In-Hospital and 1-Year Outcomes Among Percutaneous Coronary Intervention Patients With Chronic...

doi:10.1016/j.jcin.2008.06.012 2009;2;37-45 J. Am. Coll. Cardiol. Intv.

Saucedo, on behalf of the EVENT Investigators Donald E. Cutlip, David J. Moliterno, Deborah Nassif, John J. Lopez, Jorge F.

Faisal Latif, Neal S. Kleiman, David J. Cohen, Michael J. Pencina, Chen-Hsing Yen, Events) Registry

Report From the EVENT (Evaluation of Drug Eluting Stents and IschemicPatients With Chronic Kidney Disease in the Era of Drug-Eluting Stents: A

In-Hospital and 1-Year Outcomes Among Percutaneous Coronary Intervention

This information is current as of May 10, 2011

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n-Hospital and 1-Year Outcomes Among Percutaneousoronary Intervention Patients With Chronic Kidneyisease in the Era of Drug-Eluting StentsReport From the EVENT (Evaluation of Drug Eluting Stents and

schemic Events) Registry

aisal Latif, MD,* Neal S. Kleiman, MD,† David J. Cohen, MD, MSC,‡ichael J. Pencina, PHD,§ Chen-Hsing Yen, MS,§ Donald E. Cutlip, MD,§avid J. Moliterno, MD,� Deborah Nassif, PHD,§ John J. Lopez, MD,¶ Jorge F. Saucedo, MD,*

n behalf of the EVENT Investigatorsklahoma City, Oklahoma; Houston, Texas; Kansas City, Missouri; Boston, Massachusetts;exington, Kentucky; and Chicago, Illinois

bjectives This study sought to evaluate ischemic and bleeding outcomes in patients with chronic kid-ey disease (CKD) undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES).

ackground Previous studies have shown that CKD is associated with poor outcomes after PCI.owever, these studies were largely conducted before the introduction of DES and aggressive anti-hrombotic therapy or were performed in the setting of randomized trials. With data from a con-emporary registry, we evaluated the influence of CKD on major cardiovascular events and bleedingomplications in unselected “real-world” patients undergoing PCI.

ethods Data from 4,791 patients enrolled in the EVENT (Evaluation of Drug Eluting Stents andschemic Events) Registry between July 2004 and September 2005 were analyzed. Patients weretratified into 4 groups: creatinine clearance (CrCl) �75, 50 to 75, 30 to 49 and �30 ml/min.

esults During the index hospital stay, there was a step-wise increase in bleeding complicationsith decreasing CrCl (3.3%, 5.0%, 8.8%, and 14.3%; p � 0.0001 for trend). Lower CrCl was also asso-iated with more frequent death or myocardial infarction (MI) during the initial hospital stay (p �

.001) and at 1 year (p � 0.001). These findings were confirmed in multivariate analyses that ad-usted for baseline differences in demographic, clinical, and angiographic factors. Use of guideline-ecommended medications at 1 year, including aspirin, clopidogrel, angiotensin-converting enzymenhibitors, and statins, also decreased with declining renal function.

onclusions Renal function is an independent and powerful predictor of bleeding and ischemicomplications in the era of DES and contemporary antithrombotic therapy in patients undergoingCI. The low use of guideline-recommended drugs among patients with CKD undergoing PCI mightontribute to these adverse outcomes and warrants further evaluation. (J Am Coll Cardiol Intv009;2:37–45) © 2009 by the American College of Cardiology Foundation

rom the *University of Oklahoma, Oklahoma City, Oklahoma; †Methodist DeBakey Heart Center, Houston, Texas; ‡Saintuke’s Mid America Heart Institute, Kansas City, Missouri; §Harvard Clinical Research Institute, Boston, Massachusetts;

University of Kentucky, Lexington, Kentucky; and the ¶University of Chicago, Chicago, Illinois. Funding for the EVENTegistry and its analysis was provided by grants from Millennium Pharmaceuticals and Schering Plough Inc. Dr. Saucedo reportsesearch support from Eli Lilly, Schering Plough, Medicines Co., and Abbott and served as consultant for Schering Plough. Dr.leiman reports research support from Cordis Inc., Eli Lilly, Medtronic, Sanofi-Aventis, and Medicines Co.; received honoraria

or speaking engagements from Sanofi-Aventis, Cordis, Medtronic, and Medicines Co., and served as a consultant to Bostoncientific and Medtronic. Dr. Cohen received grant support from Cordis, Boston Scientific, Bristol-Myers Squibb, and Eli Lilly.r. Lopez received educational grants from Cordis; served on an advisory board for Medicines Co.; and received research support

rom Conor, Cordis, Medicines Co., and Guidant.

anuscript received February 4, 2008; revised manuscript received June 4, 2008, accepted June 13, 2008.



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Latif et al.

