European Heart Journal Advance Access published March 6, 2014

CLINICAL RESEARCH

European Heart Journal doi:10.1093/eurheartj/ehu063

Interventional cardiology

Contrast-induced acute kidney injury after primary percutaneous coronary intervention: results from the HORIZONS-AMI substudy

1

NYU Langone Medical Center, New York, NY, USA; 2Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3Cardiovascular Research Foundation, New York, NY, USA; Columbia University Medical Center, New York, NY, USA; 5Shaare Zedek Medical Center, Jerusalem, Israel; 6Hoˆpital du Sacre´-Coeur de Montre´al, Montre´al, Que´bec, Canada; 7Rambam Health Care Campus and the Technion – Israel Institute of Technology, Haifa, Israel; 8New York Methodist Hospital, Brooklyn, NY, USA; 9Amper Kliniken AG, Dachau, Germany; 10 Ospedale Papa Giovanni XXIII, Bergamo, Italy; 11The Warren Alpert Medical School of Brown University, Providence, RI, USA; and 12LeBauer Cardiovascular Research Foundation and Moses Cone Heart and Vascular Center, Greensboro, NC, USA 4

Received 17 September 2013; revised 6 January 2014; accepted 29 January 2014

Aim

We sought to examine the short- and long-term outcomes of patients who developed contrast-induced acute kidney injury (CI-AKI; defined as an increase in serum creatinine of ≥0.5 mg/dL or a 25% relative rise within 48 h after contrast exposure) from the large-scale HORIZONS-AMI trial. ..................................................................................................................................................................................... Methods Multivariable analyses were used to identify predictors of CI-AKI, as well predictors of the primary and secondary endand results points. The incidence of CI-AKI in this cohort of ST-segment elevation myocardial infarction (STEMI) patients was 16.1% (479/2968). Predictors of CI-AKI were contrast volume, white blood cell count, left anterior descending infarct-related artery, age, anaemia, creatinine clearance ,60 mL/min, and history of congestive heart failure. Patients with CI-AKI had higher rates of net adverse clinical events [NACE; a combination of major bleeding or composite major adverse cardiac events (MACE; consisting of death, reinfarction, target vessel revascularization for ischaemia, or stroke)] at 30 days (22.0 vs. 9.3%; P , 0.0001) and 3 years (40.3 vs. 24.6%; P , 0.0001). They also had higher rates of mortality at 30 days (8.0 vs. 0.9%; P , 0.0001) and 3 years (16.2 vs. 4.5%; P , 0.0001). Multivariable analysis confirmed CI-AKI as an independent predictor of NACE [hazard ratio ([HR), 1.53; 95% confidence interval (CI), 1.23 –1.90; P ¼ 0.0001], MACE (HR, 1.56; 95% CI, 1.23 –1.98; P ¼ 0.0002), non-coronary artery bypass grafting major bleeding (HR, 2.07; 95% CI, 1.57 –2.73; P , 0.0001), and mortality (HR, 1.80; 95% CI, 1.19–2.73; P ¼ 0.005) at 3-year follow-up. ..................................................................................................................................................................................... Conclusion Contrast-induced acute kidney injury is associated with poor short- and long-term outcomes after primary percutaneous coronary intervention in STEMI.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Contrast media † Kidney † Myocardial infarction

Introduction Contrast-induced acute kidney injury (CI-AKI) after percutaneous coronary intervention (PCI) is associated with significant in-hospital as well as long-term morbidity and mortality. The incidence of CI-AKI varies from 2% in the general population to over 50% in high-risk

groups.1 Given this, individual risk factors that predict CI-AKI have been identified, and cumulative risk scores developed.1,2 Patients at higher risk include those with baseline chronic kidney disease, diabetes mellitus, congestive heart failure (CHF), hypotension, and anaemia; procedural variables such as use of intra-aortic balloon pump (IABP) and contrast volume also contribute. Efforts to

*Corresponding author. Tel: +1 2126599641, Fax: +1 6465378547, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected]

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Amar Narula1, Roxana Mehran2,3*, Giora Weisz3,4,5, George D. Dangas2,3, Jennifer Yu2, Philippe Ge´ne´reux3,4,6, Eugenia Nikolsky7, Sorin J. Brener3,8, Bernhard Witzenbichler9, Giulio Guagliumi10, Avery E. Clark11, Martin Fahy3, Ke Xu3, Bruce R. Brodie12, and Gregg W. Stone3,4

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A. Narula et al.

modify the risk of CI-AKI have included the investigation of various hydration strategies, N-acetylcysteine use, different contrast agents, haemofiltration protocols, and most recently statin therapy with often mixed and conflicting results.3 – 19 The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial demonstrated lower rates of major bleeding and mortality with bivalirudin compared with unfractionated heparin (UFH) and glycoprotein IIb/

IIIa inhibitors (GPI).20,21 Patients with acute ST-segment elevation myocardial infarction (STEMI) are an especially high-risk group for CI-AKI and subsequent adverse events; only a few studies with small sample sizes have examined the impact of CI-AKI in this specific population.22,23 Here, we report 3 year, prospective data on outcomes in a large, primary cohort of STEMI patients who developed CI-AKI, as well as the predictive variables for CI-AKI in this cohort.

