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Journal of the American College of Cardiology Vol. 44, No. 9, 2004© 2004 by the American College of Cardiology Foundation ISSN 0735-1097/04/$30.00P

Percutaneous Intervention and Renal Dysfunction

ontrast-Induced Nephropathyn Patients Undergoing Primaryngioplasty for Acute Myocardial Infarction

iancarlo Marenzi, MD, Gianfranco Lauri, MD, Emilio Assanelli, MD, Jeness Campodonico, MD,onica De Metrio, MD, Ivana Marana, MD, Marco Grazi, MD, Fabrizio Veglia, PHD,ntonio L. Bartorelli, MD, FACCilan, Italy

OBJECTIVES The aim of this research was to assess the incidence, clinical predictors, and outcome ofcontrast-induced nephropathy (CIN) after primary percutaneous coronary intervention (PCI)for acute myocardial infarction (AMI).

BACKGROUND Contrast-induced nephropathy is associated with significant morbidity and mortality afterPCI. Patients undergoing primary PCI may be at higher risk of CIN because of hemody-namic instability and unfeasibility of adequate prophylaxis.

METHODS In 208 consecutive AMI patients undergoing primary PCI, we measured serum creatinineconcentration (Cr) at baseline and each day for the following three days. Contrast-inducednephropathy was defined as a rise in Cr �0.5 mg/dl.

RESULTS Overall, CIN occurred in 40 (19%) patients. Of the 160 patients with baseline Cr clearance�60 ml/min, only 21 (13%) developed CIN, whereas it occurred in 19 (40%) of those withCr clearance �60 ml/min (p � 0.0001). In multivariate analysis, age �75 years (odds ratio[OR] 5.28, 95% confidence interval [CI] 1.98 to 14.05; p � 0.0009), anterior infarction (OR2.17, 95% CI 0.88 to 5.34; p � 0.09), time-to-reperfusion �6 h (OR 2.51, 95% CI 1.01 to6.16; p � 0.04), contrast agent volume �300 ml (OR 2.80, 95% CI 1.17 to 6.68; p � 0.02)and use of intraaortic balloon (OR 15.51, 95% CI 4.65 to 51.64; p � 0.0001) wereindependent correlates of CIN. Patients developing CIN had longer hospital stay (13 � 7days vs. 8 � 3 days; p � 0.001), more complicated clinical course, and significantly highermortality rate (31% vs. 0.6%; p � 0.001).

CONCLUSIONS Contrast-induced nephropathy frequently complicates primary PCI, even in patients withnormal renal function. It is associated with higher in-hospital complication rate and mortality.Thus, preventive strategies are needed, particularly in high-risk patients. (J Am Coll

ublished by Elsevier Inc. doi:10.1016/j.jacc.2004.07.043

Cardiol 2004;44:1780–5) © 2004 by the American College of Cardiology Foundation

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ontrast-induced nephropathy (CIN) is a possible compli-ation of coronary diagnostic and interventional procedures.ts development has been associated with increased in-ospital and long-term morbidity and mortality, prolongedospitalization, and long-term renal impairment (1–7).everal risk factors for CIN have been identified. Chronicenal insufficiency, diabetes mellitus, congestive heart fail-re, intravascular volume depletion, and the use of a largemount of contrast agent are considered important predis-osing factors (5,7,8).Increasing evidence exists that primary percutaneous

oronary intervention (PCI) obtains rapid restoration oforonary artery patency and increases threatened myocar-ium salvage, thus preserving ventricular function and

mproving survival of patients with acute myocardial infarc-ion (AMI) (9,10). However, patients treated with primaryCI may represent a population at higher risk for CIN than

hose undergoing elective PCI. Several conditions may

From the Centro Cardiologico Monzino, I.R.C.C.S., Institute of Cardiology of theniversity of Milan, Milan, Italy.

iManuscript received February 20, 2004; revised manuscript received July 22, 2004,

ccepted July 28, 2004.

ontribute to renal injury in this setting. Among them,ypotension or even shock, a large volume of contrastedia, and the impossibility of starting a renal prophylactic

herapy are the factors most likely involved. The impact ofhese factors on renal function, and the clinical relevance ofIN in the setting of primary PCI remain unknown, but are

hought to be considerable. Only recently have studiesemonstrated that renal insufficiency and AMI represent aigh-risk combination (11). Moreover, other clinical obser-ations have shown that renal dysfunction is an independentisk factor for death in AMI patients (12–14).

