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Kay J, Chow WH, Chan TM, et al. Acetylcysteine for Prevention of Acute Deterioration of Renal Function Following Elective Coronary Angiography and Intervention: A Randomized Controlled Trial. JAMA. 2003;289(5):553–558. doi:10.1001/jama.289.5.553
Context The antioxidant acetylcysteine prevents acute contrast nephrotoxicity
in patients with impaired renal function who undergo computed tomography scanning.
However, its role in coronary angiography is unclear.
Objective To determine whether oral acetylcysteine prevents acute deterioration
in renal function in patients with moderate renal insufficiency who undergo
elective coronary angiography.
Design and Setting Prospective, randomized, double-blind, placebo-controlled trial conducted
from May 2000 to December 2001 at the Grantham Hospital at the University
of Hong Kong.
Participants Two hundred Chinese patients aged mean (SD) 68 (6.5) years with stable
moderate renal insufficiency (creatinine clearance <60 mL/min [1.00 mL/s])
who were undergoing elective coronary angiography with or without intervention.
Intervention Participants were randomly assigned to receive oral acetylcysteine(600
mg twice per day; n = 102) or matching placebo tablets (n = 98) on the day
before and the day of angiography. All patients received low-osmolality contrast
Main Outcome Measures Occurrence of more than a 25% increase in serum creatinine level within
48 hours after contrast administration; change in creatinine clearance and
serum creatinine level.
Results Twelve control patients (12%) and 4 acetylcysteine patients (4%) developed
a more than 25% increase in serum creatinine level within 48 hours after contrast
administration (relative risk, 0.32; 95% confidence interval [CI], 0.10-0.96; P = .03). Serum creatinine was lower in the acetylcysteine
group (1.22 mg/dL [107.8 µmol/L]; 95% CI, 1.11-1.33 mg/dL vs 1.38 mg/dL
[122.9 µmol/L]; 95% CI, 1.27-1.49 mg/dL; P =
.006) during the first 48 hours after angiography. Acetylcysteine treatment
significantly increased creatinine clearance from 44.8 mL/min (0.75 mL/s)
(95% CI, 42.7-47.6 mL/min) to 58.9 mL/min (0.98 mL/s) (95% CI, 55.6-62.3 mL/min)
2 days after the contrast administration (P<.001).The
increase was not significant in the control group (from 42.1 to 44.1 mL/min
[0.70 to 0.74 mL/s]; P = .15). The benefit of acetylcysteine
was consistent among various patient subgroups and persistent for at least
7 days. There were no major treatment-related adverse events.
Conclusion Acetylcysteine protects patients with moderate chronic renal insufficiency
from contrast-induced deterioration in renal function after coronary angiographic
procedures, with minimal adverse effects and at a low cost.
Contrast nephropathy is a recognized complication after coronary angiography
and intervention that has been associated with prolonged hospitalization and
adverse clinical outcomes.1-3 It
is reported that 14.5% of patients develop a 25% increase in serum creatinine
levels following cardiac catheterization.2 This
problem assumes greater and greater importance with increased use of invasive
radiological procedures to diagnose and treat coronary artery disease.
Contrast nephropathy is potentially preventable because the administration
of radiocontrast agent is predictable and high-risk populations also have
been identified.4 Patients at greatest risk
are those with impaired renal function,5 particularly
that caused by diabetic nephropathy.6 However,
other than the use of intravenous hydration2 and
low-osmolality contrast media,7 no previous
strategies have been convincingly shown to prevent contrast nephropathy in
high-risk patients. Efficacious and safe prophylactic intervention of contrast
nephropathy is expected to decrease morbidity and mortality during hospitalization,
including the need for dialysis, and thus reduce health costs.
Acetylcysteine is an antioxidant that has been shown to attenuate ischemic
renal failure in animal studies.7,8 It
prevents acute renal dysfunction in noncardiac patients with chronic renal
insufficiency exposed to small doses of contrast agents during computed tomography.9 Patients with renal disease also frequently have severe
coronary disease and are referred for coronary angiography and intervention.10 In addition to the use of larger volumes of contrast
media, cardiac catheterization involves greater renal vasoconstriction with
intra-arterial injections in patients with variable hemodynamic status. A
higher incidence of contrast media–induced nephrotoxicity has been demonstrated
in patients undergoing cardiac catheterization.11 The
low cost of acetylcysteine, its ease of administration, and its limited adverse
effects are all compelling reasons to further investigate its role in patients
undergoing angiography. We therefore conducted a prospective randomized clinical
trial with detailed measurement of renal function to determine the effect
of oral acetylcysteine in patients with chronic renal impairment who were
at high risk for contrast nephrotoxicity after elective diagnostic and/or
interventional coronary angiographic procedures.