Table 1 Baseline characteristics of patients who suffered contrast-induced acute kidney injury vs. no contrast-induced acute kidney injury CI-AKI (n 5 479)

No CI-AKI (n 5 2489)

P-value

Propensity CI-AKI (n 5 338)

Matched cohort no CI-AKI (n 5 338)

P-value

............................................................................................................................................................................... Age, years

0.59

77.0%

59.4 (51.7– 68.7)

0.12

75.7%

63.7 (55.0– 72.9)

76.3%

0.86

Body mass index, kg/m2 Diabetes

26.7 (24.4– 29.8) 21.5%

27.1 (24.6– 30.3) 15.4%

0.13 0.0009

26.9 (24.6– 29.8) 21.3%

26.8 (24.2–30.1) 20.7%

0.89 0.85

Hypertension

56.8%

52.4%

0.07

55.0%

55.0%

1.00

Hyperlipidaemia History of smoking

43.4% 59.7%

42.6% 64.9%

0.73 0.03

45.6% 60.4%

47.6% 59.5%

0.59 0.81

Family history of CAD

26.7%

31.4%

0.04

28.4%

32.3%

0.28

Prior myocardial infarction

12.5%

10.4%

0.17

11.2%

11.2%

1.00

Prior percutaneous coronary intervention

12.1%

10.5%

0.31

11.0%

11.2%

0.91

Prior CABG Killip class .1

3.8% 13.2%

2.7% 7.9%

0.18 0.0002

3.8% 11.3%

2.1% 11%

0.17 0.90

Anaemia*

15.7%

9.6%

0.0001

14.5%

14.5%

1.00

5.2% 5.0%

4.3% 2.8%

0.35 0.01

4.7% 4.7%

4.4% 3.0%

0.85 0.23

19.2%

15.8%

0.06

17.2%

23.7%

0.04

...............................................................................................................................................................................

Procedure variables Total contrast volume, cc Hypotension

245 (190– 320) 1.9%

225 (180–290) 1.7%

0.0003 0.82

245 (190– 320) 2.4%

230 (180– 290) 3.0%

0.06 0.63

Cardiogenic shock

1.7%

0.6%

0.02

1.8%

1.5%

0.76

LVEF ,40% (site reported)

23.2%

12.0%

,0.0001

22.8%

23.7%

0.79

IABP use Use of bivalirudin

11.1% 50.7%

4.5% 48.4%

,0.0001 0.36

9.5% 51.8%

5.9% 49.7%

0.08 0.59

LAD infarct-related artery

47.3%

38.5%

0.0003

45.8%

43.1%

0.47

Per cent with TAXUS stent

68.1%

68.8%

0.78

68.3%

67.7%

0.88

Femoral access

94.4%

94.2%

0.87

100.0%

100.0%

1.00

97.5% 93.9%

97.7% 93.9%

0.87 1.00

97.8% 98.4%

98.2% 99.1%

0.70 0.49

............................................................................................................................................................................... Discharge medications Aspirin Thienopyridine ACEI or ARB

86.7%

80.5%

0.002

90.8%

80.5%

0.002

Beta-blocker Statin

86.5% 95.0%

90.3% 94.1%

0.01 0.43

88.0% 96.2%

93.8% 95.5%

0.009 0.66

Values are median (inter-quartile range) or per cent. *Haemoglobin ,13 g/dL for men, ,12 g/dL for women. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CI-AKI, contrast-induced acute kidney injury; LVEF, left ventricular ejection fraction; IABP, intra-aortic balloon pump.

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63.1 (54.5–73.2)

73.7%

Peripheral artery disease History of congestive heart failure Baseline creatinine clearance ,60 mL/min

65.6 (56.0– 74.2)

,0.0001

Male

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CI-AKI After primary PCI

Methods Patient population, randomization, and study protocol

Study endpoints and definitions The HORIZONS-AMI trial was powered for two 30-day endpoints: major bleeding (not related to CABG) and combined net adverse clinical events (NACE, consisting of major bleeding not related to CABG or a composite of major adverse cardiac events (MACE), including death, reinfarction, target vessel revascularization (TVR) for ischaemia, or stroke).20,21,24 Outcomes for the primary endpoints were assessed out to 3 years. An independent clinical events committee blinded to treatment assignment adjudicated all events. Contrast-induced acute kidney injury was defined as an increase in serum creatinine of ≥0.5 mg/dL, or a 25% relative rise in creatinine, within 48 h after contrast exposure.25

