Acetylcysteine in the prevention of contrast-induced nephropathy after coronary angiography

Article Outline

• Abstract
• Methods
  • Patients
  • Study design
  • Statistical analysis
• Results
• Discussion
• References
• Copyright

Abstract 

Background

Contrast-induced nephropathy (CIN) after coronary angiography is associated with increased morbidity and mortality rates. Preliminary studies with N-acetylcysteine (NAC) have found conflicting results in the prevention of CIN in patients undergoing coronary angiography. This study was designed to evaluate the efficacy and safety of NAC in the prevention of CIN in patients undergoing coronary angiography.

Methods

This study was prospective, randomized, double-blind, and placebo-controlled. Patients referred for elective coronary angiography with a baseline creatinine clearance level <50 mL/min and serum creatinine >1.2 mg/dL were randomly assigned to 1500 mg NAC or placebo, starting the evening before angiography and given every 12 hours for 4 doses. The primary study end point was the development of CIN, which was defined as an increase of >0.5 mg/dL or an increase of ≥25% in serum creatinine over baseline within 48 hours of angiography. Secondary end points included changes in serum creatinine and blood urea nitrogen, requirement of dialysis, side effects of study medication, hospital length of stay, and hospital charges.

Results

CIN occurred in 8.2% (4/49) of patients taking NAC and 6.4% (3/47) of patients taking placebo. Changes in BUN and serum creatinine from baseline were not significantly different in the two treatment groups. Baseline BUN and volume of contrast were the only independent predictors of CIN. More patients with diabetes had development of CIN (5/43; 12%) compared with nondiabetic patients (2/52; 4%), but the difference was not significant (P = .15). The incidence of CIN in diabetic patients was not different in the two treatment groups. No patient with development of CIN required dialysis. Side effects (mostly gastrointestinal) occurred in 16% of patients taking NAC and in none of the patients taking placebo. Length of stay and hospital charges were not different between the treatment groups.

Conclusions

In patients with reduced renal function undergoing elective coronary angiography, NAC does not reduce the risk of CIN.

Contrast-induced nephropathy (CIN) after coronary angiography and/or percutaneous coronary intervention occurs most commonly in patients with chronic renal insufficiency.¹, ², ³ CIN has been reported to occur in 11% to 44% of patients with moderate renal insufficiency. It is relatively rare in patients with normal renal function. The risk of development of CIN is highest in patients with a combination of chronic renal insufficiency, diabetes mellitus, and dehydration.⁴ Larger doses of contrast and intracoronary or intra-aortic injection of contrast are also associated with a higher incidence of CIN.⁵

The development of CIN probably is related to the ability of contrast to cause renal vasoconstriction and to shunt blood from the medullary segments of the kidney to the cortical segments.⁶, ⁷ CIN typically occurs 1 to 7 days after exposure to contrast. Serum creatinine rises 24 to 48 hours after contrast exposure, with a peak occurring at 3 to 5 days. CIN contributes to morbidity, long hospital stays, in-hospital death, and increased health care costs.⁴

Many types of prophylaxis have been used in an attempt to prevent CIN. Hydration before and after exposure to contrast is more effective than diuresis with furosemide or mannitol.⁸, ⁹, ¹⁰ Hydration with isotonic saline has been shown to be superior to hydration with half-isotonic saline.¹¹ Although hydration is considered the standard practice in the prevention of CIN, a substantial proportion of patients at risk continue to have CIN. Other agents that have not been shown to be of benefit in the prevention of CIN include dopamine, captopril, theophylline, atrial natriuretic peptide, and calcium channel blockers.¹²

N-acetylcysteine (NAC) is an antioxidant and free radical scavenger that has been shown to reduce the risk of CIN in patients undergoing computed tomography.¹³ Preliminary studies with NAC in the prevention of CIN after coronary angiography have produced mixed results.¹⁴, ¹⁵ Accordingly, the current study tested the hypothesis that compared with placebo, prophylactic NAC would reduce the incidence of CIN in patients undergoing coronary angiography with or without concomitant coronary intervention.

