Cardiac Catheterizationcircinterventions.ahajournals.org/content/circcvint/6/1/37.full.pdf · James et al Outcomes of Contrast-Induced Acute Kidney Injury 39 formula RR=OR/[(1-P 0)+(P

37

Acute kidney injury (AKI) after coronary angiography is often attributed to radiocontrast-associated kid-

ney injury,1,2 the third leading cause of AKI in hospitalized patients.3 Patients with preexisting comorbidities, including those with diabetes mellitus, chronic kidney disease (CKD), and heart failure, are at particularly high risk of contrast-induced AKI (CI-AKI).4–6 The primary manifestation is a small decline in kidney function, occurring 1 to 3 days after the procedure.1 Kidney function usually returns to preexisting levels within 7 days,7 and AKI after radiocontrast administra-tion rarely requires acute dialysis treatment.1,8

Several observational studies suggest that these small declines in kidney function after contrast media exposure are associ-ated with adverse clinical outcomes, including longer hospi-tal admission, subsequent cardiovascular events, and increased

mortality.2,4–6,9 Although some of these findings have been sum-marized in narrative reviews,2,6,10 the interpretation of these find-ings has remained controversial given the correlation between preexisting clinical variables that are associated with both CI-AKI and adverse clinical outcomes, variability in adjustment for potential confounders across observational studies, and uncer-tainty whether reported risks are indeed attributable to CI-AKI.

To address these knowledge gaps, we conducted a systematic review and meta-analysis of observational studies that examined the association between CI-AKI after coronary angiography and adverse clinical outcomes, including mortality, cardiovas-cular events, end-stage renal disease (ESRD), and prolongation of hospitalization. Specifically, we sought to clarify the quality of existing studies, and study features that may contribute to the heterogeneity of results across published studies.

Background—Contrast-induced acute kidney injury (CI-AKI) has been associated with mortality, although it has been suggested this association may be attributable to confounding. We performed a systematic review and meta-analysis to characterize the associations between CI-AKI and subsequent clinical outcomes.

Methods and Results—We identified studies using MEDLINE (1950 to June 2011) and Embase (1980 to June 2011), manual bibliographic searches, and contact with experts. We included observational studies that characterized outcomes among patients with and without AKI (based on changes in serum creatinine) after coronary angiography. Eligible studies reported at least 1 of mortality, cardiovascular events, end-stage renal disease, or length of hospital stay. Thirty-nine observational studies met inclusion criteria. Of 34 studies reporting mortality (including 139 603 participants), 33 reported an increased risk of death in those with CI-AKI, although the effect size varied between studies (I2=93.5%). Between-study heterogeneity was partially explained by whether adjustment for confounding features was performed (11 studies without adjustment; pooled crude risk ratio, 8.19; 95% confidence interval, 4.30–15.60; I2=77.3% versus 23 studies with adjustment; pooled adjusted risk ratio, 2.39; 95% confidence interval, 1.98–2.90; I2=88.3%). CI-AKI was consistently associated with an increased risk of cardiovascular events in 14 studies, end-stage renal disease in 3 studies, and prolonged hospitalization in 11 studies.

Conclusions—CI-AKI is associated with an increased risk of mortality, cardiovascular events, renal failure, and prolonged hospitalization. However, the association between CI-AKI and mortality is strongly confounded by baseline clinical characteristics that simultaneously predispose to both kidney injury and mortality, and the risk attributable to CI-AKI is much lower than that reported from unadjusted studies. (Circ Cardiovasc Interv. 2013;6:37-43.)

Key Words: angiography ◼ epidemiology ◼ kidney

© 2013 American Heart Association, Inc.

Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org DOI: 10.1161/CIRCINTERVENTIONS.112.974493

Received May 4, 2012; accepted November 19, 2012.From the Department of Medicine (M.T.J., M.A.M., W.A.G., M.L.K., B.R.H.), Department of Community Health Sciences (M.T.J., S.M.S., W.A.G.,

P.F., B.R.H.), and Department of Pediatrics (S.M.S.), University of Calgary, Calgary, Alberta, Canada; and Department of Medicine, University of Alberta, Edmonton, Alberta, Canada (M.T., N.P.).

The online-only Data Supplement is available at http://circinterventions.ahajournals.org/lookup/suppl/doi:10.1161/CIRCINTERVENTIONS. 112.974493/-/DC1.

Correspondence to Dr Matthew T. James, Foothills Medical Centre, 1403 29th St NW, Calgary, Alberta T2N 2T9, Canada. E-mail [email protected]

Contrast-Induced Acute Kidney Injury and Risk of Adverse Clinical Outcomes After Coronary Angiography

A Systematic Review and Meta-Analysis

Matthew T. James, MD, PhD; Susan M. Samuel, MD, MSc; Megan A. Manning, BSc; Marcello Tonelli, MD, SM; William A. Ghali, MD, MPH; Peter Faris, PhD;

Merril L. Knudtson, MD; Neesh Pannu, MD, MSc; Brenda R. Hemmelgarn, MD, PhD

Cardiac Catheterization

by guest on July 10, 2018http://circinterventions.ahajournals.org/

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mailto:[email protected]

http://circinterventions.ahajournals.org/





















38 Circ Cardiovasc Interv February 2013

MethodsWe adhered to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines11 and followed a prespecified study protocol.

Data Sources and SearchesWe systematically searched MEDLINE (1950 to June 2011) and Embase (1980 to June 2011) for studies describing the association between CI-AKI (identified based on changes in serum creatinine concentration) and death, cardiovascular events (including cardio-vascular mortality, myocardial infarction, target vessel reocclusion or need for revascularization, cerebrovascular accident or heart failure), chronic dialysis, or ESRD, and length of hospital stay among patients undergoing coronary angiography. We also searched the reference lists of all identified relevant publications and contacted experts in coronary angiography and AKI. We limited inclusion to studies pub-lished in English.

Three search themes were combined using the Boolean opera-tor and. The first theme, coronary angiography, combined exploded versions of Medical Subject Headings angiography, contrast media, angiocardiography, heart catheterization, angioplasty, transluminal, percutaneous coronary angioplasty, or myocardial revascularization, or text words coronary angiography, cardiac catheterization, percu-taneous coronary intervention, PCI, angiography, coronary revas-cularization, or cardiac angiography. The second theme, combined exploded version of the Medical Subject Headings terms acute kidney failure or creatinine or text words acute kidney injury, acute kidney failure, acute renal failure, acute renal insufficiency nephropathy, con-trast nephropathy, or contrast-induced nephropathy. We used the ap-proach of Egger et al12 to identify studies with an observational design.

Study SelectionTwo reviewers independently identified potentially eligible articles by performing an initial screen of titles and abstracts. Articles were considered for inclusion if they reported data from an original study (review articles were excluded) and reported on clinical outcomes

according to CI-AKI status after diagnostic or therapeutic coronary angiography. We used broad inclusion criteria for studies, includ-ing varying definitions for AKI data and information on any clinical outcomes as they were defined by the primary studies. Articles were retained when either of the reviewers believed that it should be re-tained or when there was uncertainty as to eligibility based on title and abstract alone.

