Background Patients with acute myocardial infarction undergoingprimary angioplasty are at high risk for contrast-medium–inducednephropathy because of hemodynamic instability, the need fora high volume of contrast medium, and the lack of effectiveprophylaxis. We investigated the antioxidant N-acetylcysteinefor the prevention of contrast-medium–induced nephropathyin patients undergoing primary angioplasty.
Methods We randomly assigned 354 consecutive patients undergoingprimary angioplasty to one of three groups: 116 patients wereassigned to a standard dose of N-acetylcysteine (a 600-mg intravenousbolus before primary angioplasty and 600 mg orally twice dailyfor the 48 hours after angioplasty), 119 patients to a doubledose of N-acetylcysteine (a 1200-mg intravenous bolus and 1200mg orally twice daily for the 48 hours after intervention),and 119 patients to placebo.
Results The serum creatinine concentration increased 25 percentor more from baseline after primary angioplasty in 39 of thecontrol patients (33 percent), 17 of the patients receivingstandard-dose N-acetylcysteine (15 percent), and 10 patientsreceiving high-dose N-acetylcysteine (8 percent, P<0.001).Overall in-hospital mortality was higher in patients with contrast-medium–inducednephropathy than in those without such nephropathy (26 percentvs. 1 percent, P<0.001). Thirteen patients (11 percent) inthe control group died, as did five (4 percent) in the standard-doseN-acetylcysteine group and three (3 percent) in the high-doseN-acetylcysteine group (P=0.02). The rate for the compositeend point of death, acute renal failure requiring temporaryrenal-replacement therapy, or the need for mechanical ventilationwas 21 (18 percent), 8 (7 percent), and 6 (5 percent) in thethree groups, respectively (P=0.002).
Conclusions Intravenous and oral N-acetylcysteine may preventcontrast-medium–induced nephropathy with a dose-dependenteffect in patients treated with primary angioplasty and mayimprove hospital outcome. (ClinicalTrials.gov number, NCT00237614
[ClinicalTrials.gov]
.)
Contrast-medium–induced nephropathy is a recognized complicationin coronary diagnostic and interventional procedures and isassociated with prolonged hospitalization and adverse clinicaloutcomes.1,2,3,4,5 Patients with acute myocardial infarctiontreated with primary angioplasty are at higher risk of contrast-medium–inducednephropathy than are those undergoing elective interventions.6,7In patients with acute myocardial infarction, several conditionsmay contribute to the development of renal dysfunction. Impairedsystemic perfusion due to left ventricular dysfunction, a largevolume of contrast medium, and the impossibility of startingrenal prophylactic therapies before exposure to contrast mediumare among the major factors that seem to be involved. Indeed,more complicated clinical courses and significantly higher in-hospitalmortality have been reported when contrast-medium–inducednephropathy occurs after primary angioplasty, even in patientswho present with normal renal function.7 Thus, there is a pressingneed to find effective strategies for the prevention of contrast-medium–inducednephropathy in this clinical setting in order to improve theoutcome of patients treated with primary angioplasty.
Tepel et al.8 reported that the potent antioxidant N-acetylcysteinemay prevent acute renal dysfunction in patients with chronickidney disease who are undergoing procedures requiring the useof a radiocontrast medium. The ability of scavenging a varietyof oxygen-derived free radicals and the improvement of endothelium-dependentvasodilation are properties of N-acetylcysteine that may conferprotection against contrast-medium–induced renal dysfunction.9,10Several studies on the prophylactic effect of N-acetylcysteinehave been published, with contradictory results.11,12,13,14,15,16,17,18,19,20,21
However, N-acetylcysteine has not been evaluated for the preventionof contrast-medium–induced nephropathy in patients undergoingprimary angioplasty. N-acetylcysteine has several features thatmay play a favorable role in such patients. Notably, it canbe administered as an intravenous bolus or rapid infusion22,23immediately before intervention, unlike other measures suchas saline hydration24 or newer preventive treatments25,26 thatneed to be started many hours before exposure to a contrastmedium. Moreover, N-acetylcysteine has shown specific cardiaceffects. Its administration in patients with acute myocardialinfarction has been associated with less oxidative stress, atrend toward more rapid coronary reperfusion, a reduction ininfarct size, and the preservation of left ventricular function.27Finally, recent studies support the hypothesis of a dose-dependenteffect of N-acetylcysteine,22,28 suggesting that a higher doseis needed when a greater amount of contrast medium is required.To evaluate the effect of N-acetylcysteine, both at standardand high doses, on the prevention of contrast-medium–inducednephropathy, we performed a prospective, randomized clinicalstudy in patients with acute myocardial infarction who wereundergoing primary angioplasty.