DES in Chronic Kidney Disease

38

ore than 19 million people in the U.S. suffer from chronicidney disease (CKD); cardiovascular disease is the majorause of mortality in these patients (1,2). Many clinicaltudies have demonstrated that patients with CKD haveoor outcomes after percutaneous coronary interventionPCI), including increased rates of death and myocardialnfarction (MI) relative to patients with preserved renalunction (3,4). However, most of these studies were per-ormed before the introduction of drug-eluting stentsDES) and modern antithrombotic therapy (5,6). More-ver, major cardiovascular disease trials often exclude orimit enrollment of patients with significant kidney disease7). As such, the clinical outcomes in this patient populationre largely unexplored yet remain relevant to the practice of

cardiology. The EVENT (Eval-uation of Drug Eluting Stentsand Ischemic Events) registry isan ongoing multicenter studythat aims to evaluate the out-comes of unselected patients un-dergoing PCI in the era of DES(8,9) and thus provides a uniqueopportunity to evaluate ischemicand bleeding outcomes of pa-tients with CKD after PCI inthe “real-world” setting.

Methods

A detailed description of the pa-tient population and the designof the EVENT registry havebeen published (8). Briefly, it isan ongoing multicenter registrythat prospectively enrolls uns-elected patients undergoing PCIat 42 U.S. centers. Enrollmentoccurs in discrete “waves” of ap-proximately 2,500 patients atapproximately yearly intervals.

he current analysis includes patients enrolled in the first 2aves of the registry. Patients in whom stent implantationas not attempted during PCI or who had undergone PCIr cardiac surgery within the preceding 4 weeks werexcluded. Patients underwent PCI for a variety of clinicalndications, including ST-segment elevation myocardialnfarction (STEMI), acute coronary syndrome (ACS), asell as chronic stable angina or a positive stress test. Data

oncerning patient characteristics, presentation, and treat-ent were collected prospectively on standardized case

eport forms and submitted to the data coordinating center.rotocol-mandated creatine kinase (CK) and creatineinase-myocardial band (CK-MB) levels were assessed at

bbreviationsnd Acronyms

CS � acute coronaryyndrome

K � creatine kinase

K-MB � creatine kinase-yocardial band

KD � chronic kidneyisease

rCl � creatinine clearance

ES � drug-eluting stent(s)

TI � direct thrombinnhibitor

P � glycoprotein

I � myocardial infarction

CI � percutaneousoronary intervention

TEMI � ST-segmentlevation myocardialnfarction

IMI � Thrombolysis Inyocardial Infarction

LR � target lesionevascularization

aseline and every 8 h for a minimum of 2 samples after the binterventions.onlinDownloaded from

rocedure and assayed with each site’s clinical laboratorynd reference values. If MI was suspected clinically at a lateroint, additional biomarkers were obtained. The institu-ional review board of each hospital approved the facility’sarticipation in the EVENT registry. Informed consent wasbtained from each participating patient. Telephoneollow-up was performed at 6 and 12 months after the PCIo ascertain the occurrence of major cardiovascular events.ssessment of renal function and stratification. Serum cre-tinine levels were recorded at baseline for all patients. Forhe purposes of this study, renal function was assessedccording to creatinine clearance (CrCl), which was calcu-ated on the basis of age, gender, ideal body weight (kg), anderum creatinine (mg/dl) with the Cockcroft-Gault equa-ion (10). Patients were separated into 4 groups on the basisf CrCl: �75 ml/min, 50 to 75 ml/min, 30 to 49 ml/min,nd �30 ml/min. Because the focus of this analysis was onenal function, patients for whom baseline CrCl could note calculated were excluded from the current study.efinitions. All deaths, MIs, and stent thromboses weredjudicated centrally by 2 cardiologists blinded to CrCl.

yocardial infarction was defined as elevation of CK orK-MB at least 3� the local upper limit of normal (or CK

f CK-MB levels were not available). Among patients inhom CK or CK-MB were elevated at baseline, an increasef at least 2� compared with the baseline was necessary asell. Lesion complexity was assessed according to theodified American College of Cardiology/American Heartssociation classification system (11). Target lesion revas-

ularization (TLR) was defined as any repeat percutaneousntervention or bypass surgery to treat recurrent stenosis ofhe original target lesion. Stent thrombosis was defined asngiographic thrombus or subacute closure within thetented vessel at the time of coronary angiography forocumented ischemia (chest pain and electrocardiographichanges) as well as any death not attributed to a noncardiacause within the first 30 days in the absence of documentedngiographic stent patency. Bleeding was defined usinghrombolysis In Myocardial Infarction (TIMI) major andinor criteria (12). Vascular access site complications in-

luded retroperitoneal bleeding, thrombosis of the accessessel, femoral arterial aneurysm or hematoma necessitatingurgical repair, blood transfusion, and increase in the lengthf hospital stay by at least 1 day. Composite bleedingncluded access site complication, TIMI major and minorleeding, and blood transfusion.nd points. The principal end points for this study were allause mortality, MI, the composite of death or MI, and aomposite of bleeding complications consisting of access siteomplications, TIMI major and minor bleeding, or bloodransfusion during the index hospital stay. One-year out-omes included death, MI, and the composite of death or

I. Secondary outcomes included TIMI major and minor
leeding and post-procedure length of stay during index
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Latif et al.