Selected articles were subsequently screened based on a full-text review. To be included, studies had to be observational studies of participants following diagnostic or interventional coronary angiog-raphy, with a comparison between those with CI-AKI (based on a relative or absolute change in serum creatinine) and those without CI-AKI. Studies that reported outcomes only on the basis of contrast volume or as a ratio of contrast dose to serum creatinine were not included. We included any study reporting on 1 or more of mortal-ity, cardiovascular events (including including cardiovascular mor-tality, myocardial infarction, target vessel reocclusion or need for revascularization, stroke, or heart failure), ESRD (including chronic dialysis), or length of hospital stay. When >1 publication was identi-fied from the same cohort examining the same study outcome, we included data from the article with the larger sample size. Information from randomized trials was included where publications reported as-sociations between CI-AKI and outcomes of interest.

Data Extraction and Quality AssessmentTwo reviewers independently extracted data on baseline patient char-acteristics, procedural characteristics, criteria to define CI-AKI, and duration of follow-up. We also collected data on methodological fea-tures indicative of study quality, following the MOOSE guidelines.11 These included specification of the inclusion/exclusion criteria, the inclusion of consecutive participants in the cohort, losses to follow-up <10% or appropriate handling of losses to follow-up, blinding of exposure status for outcome assessment, and statistical adjustment for confounders. The exposure variable of interest was CI-AKI, and the reference group was those without CI-AKI in each study. Most studies (n=36) identified dichotomous groups (with CI-AKI versus without CI-AKI); however 3 studies categorized severity of CI-AKI based on magnitude of the change in serum creatinine, and 1 study categorized CI-AKI based on whether it persisted for >7 days. To enable pooling, we combined results for these additional categories within a single exposure group (with CI-AKI), and performed meta-regression and subgroup analyses, according to the serum creatinine criteria used to define groups with CI-AKI (ie, increase in serum cre-atinine concentration >25% or 0.5 mg/dL versus >50% or 1.0 m/dL) in each study.

The primary outcome was all-cause mortality. Secondary out-comes included cardiovascular events, ESRD, and length of hospital stay. We considered major adverse cardiovascular events to include cardiovascular mortality, myocardial infarction, target vessel reocclu-sion or need for revascularization, stroke, heart failure, or a compos-ite of these events. We defined ESRD as the requirement for chronic dialysis after hospital discharge. Length of stay was defined based on the number of days from either hospital admission or angiography to discharge, depending on the study design. The duration of follow-up for clinical outcomes varied across studies. We grouped studies on the basis of short-term (in-hospital or at 30 days) or long-term follow-up (postdischarge or ≥6 months) and performed meta-regression and subgroup analysis on the basis of this distinction.

We recorded risk ratios (RR), hazard ratios, or odds ratios (OR) for quantifying the association between CI-AKI and the dichotomous clinical outcomes of interest (mortality, major adverse cardiovascular events, and ESRD), and the means and SDs for measured continu-ous outcomes (days in hospital) for patients with CI-AKI compared with those without CI-AKI. Adjusted values were obtained wherev-er reported. We collected crude values if adjusted results were not presented.

Data Synthesis and AnalysisWe pooled RRs for dichotomous outcomes, and means for continu-ous outcomes across studies. To transform ORs to RRs, we used the

WhAT IS KNOWN

•Contrast-induced acute kidney injury (CI-AKI) has been associated with high morbidity and mortality, although it remains controversial to what degree this association is confounded by preexisting clinical features associated with both CI-AKI and adverse clinical outcomes.

WhAT ThE STuDy ADDS

• In this systematic review and meta-analysis, significant associations between CI-AKI and adverse clinical out-comes were observed.

• In 11 studies without adjustment for confound-ing features, CI-AKI was associated with an 8-fold increase in risk of mortality (pooled RR, 8.19; 95% CI, 4.30–15.60); however, this association was attenu-ated among 23 studies that performed adjustment for confounders (pooled RR, 2.39; 95% CI, 1.98–2.90) and publication bias (RR, 1.79; 95% CI, 1.47–2.18).

•These findings suggest that the association between CI-AKI and death is related to baseline clinical char-acteristics and that the risk attributable to CI-AKI is lower than that implied from unadjusted analyses.


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James et al Outcomes of Contrast-Induced Acute Kidney Injury 39

formula RR=OR/[(1-P0)+(P

0×OR)], where P

0 is the incidence of the

outcome of interest in the unexposed group.13 Estimates of variance of ORs were converted to RRs using the Miettinen test-based approach; variance lnRR=variance lnOR×(lnRR/lnOR).14 We pooled the natu-ral logarithm of the RRs of binary outcomes and determined the weighted mean difference of continuous outcomes using the random effects model of DerSimonian and Laird.15 We used the Cochrane Q statistic (at a significance level of P<0.10), and the I2 statistic to as-sess for heterogeneity across studies.16,17 Subgroup analyses, stratified by study population characteristics and study methodology criteria, were also performed. We evaluated funnel plots and used Begg test to detect small study effects suggestive of publication bias.18,19 We used the Duval and Tweedie20 nonparametric trim-and-fill procedure to de-termine the possible effect of publication bias on pooled estimates by imputing the estimate of effect of hypothetical missing studies, and imputing a pooled estimate that included these studies. All analy-ses were performed in Stata version 11 (StataCorp, College Station, Texas) using the metan, metareg, metabias, and metatrim commands.

ResultsOur search strategy yielded 4142 unique citations. We excluded 4058 citations based on screening of title and abstract, leav-ing 84 articles for full-text review. We subsequently excluded 45 studies that did not meet inclusion criteria; of which 14 articles comprised overlapping cohorts of patients and were excluded to avoid duplicate inclusion of data (Figure 1). There was good agreement between reviewers on the final articles eligible for inclusion (κ=0.824).

Study CharacteristicsCharacteristics of the 39 studies included in the systematic review are provided in Tables I and II in the online-only Data Supplement. Studies were published between 1990 and 2011, and 19 were from North America, 13 from Europe, 5 from Asia, and 2 from Israel. The number of participants ranged from 78 to 27 608 (152 459 participants in total), and the mean age ranged from 56.4 to 75.4 years across studies. Most studies included patients with and without CKD at baseline (range 3.2%–69.6% according to individual study definitions

of CKD), although 4 studies included only patients with impaired baseline kidney function, and 2 studies excluded patients with elevated serum creatinine at baseline. Twenty-six studies included only patients receiving percutaneous cor-onary interventions (including 8 studies of patients receiving primary percutaneous intervention for ST segment elevation myocardial infarction), whereas 9 studies included patients receiving diagnostic coronary angiography.

The definition of CI-AKI was based on a relatively small increase in serum creatinine in all studies; 32 studies identified CI-AKI on the basis of an increase in serum creatinine con-centration from baseline exceeding either 25% or 0.5 mg/dL, whereas 5 studies identified CI-AKI based on a >50% or 1.0 mg/dL increase in serum creatinine concentration, and 2 stud-ies categorized the severity of CI-AKI based on the magnitude of this increase (Table I in the online-only Data Supplement). The duration of follow-up varied among studies, with 12 stud-ies using follow-up to hospital discharge, 2 studies with fol-low-up 30 days postprocedure, and 25 studies with long-term follow-up ranging between 6 months and 5 years.

Inclusion and exclusion criteria were clearly specified in all but 2 studies, and all but 2 studies enrolled consecutive patients in the cohort. There were no losses to follow-up in 32 studies, 2 studies did not report on losses to follow-up, and 6 studies reported losses to follow-up ranging from <1% to 36% (Table II in the online-only Data Supplement). Study person-nel who evaluated outcomes were blinded to exposure status in only 1 study.