Methods
Study Population
Between February 20, 2003, and May 1, 2005, we screened allconsecutive patients admitted to the coronary care unit at ourinstitution, Centro Cardiologico Monzino in Milan, for ST-segmentelevation acute myocardial infarction who underwent primaryangioplasty. Patients were asked to be in the study if theypresented within 12 hours (18 hours in cases of cardiogenicshock) after the onset of symptoms. Exclusion criteria werelong-term dialysis and known allergy to N-acetylcysteine. Thestudy was approved by the ethics committee of our institute,and written informed consent was obtained from all patients.
Study Protocol
Eligible patients were randomly assigned in a 1:1:1 ratio toreceive N-acetylcysteine at a standard dose (standard-dose group),N-acetylcysteine at a double dose (high-dose group), or placebo(control group). Computer-generated random numbers determinedrandomization. Patients in the standard-dose group receivedan intravenous bolus of 600 mg of N-acetylcysteine (Fluimucil,Zambon Group) before primary angioplasty and a 600-mg tabletorally twice daily for the 48 hours after intervention (totaldose of N-acetylcysteine, 3000 mg). Patients in the high-dosegroup received an intravenous bolus of 1200 mg of N-acetylcysteinebefore intervention and 1200 mg orally twice daily for the 48hours after intervention (total dose of N-acetylcysteine, 6000mg). After intervention, all treated patients and control patientsunderwent hydration with intravenous isotonic saline (0.9 percent)at a rate of 1 ml per kilogram of body weight per hour (or 0.5ml per kilogram per hour in cases of overt heart failure) for12 hours.
The decision to use an intraaortic balloon pump, inotropic drugs,abciximab, beta-blockers, angiotensin-converting–enzymeinhibitors, and diuretics was left to the discretion of interventionaland coronary care unit cardiologists, as directed by internationalguidelines.29 Left ventricular function was evaluated by echocardiographyin all patients within 24 hours after admission. Investigatorsinvolved in the procedures and those reading echocardiogramswere blinded to the treatment randomization.
The primary end point of the study was the occurrence of contrast-medium–inducednephropathy, defined as an increase in the serum creatinineconcentration of 25 percent or more from the baseline valuewithin the 72-hour period after primary angioplasty. Creatinineconcentration was measured at admission, every day for the nextthree days, and at hospital discharge. Creatinine clearancewas calculated by applying the Cockcroft–Gault formulato the serum creatinine value.30 The major in-hospital clinicalevents, including death, were recorded.
Primary Angioplasty
Primary angioplasty was performed according to standard clinicalpractice. Patients in the coronary care unit received a bolusof 5000 U of heparin, followed by additional intraproceduralboluses to maintain the activated clotting time of 300 secondsor more (or 200 to 250 seconds when abciximab was used). A nonionic,low-osmolality contrast agent, iohexol (350 mg of iodine permilliliter; Omnipaque, Amersham Health), was used in all patients.Bare-metal stents were implanted in all patients according tostandard techniques. Post-stenting antithrombotic treatmentconsisted of aspirin and either clopidogrel or ticlopidine atstandard dosages. N-acetylcysteine (Fluimucil, Zambon Group)was purchased by our institute.