The purpose of this prospective study was to determinehe incidence, the clinical predictors, and the clinical con-equences of CIN development in an unselected populationf consecutive patients undergoing primary PCI for AMI.

ETHODS

tudy population. Between January 1, 2001, and June 30,003, we enrolled all consecutive patients admitted to ouroronary care unit (CCU) for ST-segment elevation AMIho were treated with primary PCI. According to our

nstitute protocol, patients were included if they presented

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1781JACC Vol. 44, No. 9, 2004 Marenzi et al.November 2, 2004:1780–5 Contrast Nephropathy After Primary PCI

ithin 12 h (18 h for AMI complicated by cardiogenichock) from the onset of symptoms (characteristic chestain lasting for at least 30 min, not responsive to nitrates,ith electrocardiographic ST-segment elevation of at least.2 mV in two or more contiguous leads, or left bundle-ranch block). Patients were excluded if the coronarynatomy was not suitable for PCI or if emergency bypassrafting was required. Patients in chronic peritoneal oremodialytic treatment were also excluded. The study waspproved by the ethics committee of our institution, andnformed consent was obtained from all patients.tudy protocol. After contrast exposure, physiologic

0.9%) saline was given intravenously at a rate of 1 ml/kg/hor 12 h. In patients with left ventricular dysfunctionejection fraction �40%) or overt heart failure, the hydra-ion rate was reduced to 0.5 ml/kg/h. The use of beta-drenergic blocking agents, angiotensin-converting enzymenhibitors, platelet glycoprotein IIb/IIIa receptor inhibitorsabciximab), diuretics, or the indication to intraaortic bal-oon pump or inotropic drugs support, was left to theiscretion of the interventional and CCU cardiologists,ccording to our institute’s clinical protocols and interna-ional experience guidelines (15). An echocardiographicvaluation was performed in all patients within 12 h fromospital admission. Serum creatinine concentration (Cr)as measured at the time of admission (just before primaryCI), every day for the following three days, and atischarge from the CCU. Creatinine clearance was calcu-

ated by applying the Cockcroft-Gault formula to the Cr16). During hospitalization the following adverse clinicalvents were considered: major bleeding requiring �2 U oflood, acute pulmonary edema, acute renal failure requiringmergency renal replacement therapy (hemofiltration oremodialysis), cardiogenic shock, tachyarrhythmias andradyarrhythmias, and death.rimary PCI. Primary PCI was performed by a 24-hn-call interventional team, according to standard clinicalractice, using the femoral approach and 7-F guidingatheters. Type of contrast agent and contrast dose, angio-lasty technique, and supportive pharmacologic therapiesere left to the discretion of the interventional cardiologist.atients received a bolus of 5,000 U heparin in the CCU,

ollowed by an additional bolus during the procedure, ifeemed necessary.efinitions. Contrast-induced nephropathy was defined as

Abbreviations and AcronymsAMI � acute myocardial infarctionCCU � coronary care unitCI � confidence intervalCIN � contrast-induced nephropathyCr � serum creatinine concentrationOR � odds ratioPCI � percutaneous coronary intervention

n absolute increase in Cr �0.5 mg/dl after PCI (17). a

ccording to our clinical protocol, emergency renal-eplacement therapy (hemofiltration or hemodialysis) waserformed if there was oligoanuria for more than 48 h,espite the administration of more than 1 g of intravenousurosemide per 24 h. Emergency renal-replacement therapyas performed earlier in the event of concomitant overteart failure (18). Blood transfusion was initiated in case ofemoglobin reduction below 8.0 g/l. Time-to-reperfusionas measured as the time from symptom onset to coronary