RRs of mortality were adjusted for baseline severity of ill-ness variables that may be confounders in 23 studies, whereas only RRs of mortality that were unadjusted were reported in 11 studies (Table II in the online-only Data Supplement). One study did not contribute to the pooled analysis for mortality because no deaths were recorded. RRs of major adverse car-diovascular events were adjusted for potential confounders in 9 studies, but only unadjusted RRs were reported in 5 studies (Table II in the online-only Data Supplement). Cardiovascular events included cardiovascular mortality from 4 studies, myo-cardial infarction from 10 studies, coronary artery reocclusion or revascularization from 7 studies, heart failure from 2 studies, and stroke from 2 studies. Only 1 study reported the adjusted RR of ESRD, and 2 studies provided only data to determine the unadjusted RR. Ten studies reported the mean length of hospital stay without adjustment for other baseline severity of illness factors; however, only 1 study reported the adjusted increase in length of hospital stay associated with CI-AKI after adjustment for potential confounders. Adjustment was performed for age in 24 studies, diabetes mellitus in 20 stud-ies, severity of coronary artery disease in 14 studies, heart fail-ure (based on left ventricular function, pulmonary edema, or cardiogenic shock) in 24 studies, and baseline kidney function (serum creatinine or estimated glomerular filtration rate) in 15 studies (Table II in the online-only Data Supplement).

Association Between CI-AKI and MortalityResults from 34 studies examining mortality, including a total of 139 603 participants, showed evidence of statistical heterogeneity (Q statistic P<0.001; I2=93.5%). However, 33 of the 34 studies reported an increased risk of death in those

Potentially relevant citations identified and screened for retrieval from MEDLINE and Embase from 1950 through 11 June 2011 (n=4142)

Citations excluded (n=4058)

Articles retrieved for more detailed evaluation (n=84)

Articles excluded (n=45)

Not an observational study (n=5)Overlapping cohort / duplicate publication (n=14)Study population not coronary angiography (n=3)Exposure not defined as specified (n=9)No comparison to patients without exposure (n=2)Outcome of interest not reported (n=6)Not English (n=6)

Articles included in the systematic review (n=39)

Figure 1. Study selection flowchart.


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with CI-AKI after coronary angiography. RR from studies that did not adjust for baseline severity of illness variables were significantly greater than those obtained from studies that adjusted estimates for these potential confounders (meta-regression, P<0.001). Based on 11 studies (with 27 190 participants) that reported unadjusted results, the pooled crude RR of death was 8.19 (95% CI, 4.30–15.60; Q statistic P=0.008; I2=77.3%), whereas the pooled adjusted RR from 23 studies (with 112 413 participants) with adjusted results was 2.39 (95% CI, 1.98–2.90; Q statistic P<0.001; I2=88.3%; Figure 2).

We performed further meta-regression to explore reasons for remaining heterogeneity across the 23 studies that reported adjusted RRs. Studies with short follow-up (to hospital dis-charge or 30 days postprocedure) reported higher adjusted RRs of death associated with CI-AKI than studies with lon-ger (≥6 month) follow-up (Table III in the online-only Data Supplement). Different definitions of CI-AKI (increase in serum creatinine concentration >50% or 1.0 mg/dL versus >25% or 0.5 mg/dL) did not influence the risk of mortality associated with AKI, although both studies that categorized the severity of AKI reported higher risks of mortality with larger increases in serum creatinine concentration.9,21 Results from studies without substantial (<10%) losses to follow-up (18 studies; 104 825 participants; RR, 2.28; 95% CI, 1.86–2.80; Q statis-tic P<0.001; I2=90.4%) did not significantly differ from those with >10% of participants lost to follow-up or no reporting of losses to follow-up. Results were also similar regardless of dif-ferences in the study distributions of age, diabetes mellitus, presence or absence of CKD before angiography, ST segment elevation myocardial infarction, and type of procedure (percu-taneous coronary intervention only versus diagnostic or inter-ventional procedure).

The funnel plot for studies reporting adjusted RRs for mor-tality was asymmetrical (Figure IA in the online-only Data Supplement). The possibility of publication bias was further suggested by Egger test (z=1.74; P=0.034). When the trim-and-fill procedure was used to impute results for hypoth-esized unpublished studies20 (Figure IB in the online-only Data Supplement), the pooled adjusted RR was attenuated but continued to show a significant association between AKI and mortality (RR, 1.79; 95% CI, 1.47–2.18).

Association Between CI-AKI and Cardiovascular Events, ESRD, and Length of hospitalizationOf 14 studies (70 031 participants) reporting on cardiovas-cular events, all reported an increased risk associated with CI-AKI after coronary angiography (Figure 3). The pooled RR from these studies for cardiovascular events was 2.42 (95% CI, 1.62–3.64), although there was again evidence of statistical heterogeneity (Q statistic P<0.001; I2=96.0%). The reporting of crude versus adjusted RRs did not significantly alter estimates of risk of cardiovascular events associated with CI-AKI (meta-regression P=0.745). Based on 6 studies (with 43 959 participants) that reported unadjusted results, the pooled crude RR of cardiovascular events was 2.59 (95% CI, 1.05–6.27; Q statistic P<0.001; I2=98.3%), whereas the pooled adjusted RR from 8 studies (with 26 072 participants) with adjusted results was 1.98 (95% CI, 1.52–2.59; Q sta-tistic P=0.001; I2=71.1%). Neither study design features nor study population characteristics further explained heteroge-neity (P<0.10 for all analyses). There was no evidence of fun-nel plot asymmetry among studies evaluating cardiovascular events (Egger test, z=1.81; P=0.225), suggesting no publica-tion bias was present.

Figure 2. Risk ratios for mortality associ-ated with contrast-induced acute kidney injury (CI-AKI), stratified by whether models were unadjusted or adjusted for baseline severity of illness variables. CI indicates confidence interval.


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Three studies (18 457 participants) reported on the risk of progression to ESRD, which ranged from 0% to 0.2% in those without CI-AKI, and from 0.2% to 4.5% in those with CI-AKI. CI-AKI was associated with ESRD without evidence of heterogeneity (Figure 3; Q statistic P=0.804; I2=0%). Two studies reported only unadjusted risks of ESRD (pooled crude RR, 15.26; 95% CI, 1.86–125.01), whereas 1 study reported adjusted results (adjusted RR, 6.95; 95% CI, 2.51–19.26). All studies examining length of hospital stay reported longer admissions in patients with CI-AKI compared with those without AKI. Ten studies (19 674 participants) reported an unadjusted mean length of hospital stay that ranged from 0.5 to 8.3 days longer for participants with AKI, although there was heterogeneity in the size of this difference (Q statistic P<0.001; I2=99.2%), with substantial variability in length of hospitalization between studies (Figure II in the online-only Data Supplement). Only 1 study reported an increase in length of hospital stay that was adjusted for baseline severity of illness variables, and this difference was equivalent to 1.6 additional days of hospitalization attributable to CI-AKI (P=0.005).

