|Year : 2016 | Volume
| Issue : 1 | Page : 55-61
|N-acetylcysteine and/or ascorbic acid versus placebo to prevent contrast-induced nephropathy in patients undergoing elective cardiac catheterization: The NAPCIN trial; A single-center, prospective, randomized trial
Mohammed Habib1, Alaa Hillis2, Amen Hammad3
1 Department of Cardiology, European Gaza Hospital, Gaza, Palestine
2 Department of Pharmacy, European Gaza Hospital, Gaza, Palestine
3 Pharmacy Faculty, Al Azhar University, Gaza, Palestine
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|Date of Web Publication||15-Jan-2016|
| Abstract|| |
Several protective measures have been described to prevent contrast-induced nephropathy (CIN). This study is aimed to evaluate the effect of a high dose of N-acetylcysteine (NAC) plus hydration, a low dose of NAC plus ascorbic acid and hydration or hydration alone on the prevention of CIN in high-risk patients undergoing elective coronary artery intervention. We conducted a randomized, prospective, placebo-controlled trial of 105 high-risk patients undergoing elective cardiac catheterization. The patients were divided into three different groups: Group A (n = 30), NAC 1200 mg orally before angiography and 1200 mg orally twice daily for three doses along with good hydration; Group B (n = 30), NAC 600 mg before angiography and 600 mg orally twice daily for three doses plus ascorbic acid (3000 mg one dose) before angiography and 2000 mg two doses after angiography and good hydration; and Group C (n = 45), hydration with 0.9% saline started just before contrast media injection and continued for 12 h at a rate 1.0 mL/kg/min after angiography or 0.5 mL/kg/h in cases with overt heart failure for 12 h. CIN was defined as an increase in serum creatinine of >25% of baseline or an absolute increase of 0.5 mg/dL above baseline after 48 h. The incidence of CIN was significantly lower in Group A (6.66%) compared with Group B (16.66%) or Group C (17.77%). The difference between Groups A and B and between Groups A and C was also highly significant (P = 0.001). In contrast, the difference between Groups B and C was not statistically significant (P = 0.37). Our study indicates that high doses of NAC plus hydration provide better protection against CIN than combination therapy of NAC and ascorbic acid plus hydration, or hydration alone.
|How to cite this article:|
Habib M, Hillis A, Hammad A. N-acetylcysteine and/or ascorbic acid versus placebo to prevent contrast-induced nephropathy in patients undergoing elective cardiac catheterization: The NAPCIN trial; A single-center, prospective, randomized trial. Saudi J Kidney Dis Transpl 2016;27:55-61
|How to cite this URL:|
Habib M, Hillis A, Hammad A. N-acetylcysteine and/or ascorbic acid versus placebo to prevent contrast-induced nephropathy in patients undergoing elective cardiac catheterization: The NAPCIN trial; A single-center, prospective, randomized trial. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2019 Nov 16];27:55-61. Available from: http://www.sjkdt.org/text.asp?2016/27/1/55/174072
| Introduction|| |
Contrast-induced nephropathy (CIN) is a serious complication of diagnostic and therapeutic procedures requiring contrast media; they account for more than 10% of hospital-acquired cases of acute renal failure. CIN is associated with an increase in hospital morbidity and mortality. , It is the third most common cause of in-hospital acute renal failure after hypotension and surgery. The incidence varies widely and depends on the diagnostic criteria used and the presence of associated risk factors. In the presence of normal renal function, the incidence of CIN is 1% with intravenous and 2-7% with intra-arterial administration of contrast media. ,,
Multiple strategies have been explored to reduce the occurrence of CIN after percutaneous coronary intervention,  although the only proven strategies remain adequate periprocedural hydration, avoidance of hyperosmolar contrast media and minimization of volume of contrast media. ,
The mainstay of preventive therapy has been fluid hydration before contrast exposure. Many trials have shown a significantly reduced incidence of CIN in patients receiving adequate hydration. 
N-acetylcysteine (NAC) reduces the nephrotoxicity of contrast media through antioxidant effects. ,, It also enhances the effect of the endogenous vasodilator nitric oxide.  Some studies have revealed successful protective effects of NAC, used as an adjunct to saline hydration in low-risk patients. , However, contradictory results regarding the efficacy of NAC have also been reported and the protective effect of NAC is not universal. ,,,
Ascorbic acid is a water-soluble anti-oxidant and aids in scavenging a wide array of reactive oxygen species that can cause damage to macromolecules such as lipids, DNA and proteins.  Additionally, ascorbic acid acts in regenerating other anti-oxidants.  Its prophylactic use in patients undergoing catheterization would therefore provide a potentially cheap, safe and readily available medication. Ascorbic acid has been shown to reduce renal damage caused by other insults, such as post-ischemic stress, and has a place as a dietary supplement in humans. 