eperfusion obtained with balloon inflation. Cardiogenichock was defined as prolonged hypotension (systolic bloodressure �85 mm Hg) with evidence of decreased organerfusion caused by severe left ventricular dysfunction, rightentricular infarction, or mechanical complications of in-arction and not due to hypovolemia, bradyarrhythmias, orachyarrhythmias.tatistical analysis. Continuous data are reported as theean value � SD, unless otherwise specified. Categorical

ata are presented as absolute values and percentages.omparison of continuous variables was performed byeans of Student t test. Chi-square and Fisher exact testsere used for comparison of categorical variables as appro-riate. The trend of CIN incidence and in-hospital mortal-ty according to ordinal variables was assessed by the

antel-Haenszel chi-square for trend. A multivariableogistic regression model was applied including all theotential confounding variables (i.e., age �75 years, anteriorMI, time-to-reperfusion �6 h, contrast agent volume300 ml, and use of intraaortic balloon pump). A p value0.05 was considered statistically significant. Analyses were

onducted using SAS statistical software (Version 8.02,AS Institute Inc., Cary, North Carolina).

ESULTS

ncidence of CIN and clinical characteristics. Of a totalf 218 AMI patients, 10 were excluded (7 because there waso indication for PCI, 2 who were treated with coronaryypass surgery because of coronary anatomy not suitable forCI, and 1 because of chronic dialysis). Hence, a total of08 patients (165 men, 43 women; mean age 62 � 11 years)ere included in this study. Of them, 40 (19%) developedIN. The incidence of this complication was 17% whenatients with baseline increased Cr (�1.5 mg/dl) werexcluded. Table 1 shows the baseline clinical and proceduralharacteristics of patients who developed CIN and of thoseho did not present this complication after primary PCI.atients developing CIN were older and more frequentlyad anterior AMI, higher baseline Cr value, longer time-o-reperfusion, higher enzymatic peak, and lower left ven-ricular ejection fraction. In addition, they received a higherolume of the contrast agent during PCI than patientsithout CIN. Of note, contrast volume was higher in

nterior AMI (335 � 158 ml) compared with inferior AMI270 � 128 ml; p � 0.001). In 11 (5%) of the 208 patients,

bnormal Cr (�1.5 mg/dl) was present at hospital admis-

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1782 Marenzi et al. JACC Vol. 44, No. 9, 2004Contrast Nephropathy After Primary PCI November 2, 2004:1780–5

ion. Seven of these patients had no history of pre-existingenal insufficiency; this suggests that the increased Cr valueas likely due to changes in renal hemodynamics associatedith impaired systemic perfusion during the acute cardiac

vent. When creatinine clearance was estimated (16), 4823%) of the 208 patients had a moderately impaired renalunction (�60 ml/min). Of them, 19 (40%) developed CIN.n contrast, of the 160 patients with a baseline Cr clearancealue �60 ml/min, only 21 (13%) developed CIN afterrimary PCI (p � 0.0001).Figure 1 shows the Cr values in the two groups during theCU stay. When the maximal Cr increase versus baselineas considered, regardless of the time point of occurrence,mean value of 106 � 93% was found in patients with CINnd of 8 � 13% in patients without CIN.he relation of CIN with in-hospital outcome. Patientsith CIN experienced a more complicated in-hospital

linical course (Table 2). All of the major adverse clinicalvents occurred more frequently in this group. Furthermore,he average length of hospital stay in patients with CIN waspproximately 1.5 � longer than that in patients withoutIN (13 � 7 days vs. 8 � 3 days; p � 0.001). Nine patients

one with CIN and eight without CIN) underwent electiveoronary bypass after successful primary PCI to completeoronary revascularization; the length of their in-hospitaleriod was not considered.