This prospective, randomized double-blind, placebo-controlled trial
was conducted at the Grantham Hospital at the University of Hong Kong between
May 2000 and December 2001, in accordance with the principles of good clinical
practice and the Declaration of Helsinki. The study protocol was approved
by the Research and Ethics Committee of Grantham Hospital. All patients gave
written informed consent.
Patients scheduled for elective coronary angiography and/or intervention
were eligible for the study if they had a serum creatinine concentration above
1.2 mg/dL (106 µmol/L) or creatinine clearance below 60 mL/min (1.0
mL/s). Creatinine clearance was estimated from serum creatinine concentration
using the Cockcroft-Gault formula12 and subsequently
confirmed by collection of urinary creatinine over 24 hours. Eligible patients
were adults with known chronic renal impairment and stable serum creatinine
concentrations. Dialyzed patients were excluded from participation, as were
patients who had acute renal failure, who had a change in use of diuretic
or antihypertensive agents, or who had received iodinated contrast media or
nephrotoxic agents within the 30 days prior to the study entry. We did not
enroll patients with overt congestive heart failure, severe valvular disease,
or advanced left ventricular systolic dysfunction defined as left ventricular
ejection fraction less than 35%. Patients who had acute chronic obstructive
lung disease or asthma exacerbation, or allergy to acetylcysteine, were ineligible.
All eligible patients (N = 200; mean [SD] age, 68 [6.5] years) were
randomly allocated to either the acetylcysteine group or the control group
based on random numbers generated by computer. Participants, those administrating
the interventions, and those assessing the outcomes were unaware of the group
assignment. Patients were randomized to receive either oral acetylcysteine
(Fluimucil [Zambon Group SpA, Milan, Italy], 600-mg tablet twice daily) or
matching placebo on the day before and on the day of administration of the
contrast agent, for a total of 2 days. Three doses were given before and 1
dose after cardiac catheterization. Physiological (0.9%) saline was given
intravenously at a rate of 1 mL/kg of body weight per hour for 12 hours before
and for 6 hours after the contrast exposure. Liberal intake of oral fluid
was encouraged to ensure good hydration status, except for the 4 hours preprocedure
or when clinically contraindicated. Volume status and body weight were monitored
closely. Serum creatinine and urea levels were measured at the time of admission,
then at 24 hours, 48 hours, and 7 days following the administration of contrast
medium. Twenty-four–hour urine creatinine levels were collected at the
time of admission, then at 48 hours and 7 days after contrast administration.
Bromhexine was used as a mucolytic agent if clinically indicated. Metformin
was withheld before cardiac catheterization due to its potential toxic accumulation
after acute contrast nephrotoxicity13 and reinstituted
after the completion of study. Oral sulphonylurea or insulin was used to optimize
blood sugar levels if necessary.
Standard coronary angiography and/or percutaneous coronary intervention
were performed. All patients received a nonionic, low-osmolality contrast
agent (iopamidol). Adjunctive drug therapy and the dose of contrast agent
were left to the discretion of the attending cardiologist.
The primary outcome was the occurrance of acute contrast-induced reduction
in renal function; the second primary outcome was change in creatinine clearance
and serum creatinine concentration. Secondary outcomes were acute pulmonary
edema, major adverse cardiac events, need for dialysis, and length of hospitalization.
Stable serum creatinine concentration was defined as a difference of
0.1 mg/dL (8.8 µmol/L) or less between serum creatinine levels measured
1 to 2 months before angiography and baseline levels measured 12 to 24 hours
before coronary angiography. Acute contrast-induced reduction in renal function
was defined as a greater than 25% increase in serum creatinine level2,14-16 that
occurred within 48 hours after contrast exposure and for which alternative
explanations for renal impairment had been excluded. Major adverse cardiac
events were defined as cardiac death, nonfatal myocardial infaion (defined
as >3 times upper limit of creatine kinase-MB levels), or revascularization
of the target lesion.
Based on previous findings that the SD of serum creatinine levels in
the angiographic population at high risk for contrast nephropathy would be
0.85 mg/dL (75.1 µmol/L),17 a sample
size of approximately 80 patients in each treatment group (a 2-tailed significance
level of .05 and a statistical power of 0.95) was required to detect a difference
in serum creatinine level of 0.5 mg/dL (44.2 µmol/L) (a standardized
difference of 0.59 or an effect size of 0.29), a difference that is comparable
to that detected in previous studies.9,17 To
account for the possibility of patients lost to follow-up and to ensure a
real clinical difference, the planned sample size was 200 patients.