Statistical Analysis
We calculated the sample size on the basis of a power analysisthat assumed a reduction in the average rate of the primaryend point of 50 percent in patients treated with N-acetylcysteineas compared with the control group (from 30 to 15 percent).The inclusion of 100 patients in each group allowed for a statisticalpower of 80 percent, with a type I error of 0.05. Continuousdata are reported as means ±SD or medians and interquartileranges where appropriate. Categorical data are presented asabsolute values and percentages. The clinical characteristicsof the three groups were compared with the use of the analysisof variance for continuous variables and the chi-square testor Fisher's exact test for categorical variables. The analysisof covariance was used to compare the time course of creatininevalues among the three groups. Incidence of complications wascompared among the three groups by the Wald chi-square testwith two degrees of freedom and by the Mantel–Haenszelchi-square test for trend. A multivariable logistic-regressionmodel, which included all the potential confounding factors(i.e., age, sex, baseline serum creatinine concentration, volumeof contrast medium, and left ventricular ejection fraction),was applied. A P value of less than 0.05 was considered to indicatestatistical significance. All calculations were computed withthe aid of SAS software (version 8.02).
Results
A total of 354 patients (mean age, 62±12 years; 286 men)were initially enrolled. Of these patients, 119 were randomlyassigned to receive placebo, 116 to receive a standard doseof N-acetylcysteine, and 119 to receive a high dose of N-acetylcysteine.Two patients were excluded after randomization, one from thestandard-dose group because of death during angioplasty andone from the high-dose group because of emergency coronary bypasssurgery due to critical left main stenosis.
Table 1 shows demographic, clinical, and angiographic characteristicsof the three groups. There were no significant differences inbaseline renal function or the size of myocardial infarction(estimated by creatine kinase MB peak value and left ventricularejection fraction). At hospital admission, the baseline creatinineconcentration was elevated (1.5 mg per deciliter [133 µmolper liter]) in 20 patients (5.7 percent). However, reduced renalfunction (creatinine clearance rate, 60 ml per minute) was presentin 35 patients in the control group (29 percent), 33 in thestandard-dose group (29 percent), and 26 in the high-dose group(22 percent) (P=0.36). The volume of contrast medium receivedwas also similar among groups, as were other risk factors forcontrast-medium–induced nephropathy (e.g., age >75years, anterior infarction, intraaortic counterpulsation, morethan six hours from the onset of symptoms to reperfusion, anda volume of contrast medium of 300 ml).7
Table 1. Baseline Characteristics of the Patients.
Overall, contrast-medium–induced nephropathy occurredin 66 (19 percent) of the 352 patients. Its incidence was independentlyrelated to the presence of reduced renal function (creatinineclearance, 60 ml per minute) at baseline and depressed cardiacfunction (left ventricular ejection fraction, 40 percent) (Figure 1)at baseline.
Figure 1. Incidence of Contrast-Medium–Induced Nephropathy in the Study Population Stratified According to Creatinine Clearance and Left Ventricular Ejection Fraction (LVEF).
The P value was assessed by the Mantel–Haenszel chi-square test for trend.
Table 2 shows in-hospital complications and deaths in the threegroups. One patient in the standard-dose N-acetylcysteine grouphad a transient systemic rash, probably a side effect of N-acetylcysteine.The rate of contrast-medium–induced nephropathy was 33percent in the control group, 15 percent in the standard-doseN-acetylcysteine group, and 8 percent in the high-dose N-acetylcysteinegroup (P<0.001). The frequency of contrast-medium–inducednephropathy was 18 percent, 6 percent, and 3 percent, respectively,when an absolute rise in creatinine (0.5 mg per deciliter [44µmol per liter]) was used as the case definition (P<0.001).The multivariate analysis, adjusting for age, sex, baselineserum creatinine, volume of contrast medium, and left ventricularfunction, resulted in an odds ratio of contrast-medium–inducednephropathy in the control group as compared with the standard-dosegroup of 2.60 (95 percent confidence interval, 1.30 to 5.18;P=0.007) and in the control group as compared with the high-dosegroup of 5.78 (95 percent confidence interval, 2.56 to 13.16;P<0.001).
