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Clin Exp Thromb Hemost > Volume 2(2); 2015 > Article
Park, Jeong, Park, Choi, Rhee, Kim, Park, Sim, Hong, Kim, Ahn, and Kang: Protective Effect of Nicorandil Against Contrast-Induced Nephropathy in Patients with Acute Myocardial Infarction

Abstract

Purpose:

Contrast-induced nephropathy (CIN) has resulted in significant hospital morbidity and mortality as use of contrast media (CM) for percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) has been increasing. Nicorandil, a K-ATP channel opener and a nitric oxide donor, is used to treat angina pectoris. Therefore, we investigated whether the use of nicorandil would reduce the incidence of CIN in patients with AMI undergoing PCI.

Methods:

From November 2005 to August 2011, we evaluated 1,492 AMI patients with Killip class I and serum creatinine (sCr) less than 3.0 mg/dL who underwent PCI. The patients were divided into two groups: group I receiving nicorandil (n= 442) and group II not receiving nicorandil (n= 1,050).

Results:

Among the 1,492 patients, CIN developed in 398 (26.7%). There were no significant differences in baseline clinical characteristics between the two groups. The incidence of CIN also did not differ between two groups (25.1% vs. 27.3%, P= 0.405). The incidence of CIN and the increase in average percentage of sCr (ΔsCr) were not significantly different between the two groups (18.2% vs. 20.4%, P= 0.296). In univariate analysis, nicorandil was not an independent predictor of CIN (OR: 1.122 95%, CI: 0.87-1.446, P= 0.376).

Conclusion:

The use of nicorandil did not decrease the incidence of CIN in patients with AMI undergoing PCI.

Introduction

Contrast-induced nephropathy (CIN), also called contrast-induced acute kidney injury (AKI), is the third most common cause of hospital-acquired AKI after impaired renal perfusion and use of nephrotoxic medications [1]. CIN can result from intravenous or intra-arterial injections of iodine-based contrast media (CM) during enhanced computerized tomography (CT) imaging examinations or percutaneous coronary intervention (PCI). It accounts for 11-12% of all cases of in-hospital AKI and is associated with an overall in-hospital mortality rate of 6% [2,3]. Risk factors of CIN include chronic kidney disease, diabetes mellitus, advanced age, congestive heart failure, nephrotoxic drug use, hypovolemia, acute hyperglycemia, increased left ventricular dysfunction, and excessive CM volume. The incidence of CIN is less than 5% in patients without risk factors but can increase to 50% among patients with multiple risk factors [4,5].
Although several risk factors for CIN have been identified, the exact mechanism is not yet clear. Reducing renal perfusion due to direct effect of CM on the kidney lead to the development of CIN [6,7]. Therefore, many clinical trials have studied various pharmacological agents and periprocedural factors in an effort to identify successful strategies for reducing the risk [8-10]. Pharmacological agents including vasodilators and antioxidants have been researched for their potential role in reducing CIN risk, a reflection of the current understanding of the pathophysiology of contrast-induced renal injury. Vasodilatory intervention with dopamine, fenoldopam, calcium channel blockers, and theophylline has been investigated, but results are inconsistent [11-14]. Thus, additional large, prospective, randomized studies are required. The effect of cardioprotective agents on the kidney should be reconsidered.
Nicorandil is not only a nitric oxide donor, but also an ATP-sensitive potassium (KATP) channel opener [15]. A recent study showed that activation of the KATP channel prevented renal injury due to ischemia and reperfusion by reducing accumulation of reactive oxygen species (ROS) [16]. Nicorandil is widely used as a coronary vasodilator and is associated with better long-term prognosis in patients with stable angina and in hemodialysis patients [17,18]. Nicorandil presumably acts as a pharmacological preconditioning agent and/or improves endothelial function [19]. However, recent studies reported inconsistent effects of intravenous nicorandil for the prevention of CIN [20,21]. Therefore, we investigated the protective effect of oral nicorandil against CIN in patients with AMI undergoing PCI.