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Methods 

Patients 

Consecutive patients referred for elective coronary angiography who met the inclusion/exclusion criteria were eligible to participate in the trial. Eligible patients included those ≥19 years of age with a baseline calculated creatinine clearance <50 mL/min and a serum creatinine >1.2 mg/dL, scheduled for coronary angiography with or without concomitant coronary intervention, with an anticipated use of ≥75 mL of contrast. Patients were not excluded on the basis of sex or race. Patients were excluded if they were in acute kidney failure, were undergoing dialysis, or had unstable renal function as evidenced by a change in serum creatinine of ≥0.5 mg/dL or ≥25% in the prior 10 days. Other exclusion criteria were a known allergy to contrast or acetylcysteine, administration of mannitol, intravenous catecholamines, parenteral diuretics, theophylline, or a contrast agent within 7 days of study entry, mechanical ventilation, cardiogenic shock, or emergent angiography.

Study design 

This prospective, randomized, double-blind, placebo-controlled trial was conducted according to the principles of the Declaration of Helsinki and was approved by our university's institutional review board. Subjects gave written informed consent before study entry.

All subjects received half-isotonic (0.45%) saline at 1 mL/kg per hour for 12 hours before and 12 hours after angiography. Patients were randomly assigned, through the use of a computer-generated 1:1 randomization sequence, to receive 1500 mg NAC or placebo, starting the evening before angiography and every 12 hours for 4 doses. NAC doses were given orally in 120 mL of carbonated beverage, using the 10% acetylcysteine inhalation solution. Placebo was given as an equivalent volume of normal saline in 120 mL of carbonated beverage.

Coronary angiography was performed in standard fashion, through either the radial or femoral approach. The choice of approach was left to the discretion of the attending interventional cardiologist. If therapeutic coronary interventions were used, these procedures were performed immediately after angiography. Decisions regarding the use of these procedures were left to the discretion of the attending interventional cardiologist. All procedures were performed with the use of low-osmolar, nonionic contrast media (Isovue; iopamidol 0.76 mg/mL, 370 mg iodine/mL; Bracco Diagnostics, Princeton, NJ).

A venous blood sample for serum creatinine and blood urea nitrogen (BUN) determinations was drawn 12 hours before and at 24 and 48 hours after angiography. Creatinine clearance (CrCl) was calculated by means of the Cockroft-Gault equation, where CrCl = ([140 −- age] × weight (kg)/serum creatinine (mg/dL) × 72). CrCl in women was adjusted ×0.85.¹⁶

The primary study end point was the development of CIN, which was defined as an absolute increase in serum creatinine of ≥0.5 mg/dL or a relative increase of ≥25% in serum creatinine at 24 or 48 hours after the procedure compared with baseline. Secondary end points included changes in serum creatinine and BUN at 24 and 48 hours after the procedure, requirement of dialysis, side effects of study medication, hospital length of stay, and hospital charges.

Statistical analysis 

Clinical, demographic, and outcome characteristics of the study groups were compared by means of the Student t test for continuous measures and the χ² statistic for categorical measures. For categorical variables with expected values of <5, the Fisher exact test was used. The influence of contrast media volume on the change in serum creatinine at 24 and 48 hours after the procedure in each treatment group was evaluated by means of univariate analysis of variance. The effect of other significant covariates on the development of CIN in the treatment groups such as age, sex, ejection fraction, diabetes, weight, baseline creatinine clearance, baseline BUN, and baseline serum creatinine were evaluated by means of stepwise logistic regression.

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Results 

Clinical and demographic characteristics of the study patients are summarized in Table I. There were no significant differences in baseline indexes of renal function or any baseline characteristic between the treatment groups. Characteristics of the angiographic procedures are summarized in Table II. The vascular access approach was similar in the two treatment groups. Patients receiving NAC were more likely to undergo angiography alone (71%) compared with patients receiving placebo (62%) (P = .03). The volume of contrast, however, was not significantly different between the treatment groups (P = .63).