Statistical analysis All analyses are by intention to treat. Chi-square tests were used to compare categorical variables. Continuous variables are presented as medians with inter-quartile ranges and were compared using the Wilcoxon rank-sum test. Follow-up analysis was performed using time-to-event data (for which patients were censored at the time of withdrawal from the study or at the last follow-up), with the event rates estimated by Kaplan–Meier methods and compared with the log-rank test. Additionally, a landmark analysis was conducted for all major endpoints, which included all patients without events beginning at 30 days and continuing to last follow-up available. A stepwise logistic regression model with an entry and exit level of significance of 0.1 was used to identify independent predictors of CI-AKI. Cox regression models were used to identify independent predictors of NACE, MACE, major bleeding, and mortality at 3 years. The number of variables included was carefully chosen based on the total number of events to ensure parsimony of each model (see footnote to respective table for complete list of variables included). The final Cox models used

Results Incidence and predictors of contrast-induced acute kidney injury Among 3602 patients enrolled in the HORIZONS-AMI trial, 2968 (82.4%) had baseline and follow-up creatinine data and met inclusion criteria for this analysis. Contrast-induced acute kidney injury occurred in 479 patients (16.1%); 459 of those patients (95.8%) had an increase in serum creatinine ≥25% above baseline, while 144 (30.1%) had an increase in creatinine ≥0.5 mg/dL above baseline. Patients who developed CI-AKI were older and at baseline, were Table 2 Multivariate predictors of contrast-induced acute kidney injury in all patients and those without chronic kidney disease Patient group (# of patients in model) and risk factors

Hazard ratio (95% confidence interval)

P-value

................................................................................ All patients (401/2110) Contrast volume

1.02 (1.01– 1.03)

0.002

White blood cell count

1.03 (1.00– 1.07)

0.02

Left anterior descending infarct-related artery

1.31 (1.02– 1.68)

0.04

Age Anaemia

1.47 (1.31– 1.65) 1.48 (1.06– 2.05)

,0.0001 0.02

Creatinine clearance ,60 mL/min

1.67 (1.19– 2.38)

0.003

History of congestive heart failure

1.79 (1.04– 3.06)

0.04

Final TIMI 3 flow

0.69 (0.52– 0.93)

0.01

Body mass index

0.97 (0.95– 1.00)

0.03

................................................................................ Patients without chronic kidney disease (346/1922) Contrast volume Left anterior descending infarct-related artery Age

1.02 (1.00– 1.03) 1.38 (1.05– 1.80)

0.005 0.02

1.39 (1.24– 1.56)

,0.0001

History of congestive heart failure

1.85 (1.00– 3.43)

0.05

Body mass index

0.97 (0.94– 1.00)

0.03

Potential co-variables included in model: age, sex, race, body mass index (per 1 unit increase), Killip class 2–4, anaemia, platelet count (per 100 000 increase), white blood cell count (per 1000 increase), ejection fraction (per 10 unit decrease), creatinine clearance ,60 mL/min, contrast volume (per 10 cc increase), randomization to bivalirudin, history of hypertension, hyperlipidaemia, anaemia, smoking, diabetes, insulin-treated diabetes, myocardial infarction, coronary artery bypass grafting, coronary artery disease, angina, congestive heart failure, peripheral arterial disease, drug-eluting stent use, ≥2 stent implanted, post-dilation balloon, left anterior descending infarct-related artery, and final TIMI 3 flow. TIMI, thrombolysis in myocardial infarction; chronic kidney disease: creatinine clearance ,60 mL/min.

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The design, inclusion and exclusion criteria, and results of the HORIZONS-AMI trial have been previously published.20,21,24 Briefly, HORIZONS-AMI was a prospective, open-label, 2 × 2 factorial randomized trial involving patients with STEMI who were undergoing primary PCI as a management strategy. A total of 3602 patients with STEMI presenting within 12 h of symptom onset were prospectively randomized to UFH plus the routine use of a GPI vs. bivalirudin plus provisional use of a GPI reserved for pre-defined refractory thrombotic complications. After angiography, eligible patients were randomly assigned to either a TAXUS Express paclitaxel-eluting stent (Boston Scientific, Natick, MA, USA) or to an otherwise identical Express bare metal stent (Boston Scientific). Serum creatinine measurement was recommended per protocol at baseline as part of the initial blood work obtained in the emergency room, and daily post-procedure for a minimum of 2 days; if the serum creatinine was elevated by ≥0.3 mg/dL from baseline, it was recommended to obtain daily creatinine levels until renal function demonstrated improvement. Creatinine clearance was calculated by applying the Cockroft – Gault formula. Data were not collected regarding need for haemodialysis during or after initial hospitalization. The protocol allowed for the use of the following contrast types: the iso-osmolar agent, iodixanol, or the low-osmolar agents: iopamidol, ioxaglate, iohexol, iopromide, iotrolan, and ioversol. There was no exclusion based on creatinine clearance or haemodialysis at baseline in the HORIZONS-AMI trial. However, patients with a history of dialysis were excluded from this analysis.

were selected using a stepwise selection algorithm, with an entry and exit level of significance of 0.10. All statistical analyses were performed by SAS version 9.2 (SAS Institute, Cary, NC, USA). Finally, a propensitymatched cohort was created for CI-AKI matching on the variables of age, gender, diabetes mellitus, smoking, Killip class .1, LVEF, and anaemia.