Methods

Study population

A retrospective analysis was performed using clinical, laboratory, and angiographic data of 1,492 AMI patients undergoing PCI within 24 hours after symptom onset between November 2005 and August 2011 at the Heart Center of Chonnam National University Hospital (Fig. 1). The patients were divided into two groups: group I receiving nicorandil (n=442) and group II not receiving nicorandil (n=1,050). After PCI in all patients, isotonic (0.9%) saline was administered intravenously at a rate of 1 mL/kg/h (0.5 mL/kg/h in cases of left ventricular ejection fraction [LVEF] < 40%) for 12 hours. In both groups, isotonic (0.9%) saline was infused using the abovementioned method. Nicorandil (Sigmart Tab. Joongwae Pharma, Seoul, Korea) 10 mg was administered orally twice a day prior to PCI in the nicorandil group, while the control group did not receive nicorandil. All PCI procedures used nonionic, dimeric, iso-molar CM iodixanol (Visipaque 320; GE Healthcare AS, Oslo, Norway).

Study definitions

AMI was defined based on clinical signs or symptoms, including increased cardiac biomarkers, elevated enzyme levels (creatine kinase, creatine kinase-myocardial band isoenzyme, troponin-I, or troponin-T), and 12-lead electrocardiographic (ECG) findings. ST-elevation myocardial infarction (STEMI) was defined by the presence of new ST-segment elevation >2 mm (0.2 mV) in ≥2 pericardial leads, ST-segment elevation >1 mm (0.2 mV) in ≥2 limb leads, or new left bundle-branch block on the 12-lead ECG with a concomitant increase in troponin-I or T ≥99th percentile up to 12 hours from the onset of symptoms. Non-ST-elevation myocardial infarction (NSTEMI) was defined by the elevation of cardiac markers (CK-MB or troponin) in the blood without the ECG change of ST-segment elevation and based on a typical history of chest pain. Left ventricular ejection fraction (LVEF) was determined using two-dimensional echocardiography. High glucose level was defined as glucose level > 198 mg/dL (11.1 mmol/L) [22]. CIN was defined as an increase ≥25% or ≥0.5 mg/dL in pre-procedure serum creatinine (sCr) after the procedure. Serum Cr level was measured at baseline and daily for three days after the procedure for most of the patients. Two daily measurements of Cr were performed in patients undergoing coronary angiography without PCI, as they were discharged earlier. Creatinine clearance (CrCl) was calculated by applying the Cockcroft-Gault formula using baseline serum creatinine: CrCl=([140-age]× weight/serum creatinine×72), with female gender adjustment (CrClfemale= CrCl× 0.85) [23].

Coronary angiography

Coronary angiogram was analyzed with a validated quantitative coronary angiography system. Using the outer diameter of the contrast-filled catheter as the calibration standard, the minimal lumen diameter, reference diameter, and lesion length were measured in diastolic frames from orthogonal projections. The lesion morphology in coronary angiography was classified using criteria established by the American College of Cardiology (ACC)/American Heart Association (AHA) [24]. Perfusion was evaluated according to Thrombolysis In Myocardial Infarction (TIMI) criteria [25].

Study primary endpoint

The primary end point of the study was development of CIN, defined as a ≥25% increase in sCr concentration or a ≥0.5 mg/dL absolute increase in sCr from baseline within 48-72 hours after contrast exposure.

Statistical analysis

The Statistical Package for Social Sciences (SPSS) for Windows, version 19.0 (SPSS Inc., Chicago, IL, USA) was used for all analyses. Discrete variables were presented as percentages and relative frequencies and were tested with Fisher’s exact test. Continuous variables were expressed as the mean value±standard deviation (SD), and categorical variables were described as number (percentage). Differences in baseline characteristics were compared using Student t-test for continuous variables and Pearson’s Chi-square test for categorical variables.
The impact of the pretreatment of nicorandil on the incidence of CIN was evaluated using a binary logistic regression model. To more accurately clarify the impact, multivariate logistic regression analysis was performed. The covariates of high glucose level (> 198 mg/dL), decreased LVEF (<40%), old age (>65 years), diabetes mellitus, hypertension, baseline sCr level (> 1.3 mg/dL), body mass index, and gender were adjusted in this analysis. Statistical significance was defined as a P-value<0.05.