Overall, in-hospital mortality was 5.9 percent and, as previouslyreported,7 was significantly higher in patients with contrast-medium–inducednephropathy than in those without (26 percent vs. 1.4 percent,P<0.001). In-hospital mortality was significantly reducedby N-acetylcysteine. The odds ratio of in-hospital death inthe control group, as compared with the standard-dose and high-dosegroups, was 1.85 (95 percent confidence interval, 0.54 to 6.37;P=0.32) and 5.43 (95 percent confidence interval, 1.24 to 23.81;P=0.03), respectively.
When the combined end point of death, acute renal failure requiringtemporary renal replacement therapy, or the need for mechanicalventilation during the acute phase of myocardial infarctionwas considered, the rate was 18 percent in the control group,7 percent in the standard-dose group, and 5 percent in the high-dosegroup (P=0.002). Multivariate analysis resulted in an odds ratioof the composite end point in the control group, as comparedwith the standard-dose and high-dose N-acetylcysteine groups,of 2.39 (95 percent confidence interval, 0.89 to 6.45; P=0.09)and 4.93 (95 percent confidence interval, 1.61 to 15.15; P=0.006),respectively.
A greater increase in the creatinine concentration was observedin the control patients than in patients treated with N-acetylcysteine(Figure 2). Notably, N-acetylcysteine seemed to help preventcontrast-medium–induced nephropathy in patients with normalrenal function and in those with reduced renal function, aswell as in those with mildly or severely reduced left ventricularfunction (Figure 3). No significant interactions were foundbetween treatment and creatinine clearance (P=0.25) or leftventricular ejection fraction (P=0.71).
Figure 2. Median and Interquartile Range of Serum Creatinine Concentration before Primary Angioplasty (Baseline), at Days 1, 2, and 3, and at Discharge.
P for trend=0.004. The filled squares, triangles, and circles represent medians, and the I bars represent the interquartile range for each data point.
Figure 3. Incidence of Contrast-Medium–Induced Nephropathy in the Three Study Groups Stratified According to the Creatinine Clearance Rate and Left Ventricular Ejection Fraction (LVEF).
Panel A shows normal and reduced creatinine clearance rates (>60 ml per minute and 60 ml per minute, respectively), and Panel B LVEF of more than 40 percent and 40 percent or less. P values refer to comparisons among the placebo group, the group receiving a standard dose of N-acetylcysteine, and the group receiving a double dose of N-acetylcysteine (calculated with the use of chi-square for trend). No significant interactions were found between groups and creatinine clearance (P=0.25) or between groups and LVEF (P=0.71).
Discussion
The major finding of this study is that, among patients withacute myocardial infarction who are undergoing primary angioplasty,prophylactic treatment with an intravenous bolus of N-acetylcysteinefollowed by oral treatment for 48 hours and saline hydrationfor 12 hours seems to reduce the rate of contrast-medium–inducednephropathy as compared with a post-procedure 12-hour protocolof saline hydration alone. Moreover, in terms of the preventionof contrast-medium–induced nephropathy, high doses ofN-acetylcysteine seem more beneficial than standard doses, suggestinga dose-dependent effect.
The negative effect of contrast-medium–induced nephropathyon the clinical outcome of patients undergoing diagnostic andinterventional procedures is well known.1,2,3,4,5 In-hospitaland long-term morbidity and mortality are particularly affectedby contrast-medium–induced nephropathy in patients withpreexisting renal failure and are noticeably increased in patientsin whom acute renal failure requiring hemodialysis develops.3,31Patients undergoing primary angioplasty have been shown to beat high risk for contrast-medium–induced nephropathy.In a previous study, we reported a 19 percent incidence of thisserious complication in such patients and a close associationwith increased in-hospital morbidity and mortality.7
The risk of contrast-medium–induced nephropathy afterprimary angioplasty extends not only to patients with preexistingrenal failure but also to those with normal baseline function.Therefore, in an era in which primary angioplasty is the preferredreperfusion treatment, prophylactic interventions against contrast-medium–inducednephropathy are warranted. The objective is to further reducemorbidity and mortality in this clinical setting.