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A. Narula et al.

Table 3

127/1024), moderate risk (14.5%, 165/1141), high risk (24.1%, 92/ 381), and very high risk (37.0%, 37/100) (P , 0.0001). The area under the curve (AUC) of the model was 0.60 (95% CI, 0.57– 0.63). The Marenzi score assigns points for the variables: age ≥ 75, anterior myocardial infarction, time to reperfusion ≥6 h, contrast agent volume ≥ 300 mL, and use of the intra-aortic balloon pump.22 Rates of CI-AKI by group were Score 0, 10% (82/818); Score 1, 14.3% (148/1033); Score 2, 20.5% (114/555); Score 3, 28.0% (53/189); and Score 4/5, 50.0% (14/28) (P , 0.0001). The AUC for the Marenzi model was 0.62 (95% CI, 0.50–0.65).

Contrast-induced acute kidney injury and long-term outcomes Patients who suffered CI-AKI had higher rates of NACE at 30 days (22.0 vs. 9.3%, P , 0.0001) and 3 years (40.3 vs. 24.6%; P , 0.0001). They also had higher rates of MACE (11.7 vs. 3.9%; P , 0.0001; 34.0 vs. 19.8%; P , 0.0001) and non-CABG-related major bleeding (14.6 vs. 6.3%; P , 0.0001; 17.2 vs. 7.8%; P , 0.0001) at 30 days and at 3 years, respectively. Patients who suffered CI-AKI had higher rates of the individual endpoints of mortality, cardiac death, reinfarction, and ischaemic TVR at short- and long-term follow-up (Table 3). For stent thrombosis, there was no difference at 30 days, but at 3-year follow-up, patients who suffered CI-AKI

Contrast-induced acute kidney injury and short- and long-term outcomes CI-AKI (n 5 479)

No CI-AKI (n 5 2489)

Hazard ratio (95% confidence interval)

P-value

Propensity CI-AKI (n 5 338)

Matched CI-AKI (n 5 338)

Cohort hazard ratio (95%CI)

P-value

............................................................................................................................................................................... 30 Days NACE

22.0% (105)

9.3% (232)

2.48 (1.97–3.12)

,0.0001

19.6% (66)

12.2% (41)

1.66 (1.12– 2.45)

0.009

MACE Death

11.7% (56) 8.0% (38)

3.9% (97) 0.9% (23)

3.10 (2.23–4.30) 8.88 (5.29–14.90)

,0.0001 ,0.0001

10.1% (34) 7.4% (25)

3.9% (13) 1.8% (6)

2.71 (1.43– 5.14) 4.30 (1.76– 10.48)

0.001 0.0005

Cardiac death

7.2% (34)

0.8% (20)

9.12 (5.25–15.84)

,0.0001

6.8% (23)

1.5% (5)

4.74 (1.80– 12.46)

0.0005

Reinfarction Major bleeding

3.0% (14) 14.6% (69)

1.7% (43) 6.3% (156)

1.74 (0.95–3.17) 2.40 (1.81–3.18)

0.07 ,0.0001

3.0% (10) 13.8% (46)

1.5% (5) 9.2% (31)

2.07 (0.71– 6.04) 1.51 (0.96– 2.38)

0.18 0.07

Ischaemic TVR

3.8% (18)

2.2% (55)

1.73 (1.02–2.95)

0.04

3.0% (10)

1.5% (5)

2.06 (0.70– 6.02)

0.18

Definite or probable stent thrombosis

3.4% (14)

2.2% (49)

1.53 (0.85–2.78)

0.15

2.8% (9)

1.5% (50)

1.88 (0.62– 5.54)

0.26

............................................................................................................................................................................... 3 Years NACE MACE

40.3% (190) 34.0% (159)

Death

24.6% (594) 19.8% (474)

1.87 (1.59–2.20) 1.91 (1.60–2.29)

,0.0001 ,0.0001

40.4% (135) 34.6% (115)

27.1% (90) 19.4% (64)

1.64 (1.25– 2.14) 1.98 (1.46– 2.69)

0.0002 ,0.0001

16.2% (76)

4.5% (106)

4.00 (2.98–5.37)

,0.0001

15.0% (50)

5.2% (17)

3.12 (1.80– 5.40)

,0.0001

Cardiac death Reinfarction

9.4% (44) 9.6% (41)

2.3% (55) 6.9% (163)