Results

Baseline clinical and laboratory characteristics

Among the total of 1,492 patients, 1,120 (75.1%) were male, and the mean age was 68.9±12.3 years (59.6±12.2 years in males, 69.0 ±10.3 years in females). The patients were divided into two groups, 442 patients receiving nicorandil (Group I) and 1,050 patients not receiving nicorandil (Group II). The patient baseline characteristics, including laboratory characteristics during the study, are summarized in Table 1. No significant differences were found between the groups in age, gender, body mass index, LVEF, prevalence of coronary risk factors of hypertension, diabetes, dyslipidemia, or smoking. Also, no significant differences in physical or laboratory finding were found between the two groups (Table 1).

Coronary angiographic findings and procedural characteristics

No significant differences in culprit lesion, ACC/AHA lesion type, pre- and post-TIMI flow, or type of intervention were found between the two groups.

In-hospital medical treatment

The in-hospital medical therapy is shown in Table 2. There was no significant difference between the two groups with regard to proportion of patients receiving beta blockers, angiotensin-converting enzyme inhibitors, or statins during hospitalization.

Incidence of contrast-induced nephropathy

The primary endpoint (incidence of CIN) was similar between groups I and II (25.1% vs. 27.3%, P= 0.405). Prophylactic pretreatment with oral nicorandil did not reduce the risk of CIN. Relative changes in sCr from baseline to maximal sCr level within 48-72 hours were not significant between the wo groups (Fig. 2).

Multivariate analysis of risk factors for development of contrast-induced nephropathy

Multivariate analysis was conducted using factors determined to be significant in the univariate analysis. The predictors of CIN were higher glucose, old age, lower ejection fraction, and hypertension (Table 3).

Discussion

The hypothesis of this study is that oral nicorandil has a preventive effect on the development of CIN after AMI. However, the results of this study show that there is no significant preventive effect of nicorandil on the development of CIN.
Although several risk factors of CIN have been identified, the exact mechanism is not yet clear. Most likely, a combination of various mechanisms is responsible for development of CIN [26]. Nicorandil, an KATP channel opener and NO donor, is used in the treatment of angina and acute heart failure [27]. Many studies in cardiac protection with ischemic preconditioning (IPreC) suggest that the mechanism of cardiac IPreC involves the activation and opening of KATP channels [28,29]. KATP channel agonists may thus have a direct effect on the underlying pathophysiological mechanism of the tissue injury after ischemia-reperfusion (I-R) injury. For example, KATP channel agonists are known to exert cytoprotective effects in the myocardium [30]. Nicorandil has been found to prevent reperfusion injury and protect the heart against ischemic injury by promoting ischemic preconditioning [31]. In addition, a recent study has shown that the KATP channel opener diazoxide prevents renal I-R injury [32].
According to a previous study, the incidence of CIN in patients with STEMI is about 33% [33]. In the current study, the incidence of CIN was similar to that previous study (25.1% in the nicorandil group and 27.3% in the control group). However, our study did not demonstrate a preventive effect of nicorandil on the development of CIN. Nicorandil might be effective when administered at a different dosage or frequency. The dosage was derived from the regimen for the pretreatment of patients with STEMI prior to reperfusion in clinical studies [34,35]. The required dosage for the prevention of CIN may be different from the dosage used for protection against ischemia-reperfusion injury in the myocardium. It is important to minimize the quantity of CM in order to prevent CIN during the PCI procedure.
In this study, we found that acute hyperglycemia is also associated with a higher incidence of CIN in STEMI patients undergoing primary PCI. Acute hyperglycemia may have a direct negative impact on kidney function and might increase renal toxicity of contrast agents. Acute hyperglycemia suppresses flow-mediated vasodilatation, likely through increased production of oxygen-derived free radicals, and increases oxidative stress. Oxidant stress-mediated injury and renal medullary hypoxia and ischemia, due to vasoconstriction in response to contrast medium administration, have been implicated as causative factors of CIN [36].
There are several limitations to this study. First, this was a single-center retrospective study and was not randomized or controlled. Therefore, there could have been a selection bias in enrolling patients. Second, the dosage of medication used in this study was based on STEMI preconditioning and may not proper to determine an effect of kidney protection. Third, even though multivariate regression analysis was conducted with adjustment of various basic characteristics, a randomized control study would be more appropriate in order to adjust for differences of basic characteristics. Fourth, this study might have involved potential bias due to several exclusion criteria. Patients with sCr greater than 3.0 mg/dL, which is related to renal dysfunction, were excluded from this study. In addition, patients with Killip class > I, which can lead to ventricular dysfunction and myocardial infarction, were not included in this study [37]. Finally, to correctly evaluate the incidence rate of CIN in the nicorandil group and the control group, a prospective, multi-center, randomized control trial should be conducted with adjustments for these limitations.
In conclusion, this study did not demonstrate a preventive effect of oral nicorandil treatment on the development of CIN in patients with AMI undergoing PCI.