Recent attention has been focused on N-acetylcysteine as a drugto attenuate contrast-medium–induced toxicity, owing toits ability to scavenge oxygen free radicals, thereby preventingdirect oxidative tissue damage, and to its ability to counteractdye-induced renal vasoconstriction.9,10,32 Tepel et al.8 reportedthat oral N-acetylcysteine (600 mg twice daily) plus hydration,before and after exposure to contrast medium, offers significantprotection against contrast-medium–induced nephropathy,as compared with hydration alone, in patients with chronic renalfailure receiving a low dose (75 ml) of intravenously administeredcontrast agent. These results have been confirmed by some, butnot all, subsequent trials, so no conclusive evidence on theeffectiveness of N-acetylcysteine has been provided.16,21
Two recent studies support the hypothesis that a greater doseof N-acetylcysteine may be needed when a large volume of contrastmedium is used.22,28 In the Rapid Protocol for the Preventionof Contrast-Induced Renal Dysfunction (RAPPID) trial,22 patientswith mild-to-moderate chronic renal failure undergoing electivecoronary interventions received intravenous N-acetylcysteineat a dose of 150 mg per kilogram before exposure to the contrastmedium (volume of contrast medium, >200 ml) and a dose of50 mg per kilogram over the following four-hour period. In apatient weighing 70 kg, this corresponds to a cumulative doseof N-acetylcysteine of 14,000 mg, which is significantly higherthan that used in the study by Tepel et al.8 (2400 mg). TheRAPPID trial showed a significantly lower incidence of contrast-medium–inducednephropathy in treated patients as compared with controls (5percent vs. 21 percent, P=0.04).
In another study involving patients with chronic renal failure,28the results of standard (600-mg) or high (1200-mg) doses ofN-acetylcysteine orally twice daily were compared before andafter administration of the contrast medium. The rate of contrast-medium–inducednephropathy was lower in patients receiving the high dose (4percent vs. 11 percent, P=0.03). The benefit of high-dose N-acetylcysteinewas greater in patients receiving a larger volume of contrastmedium (i.e., 140 ml). In agreement with these observations,our findings support a dose-dependent protective effect of N-acetylcysteine.In our study, the incidence of contrast-medium–inducednephropathy was significantly lower in patients receiving acumulative dose of 6000 mg than in those treated with a cumulativedose of 3000 mg. The rate of contrast-medium–induced nephropathywas independently related to the presence of both renal-functionimpairment at baseline and more depressed left ventricular function.This suggests that renal and cardiac impairment may substantiallyamplify the risk of contrast-medium–induced nephropathyin such patients and that the observed acute worsening in renalfunction may be the result of the joint effects of the toxicityof the contrast medium and acute ischemic injury. The preventiveand dose-dependent effect of N-acetylcysteine was observed inpatients with normal and in those with impaired renal functionat baseline, as well as in those with mildly and those withseverely impaired ventricular function. This suggests that N-acetylcysteinenot only prevents direct contrast-medium–induced nephrotoxicitybut also exerts a broader kidney-protective effect.
Given the strong association between contrast-medium–inducednephropathy and in-hospital morbidity and mortality in patientswith acute myocardial infarction treated with primary angioplasty,7a critical question is whether the prevention of contrast-medium–inducednephropathy has any effect on the clinical outcome. A majorlimitation of previous studies that used N-acetylcysteine forthe prevention of contrast-medium–induced nephropathyis that no conclusive data on morbidity and mortality were reported.