4.40 (2.96–6.54) 1.40 (1.00–1.97)

,0.0001 0.05

9.3% (31) 10.4% (32)

2.7% (9) 5.6% (18)

3.60 (1.71– 7.56) 1.91 (1.07– 3.41)

0.0003 0.03

Major bleeding

17.2% (80)

7.8% (190)

2.32 (1.79–3.02)

,0.0001

18.1% (60)

13.2% (44)

1.41 (0.96– 2.08)

0.08

Ischaemic TVR Definite or probable stent thrombosis

17.8% (76) 7.1% (28)

12.8% (300) 4.5% (98)

1.44 (1.12–1.85) 1.58 (1.04–2.40)

0.005 0.03

20.0% (61) 6.6% (20)

11.8% (38) 3.1% (10)

1.77 (1.18– 2.65) 2.12 (0.99– 4.52)

0.005 0.05

CI-AKI, contrast-induced acute kidney injury; MACE, major adverse cardiac events; NACE, net adverse clinical events; TVR, target vessel revascularization.

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more likely to have diabetes, CHF, and anaemia. Regarding procedural variables, they were more likely to have cardiogenic shock, left anterior descending (LAD) as the infarct-related artery, IABP use, and left ventricular ejection fraction ,40% (Table 1). The median amount of contrast used was 245 cc (inter-quartile range 190– 320) in the group that developed CI-AKI vs. 225 cc (180 –290) in the group without CI-AKI (P ¼ 0.0003). Contrast-induced acute kidney injury occurred in 248 of 1475 (16.8%) patients randomized to the bivalirudin arm vs. 231 of 1493 (15.5%) patients randomized to the UFH + GPI arm (P ¼ 0.32). After multivariable analysis, the independent predictors of CI-AKI were contrast volume, white blood cell count, LAD infarct-related artery, age, anaemia, creatinine clearance ,60 mL/min, and history of CHF (Table 2). When the patients with baseline chronic kidney disease were excluded, contrast volume, LAD infarct-related artery, age, and history of CHF remained independent predictors of CI-AKI. We applied the Mehran and Marenzi scores for prediction of CI-AKI after percutaneous intervention. The Mehran risk score assigns points for the risk factors: hypotension, use of intra-aortic balloon pump, CHF, age .75 years, anaemia, diabetes mellitus, contrast volume, and serum creatinine or chronic kidney disease.1 Patients were stratified into low-risk (≤5 points), moderate-risk (6– 10 points), high-risk (11–15 points), and very high-risk (≥16 points) groups. Rates of CI-AKI by group were low risk (12.4%,

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CI-AKI After primary PCI

had significantly higher rates of definite or probable stent thrombosis (7.1 vs. 4.5%; P ¼ 0.03). In a landmark analysis beginning at 30 days, patients who suffered CI-AKI had a continuing late hazard for adverse cardiovascular events and mortality compared with those that did not (Figure 1 A–D). These findings were confirmed in a propensity-matched cohort, with significantly higher rates of NACE, MACE, cardiac death, and mortality at both short- and long-term follow-up (Table 3). Furthermore, in multivariable analyses, CI-AKI was an independent predictor of NACE (HR, 1.53; 95% CI, 1.23–1.90; P ¼ 0.0002), MACE (HR, 1.56; 95% CI, 1.23 –1.98; P ¼ 0.0002), non-CABG major bleeding (HR, 2.07; 95% CI, 1.57–2.73; P , 0.0001), and mortality (HR, 1.80; 95% CI, 1.19–2.73; P ¼ 0.005) at 3-year follow-up (Table 4).

who received low-osmolar contrast had lower 30-day rates of NACE (10.2 vs. 14.4%; P ¼ 0.01), MACE (3.8 vs. 7.1%; P ¼ 0.003), and stent thrombosis (1.8 vs. 3.5%; P ¼ 0.04), but these differences did not persist at 3-year follow-up. They also had lower 30-day rates of ischaemic TVR (1.7 vs. 3.8%; P ¼ 0.01); this difference was not significant at 3-year follow-up (13.9 vs. 13.9%; P ¼ 0.89). Rates of non-CABG-related major bleeding, mortality, and reinfarction were not different at short- and long-term follow-up (Table 5). In multivariable analysis, iso-osmolar contrast use was associated with increased 30-day rates of MACE (HR, 1.76, 1.13–2.75), but not NACE or major bleeding. However, contrast osmolality was not a significant predictor of long-term outcomes in multivariable analysis.