Table 1. Baseline Clinical and Procedural Cha

C(n

Age (yrs) 67Age �75 yrs 14 (3Men 36 (9Smokers 17 (4Diabetes mellitus 3 (7Hypertension 21 (5Dyslipidemia 7 (1Previous myocardial infarction 10 (2Previous CABG 3 (7Anterior infarction 29 (7Time-to-reperfusion (h) 5.6Mean LVEF (%) 41LVEF �40% 20 (5Serum creatinine (mg/dl)† 1.2 (1Serum creatinine �1.5 mg/dl 7 (1Creatinine clearance (ml/min) 61Highest total creatine kinase (IU/l) 3,445Culprit lesion

Left anterior descending 30 (7Left circumflex 2 (5Right coronary artery 8 (2Bypass graft 0 (0

Coronary stenting 39 (9Abciximab 19 (4Contrast volume (ml) 378Contrast volume �300 ml 26 (6

*By Fisher exact test; †median and interquartile ranges; ‡byCABG � coronary artery bypass graft surgery; CIN �

fraction; PCI � percutaneous coronary intervention.

The overall in-hospital mortality in the entire populationbc

as 6.2% (n � 13). However, the mortality rate wasignificantly higher in patients developing CIN. Indeed, 1231%) patients died in the CIN group (5 for cardiogenichock, 3 for multiorgan failure, 2 for refractory heart failure,for sudden death, and 1 for ischemic stroke), whereas onlydeath (0.6%; p � 0.0001) occurred in the group withoutIN, due to left ventricular free-wall rupture with cardiac

amponade.

ristics of the Study Patients

No CIN(n � 168) p Value

61 � 11 0.00217 (10%) �0.0001

129 (77%) 0.0693 (55%) 0.1420 (12%) 0.58*68 (42%) 0.1754 (32%) 0.0722 (13%) 0.064 (2%) 0.0011*

77 (46%) 0.00153.8 � 2.4 �0.000151 � 9 �0.0001

18 (11%) �0.00016) 1.0 (0.9–1.15) �0.0001‡

4 (2%) �0.000180 � 24 �0.0001

48 1,897 � 1,786 �0.00010.003*

72 (43%)29 (17%)64 (38%)3 (2%)

165 (98%) 0.7686 (51%) 0.67

0 286 � 125 0.00865 (39%) 0.003

rametric Wilcoxon rank test.st-induced nephropathy; LVEF � left ventricular ejection

igure 1. Median and interquartile ranges of serum creatinine concentra-ion in patients developing (squares) and in those not developing (circles)ontrast-induced nephropathy after primary angioplasty. Data are shown at

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1783JACC Vol. 44, No. 9, 2004 Marenzi et al.November 2, 2004:1780–5 Contrast Nephropathy After Primary PCI

ndependent correlates of CIN. In multivariate analysis,he following variables remained significant independentorrelates of CIN: age �75 years (odds ratio [OR] 5.28,5% confidence interval [CI] 1.98 to 14.05; p � 0.0009),nterior AMI (OR 2.17, 95% CI 0.88 to 5.34; p � 0.09),ime-to-reperfusion �6 h (OR 2.51, 95% CI 1.01 to 6.16;� 0.04), contrast agent volume �300 ml (OR 2.80, 95%I 1.17 to 6.68; p � 0.02), and use of intra-aortic balloonump (OR 15.51, 95% CI 4.65 to 51.64; p � 0.0001).Using these variables as risk indicators for CIN, we

eveloped a risk scoring system. A value of 1 was assignedhen a factor was present, and 0 when it was absent. For

ach patient, the score was calculated as the sum of theumber of independent variables (range 0 to 5) recorded inhe initial hours of hospital stay (at admission and at the endf primary PCI). The incidence of CIN (Fig. 2), as well ashe in-hospital mortality rate (Fig. 3), revealed a significantradation as the risk score increased in the study population.