Acknowledgments

This study was supported by grants of The Korean Health Technology R&D Project (HI13C1527), Ministry of Health & Welfare, Republic of Korea.

Conflicts of Interest

No authors have a relevant financial relationship to this study to disclose.

Fig. 1.
The flow chart of our study.
ceth-2-2-19f1.tif
Fig. 2.
Incidence of contrast-induced nephropathy in the nicorandil and control groups and changes in serum creatinine concentration before and after injection of contrast media in the nicorandil and control groups. Individual values of contrast-induced nephropathy in the nicorandil (orange) and control (green) groups are depicted. Individual changes in average serum creatinine concentration before and after injection of contrast media with nicorandil (blue) and control (red) are depicted.
ceth-2-2-19f2.tif
Table 1.
Baseline clinical and laboratory characteristics
Variables Group I
Group II
P-value
(n = 442) (n = 1,050)
Age (year) 61.9 ± 12.5 61.9 ± 12.4 0.966
Male (%) 323 (73.1) 797 (71.2) 0.265
Body mass index (kg/m2) 24.2 ± 3.2 24.3 ± 3.0 0.507
Risk factor (%)
 Hypertension 204 (46.3) 469 (44.7) 0.608
 Diabetes mellitus 112 (25.3) 256 (24.4) 0.732
 Hyperlipidemia 12 (2.7) 56 (5.3) 0.029
 Current smoker 290 (65.6) 684 (65.1) 0.905
Killip class I (%) 442 (100) 1,050 (100) 1.000
Physical finding
 SBP (mmHg) 131.9 ± 23.1 133.4 ± 24.4 0.290
 DBP (mmHg) 82.0 ± 13.7 82.9 ± 14.4 0.300
 LVEF (%) 56.7 ± 11.5 56.9 ± 11.4 0.756
Troponin T (ng/mL) 4.7 ± 6.6 5.1 ± 8.2 0.408
Troponin I (ng/mL) 54.5 ± 86.0 53.9 ± 99.0 0.921
CK-MB (U/L) 82.8 ± 104.8 86.7 ± 124.3 0.562
Total cholesterol (mg/dL) 183.1 ± 42.0 182.7 ± 42.3 0.878
Triglyceride (mg/dL) 119.0 ± 92.3 119.6 ± 82.0 0.895
HDL-C (mg/dL) 46.7 ± 12.9 46.5 ± 20.6 0.871
LDL-C (mg/dL) 119.5 ± 37.5 119.3 ± 37.0 0.922
hs-CRP (mg/dL) 1.8 ± 3.0 2.0 ± 3.5 0.321
NT-proBNP (pg/mL) 1,405.7 ± 2,696.3 1,588.0 ± 3,076.9 0.286
Glucose (mg/dL) 162.5 ± 70.0 161.6 ± 67.8 0.810
Baseline serum creatinine (mg/dL) 0.84 ± 0.3 0.85 ± 0.3 0.660
Creatinine clearance (mL/min) 83.5 ± 31.0 83.4 ± 32.2 0.625
Contrast media
 Isomolar (Visipaque) 442 (100.0) 1,050 (100) 1.000
 Volume (mL) 148.8 ± 68.5 149.7 ± 73.4 0.776