DiscussionWe identified several observational studies examining the risks of mortality, cardiovascular events, and kidney failure associ-ated with CI-AKI after coronary angiography. CI-AKI was associated with a pooled 8-fold increase in the risk of death after coronary angiography among studies without adjust-ment. Among studies that adjusted for baseline clinical char-acteristics that simultaneously predispose to both CI-AKI and mortality, CI-AKI remained independently predictive of long-term mortality, but with a reduced pooled RR of about 2. Our results show that although CI-AKI has been consistently asso-ciated with mortality after coronary angiography, the strength of this association has varied between studies, and that the risk associated with CI-AKI in adjusted studies is a fraction of the overall risk reported from unadjusted observational studies. These results suggest that the independent association

between CI-AKI and mortality is more modest, and further attenuated after accounting for publication bias, resulting in a remaining independent 79% increase in the adjusted risk of death associated with CI-AKI in our meta-analysis.

Even with adjustment, observational studies remain inher-ently limited by the potential for residual confounding and cannot prove a causal relationship between CI-AKI and death. We did observe features in-keeping with a causal rela-tionship including a temporal relationship between CI-AKI and adverse clinical outcomes after coronary angiography. Furthermore, the associations between CI-AKI and mortality were similar, regardless of the definition used for CI-AKI and, in 2 studies that categorized CI-AKI severity according to the magnitude of serum creatinine increase after coronary angi-ography, larger changes in creatinine, representative of more severe AKI, were associated with a higher risk of death.9,21 Such a dose–response relationship with risk of death has also been seen in other studies of AKI outside the setting of coro-nary angigraphy.22–24 However, the biological mechanism by which CI-AKI may lead to death remains unclear. Severe forms of AKI (that often require dialysis) could predispose to early mortality after coronary angiography because of vol-ume overload, electrolyte disturbances, or uremia; however, it is less clear how relatively small changes in kidney func-tion (that subsequently resolve) might increase this risk. It has been hypothesized that patients who develop CI-AKI after radiocontrast exposure are treated more conservatively so as to preserve remaining kidney function.25,26 Further research is needed to delineate how patients who develop CI-AKI are subsequently managed, including studies to examine whether there are any disparities in subsequent use of cardiovascular therapies.

Because these observational studies are limited by the potential for residual confounding, it also remains possible that CI-AKI is a marker of severity of illness that accompanies hemodynamic instability and ischemia, rather than a causal agent itself. Thus, there is a need for experimental studies to

Figure 3. Risk ratios for major adverse cardiovascular events and end-stage renal disease associated with contrast-induced acute kidney injury (CI-AKI).


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determine whether CI-AKI prevention strategies also lead to improved survival. Randomized trials of prevention strategies for CI-AKI will require large sample sizes to achieve adequate power to detect differences in clinical outcomes and are best suited to determining the efficacy of specific interventions in this setting. Reductions in the rates of clinical outcomes, such as death, cardiovascular events, and ESRD in the interven-tion arms of such trials, would be important to demonstrate, although interventions could reduce the risk of clinical out-comes via mechanisms separate from prevention of CI-AKI.

We identified several studies that examined cardiovascular outcomes after coronary angiography and found that CI-AKI was also associated with an increased risk of these events. The risks of coronary vascular disease and cardiovascular events associated with CKD are well established27,28 and are thought to involve mechanisms, including accelerated atherosclerosis, vascular calcification, left-ventricular hypertrophy, and sud-den death.29,30 It remains unclear whether CI-AKI is associ-ated with these processes or whether the relationship between CI-AKI and these cardiovascular events is mediated through preexisting cardiovascular risk factors or CKD.28,31

The effect of CI-AKI on long-term renal outcomes after angiography has been controversial. Most studies have reported resolution of renal impairment within days in most patients,7 although some observational data have suggested an increased risk of ESRD associated with radiocontrast media exposure.32 We identified 3 studies that reported an increased risk of progression to ESRD in participants with CI-AKI, and even small changes in kidney function that defined CI-AKI in this systematic review were a prognostic factor for an increased long-term risk of renal failure. Further research is needed to determine whether progressive CKD mediates the increased long-term risks of cardiovascular events and death associated with CI-AKI.

The results of this systematic review should be interpreted with some caveats. First, we observed substantial statistical heterogeneity in the magnitude of effect sizes between stud-ies for several outcomes. For differences in the length of hospital stay, this heterogeneity may be explained by differ-ences in clinical practices between institutions, whereas, for all outcomes, variations in study design (including the nature of adjustment for confounders and the length of follow-up) appeared to explain some of this variation. Nonetheless, despite quantitative differences in the magnitude of risk, the qualitative findings from our systematic review were consis-tent for all outcomes examined. A further limitation was evi-dence of publication bias detected among studies that reported on mortality. However, we found that the relation between CI-AKI and risk of death remained after applying imputation techniques to adjust for potential unpublished studies, sug-gesting that such bias is unlikely to completely explain this association. Finally, our systematic review included observa-tional studies that remain vulnerable to residual confounding, even when adjustment has been performed.

In conclusion, this systematic review demonstrates that CI-AKI is consistently associated with mortality, cardiovas-cular events, kidney failure, and prolongation of hospital stay. However, there is substantial attenuation of the relative risk of death associated with CI-AKI among studies that adjusted

for baseline clinical characteristics that simultaneously pre-dispose to both CI-AKI and mortality. This meta-analysis sug-gests that the relationships between CI-AKI and subsequent clinical outcomes are substantially influenced by confound-ing, and that the risk of these outcomes attributable to CI-AKI appears to be lower than has been widely emphasized. These findings highlight important caveats in interpreting the results of prognostic studies of CI-AKI.

Sources of FundingDr James was supported by a Kidney Research Scientist Core Education and National Training (KRESCENT) fellowship and an Alberta Innovates Health Solutions (AIHS) Fellowship Award. M. A. Manning. was supported by an AIHS Summer Studentship Award. Dr Samuel was supported by a joint Canadian Child Health Clinician Scientist Program Career Development Award and KRESCENT New Investigator Award. Dr Tonelli and Dr Ghali were supported by a Health Scholar Award from AIHS. Dr Knudtson received part support from the Libin Trust Fund. Dr Hemmelgarn was supported by a Population Health Investigator Award from AIHS. The authors have no financial interests in the information contained in this article. Sponsors had no role in the design and conduct of the study; collec-tion, management, analysis, and interpretation of the data; and prepa-ration, review, or approval of the article.

DisclosuresDr Knudtson has received honoraria for presentations from the Canadian Cardiovascular Society and Medtronic.

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Peter Faris, Merril L. Knudtson, Neesh Pannu and Brenda R. HemmelgarnMatthew T. James, Susan M. Samuel, Megan A. Manning, Marcello Tonelli, William A. Ghali,

Coronary Angiography: A Systematic Review and Meta-AnalysisContrast-Induced Acute Kidney Injury and Risk of Adverse Clinical Outcomes After

Print ISSN: 1941-7640. Online ISSN: 1941-7632 Copyright © 2013 American Heart Association, Inc. All rights reserved.

Avenue, Dallas, TX 75231is published by the American Heart Association, 7272 GreenvilleCirculation: Cardiovascular Interventions

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SUPPLEMENTAL MATERIAL

Supplemental Table 1 – Study Characteristics of Participants and Procedures, Definition of CI-AKI, and Duration of Follow-up.