Table I. Clinical characteristics of the treatment groups

Table II. Characteristics of the catheterization procedures

CIN occurred in 8.2% (4/49) of patients in the NAC group and in 6.4% (3/47) of patients in the placebo group (P = .74). Stepwise logistic regression was used to identify independent predictors of CIN. Volume of contrast (P = .007) and BUN at baseline (P = .008) were the only independent predictors of CIN. Contrast volume in the patients with development of CIN was 180.0 ± 93.9 mL compared with 127.1 ± 68.9 in patients without development of CIN. Baseline BUN was 46.3 ± 25.9 mg/dL in patients with development of CIN compared with 32.4 ± 14.4 mg/dL in patients without development of CIN. Changes in serum creatinine from baseline to 24 and 48 hours after the procedure in the treatment groups were not significant (Figure 1). Changes in BUN after angiography were also not different in the two treatment groups. Univariate analysis of variance demonstrated that the only variable that influenced serum creatinine after the procedure was volume of contrast.

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• Figure 1. 

  Serum creatinine concentration at baseline (gray bar), at 24 hours (black bar) after the procedure, and at 48 hours (white bar) after the procedure in the acetylcysteine and placebo treatment groups.

CIN occurred in 5 of 43 (12%) diabetic patients and in 2 of 52 (4%) of nondiabetic patients (P = .15). Changes in serum creatinine over time were also not significantly different in diabetic patients compared with nondiabetic patients (P = .58). In diabetic patients, CIN occurred in 3 of 20 (15%) NAC-treated patients and in 2 of 23 (9%) placebo-treated patients (P = .52).

No patient with development of CIN required dialysis. Adverse effects attributed to double-blind treatment occurred in 8 of 49 (16%) NAC-treated patients and in none of the placebo-treated patients. Adverse effects of NAC included gastrointestinal (nausea, stomach discomfort, diarrhea, constipation) complaints in 6 patients, headache in 1 patient, and chest tightness in 1 patient.

The length of hospital stay was significantly increased in patients with development of CIN (8.7 vs 4.9 days without CIN; P = .001). The length of hospital stay, however, was not different between the NAC (4.8 ± 3.8 days) and placebo (4.9 ± 4.0 days) groups. Hospital charges were also increased in patients who had CIN ($16,085 vs $12,810 without CIN; P = .002). Hospital charges were, however, not different between the NAC ($13,040 ± $8175) and placebo ($12,780 ± $9021) groups.

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Discussion 

Administration of radiocontrast media for diagnostic procedures is the most common cause of kidney failure in hospitalized patients.⁷ Kidney failure occurring in this setting is associated with increased morbidity and mortality rates, prolonged hospital stay, and substantial health care costs.¹, ², ⁴ The incidence of CIN varies according to the prevalence of risk factors in the population under study. Risk factors for CIN include chronic renal insufficiency, diabetes mellitus, contrast media volume, and repeated radiocontrast administration.² Identification of renoprotective agents that can prevent CIN has proven to be difficult. Dopamine, furosemide, mannitol, aminophylline, atrial natriuretic peptide, captopril, calcium channel blockers, and alprostadil are not effective in reducing the risk of CIN.¹⁰, ¹¹, ¹² Only hydration with saline or half-normal saline has consistently been shown to be more effective than placebo in reducing the risk of CIN.⁸, ⁹, ¹⁰

In a recent study, NAC was shown to significantly reduce the risk of CIN in patients with chronic renal insufficiency who received an average 75-mL dose of intravenous contrast dye before undergoing computed tomography.¹³ At the time this study was published, no data were available concerning the effectiveness of NAC in the prevention of CIN in patients undergoing coronary angiography, a diagnostic procedure typically using 2 to 3 times more contrast than computed tomography. The current study was initiated subsequent to the publication of that report to evaluate the effectiveness of NAC in the prevention of CIN in patients with chronic renal insufficiency undergoing coronary angiography with or without concomitant percutaneous coronary intervention.

In our study, prophylactic NAC did not reduce the incidence of CIN after coronary angiography. In addition, changes in serum creatinine and BUN after coronary angiography were not different in patients receiving NAC or placebo. NAC did not reduce the risk of CIN or changes in serum creatinine in the subgroup of patients with diabetes mellitus. It was not surprising, then, that the length of hospital stay and hospital charges were not different between the treatment groups. The only predictors of CIN in our study were the baseline BUN and the volume of contrast. Although the volume of contrast is a well-recognized risk factor for CIN, our study is the first to identify baseline BUN as an independent risk factor for CIN. An elevated BUN, particularly when the BUN to serum creatinine ratio exceeds 20:1, indicates that relative blood flow to the kidneys is reduced (prerenal azotemia).

