Cardiac Imaging
This study sought to evaluate the safety and efcacy of rosuvastatin in preventing contrast-induced acute kidney
injury (CI-AKI) in patients with diabetes mellitus (DM) and chronic kidney disease (CKD).
Background
CI-AKI is an important complication after contrast medium injection. While small studies have shown positive results
with statin therapy, the role of statin therapy in prevention of CI-AKI remains unknown.
Methods
We randomized 2,998 patients with type 2 DM and concomitant CKD who were undergoing coronary/peripheral
arterial angiography with or without percutaneous intervention to receive rosuvastatin, 10 mg/day (n 1,498), for
5 days (2 days before, and 3 days after procedure) or standard-of-care (n 1,500). Patients renal function was
assessed at baseline, 48 h, and 72 h after exposure to contrast medium. The primary endpoint of the study was the
development of CI-AKI, which was dened as an increase in serum creatinine concentration 0.5 mg/dl
(44.2 mmol/l) or 0.25% above baseline at 72 h after exposure to contrast medium.
Results
Patients randomized to the rosuvastatin group had a signicantly lower incidence of CI-AKI than controls (2.3% vs.
3.9%, respectively; p 0.01). During 30 days follow-up, the rate of worsening heart failure was signicantly lower in
the patients treated with rosuvastatin than that in the control group (2.6% vs. 4.3%, respectively; p 0.02).
Conclusions
Rosuvastatin signicantly reduced the risk of CI-AKI in patients with DM and CKD undergoing arterial contrast
medium injection. (Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes [TRACK-D];
NCT00786136) (J Am Coll Cardiol 2014;63:6270) 2014 by the American College of Cardiology Foundation
Open access under CC BY-NC-ND license.
See page 80
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Statins to Prevent Contrast-Induced Kidney Injury
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64
Figure 1
Han et al.
Statins to Prevent Contrast-Induced Kidney Injury
Patient Flowchart
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Han et al.
Statins to Prevent Contrast-Induced Kidney Injury
Table 1
Table 1
65
Continued
Rosuvastatin Group
(n 1,498)
Control Group
(n 1,500)
Rosuvastatin Group
(n 1,498)
Control Group
(n 1,500)
p Value
Age (yrs)
61.45 8.64
61.44 8.64
0.97
Medications
Weight (kg)
72.32 10.42
72.88 10.29
0.14
Aspirin
1,397 (93.3)
1,419 (94.6)
Height (cm)
168.33 7.81
168.52 7.64
0.52
ACEI
981 (65.5)
947 (63.3)
0.20
363 (24.2)
353 (23.6)
0.67
1,224 (81.7)
1,201 (80.2)
0.30
Variable
Variable
p Value
0.127
Male
963 (64.3)
991 (66.1%)
0.31
ARB
Smoking
463 (30.9)
491 (32.7)
0.17
Beta-blocker
Family history of
coronary heart
disease
112 (7.5)
104 (6.9)
0.57
Insulin
486 (32.4)
457 (30.5)
0.254
Diuretic
321 (21.4)
329 (22.0)
0.72
Calcium antagonist
624 (41.7)
614 (41.0)
0.70
Heparin
923 (61.6)
944 (63.0)
0.44
Digitalis
132 (8.8)
131 (8.7)
0.95
Vitamin C
25 (1.7)
29 (1.9)
0.59
Dopamine
23 (1.5)
22 (1.5)
0.88
Sodium bicarbonate
21 (1.4)
26 (1.7)
0.46
673 (44.9)
642 (42.8)
0.25
61.96 8.91
0.42
0.85
Statin-naive
878 (58.6)
873 (58.2)
620 (41.4)
627 (41.8)
1,337 (91.3)
1,344 (91.9)
127 (8.7)
118 (8.1)
Anemia status*
No anemia
Anemia
0.59
Diabetes history
Hydration
0.95
5 yrs
831 (55.5)
840 (56.0)
284 (18.9)
283 (18.9)
LVEF, %
62.27 8.87
NYHA functional
classication
0.54
10 years
383 (25.6)
377 (25.1)
1,152 (76.9)
1,149 (76.6)
Hypertension
1,066 (71.3)
1090 (72.7)
0.39
II
302 (20.2)
318 (21.2)
Hypertriglyceridemia
139 (9.3)
117 (7.8)
0.15
III
44 (2.9)
33 (2.2)
TIA/stroke
188 (12.6)
208 (13.9)
0.28
228 (15.2)
237 (15.8)
0.66
45 (3.0)
37 (2.5)
0.37
Total cholesterol
(mg/dl)
Peripheral vascular
disease
History of liver disease
Prior myocardial
infarction
Silent myocardial
ischemia
Stable angina
Unstable angina
NSTEMI
177.88 46.02
177.11 45.24
0.67
34 (2.3)
24 (1.6)
0.18
LDL-C (mg/dl)
98.61 31.71
97.45 30.55
0.35
322 (21.5)
296 (19.7)
0.24
Fasting glucose
(mg/dl)
134.07 51.18
132.81 49.37
0.48
25.49 3.01
25.64 2.93
0.16
227 (15.1)
267 (17.8)
12 (0.8)
12 (0.8)
Myocardial ischemia
None
Laboratory
determinations:
0.09
76 (5.1)
95 (6.3)
1,071 (71.5)
1,005 (67.0)
112 (7.5)
121 (8.1)
BMI (kg/m2)
*Values are mean SD or n (%). Denition of anemia hemoglobin concentration <120 g/l in
males or <110 g/l in females.