Author, Country, Year

Number Participants

Participant and Procedural Characteristics CI-AKI Definition

Duration of Follow-Up Age

(mean), years

Diabetes mellitus,

%

Prevalence and Definition of

CKD

PCI, %

Indication for

Angiogram Assali, Israel, 2007

324 63.8 28.1 25.3% eGFR<60 ml/min/1.73m²

100.0 100.0% STEMI

>25% or 0.5 mg/dLincrease above baseline in SCr after PCI 30 days

Aronow, United States, 2001

359 Median 62 21.2 5.6% SCr above upper limit of normal

100.0 8.1% AMI within 24h

increase in SCr to >2.0 mg/dL or a 50% increase above a pre-procedure baseline

hospital discharge

Bartholomew, United States, 2004

20,479 64.5 26.5 Mean CrCl 78 ml/min

100.0 NR ≥1.0 mg/dL increase in SCr from the baseline level after PCI hospital discharge

Bouzas-Mosquera, Spain, 2007

315 Median 67 25.1 19.4% eGFR<60 ml/min/1.73m²

100.0 100.0% STEMI

increase in the SCr ≥0.5 mg/dL in the 72 h following the procedure compared to SCr concentration at hospital admission

median 1.3 years

Brown, United States, 2008

7,759 65.0 27.8 28.1% eGFR<60 mL/min/1.73m²

100.0 NR >25% increase in SCr from baseline within 48 hours 7.5 years

Budano, Italy, 2011

755 66.0 19.2 20.9% eGFR<60 mL/min/1.73m²

56.4 26.2% AMI absolute increase in SCr ≥0.5 mg/dL over baseline within 48 hours

mean 1.7 years

Caruso, Italy, 2011

150 65.9 37.3 16.0% eGFR<60 mL/min/1.73m²

100 9.3% STEMI relative increase in SCr ≥25% over baseline

mean 18.3 months

Chen, China, 2008

936 60.9 12.2 29.5% SCr ≥ 1.5 mg/dl

100.0 0.0% absolute increase in SCr>0.5 mg/dL at 48h after PCI 6 months

Cho, Korea, 2010

510 69.2 44.7 mean CrCl 40.8 mL/min

NR 34.7% AMI increase of ≥25% or ≥0.5 mg/dL in pre-procedure SCr within 3 days after procedure

1 year

Chong, Singapore, 2010

3037 57.7 36.2 21.9 %eGFR<60 mL/min/1.73m²

100 20.5% STEMI, 43.4% NSTEMI or Unstable Angina

increase of ≥25% or ≥0.5 mg/dL from baseline SCr within 48 hours after PCI

6 months

Dangas, United States, 2005

7230 64.4 30.2 27.4% eGFR<60 mL/min/1.73m²

100.0 35.5% NSTEMI

an increase of ≥25% and/or ≥0.5 mg/dL in pre-procedure SCr at 48 hours after the procedure

1 year

Ergelen, Turkey, 2010

2529 56.4 24.2 NR 100.0 100.0% STEMI

increase in SCr of at least 0.5 mg/dL or at least 25% from baseline within 72h of radiocontrast administration

hospital discharge

From, United States, 2008

3236 64.0 22.5 38.3% eGFR<60 mL/min/1.73m²

NR NR SCr elevation of 25% or of more than 0.5 mg/dL within 7 days of contrast exposure

mean 16 months

Goldenberg, Israel, 2009

78 56.4% ≥70 years

41 100% eGFR<60 mL/min/1.73m²

62.8 0.0 increase in SCr of ≥0.5 mg/dL or a >25% increase above baseline within 48h after contrast agent administration

median 4.9 years

Gruberg, United States, 2000

439 70.0 47.2 100.0% SCr ≥1.8 mg/dL

100.0 NR Increase in SCr ≥25% within 48h or procedure or requiring dialysis

1 year

Gupta, United States, 2005

9067 64.1 29 4.1% SCr>1.5 mg/dL

100.0 7.4% AMI rise in SCr greater than 1 mg/dL from the baseline value mean 3.2 years

Harjai, United States, 2008

973 64.9 25.7 25.4% CrCl<60 mL/min

100.0 NR (1) a twofold increase in SCr over baseline value with increase>2.0 mg/dL or dialysis, (2) increase in SCr>1.0 mg/dL, (3) increase in SCr>0.5 mg/dL, (4) increase in SCr>25%

6 months

Hölscher, Germany, 2008

412 67.1 29.4 100.0% SCr>1.3 mg/dL

NR 0.0% increase in SCr of 0.5 mg/dL or more within 72h of contrast agent administration

mean 649 days

Jabara, United States, 2009

275 62.0 37 24.0% eGFR>60 mL/min/1.73m²

100.0 45.0% ACS, 4.0% STEMI

an absolute increase in SCr ≥0.5 mg/dL over baseline, or a relative decrease in eGFR ≥25% from baseline, or a relative increase in SCr ≥25% over baseline 3 to 5 days post procedure

hospital discharge

James, Canada, 2011

14,782 63.1 25.6 24.0% eGFR>60 mL/min/1.73m²

54.1 71.8% ACS AKI Stage 1: ≥0.3 mg/dL absolute or 1.5 to 2.0 fold relative increase in SCr within 7 days following angiography; AKI Stage 2: >2 to 3 fold increase in SCr within 7 days following angiography; AKI Stage 3: >3 fold increase in SCr or SCr ≥4.0 mg/dL with an acute rise of >0.5 mg/dL

median 19.7 months

Kini, United States, 2009

12997 63.7 39.1 14.3% SCr ≥1.5 mg/dL

100.0 NR increment of 25% or more in baseline SCr post-procedure on days 1 through 4 after contrast exposure

1 year

Kowalczyk, Poland, 2007

1486 58.4 27.3 19.0% eGFR<60 mL/min/1.73m²

100.0 100.0% AMI rise in SCr or 0.5 mg/dL or a 25% increase from the baseline value within 48 hours after PCI

mean 29.7 months

Levy, United States, 1996

348 Median 66 30.7 Median Baseline SCr 141 µmol/L

NR 14.6% AMI increase in SCr of at least 25% from baseline, to at least 177 µmol/L (2 mg/dL), within 2 days of radiocontrast administration

hospital discharge

Lindsay, United States, 2003

5967 62.8 24.1 Normal baseline SCr

100.0 0.0% increase in SCr of ≥50% from baseline after PCI 1 year

Ma, China, 2010

69 68.8 21.7 69.6% CrCl<60 mL/min

NR 95.6% STEMI

Relative increase or >25% or an absolute increase of ≥0.5 mg/dL in SCr from the bseline value 72 h after exposure to the contrast medium

hospital discharge

Marenzi, Italy, 2004

208 62.0 11 23.1% CrCl<60 mL/min

100.0 100.0% STEMI

an absolute increase in SCr>0.5 mg/dL after PCI hospital discharge

Marenzi, Italy, 2009

561 61.2 14.1 30.5% CrCl<60 mL/min

100.0 100.0% STEMI

greater than 25% increase in SCr concentration from the baseline value in the 72 hours after primary PCI

hospital discharge

Patti, Italy, 2008

434 65.8 37.1 14.5% SCr ≥1.5 mg/dL or CrCl<70 mL/min

100.0 53.2% NSTEMI

postprocedural increase in serum SCr of ≥0.5 mg/dL or >25% from baseline

4 years

Rich, United States, 1990

183 75.4 16.4 15.1% SCr>133 µmol/L

23.6 NR rise in SCrof 44 µmol/L or greater above baseline within 48 hours after catheterization

hospital discharge

Rihal, United States, 2002

7586 65.0 21.7 47.7% >1.1 mg/dL

100.0 14.9% increase in SCr concentration of ≥0.5 mg/dL from pre-procedure values