Group I: With nicorandil, Group II: Without nicorandil. Data are presented as mean ± standard deviation for continuous variables: number (%) for categorical variables.

SBP, Systolic blood pressure; DBP, Diastolic blood pressure; LVEF, Left ventricular ejection fraction; CK-MB fraction, Creatine kinase MB fraction; HDL-C, High-density lipoprotein-cholesterol; LDL-C, Low-density lipoprotein-cholesterol; hs-CRP, High-sensitivity C-reactive protein; NT-proBNP, N-terminal pro B-type natriuretic peptide.

Table 2.
In-hospital medical treatment
Variables Group I
Group II
P-value
(n = 442) (n = 1,052)
Aspirin 440 (99.6) 1,041 (98.4) 0.039
Low-molecular weight heparin 130 (29.4) 292 (27.8) 0.530
Beta blockers 384 (86.9) 904 (86.1) 0.742
Abcixmab 107 (24.2) 241 (23.0) 0.593
Calcium channel blockers 45 (10.2) 103 (9.8) 0.850
Angiotensin-converting enzyme inhibitors 394 (89.1) 935 (89.0) 1.000
Angiotensin receptor blockers 88 (19.9) 196 (18.7) 0.613
Diuretics 98 (22.2) 209 (19.9) 0.327
Statins 329 (74.4) 764 (72.8) 0.522
Nitroglycerin 433 (98.0) 1,026 (97.7) 0.849

Group I: With nicorandil, Group II: Without nicorandil. Data are presented as mean ± standard deviation for continuous variables: number (%) for categorical variables.

Table 3.
Multivariate analysis of risk factors for the development of contrast-induced nephropathy
Variables Univariate
Multivariate
Unadjusted OR (95% Cl) P-value Adjusted OR (95% Cl) P-value
Glucose (> 198 mg/dL) 1.738 (1.323-2.284) < 0.001 1.575 (1.143-2.171) 0.006
Age (≥ 65 years) 1.540 (1.223-1.939) < 0.001 1.419 (1.080-1.864) 0.012
LVEF (≤ 40%) 1.824 (1.267-2.625) 0.001 1.628 (1.116-2.373) 0.011
Hypertension 1.441 (1.144-1.813) 0.002 1.333 (1.045-1.700) 0.021
sCr (≥ 1.3 mg/dL) 1.659 (1.049-2.625) 0.031 1.499 (0.885-2.537) 0.132
BMI (≥ 25 kg/m2) 1.167 (0.919-1.481) 0.205 1.173 (0.909-1.515) 0.220
CrCl (≤ 60 mL/min) 1.264 (0.966-1.652) 0.087 0.816 (0.580-1.149) 0.244
Gender (male) 1.301 (1.005-1.684) 0.046 0.872 (0.658-1.156) 0.342
DM 1.550 (1.200-2.002) 0.001 1.154 (0.851-1.565) 0.357
Nicorandil 1.122 (0.870-1.446) 0.376

All variables found to be associated with contrast-induced nephropathy in univariate analysis with P < 0.2 were included as covariates.

CI, Confidence interval; DM, Diabetes mellitus; LVEF, Left ventricular ejection fraction; sCr, Serum creatinine; CrCl, Creatinine clearance; BMI, Body mass index.

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