Table 2. In-Hospital Clinical Complications

CPR, VT, or VFHigh-rate atrial fibrillationHigh-degree conduction disturbances requiring

permanent pacemakerAcute pulmonary edemaRespiratory failure requiring mechanical

ventilationCardiogenic shock requiring intra-aortic

balloon counterpulsationMajor bleeding requiring blood transfusionAcute renal failure requiring renal replacement

therapyPatients with two or more clinical

complications

*By Fisher exact test.CIN � contrast-induced nephropathy; CPR � cardio

ventricular tachycardia.

igure 2. Incidence of contrast-induced nephropathy (CIN) in studyatients according to the risk score. p � 0.0001.

Fr

ISCUSSION

his study demonstrates that CIN is a frequent complica-ion after primary PCI in AMI, even in patients withormal baseline renal function, and is associated with

ncreased in-hospital morbidity, mortality, and prolongedospitalization.Growing evidence indicates that primary PCI is the most

ffective treatment of AMI, and many studies have demon-trated both that ventricular function is preserved and thaturvival improved when AMI patients with acute ST-egment elevation undergo this therapeutic approach (9,10).he aim of reperfusion therapy in AMI is to reduceortality and morbidity, and this goal is best achieved when

atency of the infarct-related coronary artery is obtained asarly as possible. In our study population, the in-hospitalortality rate was 6.2%, a value comparable with those

eported in larger clinical trials (10). In this prospectivenalysis, we have focused our evaluation on the developmentf CIN during AMI as a possible complication of primary

CIN(n � 40)

No CIN(n � 168) p Value

3 (8%) 7 (4%) 0.41*6 (15%) 6 (4%) 0.01*2 (5%) 0 (0%) 0.04*

5 (13%) 3 (2%) 0.008*8 (20%) 2 (1%) �0.0001*

13 (33%) 7 (4%) �0.0001*

4 (10%) 5 (3%) 0.07*6 (15%) 0 (0%) �0.0001*

14 (35%) 4 (3%) �0.0001*

nary resuscitation; VF � ventricular fibrillation; VT �

igure 3. Incidence of in-hospital death in study patients according to theisk score. p � 0.0001.

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1784 Marenzi et al. JACC Vol. 44, No. 9, 2004Contrast Nephropathy After Primary PCI November 2, 2004:1780–5

CI. Acute renal deterioration occurred in 19% of allatients undergoing primary PCI, and was a strong predic-or of in-hospital morbidity and mortality. Patients withIN had a more prolonged and complicated clinical course

nd a strikingly higher in-hospital mortality (31%). It isoteworthy that the in-hospital mortality of patients whoid not develop CIN after primary PCI was only 0.6%.Most of our patients had a normal renal function before

hey experienced the acute coronary event. Nevertheless, then-hospital mortality rate of those who developed CINpproached, or was even greater than, that observed inhronic renal failure patients undergoing elective PCI6,19), and in patients with chronic renal failure admittedith AMI to a CCU (11–13,20). On the other hand,atients with normal renal function undergoing electiveCI have a significantly lower incidence of CIN (1.2% to.6%) than our study population (17%) who had normal Crt hospital presentation (1,8). Patients with baseline chronicenal failure were only a minority of our population. Thus,o final conclusion can be drawn from their outcome. Therere few doubts that poorer clinical outcome can be expectedn such patients. Recent results from a clinical study andata from the New York State angioplasty registry showedhat baseline Cr and end-stage renal disease are independentisk factors for death after primary PCI (14,21). Whenreatinine clearance was calculated in our population, areater number of patients showed reduced baseline renalunction (creatinine clearance �60 ml/min). The incidencef CIN was higher in these patients as compared with thoseith preserved renal function (40% vs. 13%).An increased CIN risk has been reported in patients with

hronic renal failure subjected to an early invasive approachor acute coronary syndromes without ST-segment eleva-ion (22,23). In such a population, prophylaxis for CIN isossible, and hemodynamic stability is usually obtainedefore PCI. In contrast, there is no possibility to performdequate hydration in AMI patients undergoing primaryCI.Our data strengthen the crucial link between cardiac and