5 years

Roghi, Italy, 2008

2860 63.0 19.5 12.3% eGFR<60 mL/min/1.73m²

100.0 0.0% STEMI increase in SCr of ≥0.5 mg/dL at 24 h after PCI compared to the pre-procedural value

2 years

Roy, United States, 2008

570 64.8 100 0.0% (all SCr ≤1.3 mg/dL)

100.0 0.0% AMI increase in SCr of ≥25% from baseline during hospital stay 6 months

Senoo, Japan, 2010

338 66.0 33.1 13.9% SCr>1.1 mg/dL

100.0 94.0% STEMI

SCr increase of 25% from baseline or an absolute increase of ≥0.5 mg/dL that appeared within 2 days

hospital discharge

Skelding, United States, 2007

3213 67.6 28 38.0% CrCl<60 mL/min

100.0 NR SCr increase of >1.0 mg/dL from baseline level hospital discharge

Uyarel, Turkey, 2009

2521 56.5 24.6 11.7% eGFR<60 mL/min/1.73m²

100.0 100.0% STEMI

increase in SCr level ≥0.5 mg/dL or ≥25% from baseline within 72h of radiocontrast administration

median 21 months

Weisbord, United States, 2006

27608 63.5 25.2 3.2% renal disease based on ICD 9 CM codes

NR NR absolute change in SCr from baseline of <0.25, 0.25 to 0.50, 0.51 to 1.0, and >1.0 mg/dL on each of the first 3d after angiography; relative change in SCr or <25, 25-50, 51-100, and >100% on each of the first 3d after angiography

30 days

Weisbord, United States, 2008

181 67.0 51 100.0% eGFR<60 mL/min/1.73m²

12.0 NR increase in SCr ≥25% and ≥0.5 mg/dL 30 days

Wickenbrock, German, 2009

392 64.0 24.5 16.3% CrCl<60 mL/min

100.0 100.0% AMI (51.8% STEMI)

absolute increase in SCr>0.5 mg/dL up to 3 days following coronary intervention

hospital discharge

Zaytseva, Russia, 2009

151 57.5 100 mean eGFR 78.4 mL/min/1.73m²

27.5 NR absolute increase in SCr of at least 44 µmol/L or by a relative increase of at least 25% over the baseline value in the absence of another cause

1.5 years

Abbreviations: CKD = Chronic Kidney Disease,CI-AKI = Contrast-Induced Acute Kidney Injury, eGFR = estimated Glomerular Filtration Rate, CrCl = Creatinine Clearance, NR = Not Reported, SCr = Serum Creatinine Concentration, PCI = Percutaneous Coronary Intervention, AMI = Acute Myocardial Infarction, STEMI = ST Segment Elevation myocardial infarction, ACS = Acute Coronary Syndrome

Supplemental Table 2 – Study Losses to Follow-up, Outcomes, Analysis, and Confounders included in Adjustment

Author, Year Losses to Follow-up

Outcomes Included Outcome Definition Analysis, (Measure of Effect)

Confounders Included in Adjusted Analysis

Assali, 2007

0% Mortality Death within 30 days of PCI

Logistic regression (OR)

Age >75 years, renal failure, Killip class, multi-vessel disease, post-TIMI 3, post-diameter stenosis, no-reflow, procedure successful, anti-GP 2B/3A, IABP use, amount of contrast used

Aronow, 2001

0% Length of Hospital Stay

Days from procedure until discharge

Linear regression (Natural logarithm of mean)

MI 0 to 24 hours, peri-procedure ischemia, intravenous heparin, cerebrovascular accident or transient ischemic attack, women, peripheral vascular disease, , post-procedure IABP, MI 1 to 30 days, post-procedure intravenous nitroglycerin, GI bleeding, repeat angiography, vascular complication, high-risk intervention, arrhythmia, chronic atrial fibrillation, transfusion

Bartholomew, 2004

0% Mortality Death during the index hospitalization

Unadjusted (OR)

None

Major adverse cardiovascular event

Death, myocardial infarction, reocclusion during the index hospitalization

Unadjusted (OR)

Length of Hospital Stay

Hospitalization >4 days

Unadjusted (RR)

Bouzas-Mosquera, 2007

0% Mortality Mortality on long term follow up

Cox regression (HR)

Age, sex, smoking habit, diabetes mellitus, hypertension, hypercholesterolemia, background of AMI, chronic renal failure, location of the AMI, cardiogenic shock, ejection fraction, multi-vessel disease, success of the procedure, time to revascularization, anemia, fasting blood glucose concentration, maximum troponin I concentration, creatinine concentration ≥1.5 mg/dL, urea concentration ≥50 mg/dL


Cardiovascular death, reinfarction, and percutaneous or surgical revascularization with objective evidence of previous myocardial ischemia on long term follow up

Cox regression (HR)


Time of hospital stay in days

Unadjusted (median)

None

Brown, 2008

0% Mortality Long term all-cause mortality

Cox regression (HR)

Age, sex, diabetes, prior myocardial infarction, ejection fraction <35%, non-elective priority, length of post-procedural hospitalization, morbid obesity, prior cardiac intervention, baseline eGFR<60 mL/min/1.73m2


New MI, cardiac arrest, coronary stent thrombosis, not including recurrent angina or new congestive heart failure during the index admission

Unadjusted (RR)

None


Length of hospitalization post procedure

Unadjusted (mean)

None

Budano, 2011

NR Mortality Long term mortality Logistic regression (OR)

Statin therapy, congestive heart failure, myocardial infarction, age >75 year, pre-procedural eGFR<60 mL/min, post-procedural eGFR<60 mL/min


Cardiac rehospitalization

Unadjusted (RR)

None

Caruso, 2011

29.3% Mortality Death in hospital or during follow up

Unadjusted (RR)

None


Infarct at follow up Unadjusted (RR)

None

Prolongation of hospital stay

Length of hospital stay

Unadjusted (mean)

None

Chen, 2008

0% Mortality Death from all causes at 6-months follow up

Unadjusted (RR)

None

Cho, 2010*

4.5% Mortality All-cause mortality to 1 year

Unadjusted (RR)

None


Composite of cardiac death, non-cardiac death, and revascularization

Cox regression (HR)

Multivariable adjusted but covariates not reported

Prolongation of hospital stay


Unadjusted (mean)

None

Chong, 2010

39.5% Mortality Death within 6 months Logistic regression (OR)

Age, gender, hypertension, diabetes mellitus, renal impairment, indication for PCI, LVEF, hypotension, anemia, number of diseased coronary arteries, location of coronary lesions

Dangas, 2005 †

0% Mortality One year mortality Logistic regression (OR)

Adjusted for eGFR, age, female, diabetes, previous AMI, previous CABG, previous PCI, hypertension, NSTEMI, stent used, LVEF <40%, hyperlipidemia, peripheral vascular disease, history of stroke, body surface area, multi-vessel PCI, CHF, NYHA III to IV, pulmonary edema on presentation, hypotension, elective IABP without hypotension, baseline hematocrit and stratified by CKD


