;151(9):631-638.
PubMed   |  Link to Article
Faubel  S, Chawla  LS, Chertow  GM, Goldstein  SL, Jaber  BL, Liu  KD; Acute Kidney Injury Advisory Group of the American Society of Nephrology.  Ongoing clinical trials in AKI. Clin J Am Soc Nephrol. 2012;7(5):861-873.
PubMed   |  Link to Article
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Multimedia

Supplement.

eMethods. CORONARY: Patient eligibility criteria

eTable 1 Baseline characteristics of all CORONARY patients and kidney substudy patients

eTable 2. Justification for any changes made to features of the prespecified protocol

eTable 3. Kidney outcome measurement and dialysis events in off-pump and on-pump coronary-artery bypass grafting (CABG) surgery

eTable 4. A comparison of the characteristics of patients who did and did not provide a one year serum creatinine measurement

eTable 5. Use of medications before and after surgery in off-pump and on-pump groups

eTable 6. Complete case as treated analysis

eTable 7. Chronic kidney disease subgroup results with alternate definitions of postoperative acute kidney injury and one year kidney function loss

eTable 8. Factors associated with loss of kidney function at one year

eTable 9. Mean serum creatinine and estimated glomerular filtration rate (eGFR) in off-pump and on-pump coronary-artery bypass grafting surgery

eFigure 1. Box plot of the maximum percent increase in serum creatinine within 30 days after surgery

eFigure 2. Box plot of the percent change in estimated glomerular filtration rate (eGFR) one year after surgery

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