enal dysfunction, and extend the observation of the nega-ive impact on survival deriving from the association be-ween cardiac and renal disease to patients with AMIndergoing primary PCI. Renal function is a major deter-inant of cardiovascular outcome in a variety of settings,

ncluding hypertension (24), chronic heart failure (25,26),cute coronary syndromes (12,23,27,28), AMI (11–14,29),lective PCI (1–7,19), surgical coronary revascularization30,31), and, more generally, in patients referred to a CCUor any reason (32). This study demonstrates that patientsndergoing primary PCI for AMI represent a population atigher risk for CIN, despite the fact that most of them haveo history or evidence of pre-existing renal insufficiency.One strength of this study is that we identified several

ndependent variables for CIN development after primaryCI. In particular, old age (�75 years), anterior AMI, large

�300 ml) contrast volume exposure (33), use of intra- a

ortic balloon pump, and a longer (�6 h) time-to-eperfusion were associated with an increased risk of CINccurrence and a higher mortality rate. Interestingly, theontrast volume needed to perform PCI was higher innterior compared with inferior AMI. Differences betweeneft and right coronary anatomy and procedural aspects mayxplain this finding.

Innovative preventive strategies aimed at protecting theidneys from contrast toxicity and ischemic burden duringhe acute phase of infarction need to be developed andested, even in patients with normal renal function. Prophy-actic measures will be particularly relevant in patients withn elevated CIN risk score. Although this simple risk scorehould be tested in an independent and not in a “learningopulation,” it may have wide applicability, and can be easilyalculated in the initial hours of hospital presentation inrder to predict the risk of CIN and the associated higherdverse event rate in AMI patients undergoing primaryCI. Moreover, it may help to better identify those patientsost likely to benefit from a renal-protective intervention.

n this regard, saline hydration infusion, performed soonfter PCI and prolonged for 12 h, had no major impact onIN prevention in our patients. Newer pharmacologic (34)r nonpharmacologic (35,36) strategies that showed a ben-fit in terms of CIN prevention among patients undergoinglective PCI should be evaluated also in high-risk AMIatients treated with primary PCI.tudy limitations. Our study has some limitations. First,ur study included a small population, admitted to a singleenter. Our findings should be confirmed and the applica-ion of the risk score validated in a large multicenter trial.econd, the definition of CIN is based on the absolute orelative increase in Cr level, compared with baseline value,fter a patient has been exposed to a contrast agent, whenlternative explanations for renal impairment have beenxcluded (37). Although all our patients effectively under-ent contrast media exposure, and 19% developed acute

enal failure within 48 h to 72 h after it, we cannot excludehe possibility that other factors, such as hemodynamicnstability, might have contributed, at least in part, to renalmpairment, and influenced the clinical outcome of ouratients. Indeed, in addition to contrast agent volume, otheractors reflecting cardiocirculatory impairment, such as an-erior AMI, long time-to-reperfusion, and need for in-raaortic balloon pump, were independently related to theevelopment of renal dysfunction. This suggests that kidneyypoperfusion, resulting in ischemic renal injury, might play

major role. However, despite the fact that no firmonclusions can be drawn at this stage, our data suggest thathe potential exists for further reduction of mortality afterrimary PCI. This could probably be obtained on one handhrough newer therapies, aimed at preventing acute renalysfunction, and on the other by shortening time-to-eperfusion and minimizing contrast volume.

onclusions. In the era of primary PCI for AMI, CIN is

frequent complication, even in patients with normal renal

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1785JACC Vol. 44, No. 9, 2004 Marenzi et al.November 2, 2004:1780–5 Contrast Nephropathy After Primary PCI

unction, and is associated with a more complicated in-ospital course and very high mortality rate. Thus, newerreventive strategies of renal protection during primary PCIre warranted, particularly in high-risk patients.

eprint requests and correspondence: Dr. Giancarlo Marenzi,entro Cardiologico Monzino, Via Parea 4, 20138 Milan, Italy.-mail address: giancarlo.marenzi@ccfm.it.

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