The Kolmogorov-Smirnov test was used to determine if continuous variables
were normally distributed. Baseline characteristics of the study groups were
compared using the 2-tailed t test, or Mann-Whitney
test where appropriate, for continuous data and the χ2 test
for categorical data. Modified intention-to-treat analysis was carried out
on all randomized patients who received at least 1 dose of the study medication
(no patients were excluded because they did not receive a first dose). Difference
in incidence of acute contrast-induced reduction in renal function between
the 2 treatment groups was tested using a χ2 test. Serial serum
creatinine concentrations and creatinine clearance were compared within and
between groups using repeated-measures analysis of variance followed by contrast.
While the overall α level was set at .05, the sharpened Bonferroni method18 was used to adjust for individual α level when
multiple tests were performed. Data were analyzed with SPSS v10.0 (SPSS Inc,
The trial profile is shown in Figure
1. In terms of baseline characteristics the 8 patients without follow-up
data did not differ significantly from the remaining population.
The mean (SD) baseline serum creatinine level and 24-hour creatinine
clearance for all patients were 1.36 (0.44) mg/dL (120.2 [38.9] µmol/L)
and 43.5 (12.3) mL/min (0.7 [0.2] mL/s), respectively. The study groups were
similar in their baseline characteristics (Table 1). The causes of chronic renal impairment were determined
by clinical assessments and were not significantly different between the groups.
Most patients were scheduled for cardiac angiography and/or intervention because
of symptomatic coronary ischemia. The mean volume of administered contrast
medium was 139 (53) mL for all patients. The study groups were similar in
terms of left ventricular ejection fraction (LVEF), angiographic diagnoses,
and volume of contrast agent administered. No patient had significant hypotension
or dysarrhythmias during or after cardiac catheterization that might have
altered renal function.
Clinical outcomes are given in Table
2. Patients receiving acetylcysteine experienced acute contrast-induced
reduction in renal function two thirds less frequently (12% vs 4%, P = .03). The average length of hospitalization was also a half-day
shorter in the group receiving acetylcysteine (P =
.02). A trend toward a lower incidence of oliguria and acute increase in serum
creatinine levels of at least 50% was noted in patients assigned to acetylcysteine
treatment. No patients in this study developed acute nephrotoxicity requiring
dialysis as a result of the administration of contrast material. One patient
receiving acetylcysteine developed congestive heart failure due to unstable
angina. There were no major adverse cardiac events except 1 patient in the
control group sustained an uncomplicated non–ST-segment elevation myocardial
infarction after coronary intervention.
The changes in the serum creatinine concentrations and creatinine clearance
after the administration of contrast material are described in Figure 2. The mean serum creatinine concentration and creatinine
clearance before radiocontrast administration were similar in the 2 groups.
The serum creatinine concentration decreased after angiography in the acetylcysteine
group compared with the control group (Figure
2). In the acetylcysteine group, the mean serum creatinine concentration
decreased significantly from 1.35 to 1.22 mg/dL (119.3 to 107.8 µmol/L, P<.001) at day 2 after the administration of the contrast
medium. In the control group, the change in mean serum creatinine concentration
(1.36 to 1.38 mg/dL [120.2 to 122 µmol/L) was not significant (P = .13). The differences in changes (from baseline) between
the control and acetylcysteine groups were significant at day 1 (1.32 vs 1.22
mg/dL [116.7 vs 107.8 µmol/L], P = .02) and
day 2 (1.38 [95% CI, 1.27-1.49] vs 1.22 [95% CI, 1.11-1.33] mg/dL [122 vs
107.8 µmol/L], P = .006) after administration
of contrast medium, but not significant at day 7 (1.38 vs 1.31 mg/dL [122
vs 115.8 µmol/L], P = .23) (Figure 2).
When 24-hour creatinine clearance was examined (Figure 2), the increase in the control group was only significant
vs baseline at day 7 (42.1 to 48.4 mL/min [0.70 to 0.81 mL/s], P<.001) after the administration of contrast (at day 2: 42.1 to
44.1 mL/min [0.70 to 0.74 mL/s], P = .15). Patients
in the acetylcysteine group, on the other hand, had a 30% increase, from 44.8
(0.75 mL/s) (95% CI, 42.7-47.6) to 58.9 (0.98 mL/s) (95% CI, 55.6-62.3) mL/min
(0.7 to 1.0 mL/s, P<.001) at day 2 after angiography.
The change was significantly different between the 2 groups (P<.001). A higher creatinine clearance was also evident at day 7
after angiography (55.2 mL/min [0.92 mL/s], P = .045).
The consistency of the benefits of acetylcysteine in a number of key
subgroups is shown in Figure 3.
There was a tendency toward a greater benefit among patients who had diabetes
mellitus (P = .001) and who received a volume of
contrast medium greater than 100 mL (P<.001).