Our study was primarily designed to evaluate the incidence ofcontrast-medium–induced nephropathy and, hence, was notaimed or powered to assess differences in morbidity and mortality.Despite this limitation, it is noteworthy that in parallel witha reduced rate of contrast-medium–induced nephropathy,the rate of in-hospital death was significantly lower amongpatients treated with N-acetylcysteine. The mortality rate inour control group was in the upper range of mortality ratesreported in registries that reflect real-world clinical practice.33,34Thus, it is possible that some of the observed difference inmortality between the control group and the groups treated withN-acetylcysteine is due to statistical chance. Alternatively,the difference may reflect a beneficial effect of N-acetylcysteineon renal function that in turn resulted in reduced mortality.
Similarly, the beneficial effect of N-acetylcysteine on thecombined end point of death and two major clinical complications— acute renal failure requiring temporary renal-replacementtherapy and acute pulmonary edema requiring mechanical ventilation— may have been related to acute impairment of kidneyfunction. It would be premature to draw inferences about theefficacy of N-acetylcysteine on the basis of these clinicallymeaningful end points. Although our findings are promising,further data are needed before any conclusions can be made.Future studies should also investigate whether the extrarenaleffects of N-acetylcysteine play some beneficial role. Indeed,in both clinical and experimental studies of acute myocardialinfarction, intravenous infusion of N-acetylcysteine has beenassociated with decreased infarct size and improvement in leftventricular function, possibly because of the antioxidant propertiesof this drug and its scavenging of free radicals.27,35,36 Thesecardiac effects may be enhanced in patients treated with thrombolysisor percutaneous coronary interventions — a clinical settingin which oxidative stress and reperfusion injury have been shownto occur.37,38 These deleterious phenomena may be more pronouncedafter primary angioplasty, owing to increased rates of coronarypatency with more rapid and complete flow restoration.39 Moreover,N-acetylcysteine also inhibits platelet aggregation.40 Unfortunately,we could not assess how much of the difference in outcome betweenpatients treated with N-acetylcysteine and control patientswas due to the expression of a specific renal protective effectof this drug or indirectly to its cardioprotective properties,resulting in greater recovery of left ventricular function and,therefore, amelioration of systemic and renal hemodynamics.
In conclusion, we found that N-acetylcysteine reduced the severityof contrast-medium–induced nephropathy in patients withacute myocardial infarction treated with primary angioplasty.The effect appears to be dose-dependent and is accompanied bya significantly improved in-hospital outcome. The mechanismsunderlying the improvement in the in-hospital clinical outcomehave not been completely elucidated, and studies of potentialextrarenal effects of N-acetylcysteine are warranted.
Supported by Centro Cardiologico Monzino and by a grant (CCS16-RC2003)from the Italian Ministry of Health.
No potential conflict of interest relevant to this article wasreported.
Source Information
From the Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Institute of Cardiology, University of Milan, Milan.
Address reprint requests to Dr. Marenzi at Centro Cardiologico Monzino, Via Parea 4, 20138 Milan, Italy, or at giancarlo.marenzi{at}ccfm.it.
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N-Acetylcysteine and Contrast-Induced Nephropathy
Aguiar-Souto P., Valero-González S., Domínguez J. F. O., Wolak A., Cafri C., Zahger D., Balderramo D. C., Ritz E., Marenzi G., Lauri G., Bartorelli A. L.
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355:1497-1500, Oct 5, 2006.
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1.5 mg per deciliter [
60 ml per minute) was present in 35 patients in the control group (29 percent), 33 in the standard-dose group (29 percent), and 26 in the high-dose group (22 percent) (P=0.36). The volume of contrast medium received was also similar among groups, as were other risk factors for contrast-medium–induced nephropathy (e.g., age >75 years, anterior infarction, intraaortic counterpulsation, more than six hours from the onset of symptoms to reperfusion, and a volume of contrast medium of 
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