Discussion

Of patients meeting inclusion criteria for this analysis with data on contrast type, 1380 of 1832 (75.3%) received low-osmolar contrast, while 452/1832 (24.7%) received iso-osmolar contrast. There were no significant differences between rates of CI-AKI by type of contrast used (low-osmolar vs. iso-osmolar, 15.6 vs. 15.3%; P ¼ 0.87). Patients

Our analysis of the HORIZONS-AMI supports the association of CI-AKI with more unfavourable short- and long-term cardiovascular and bleeding outcomes, including mortality. It has been thought that this form of acute kidney injury selects patients with increased comorbidities and that the increased rate of adverse outcomes is

Figure 1 Landmark analysis beginning at 30 days comparing patients with contrast-induced acute kidney injury vs. no contrast-induced acute kidney injury. (A) Net adverse clinical events; (B) major adverse cardiac events; (C) non-coronary artery bypass graft major bleeding; and (D) death. Hazard ratios and 95% confidence intervals for events before 30 days and between 30 days and 3 years.

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Impact of contrast type on outcomes

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Table 4

A. Narula et al.

Independent predictors of adverse clinical events at 3-year follow-up Hazard ratio (95% confidence interval)

P-value

............................................................................................................................................................................... Predictors of net adverse clinical events Male White blood cell count

0.76 (0.61–0.95) 1.03 (1.01–1.06)

0.01 0.01

Admission haemoglobin

1.09 (1.03–1.17)

0.007

Ejection fraction Age

1.12 (1.05–1.19) 1.13 (1.04–1.23)

0.001 0.005

Left anterior descending artery disease

1.25 (1.03–1.53)

0.03

Diabetes mellitus History of prior PCI

1.26 (1.01–1.56) 1.37 (1.06–1.78)

0.04 0.02

Contrast-induced acute kidney injury

1.53 (1.23–1.90)

0.0001

Baseline creatinine

1.98 (1.55–2.53)

,0.0001

1.08 (1.01–1.16)

0.02

...............................................................................................................................................................................

Ejection fraction

1.14 (1.06–1.23)

0.0004

Age Platelet count

1.17 (1.06–1.29) 1.28 (1.12–1.46)

0.001 0.0003

History of smoking

1.30 (1.05–1.62)

0.02

Diabetes mellitus Left anterior descending artery disease

1.37 (1.08–1.75) 1.48 (1.17–1.86)

0.01 0.001

Contrast-induced acute kidney injury

1.56 (1.23–1.98)

0.0002

Baseline creatinine History of prior PCI

1.62 (1.19–2.19) 1.62 (1.23–2.12)

0.002 0.0006

............................................................................................................................................................................... Predictors of non-CABG major bleeding Male

0.51 (0.39–0.67)

,0.0001

Bivalirudin randomization

0.65 (0.51–0.84)

0.0008

White blood cell count Age

1.06 (1.03–1.09) 1.24 (1.11–1.39)

0.0003 0.0002

Contrast-induced acute kidney injury

2.07 (1.57–2.73)

,0.0001

Baseline creatinine

2.09 (1.72–2.53)

,0.0001

1.10 (1.05–1.15) 1.21 (1.08–1.36)

,0.0001 0.001

Ejection fraction

1.45 (1.28–1.65)

,0.0001

Killip class 2 –4 History of prior myocardial infarction

1.64 (1.03–2.62) 1.66 (1.05–2.62)

0.04 0.03

............................................................................................................................................................................... Predictors of mortality White blood cell count Admission haemoglobin

Contrast-induced acute kidney injury

1.80 (1.19–2.73)

0.005

Age Baseline creatinine

1.81 (1.50–2.19) 2.64 (1.74–4.00)

,0.0001 ,0.0001

Potential co-variables in model for NACE and MACE: age, gender, Killip class 2–4 ( vs. 1), baseline TIMI 0/1 flow ( vs. 2/3), left ventricular ejection fraction (per 10% decrease), platelet count (per 100 000 increase), white blood cell count (per 1000 increase), current smoker, baseline haemoglobin (per 1 g/dL decrease), mitral regurgitation 3, 4 ( vs. 1, 2), baseline creatinine (per 1 mg/dL increase), bivalirudin randomization, history of diabetes, hypertension, hyperlipidaemia, diabetes, insulin-treated diabetes, congestive heart failure, peripheral arterial disease, renal insufficiency, renal sufficiency requiring dialysis, major cardiac rhythm/rate disturbance, atrial fibrillation/flutter, prior myocardial infarction, prior PCI, prior CABG, and left anterior descending infarct-related artery. Potential co-variables in model for non-CABG major bleeding: age, gender, Killip class 2–4 ( vs. 1), baseline TIMI 0/1 flow ( vs. 2/3), left ventricular ejection fraction (per 10% decrease), platelet count (per 100 000 increase), white blood cell count (per 1000 increase), current smoker, baseline haemoglobin (per 1 g/dL decrease), mitral regurgitation 3, 4 ( vs. 1, 2), baseline creatinine (per 1 mg/dL increase), bivalirudin randomization, history of diabetes, hypertension, hyperlipidaemia, diabetes, insulin-treated diabetes, congestive heart failure, peripheral arterial disease, renal insufficiency, renal sufficiency requiring dialysis, atrial fibrillation/flutter, prior myocardial infarction, prior PCI, prior CABG, and left anterior descending infarct-related artery. Potential co-variables in model for mortality: age, Killip class 2–4 ( vs. 1), left ventricular ejection fraction, platelet count, baseline haemoglobin, baseline creatinine, white blood cell count, bivalirudin randomization, history of diabetes, prior myocardial infarction, congestive heart failure. CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention.