The changes in weight after angiography were nonsignificant in both
groups. The groups also did not differ significantly in the ratio of serum
urea levels to serum creatinine levels and in total urinary output after angiography.
One patient assigned to placebo discontinued the study medication because
of nausea. No other adverse effects were reported.
This study demonstrates that acetylcysteine prevents contrast nephrotoxicity
in patients with moderate chronic renal insufficiency undergoing coronary
diagnostic and/or interventional procedures. Its renoprotective effects were
similar in various patient subgroups. The similar changes in serum urea and
creatinine concentrations suggest that the changes in glomerular filtration
underlie the prophylactic effects of acetylcysteine.
Contrast nephropathy results from direct renal tubular toxicity and
renal medullary ischemia.6 Administration of
contrast medium increases the production of nephrotoxic oxygen free radicals.19,20 Besides scavenging oxygen free radicals
that mediate cell necrosis after myocardial infarction21 and
after angioplasty,22 acetylcysteine may act
as an antioxidant to inhibit ischemic cell death in the kidney.7,8 Previous
studies also suggest that acetylcysteine has vasodilatory properties.23,24 Therefore, acetylcysteine may prevent
contrast nephrotoxicity by inhibiting direct oxidative tissue damage and by
improving renal hemodynamics.
We studied patients with moderate chronic renal insufficiency because
they represent the majority of patients at high risk of contrast nephropathy
who are selected for coronary procedures. Moderate renal insufficiency also
doubles the risks of in-hospital major adverse cardiac events.25
A more than 25% increase in serum creatinine level following contrast
administration was a marker of poor clinical outcomes in a recent study26 and was the typical definition of an acute contrast-induced
reduction in renal function in the preceding studies.2,13-16,19 Our
incidence (12%) is in agreement with a previous large epidemiologic study.2 Such complication may prolong hospitalization because
of additional laboratory testing and postponement of further radiographic
contrast exposure or surgical intervention.1,27 We
found a slight but statistically significant decrease in length of hospitalization
among the patients receiving acetylcysteine.
One percent of our patients developed a more than 50% increase in creatinine
level after contrast exposure and no patient required acute dialysis. This
reinforces the previous finding5,28,29 that
the more severe forms of contrast nephrotoxicity are uncommon. Acute dialysis
is uncommon (0.77%) after coronary intervention.2 Clinically
serious renal injury is expected to be more common in daily clinical practice
because our patients were carefully selected, optimally hydrated, and free
of other factors that may predispose them to contrast nephropathy.
Less than 5% of our patients had serum creatinine levels above 2.5 mg/dL
(221 µmol/L). Even low doses of contrast (30-100 mL) have been shown
to induce the need for dialysis in patients with severe renal disease.6,10 Little is known about the most appropriate
treatments of coronary artery disease in patients with advanced renal insufficiency.
The clinical outcomes of these patients undergoing a percutaneous coronary
intervention are poor. Best et al25 have reported
significant higher cumulative 1-year mortality and cardiac events in patients
with creatinine clearance <30 mL/min (0.5 mL/s) than those with moderate
renal disease (25% vs 10%, P<.001).
Acetylcysteine has been used to prevent acute renal damage in a small
number of patients with serum creatinine levels above 1.5 mg/dL (132.6 µmol/L)
and undergoing cardiac catheterization.30-32 Shyu
et al33 have recently demonstrated the renoprotective
effect of acetylcysteine in 121 patients with a mean serum creatinine level
of 2.8 mg/dL (247.5 µmol/L) and undergoing coronary angiography or intervention.
Their findings correlate well with our significant treatment difference in
the change of serum creatinine levels after coronary procedures. Acute dialysis
was uncommon (1.6% of control patients) and not significantly affected by
administration of acetylcysteine. Major cardiac events were not reported.
Acute nephrotoxicity following contrast administration, defined as an increase
in serum creatinine level of at least 0.5 mg/dL (44.2 µmol/L), occurred
in 15 (25%) of 61 control patients. We administered a larger mean dose of
radiocontrast agent (140 vs 120 mL). Contrast nephrotoxicity by the same definition,
however, occurred less often in our study. This may be related to the smaller
body mass index of our patients and lower baseline serum creatinine concentrations
of our samples.
We concluded that oral acetylcysteine is a safe, effective, and inexpensive
prophylactic treatment against acute renal dysfunction for patients with moderate
chronic renal insufficiency undergoing coronary angiographic procedures. Additional
larger studies will be required to determine if acetylcysteine reduces the
morbidity (eg, acute dialysis) and mortality of nephrotoxicity following administration
of contrast media.
A detailed description of the study methodology and patient flow is available from http://rctbank.ucsf.edu/Presenter?575. The RCT Presenter is not maintained by JAMA .
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