Death, myocardial infarction, target vessel revascularization at 1 year

Unadjusted (RR)

None


Post-procedure length of stay

Unadjusted (mean)

None

Ergelen, 2010

0% Mortality In hospital cardiovascular mortality


Unsuccessful procedure, Killip class 2/3, DM, age above 70 years, anemia at admission, multi-vessel disease, female sex, tirofiban use

From, 2008

0% Mortality Overall long term mortality

Cox regression (HR)

Heart failure, medications, total hydration, iodine load, prior contrast exposure, age, sex, average prior creatinine value, diabetes mellitus, computed tomography, computed tomographic angiography, noncardiac angiography or venography, coronary catheterization

Development of ESRD / Chronic Dialysis

Initiation of dialysis >122 days after contrast exposure

Unadjusted (RR)

None

Goldenberg, 2009

0% for mortality, 4% for CKD, follow-up

Mortality Long term all-cause mortality

Cox regression (HR)

Age, male gender, BMI ≥27, history of hypertension, diabetes mellitus, prior PCI or CABG, LVEF <40, the degree of kidney disease, contrast volume

Progression of CKD Reduction in eGFR Unadjusted (mean)

None



Unadjusted (median)

None

Gruberg, 2000

0% Development of ESRD / Chronic Dialysis

Chronic Dialysis Unadjusted (RR)

None

Gupta, 2005


Cox regression (HR)

Age, gender, LVEF, baseline renal function, worst coronary lesion class, the vessel being intervened on, medication use at time of PCI, AMI

Harjai, 2008


Cox regression (HR)

Age >65 years, gender, diabetes mellitus, baseline creatinine clearance <60 mL/min, abnormal cardiac biomarkers before PCI Major adverse

cardiovascular event Composite of death from any cause, myocardial infarction, or target vessel revascularization within 6 months of PCI

Cox regression (HR)

Hölscher, 2008

0% Mortality Death during the long term follow up period

Cox regression (HR)

LVEF ≤35%, phosphate, hemoglobin, angiotensin converting enzyme inhibitors, age, diabetes, GFR, loop diuretics

Jabara, 2009

0% Mortality In hospital death Unadjusted (RR)

None

James, 2011

0% Mortality All-cause mortality Cox regression, (HR)

Age, sex, diabetes mellitus, congestive heart failure, cerebrovascular disease, peripheral vascular disease, chronic pulmonary disease, liver disease, malignancy, current smoking, acute coronary syndromes, baseline eGFR, microalbuminuria/proteinuria, coronary anatomy based on Duke myocardial jeopardy score, LVEF, coronary revascularization.

ESRD / chronic dialysis

ESRD Cox regression, (HR)

Age, sex, diabetes mellitus, congestive heart failure, baseline eGFR, microalbuminuria/proteinuria, LVEF, coronary revascularization


Hospitalization for myocardial infarction hospitalization, heart failure hospitalization, or cerebrovascular accident

Cox regression, (HR)

Age, sex, diabetes mellitus, congestive heart failure, cerebrovascular disease, peripheral vascular disease, current smoking, acute coronary syndrome, baseline eGFR, microalbuminuria/proteinuria, coronary anatomy based on Duke myocardial jeopardy score, LVEF, coronary revascularization

Kini, 2009

0% Mortality 1 year mortality Cox regression (HR)

Age, sex, cholesterol, BSA, past AMI, chronic pulmonary disease, liver disease, diabetes mellitus, peripheral vascular disease, hypertension, digoxin, coronary lesion type, CK-MB elevation, LVEF, worse AHA/ACC, number of vessels attempted, hemoglobin, troponin I elevation

Kowalczyk, 2007

0% Mortality All-cause mortality during long-term follow up

Cox regression (HR)

Age, sex, cardiogenic shock, number of affected coronaries, unsuccessful intervention of infarct related artery, LVEF, hypertension, diabetes, pain duration, previous AMI

Levy, 1996

0% Mortality Death during hospitalization


Matched on age, baseline serum creatinine, type of contrast study performed and adjusted for: age, sex, race, hypertension, diabetes mellitus, liver disease, acute MI, congestive heart failure, unstable angina, acute infection, sepsis, acute mental status changes, acute stroke, acute

leukemia or lymphoma, metastatic cancer, HIV, gastrointestinal bleed, other bleed

Lindsay, 2003

17% Major adverse cardiovascular event

Myocardial Infarction Logistic regression (OR)

Diabetes mellitus, unstable angina, prior CABG, prior AMI, prior PCI, target vessel revascularization in hospital

Mortality 1 year all-cause mortality after hospital discharge


Age, history of AMI, cerebral or peripheral vascular disease, pulmonary edema

Ma, 2010


None

Marenzi, 2004

0% Length of Hospital Stay


Unadjusted (mean)

None

Marenzi, 2009

0% Mortality Overall in hospital mortality

Unadjusted (RR)

None

Patti, 2008

0.9% Mortality In hospital death Unadjusted (RR)

None


cardiac death, myocardial infarction, or repeat coronary revascularization


Age, sex, statin therapy, diabetes, mellitus, LVEF <40%, balloon angioplasty, stent length <15 mm, stent diameter <3 mm



Unadjusted (mean)

None

Rich, 1990


None

Rihal, 2002


Myocardial Infarction Unadjusted (RR)

None

Mortality In hospital death Logistic regression (OR)

Total volume of contrast medium, age, sex, BMI, Canadian Heart Association class, history of congestive heart failure, diabetes, hypertension, peripheral vascular disease, myocardial infarction in the 24 hours before the procedure

Roghi, 2008

0% Mortality 2 year all-cause mortality

Cox regression (HR)

Age, LVEF, fluoroscopy time, post procedural creatinine kinase-MB ratio, sex, hypertension, diabetes mellitus, dyslipidemia, eGFR, unstable angina, prior MI, heart failure, peripheral vascular disease, atrial fibrillation, CABG, # of coronary arteries with >70% stenosis, severe coronary calcification, type of coronary lesion, acute occlusion, collateral occlusion, angiographic procedural success

Roy, 2008


composite of death, Q-wave myocardial infarction, and target vessel revascularization

Cox regression (HR)

Age, male gender, hypertension, current smoker, congestive heart failure, BMI, hematocrit, length of procedure, blood transfusion

Mortality Death at 30 days Unadjusted (RR)

None



Unadjusted (mean)

None

Senoo, 2010


None

Skelding, 2007

0% Mortality In hospital death Logistic regression (OR)

None



Unadjusted (median)

None

Uyarel, 2009

2% Mortality Long term cardiovascular mortality

Cox regression (HR)

Gender, age ≥75, time to reperfusion >6 h, diabetes mellitus, hypertension, hypercholesterolemia, smoking habit, AMI history, multi-vessel disease, unsuccessful procedure, anterior AMI, cardiogenic shock, admission glucose, anemia Major adverse

cardiovascular event Cardiovascular death, reinfarction, target vessel revascularization

Cox regression (HR)



Unadjusted (mean)

None

Weisbord, 2006


eGFR, myocardial infarction, congestive heart failure, COPD, diabetes, chronic pulmonary disease, peripheral vascular disease, cerebrovascular disease, renal disease, metastatic solid tumor, rheumatologic disease, peptic ulcer disease, mild liver disease, any malignancy including lymphoma and leukemia, dementia, AIDS