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Predictors of major adverse cardiac events Admission haemoglobin

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CI-AKI After primary PCI

Table 5

Outcomes by type of contrast received Low osmolar (n 5 1380)

Iso osmolar (n 5 452)

Hazard ratio (95% confidence interval)

P-value

NACE

10.2% (141)

MACE Death

3.8% (53) 1.6% (22)

14.4% (65)

0.69 (0.51–0.93)

0.01

7.1% (32) 2.7% (12)

0.53 (0.34–0.82) 0.59 (0.29–1.20)

0.004 0.14

Cardiac death Reinfarction Major bleeding

1.5% (20)

2.4% (11)

0.59 (0.28–1.23)

0.15

1.6% (22) 7.6% (105)

1.8% (8) 8.9% (40)

0.89 (0.40–2.00) 0.85 (0.59–1.22)

0.78 0.37

Ischaemic TVR

1.7% (24)

3.8% (17)

0.46 (0.24–0.85)

0.01

Definite or probable stent thrombosis

1.8% (22)

3.5 (14)

0.50 (0.26–0.98)

0.04

0.12

............................................................................................................................................................................... 30 Days

............................................................................................................................................................................... 27.3% (366)

30.6% (135)

0.86 (0.70–1.04)

MACE

22.2% (295)

24.3% (106)

0.89 (0.71–1.11)

0.30

Death Cardiac death

6.3% (83) 3.3% (44)

7.8% (34) 5.0% (22)

0.79 (0.53–1.18) 0.65 (0.39–1.08)

0.24 0.09

Reinfarction

7.4% (96)

8.4% (35)

0.88 (0.60–1.30)

0.53

9.2% (125) 13.9% (180)

11.5% (51) 13.9% (59)

0.79 (0.57–1.09) 0.98 (0.73–1.31)

0.15 0.89

4.3% (52)

6.4% (25)

0.66 (0.41–1.06)

0.08

Major bleeding Ischaemic TVR Definite or probable stent thrombosis

MACE, major adverse cardiac events; NACE, net adverse clinical events; TVR, target vessel revascularization. Types of contrast received: low osmolar: iopamidol (n ¼ 187), ioxaglate (n ¼ 181), iohexol (n ¼ 372), iopromide (n ¼ 547), ioversol (n ¼ 95); iso-osmolar: iodixanol (n ¼ 452).

reflective of those co-morbidities. Furthermore, patients who develop CI-AKI may suffer loss of their residual kidney function, and part of the higher risk for adverse outcomes may be the result of the physiologic burden of chronic kidney disease. However, recent analyses showing that reduced rates of CI-AKI through an intervention reduced the rates of adverse outcomes suggest that there may be a direct causal relationship between CI-AKI and adverse cardiovascular outcomes.8,9,22,26 Our multivariable analysis further highlights the importance of CI-AKI as a predictor of adverse outcomes. These data support other cohort data that identify acute kidney injury after coronary angiography as associated with increased rates of death at long-term follow-up, even after adjustment for traditional risk factors.27 Furthermore, these data highlight that the risk persists when those that suffered short-term events were excluded from the analysis, with increased hazard and highly significant divergence in survival curves for MACE and mortality between 30 days and 3 years in our landmark analysis. In the absence of a randomized trial involving a proven and rigorous prevention strategy, it remains difficult to truly ascertain how much of the impact is related to CI-AKI rather than the potential confounding variables mentioned above. Since CI-AKI is associated with worse clinical outcomes, it is imperative to be able to predict patients at increased risk so preventive strategies can be employed. Previous data have reported on the predictors of CI-AKI in stable PCI or all comer populations,1,28 but data analysing predictors of CI-AKI in acute coronary syndromes have had small sample sizes.29,30 While it is well known that patients with baseline chronic kidney disease are at high risk, our analysis demonstrates that for all patients, including those without baseline chronic kidney