We aimed to compare the efficacy of these therapies and classic saline infusion in preventing CIN associated with coronary artery procedures.
| Methods|| |
A prospective, randomized, placebo-controlled trial was carried out on 105 consecutive patients with ischemic heart disease or peripheral vascular disease. The patients had at least one risk factor for CIN (age >70 years, baseline creatinine level >1.5 mg/dL, heart failure, diabetes mellitus or contrast media volume >300 mL). All patients underwent coronary angiography at the European Gaza Hospital. The patients were randomized into three groups: (a) Group A patients (n=30) received NAC 1200 mg orally every 12 h for two days, one dose before coronary angiography and three doses after coronary angiography (total dose of NAC, 4800 mg including intervention dose); NAC was given over 48 h and hydration with 0.9% saline was started just before injection of contrast media and continued for 12 h at a rate 1.0 mL/kg/ min after angiography or 0.5 mL/kg/h in cases with overt heart failure, for 12 h, (b) Group B patients (n=30) received, low-dose NAC 600 mg orally every 12 h for two days, one dose before coronary angiography and three doses after coronary angiography (total dose of NAC, 2400 mg including the intervention dose). Additionally, ascorbic acid 3000 mg was given orally before angiography followed by 2000 mg orally on the night and morning after the procedure (total dose of ascorbic acid was 7000 mg). Hydration with 0.9% saline was started just before injec-tion of contrast media and continued for 12 h at a rate of 1.0 mL/kg/ min after angiography intervention or 0.5 mL/kg/h in cases with overt heart failure, for 12 h and (c) Group C (n=45) was the placebo group; patients received hydration with 0.9% saline started just before injection of con-trast media and continued for 12 h at a rate of 1.0 mL/kg/min after angiography intervention or 0.5 mL/kg/h in cases with overt heart failure, for 12 h. Serum urea and creatinine levels were measured before and 48 h after the procedure.
The primary end-point of this study is the development of CIN, which, as described in a previous study by Tepel et al,  is defined as an increase in serum creatinine concentration of 0.5 mg/dL or ≥25% of the baseline value within 48 h after the procedure. The secondary end-point was the comparison of the level of creatinine, urea and creatinine clearance between the three groups.
Cardiac catheterization with coronary angiography and/or percutaneous coronary intervention was performed according to local standards using the femoral approach. The low-osmolal, non-ionic contrast agent ultravist iopromide (Bayer Health Care, Leverkusen, Germany) was used in all cases. Adjunctive therapy and the dose of contrast agent were left to the discretion of the interventional cardiologist.
The study protocol was approved by the local ethics committee and all patients gave written informed consent.
| Statistical Analysis|| |
The sample size was calculated on the basis of a power analysis that assumed a reduction in the average rate of the primary end-point of 50% in patients treated with NAC and ascorbic acid as compared with the NAC alone or control group. Continuous data are reported as means ± SD where appropriate. Categorical data are presented as absolute values and percentages.
Statistical analyses were performed using SPSS 11.5 software program, and a P-value <0.05 was considered significant.
| Results|| |
Baseline characteristics show that the study sample consisted of 105 patients [61 male (50.1%) and 44 (41.9%) female]; the mean age of the study participants was 62.3 ± 8.9 years. Eighty-four (80%) of the patients were diabetics, 4.8% had heart failure and 22% were older than 70 years. The overall mean baseline creatinine clearance was 76.63 ± 19.61 mL/min, the serum creatinine level was 0.97 ± 0.36 mg/dL and the plasma urea level was 37.58 ± 17.27 mg/dL; 8.7% of the patients had baseline serum creatinine >1.5 mg/dL [Table 1].
Contrast media-induced nephropathy
Two patients (6.66%) in Group A, five patients (16.66%) in Group B and eight patients (17.77%) in Group C developed CIN as defined earlier [Figure 1].
|Figure 1: Percentage of patients who suffered from contrast media-induced nephropathy after angiography in Groups A, B and C.|
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The difference between Groups A and B and Groups A and C was highly statistically significant, P-value = 0.001; the difference between Groups B and C was statistically not significant, P-value = 0.37.
Of the 30 patients in this group, there were 20 males (66.6%) and ten females (33.4%) with a mean age of 63 ± 8.26 years.
The baseline creatinine clearance level was 72.35 ± 22.97 mL/min, serum creatinine level was 1.09 ± 0.45 mg/dL and plasma urea level was 44.03 ± 19.33 mg/dL. After intervention with contrast media, minor changes occurred; the creatinine clearance decreased to 70.83 ± 25.92 mL/min, the creatinine level also decreased to 1.07 ± 0.45 mg/dL and the plasma urea level increased slightly to 45.03 ± 22.29 mmol/L. These changes were statistically not significant.
Of the 30 patients in this group, there were ten males (33.4%) and 20 (66.6%) females; the mean age was 62.03 ± 9.37 years. After intervention with contrast media, changes occurred in the patients' baseline values; the creatinine clearance decreased to 68.50 ± 27.76 mL/min, the serum creatinine level increased to 1.09 ± 0.52 mg/dL and the plasma urea level also increased to 42.74 ± 22.64 mg/dL.