Weisbord, 2008

0% Mortality Death within 30 days Unadjusted (RR)

None

Wickenbrock, 2009


Cardiogenic shock, creatinine kinase elevation



Unadjusted (mean)

None

Zaytseva, 2009 *

NR Mortality Long term mortality Cox regression (HR)

Age, sex



Unadjusted (mean)

None

* Inclusion and exclusion criteria were not reported in these studies. These studies did not report enrollment of consecutive patients in the cohort. † This study reported blinding of study personnel to exposure status. Abbreviations: OR = Odds Ratio, HR = Hazard Ratio, RR = Risk Ratio, AMI = Acute Myocardial Infarction, eGFR = estimated Glomerular filtration rate, CIN = Contrast Induced Nephropathy, BMI = Body Mass Index, LVEF = Left Ventricular Ejection Fraction, IABP = Intra-Arterial Balloon Pump, PCI = Percutaneous Coronary Intervention, NYHA = New York Heart Association, CABG = Coronary Artery Bypass Graft

Supplemental Table 3 - Stratified Analyses of Pooled Relative Risks of Mortality for CI-AKI

Stratification Number Pooled RR (95% CI)

I2 Meta-regression p-value Cohorts Participants

Study Design Characteristics Follow-up <6 months ≥6 months

6

17

38,787 73,626

4.35 (2.29-8.26) 1.98 (1.66-2.36)

89.6% 83.2%

0.005

Definition of CI-AKI* >25% or 0.5 mg/dL increase in creatinine >50% or 1.0 mg/dL increase in creatinine

21 4

68,302 27,065

2.31 (1.88-2.82) 2.73 (1.97-3.78)

89.8% 73.9%

0.659

Participants lost to follow-up ≥10% or not reported <10%

4

19

9,910

112,414

2.92 (2.07-4.11) 2.31 (1.88-2.85)

0.0% 90.1%

0.481

Study Participant Characteristics Mean Age < 65 years ≥ 65 years

16 7

95,160 17,253

2.09 (1.73-2.53) 3.08 (1.69-5.61)

83.4%

912.6%

0.697

Diabetes mellitus <25% ≥25%

8

15

25,846 86,567

2.95 (1.23-5.03) 2.13 (1.74-2.62)

90.9% 86.7%

0.254

Chronic kidney disease No CKD With and without CKD All with CKD

1

20 2

5,967

105,956 490

2.58 (1.48-4.43) 2.48 (2.03-3.05) 1.47 (0.45-4.87)

-

89.3% 89.0%

0. 982 0.458

ST elevation <50% >50%

11 5

52,122 6,081

2.67 (1.82-3.93) 3.47 (2.11-5.72)

86.0% 50.7%

0.413

Procedure PCI or diagnostic angiogram PCI only

8

15

47,370 65,043

2.19 (1.64-2.93) 2.54 (1.96-3.33)

75.6% 91.2%

0.546

* 2 studies categorized the severity of CI-AKI in categories corresponding to both definitions of CI-AKI and thus contributed cohorts to both strata Abbreviations: RR = Relative risk, CI-AKI = Contrast-Induced Acute Kidney Injury, PCI = Percutaneous Coronary Angiogram, CKD = Chronic Kidney Disease

Supplemental Figure 1 – Funnel Plot for the Association between CI-AKI and Mortality (A), Including Trim and Fill Procedure (B)

A - Begg's funnel plot with pseudo 95% confidence limits

SE of adjusted: logRR 0 .5 1 1.5

-2

0

2

4

Adjusted log RR

Supplemental Figure 1 Legend - Open circles represent identified studies, squared circles represent hypothesized unpublished studies from trim and fill procedure. A. The asymmetrical appearance of the funnel plot raises the possibility of publication bias. B. The trim and fill method conservatively imputes hypothetical negative unpublished studies to mirror the positive studies and produce a symmetrical funnel plot. The pooled RR incorporating the imputed unpublished studies was attenuated, but continued to show a significant association between AKI and mortality (RR 1.79, 95% CI 1.47 – 2.18). Abbreviations: RR = Risk Ratio, CI = Confidence Intervals, SE = Standard Error

B - Filled funnel plot with pseudo 95% confidence limits

SE of adjusted logRR 0 .5 1 1.5

-2

0

2

4

Adjusted log RR

Supplemental Figure 2 – Weighted Mean Difference in Hospital Length of Stay Associated with CI-AKI

Supplemental Figure 2 Legend - Black squares indicate point estimates, horizontal lines indicate widths of 95% CIs for each study. Abbreviations: CI-AKI = Contrast Induced Acute Kidney Injury, N= Number, SD = Standard Deviation

Marenzi, 2004

Dangas, 2005, +CKD

Dangas, 2005, -CKD

Brown, 2008

Patti, 2008

Roy, 2008

Uyarel, 2009

Wickenbrock, 2009

Zaytseva, 2009

Cho, 2010

Caruso, 2011

Year

Author,

5.00 (2.78, 7.22)

4.50 (3.78, 5.22)

1.80 (1.41, 2.19)

3.20 (2.31, 4.09)

0.50 (0.25, 0.75)

2.30 (1.06, 3.54)

0.90 (0.36, 1.44)

6.00 (2.72, 9.28)

8.30 (7.92, 8.68)

5.60 (2.50, 8.70)

1.90 (0.81, 2.99)

Difference (95% CI)

Mean

40, 13 (7)

381, 6.8 (7.1)

688, 3.6 (5.1)

308, 5.1 (7.9)

55, 2.7 (.9)

70, 4.5 (5.2)

630, 8 (5.9)

45, 15 (11)

61, 18.4 (1.4)

74, 14.7 (12.1)

14, 6.1 (1.9)

(SD); Treatment

N, mean

168, 8 (3)

1599, 2.3 (2.5)

4562, 1.8 (2.4)

7081, 1.9 (4.1)

379, 2.2 (.6)

500, 2.2 (2.9)

1891, 7.1 (6.1)

347, 9 (6)

90, 10.1 (.7)

436, 9.1 (15.2)

136, 4.2 (2.6)

(SD); Control

N, mean

5.00 (2.78, 7.22)

4.50 (3.78, 5.22)

1.80 (1.41, 2.19)

3.20 (2.31, 4.09)

0.50 (0.25, 0.75)

2.30 (1.06, 3.54)

0.90 (0.36, 1.44)

6.00 (2.72, 9.28)

8.30 (7.92, 8.68)

5.60 (2.50, 8.70)

1.90 (0.81, 2.99)

Difference (95% CI)

Mean

40, 13 (7)

381, 6.8 (7.1)

688, 3.6 (5.1)

308, 5.1 (7.9)

55, 2.7 (.9)

70, 4.5 (5.2)

630, 8 (5.9)

45, 15 (11)

61, 18.4 (1.4)

74, 14.7 (12.1)

14, 6.1 (1.9)

(SD); Treatment

N, mean

Author, yearMean difference(95% CI) days

CI-AKI No CI-AKIN, mean (SD) days N, mean (SD) days

Decreased with AKI Increased with AKI

00 3 6 9

Decreased with CI-AKI Increased with CI-AKI

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Cardiac Catheterizationcircinterventions.ahajournals.org/content/circcvint/6/1/37.full.pdf · James et al Outcomes of Contrast-Induced Acute Kidney Injury 39 formula RR=OR/[(1-P 0)+(P