disease analysed separately, age, contrast volume, LAD infarct-related artery, and history of CHF are predictors of CI-AKI. Of the modifiable risk factors, careful attention to contrast volume needs to be a key focus, especially in patients at a higher risk of CI-AKI. Our analyses of the Mehran and Marenzi risk scores demonstrate a significant trend between increasing scores and risk of CI-AKI. Since these scores were applied retrospectively only on patients with the requisite data available, it is possible that predictive value as assessed by the c-statistic would be more accurate if the data had been collected in a prospective manner. Rates of CI-AKI were similar in our large cohort of STEMI patients, when compared with other analyses of patients with acute coronary syndromes.22,23,31,32 While risk is higher in the setting of acute myocardial infarction compared with non-urgent PCI, from limited data, it appears risk is similar in STEMI vs. non-STEMI.30 The increased presence of haemodynamic instability in STEMI patients may be balanced by increased rates of diabetes and older age in NSTEMI patients. In our analysis of the HORIZONS-AMI study, there were no differences in rates of CI-AKI between the low-osmolar and iso-osmolar groups, similar to the results of the most recent randomized controlled trials.10,15,33 In terms of contrast media and cardiovascular outcomes, we found lower rates of NACE, MACE, stent thrombosis, and ischaemic TVR at 30 days with the use of low-osmolar contrast media compared with iso-osmolar contrast media in bivariate analysis. Our multivariable analysis suggested that the use of the isoosmolar contrast, iodixanol, may be associated with higher adverse cardiac events at short-term follow-up only. Clinical trials in this area have been divergent. In the COURT trial, the use of the isoosmolar, non-ionic agent iodixanol, was associated with lower

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3 Years NACE

Page 8 of 9

Limitations Several limitations of our study warrant mention. First, our study was not powered to detect differences in outcomes in patients with vs. without CI-AKI, thus all results must be considered hypothesis generating. Second, preventive strategies for CI-AKI were not standardized in the study protocol, and data regarding these measures were not collected in the case report forms, potentially confounding our results. Third, our definition of CI-AKI relied solely on measurements of serum creatinine, which is an imperfect measurement of renal function; no direct urinary markers of tubular dysfunction were collected in this patient population. Furthermore, baseline creatinine values may already reflect impairment from haemodynamic changes in the setting of acute myocardial infarction. Fourth, we may have potentially underestimated the true incidence of CI-AKI for two reasons: our protocol only recommended measurement of serum creatinine for 2 days post-admission unless there was a rise by 0.3 mg/dL, in which case measurement was prolonged, thus, we may have missed later rises in serum creatinine, and if the population had higher rates of cardiogenic shock or Killip class .1, rates of CI-AKI would have likely been higher. Finally, we do not know whether AKI persisted or resolved before hospital discharge, and do not have data regarding need for haemodialysis in patients during or after the index hospitalization.

Conclusions Contrast-induced acute kidney injury after primary PCI is associated with worse short- and long-term cardiovascular and bleeding outcomes, including mortality. It is a powerful independent predictor

of adverse outcomes and mortality. High-risk patients should be identified and targeted for preventive strategies.

Funding The HORIZONS-AMI trial was sponsored by the Cardiovascular Research Foundation (New York, NY, USA) with unrestricted grant support from Boston Scientific Corporation (Natick, MA, USA) and The Medicines Company (Parsippany, NJ, USA). Conflict of interest: G.D.D. and R.M. have received institutional research grant support from The Medicines Company, Bristol-Myers Squibb/Sanofi and Eli Lilly and Company/Daiichi-Sankyo, and are consultants to Abbott Vascular, AstraZeneca, Janssen Pharmaceuticals, Regado Biosciences, The Medicines Company, Bristol-Myers Squibb/Sanofi, and Merck & Co. B.W. has received lecture fees from Boston Scientific. G.G. has received grant support from Abbott Vascular, Boston Scientific, and St Jude Medical, and is a consultant to Boston Scientific and St Jude Medical. G.W.S. is a consultant to Boston Scientific.

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rates of in hospital major adverse events than with the use of the low osmolar, ionic agent, ioxaglate.33 However, other studies have either found no difference between the two agents, or more frequent in hospital MACE with the use of iodixanol.34,35 Furthermore, in vitro data have demonstrated an increased pro-thrombotic effect with iodixanol compared with the ionic low-osmolar agent, ioxaglate.36 Our analysis stratified contrast type by osmolality only, and the lowosmolar group includes the ionic agent, ioxaglate, as well as the other low-osmolar contrast agents used in the trial, which were non-ionic. Thus, our results may be influenced by the interplay between osmolality and ionicity, and their differential effects on both the coagulation cascade and platelet activation. The divergence of the literature cited highlights this as an area where more rigorous study is definitely warranted. Finally, significant attention has been dedicated in studying preventive strategies for CI-AKI; however, few have focused on STEMI patients alone. One large randomized trial by Marenzi et al.8,19 demonstrated a dose-dependent reduction in rates of CI-AKI and mortality with the use of N-acetylcysteine; however, this finding was not confirmed in a subsequent study. These findings may have been influenced by the high rate of CI-AKI observed in the control group in the trial, over twice that was observed in our cohort. However, the HORIZONS-AMI trial did not standardize or collect data regarding preventive strategies employed for CI-AKI such as N-acetylcysteine or various hydration protocols, thus, this analysis does not clarify the heterogeneity of results in earlier studies.

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