Data analysis showed statistically significant changes in the creatinine clearance level, which was reduced by 10.08%, with a P-value of 0.037; in the serum creatinine level, which was increased by 18.34%, with a P-value of 0.005; and the plasma urea level, which was increased by 31.58%, with a P-value of 0.006.
This group included 45 patients with a mean age of 63 ± 8.26 years. Thirty-four patients (75.5%) were diabetics, two patients (4.4%) had heart failure, two patients (22.2%) were older than 70 years, three patients had baseline serum creatinine >1.5 mg/dL (6.6%) and 13 patients received >300 mL of contrast media (28.8%).
Their baseline creatinine clearance was 79.78 ± 18.53, serum creatinine level was 0.92 ± 0.27 mg/dL and plasma urea level was 31.02 ± 11.2 mg/dL.
After intervention with contrast media, the creatinine clearance decreased to 70.97 ± 25.27 mL/min, serum creatinine level increased by 0.02 unit to 1.05 ± 0.36 mg/dL and plasma urea level increased to 39.82 ± 16.80 mg/dL.
The results show statistically significant changes in the creatinine clearance level, which was reduced by 11.04%, with a P-value of 0.006; the serum creatinine level, which was increased by 14.13%, with a P-value of 0.009; and in the plasma urea level, which was increased by 28.36%, with a P-value of 0.002.
Comparison between Groups A and B
The difference between these two groups was statistically significant with respect to the plasma urea level, with a P-value of 0.029, and very close to being significant with respect to serum creatinine, with a P-value of 0.054 [Table 2].
|Table 2: Creatinine clearance (mL/min), serum creatinine (mg/dL) and plasma urea level (mg/L) in Groups A and B before and after interventions.|
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Comparison between Groups A and C
The difference between these two groups was statistically significant with respect to creatinine clearance, with a P-value of 0.045, but not significant with respect to serum creatinine, with a P-value of 0.37, and plasma urea level, with a P-value of 0.11 [Table 3].
|Table 3: Respective creatinine clearance (mL/min), serum creatinine (mg/dL) and plasma urea (mg/dL) in Groups A and C before and after interventions.|
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Comparison between Groups B and C
This difference was statistically not significant with respect to creatinine clearance or serum creatinine before and after the interventions [Table 4].
|Table 4: Creatinine clearance (mL/min), serum creatinine (mg/dL) and plasma urea level (mg/dL) in groups B and C before and after interventions.|
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| Discussion|| |
This study shows that prophylactic oral administration of NAC alone or in combination with ascorbic acid lowers the incidence of CIN in patients undergoing coronary angioplasty.
This NAPCIN study for the first time compared the two well-known anti-oxidants NAC and NAC plus ascorbic acid for their relative efficacy in preventing CIN, and showed that high-dose NAC was associated with a lower increment of serum creatinine level and trended toward a lower rate of CIN rather than the combination of low-dose NAC plus ascorbic acid.
NAC is one of the anti-oxidants that has been most widely researched as a prophylactic strategy of CIN. , The effect of orally administered high-dose ascorbic acid to prevent CIN in patients with chronic renal insufficiency was first reported by Spargias et al.  A recent meta-analysis revealed that smaller trials with inadequate methodology tended to over-estimate the effect of NAC on the risk of contrast-induced acute kidney injury. 
We agree that use of two anti-oxidants may be efficacious. Hence, it is very important to determine which anti-oxidant or combination is more potent and beneficial to prevent the occurrence of CIN.
The NASPI study compared the efficacy of NAC and ascorbic acid, both of which have potential for CIN prevention, and suggested that high-dose NAC seems more beneficial than ascorbic acid in preventing contrast-induced renal functional deterioration in patients with renal insufficiency undergoing coronary angiography. 
A difference between our study and the NASPI trial was in the protocol for ascorbic acid plus NAC administration. High-dose NAC was more effective than administration of a combination of ascorbic acid plus lowdose NAC.
Recently published trials support the hypothesis that high doses of NAC seem more beneficial than standard doses in CIN prevention, both in elective and in urgent contrast administration in patients with chronic renal insufficiency. ,,
Martin Brueck reported that 600 mg of intravenous NAC and 500 mg of ascorbic acid did not prevent CIN in high-risk patients undergoing cardiac catheterization with nonionic, low-osmolality contrast agent. 
| Study Limitations|| |
The study represents a single-center experience with a limited number of patients. The patients were observed for only 48 h. Some studies have shown that the serum creatinine level may peak at three days after the contrast administration and return to normal within the next 10 days. The increase of serum creatinine level beyond this time interval has remained unnoticed.
High-dose NAC seems more beneficial than ascorbic acid and low-dose NAC for preventing CIN in high-risk patients.
Conflict of Interest: None declared.
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Cardiology Department, European Gaza Hospital, Gaza
[Table 1], [Table 2], [Table 3], [Table 4]
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