ACEI angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker; BMI
body mass index; LDL-C low-density lipoprotein cholesterol; LVEF left ventricular ejection
fraction; NSTEMI non-ST segment elevation myocardial infarction; NYHA New York Heart
Association; TIA transient ischemic attack.
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Han et al.
Statins to Prevent Contrast-Induced Kidney Injury
66
Table 2
Variable
Peripheral vascular
angiography
Rosuvastatin Group
(n 1,498)
Control Group
(n 1,500)
p Value
219 (14.6)
205 (13.7)
0.45
Coronary diagnostic
angiography
0.17
Normal
148 (10.1)
142 (9.8)
Single-vessel disease
330 (22.5)
367 (25.4)
Multi-vessel disease
991 (67.4)
935 (64.8)
Percutaneous coronary
intervention
808 (53.9)
782 (52.1)
0.32
15 (1.0)
16 (1.1)
0.86
Percutaneous peripheral
intervention
Serum creatinine (mmol/l)
Baseline
95.08 22.92
94.95 20.84
0.88
Maximal post-procedural
value
95.12 25.39
95.71 29.01
0.55
Figure 2
74.16 14.99
74.43 15.24
0.62
78.46 11.37
78.99 11.27
0.24
50.20 8.90
49.56 8.70
0.43
Baseline
29.83 46.60
30.89 44.65
0.63
Post-procedural
24.18 39.38
25.60 42.32
0.47
Baseline
0.22 1.82
0.13 1.02
0.23
Post-procedural
0.18 1.36
0.15 1.06
0.68
120 (100200)
110 (100200)
0.10
The incidence of the primary endpoint was signicantly lower in the rosuvastatin
group than in the control group (2.3% vs. 3.9%, p 0.01).
Microalbuminuria (mg/dl)
ACR
signicantly lower with rosuvastatin. Furthermore, postprocedural hsCRP levels were higher in patients with CIAKI (1.40 mg/l; interquartile range: 0.60 to 4.90 mg/l vs.
0.40 mg/l; interquartile range: 0.20 to 1.00 mg/l, respectively; p 0.0054).
Considering all patients, 7 developed both CI-AKI and
worsening heart failure, 85 developed CI-AKI only, and 96
developed worsening heart failure only, whereas 2,810
patients did not develop either of the 2 (McNemar test:
p 0.226), suggesting that the effects of rosuvastatin on
cardiac function were independent of changes in renal
function. Baseline hemoglobin levels were lower and prevalence of anemia was higher in patients who developed CIAKI (all: p < 0.05) (Table 6).
There were no signicant differences between the 2
groups in the rates of muscle pain, liver function tests results,
gastrointestinal disorders, or incidence of edema or rash.
Discussion
This is the rst large randomized, multicenter, prospective study to evaluate the safety and efcacy of statin therapy
for the prevention of CI-AKI in DM patients with
mild-to-moderate CKD. In this trial, we observed that
periprocedural administration of rosuvastatin, 10 mg daily
for a short duration (5 days), reduced the incidence of
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Han et al.
Statins to Prevent Contrast-Induced Kidney Injury
Table 3
Rosuvastatin Group
(n 1,498)
Control Group
(n 1,500)
All-cause deaths
3 (0.2)
5 (0.3)
0.73
Dialysis/hemoltration
0 (0.0)
2 (0.1)
0.50
39 (2.6)
64 (4.3)
0.02
Variables
p Value
*Values are n (%). Dened by change of New York Heart Association classication (class change 1).
Table 4
OR
95% CI
Rosuvastatin
Variable
0.60
(0.390.94)
p Value
0.03
Male
1.09
(0.671.78)
0.73
Age
0.999
(0.9731.026)
0.94
BMI
0.98
(0.911.05)
0.57
ACS
1.86
(1.172.95)
0.01
0.89
(0.501.58)
0.69
Diabetes history
0.92
(0.711.20)
0.55
1.61
(1.142.29)
0.01
Hemoglobin
0.986
(0.9720.999)
1.77
(1.312.40)
1.002
(0.9991.005)
0.12
Hydration
0.83
(0.531.31)
0.43
ACEI/ARB
1.15
(0.632.10)
0.65
Beta-blocker
0.94
(0.541.61)
0.82
0.01
<0.01
ACS acute coronary syndrome(s); CI-AKI contrast-induced acute kidney injury. All other
abbreviations are as shown in Table 1.