From the time of the publication of the first study with NAC in patients undergoing computed tomography until the completion of our trial, 5 studies evaluating the efficacy of NAC in the prevention of CIN after coronary angiography have been published in the English language literature (Table III). ¹⁴, ¹⁵, ¹⁷, ¹⁸, ¹⁹

Table III. Published studies with N-acetylcysteine in the prevention of contrast-induced nephropathy

SCr, Serum creatinine; CrCl, creatinine clearance; NAC, N-acetylcysteine; PLA, placebo; CIN, contrast induced nephropathy; BID, twice daily; NS, not significant; N/A, not available.

Diaz-Sandoval et al¹⁴ randomly assigned 54 patients with a serum creatinine level >1.4 mg/dL or a creatinine clearance <50 mL/min to NAC or placebo. The volume of contrast administered was not indicated. Two of 25 (8%) NAC-treated patients and 13 of 29 (45%) placebo-treated patients had CIN (P = .005). Serum creatinine increased significantly in placebo-treated patients (1.6 to 1.9 mg/dL) but was reduced in NAC-treated patients (1.7 to 1.5 mg/dL).

Briguori et al¹⁵ randomly assigned 181 patients with a serum creatinine level >1.2 mg/dL or a creatinine clearance <70 mL/min to NAC or placebo. Average contrast volume was 194 mL in NAC-treated patients and 200 mL in placebo-treated patients. CIN occurred in 6 of 92 (6.5%) NAC-treated patients and in 10 of 91 (11%) placebo-treated patients (P = .22). In patients receiving contrast volumes <140 mL, CIN occurred in 5 of 60 (8.5%) placebo-treated patients and in none of the 60 patients receiving NAC (P = .02). These investigators concluded that NAC prevented CIN only in patients receiving relatively small volumes of contrast.

Shyu et al¹⁷ randomly assigned 121 patients with a serum creatinine level >2 mg/dL but <6 mg/dL or a creatinine clearance <40 mL/min but >8 mL/min to NAC or placebo. Volume of contrast in NAC-treated patients was 119 mL and 115 mL in placebo-treated patients. CIN occurred in 2 of 60 (3.3%) NAC-treated patients and 15 of 61 (24.6%) placebo-treated patients (P < .001). Serum creatinine increased from 2.8 mg/dL to 3.1 mg/dL in placebo-treated patients and decreased from 2.8 mg/dL to 2.5 mg/dL in NAC-treated patients (P < .01).

Allaqaband et al¹⁸ randomly assigned 123 patients with a serum creatinine level >1.6 mg/dL or a creatinine clearance <60 mL/min to placebo, 0.1 μg/kg per minute fenoldopam, or NAC. Contrast volumes were approximately 120 mL in each treatment group. The incidence of CIN was 15.3% with placebo, 15.7% with fenoldopam, and 17.7% with NAC (P = .92). Durham et al¹⁹ randomly assigned 79 patients with a serum creatinine level >1.7 mg/dL to NAC or placebo. NAC-treated patients received an average contrast dose of 77 mL and placebo-treated patients received an average of 85 mL. CIN occurred in 26.3% of NAC-treated patients and 22.0% of placebo-treated patients (P = NS).

The results of these trials, when considered with the results of the present study, indicate that the prophylactic use of NAC in the prevention of CIN after coronary angiography is of uncertain benefit. Two trials showed clear evidence of benefit, three trials found no evidence of benefit, and one trial demonstrated that NAC was beneficial only when small contrast volumes were used. It would be intuitive to reason that NAC should be most effective in patients at the highest risk of CIN. NAC was more effective than placebo in the study with the greatest number of high-risk patients (more severe baseline renal dysfunction and a higher prevalence of diabetes).¹⁷ In the study by Briguori et al,¹⁵ NAC was only effective in lower-risk patients (ie, those receiving less contrast). In the study by Durham et al, which used very small average contrast volumes (77 to 85 mL), NAC was not effective. Why NAC was effective in some studies but not others that had similar entry criteria and numbers of patients at risk is perplexing.¹⁴, ¹⁵, ¹⁸, ¹⁹