67
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68
Figure 3
These subgroups are provided as a reference only. xn number of patients with CI-AKI; N total number of patients in each subgroup. *There were no interaction effects
between rosuvastatin and hydration therapy (p 0.058) for the incidence of CI-AKI. &Data missing at baseline in 72 patients. #Data missing at baseline in 188 patients.
Missing data were due to unprescribed tests at recruitment. CI condence interval; eGFR estimated glomerular ltration rate; NYHA New York Heart Association.
Table 5
Table 6
Rosuvastatin Group
Naive/Non-Naive (%)
Control Group
Naive/Non-Naive (%)
p Value
Statin non-naive
16/628 (2.5%)
27/619 (4.4%)
0.089
Statin-naive
18/870 (2.1%)
31/881 (3.5%)
0.081
All patients
34/1498 (2.3%)
58/1500 (3.9%)
0.01
Anemia
Statin History
Baseline
Non-CI-AKI
Patients
(n 2,837)
p Value
129.9 18.0
135.2 15.8
0.002
13 (14.8)
231 (8.1)
0.047
CI-AKI Patients
(n 88)
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Han et al.
Statins to Prevent Contrast-Induced Kidney Injury
17.
Conclusions
18.
10.
11.
12.
13.
14.
15.
16.
Rosuvastatin at 10 mg per day for 5 days reduces the incidence of CI-AKI in patients with type 2 DM and CKD,
who were not already on a statin regimen. A short course of
oral statin may reduce the incidence of CIN.
19.
Reprint requests and correspondence: Dr. Yaling Han, Department of Cardiology, Shenyang Northern Hospital, 83 Wenhua
Road, Shenyang 110016, China. E-mail: hanyl169@gmail.com.
21.
20.
22.
REFERENCES
23.
1. Solomon R, Dauerman HL. Contrast-induced acute kidney injury.
Circulation 2010;122:24515.
2. McCullough PA, Adam A, Becker CR, et al. Risk prediction of
contrast-induced nephropathy. Am J Cardiol 2006;98:27K36K.
3. Chen SL, Zhang J, Yei F, et al. Clinical outcomes of contrast-induced
nephropathy in patients undergoing percutaneous coronary intervention: a prospective, multicenter, randomized study to analyze the effect
of hydration and acetylcysteine. Int J Cardiol 2008;126:40713.
4. Tumlin J, Stacul F, Adam A, et al. Pathophysiology of contrastinduced nephropathy. Am J Cardiol 2006;98:14K20K.
5. Giusti-Paiva A, Martinez MR, Felix JV, et al. Simvastatin decreases
nitric oxide overproduction and reverts the impaired vascular responsiveness induced by endotoxic shock in rats. Shock 2004;21:2715.
6. Ridker PM, MacFadyen J, Cressman M, Glynn RJ. Efcacy of rosuvastatin among men and women with moderate chronic kidney disease
and elevated high-sensitivity Creactive protein: a secondary analysis
from the JUPITER (Justication for the Use of Statins in Preventionan Intervention Trial Evaluating Rosuvastatin) trial. J Am Coll Cardiol
2010;55:126673.
7. Abe M, Maruyama N, Yoshida Y, Ito M, Okada K, Soma M. Efcacy
analysis of the lipid-lowering and renoprotective effects of rosuvastatin
in patients with chronic kidney disease. Endocr J 2011;58:66374.
8. Quintavalle C, Fiore D, De Micco F, et al. Impact of a high loading
dose of atorvastatin on contrast-induced acute kidney injury. Circulation 2012;126:300816.
9. Patti G, Nusca A, Chello M, et al. Usefulness of statin pretreatment to
prevent contrast-induced nephropathy and to improve long-term
24.
25.
26.
27.
28.
29.
30.
31.
69
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For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
70
Han et al.
Statins to Prevent Contrast-Induced Kidney Injury
32. Scott LJ, Curran MP, Figgitt DP. Rosuvastatin: a review of its use in
the management of dyslipidemia. Am J Cardiovasc Drugs 2004;4:
11738.
33. Shepherd J, Vidt DG, Miller E, Harris S, Blasetto J. Safety of rosuvastatin: update on 16,876 rosuvastatin-treated patients in a multinational clinical trial program. Cardiology 2007;107:43343.
34. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent
vascular events in men and women with elevated C-reactive protein.
N Engl J Med 2008;359:2195207.
35. Deo SH, Fisher JP, Vianna LC, et al. Statin therapy lowers muscle
sympathetic nerve activity and oxidative stress in patients with heart
failure. Am J Physiol Heart Circ Physiol 2012;303:H37785.
36. Davignon J. Benecial cardiovascular pleiotropic effects of statins.
Circulation 2004;109:III3943.
37. Bonnet J, McPherson R, Tedgui A, et al. Comparative effects of 10-mg
versus 80-mg Atorvastatin on high-sensitivity C-reactive protein in
patients with stable coronary artery disease: results of the CAP
(Comparative Atorvastatin Pleiotropic effects) study. Clin Ther 2008;
30:2298313.
contrast medium
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diabetes mellitus