Our data indicate that when small contrast volumes are administered in patients with modest renal insufficiency, the incidence of CIN is relatively low. CIN occurred in only 6.5% of our placebo-treated patients, which is substantially lower than the incidence of CIN with placebo in the other 5 trials (25%, 45%, 11%, 22%, and 15%).¹⁴, ¹⁵, ¹⁷, ¹⁸, ¹⁹ The volume of contrast used in 3 of the studies was about the same or lower than that used in our study.¹⁷, ¹⁸, ¹⁹ The volume of contrast in the other two studies were considerably greater.¹⁴, ¹⁵ In the two studies using the greatest volume of contrast, NAC was effective one trial but not in the other.¹⁴, ¹⁵

The degree of baseline renal dysfunction in our study was similar to that in the studies by Diaz-Sandoval and Briguori but less severe than in the other three trials.¹⁴, ¹⁵, ¹⁷, ¹⁸, ¹⁹ In the study by Shyu et al,¹⁷ patients had more severe renal dysfunction (baseline serum creatinine, 2.8 mg/dL) and a higher prevalence of diabetes. As the contrast volumes used in the Shyu study were similar to those used in our study, these data may suggest that the volume of contrast is less important as a risk factor in the presence of more severe renal dysfunction in a higher-risk population.

The hydration protocol used in our study was the same as that used in four of the studies (1 mL/kg per hour for 12 hours before and 12 hours after angiography).¹⁵, ¹⁷, ¹⁸, ¹⁹ In the study by Diaz-Sandoval,¹⁴ hydration was permitted to begin as little as 2 hours before angiography. As the results of the Diaz-Sandoval trial were favorable to NAC, these findings suggest that the hydration protocol had no influence on the outcomes of these trials.¹⁴

The NAC dose was 2400 mg in four of the studies.¹⁴, ¹⁵, ¹⁷, ¹⁸ The NAC dose in the study by Shyu et al, which demonstrated the greatest benefit with NAC, was only 1600 mg. The dose of NAC in our study was 6000 mg. NAC was given as 2 doses before and 2 doses after angiography in 3 of the studies.¹⁵, ¹⁷, ¹⁸ However, Durham et al¹⁹ gave one 1200-mg dose of NAC before and one 1200-mg dose after angiography. Diaz-Sandoval¹⁴ gave one 600-mg dose before and three 600-mg doses after angiography. It is interesting to note that the study using the smallest dose of NAC produced the most impressive results (3.3% incidence of CIN with NAC in the highest risk patients). In our study, which used the largest dose, no benefit was observed. We did observe adverse effects with NAC (mostly gastrointestinal) in 16% of patients. No other trial reported any side effects with NAC. Whether the ability of NAC to prevent CIN after coronary angiography is dose-related cannot be resolved on the basis of the available data.

Limitations of our study include a relatively small sample size, the relatively brief period of monitoring for changes in renal function after angiography, and the ability to truly blind NAC therapy. The sample size in our study (n = 96) was greater than the sample size in two studies and similar to that in a third trial.¹⁴, ¹⁸, ¹⁹ Only the studies by Briguori et al¹⁵ and Shyu et al¹⁷ randomly assigned more patients. It is possible, however, that by not enrolling a larger number of patients that a type II error occurred in our study. In addition, we only evaluated renal function at 24 and 48 hours after angiography. It is possible that changes in renal function could have occurred after 48 hours. However, 48 hours was the longest duration of follow-up in all of the other 5 published NAC trials.¹⁴, ¹⁵, ¹⁷, ¹⁸, ¹⁹ NAC, when given as a solution, has a characteristic sulfur-like odor. In an attempt to mask this odor, the drug was mixed with a carbonated beverage. Patients were told at the time of informed consent that their treatment may have an offensive odor or taste. Despite these efforts, a definite double-blind may not have been achieved. This failure to double-blind therapy (from the patient's perspective) may have led to the higher-than-expected rate of gastrointestinal complaints.

It does not appear that the conflicting results observed in the six published trials with NAC in the prevention of CIN can be reconciled on the basis of differences in study design or patient characteristics. As a result, trials with larger sample sizes will be needed to more clearly define the potential role of NAC in the prevention of CIN in patients undergoing coronary angiography.

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