39

ospital stay, whereas TLR and stent thrombosis werevaluated at 1 year.tatistical analysis. For baseline, angiographic, and proceduralharacteristics, continuous variables are described as mean � 1D and compared among CrCl groups with analysis ofariance. Categorical variables are described as proportions andompared by chi-square testing. Clinical outcome andollow-up medication variables are reported as proportions orean � 1 SD and compared with logistic, exact logistic, or

inear regression as appropriate with a test for trend across therCl categories. Time-to-event curves were constructed with

he Kaplan-Meier approach. For the analyses of the associationetween CrCl and clinical outcomes, CrCl was analyzed as aategorical predictor with the 4 categories defined in thereceding text, and a test for trend in categories was conducted.n secondary models it was analyzed as a continuous log-ransformed variable. Logistic regression analysis was used forll in-hospital outcomes, and the Cox proportional hazardsodel was employed for 1-year outcomes, censoring individ-

als at the last known date of event-free status. In cases wherehere were �5 events in 1 or more CrCl strata, exact logisticegression was used.

In addition to the univariate models, multivariable regres-ion analyses were conducted (logistic or proportional haz-rds, as appropriate) adjusting for baseline differences inemographic, clinical, and angiographic factors. In additiono age and gender, the analysis of bleeding complicationsas further adjusted for hypertension, clinical indication for

he procedure (STEMI, ACS or other), hemoglobin, andhe use of antithrombotic agents (heparin alone, heparinlus glycoprotein [GP] IIb/IIIa inhibitors, direct thrombinnhibitor [DTI] alone, or heparin/DTI plus GP IIb/IIIanhibitors). The variables used for the adjustment in thenalysis of 1-year ischemic outcomes (death, death or MI)ncluded age, gender, clinical indication for the procedureSTEMI, ACS, chronic stable angina or positive stress test,r other), presence of significant left anterior descendingrtery disease, as well as composite bleeding.

All statistical analyses were performed with SAS 8.2SAS Institute, Cary, North Carolina). Unless specifiedtherwise, a 2-tailed p value of �0.05 was consideredtatistically significant.

esults

aseline characteristics. A total of 5,053 consecutive patientsere enrolled in Waves 1 and 2 of the EVENT registryetween July 2004 and September 2005. After excluding 262atients with missing baseline renal function assessment, 4,791atients constituted the study cohort. Approximately 59%2,827) of patients had normal renal function (CrCl �75l/min), whereas 26% (1,253) had mild renal impairment

CrCl 50 to 75 ml/min), 12% (571) had moderate renal
mpairment (CrCl 30 to 49 ml/min), and 3% (140) had severe K
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enal impairment (CrCl �30 ml/min). Of the 140 patientsith severe renal impairment, 51 (approximately 1% of the

otal sample) were dependent on renal dialysis.On average, patients with a CrCl below 75 ml/min were

lder than those with a CrCl above 75 ml/min and wereore likely to be female and have a history of congestive

eart failure, coronary artery bypass grafting, diabetes,ypertension, stroke, and peripheral arterial disease. Pa-ients with lower CrCl were less likely to be current smokersnd to have presented with a STEMI. Other potentialndications for PCI did not differ according to renal func-ion. Of note, among patients with at least moderate renalnsufficiency, 24% had only a slight increase in serumreatinine (level between 1.5 and 2.0 mg/dl) at baselineTable 1).

Angiographic characteristics of the study population areisplayed in Table 2. A total of 6,655 lesions were treated in,791 patients, with a similar number of lesions treated/atient across groups. Approximately 15% of patients un-erwent multivessel PCI in each group. Percutaneous cor-nary intervention was performed more frequently in leftain and saphenous vein graft lesions in the lowest CrCl

roup. Additionally, patients with worse renal function hadCI performed in more complex lesions (B2/C per Amer-

can College of Cardiology classification).Procedural characteristics of the study population are sum-arized in Table 3. Most patients received only DES. The use

f anticoagulants varied significantly among the groups (p �.0001) as shown in Table 3. Unfractionated heparin or DTIlone was used more frequently in patients with lower CrCl.onversely, GP IIb/IIIa inhibitors were used less frequently inatients with greater renal impairment. Eptifibatide was theredominant GP IIb/IIIa inhibitor used, irrespective of renalunction. However, use of abciximab increased as renal func-ion worsened, (CrCl �75 ml/min, 83% eptifibatide vs. 15%bciximab; CrCl �30 ml/min, 57% eptifibatide vs. 41%bciximab). In patients receiving heparin, higher activatedlotting time was seen in patients with CrCl between 30 and5 ml/min (p � 0.03).n-hospital outcomes. Impaired renal function was associ-ted with a graded increase in both ischemic and bleedingomplications during the index hospital stay (Table 4). Ofhe 4,791 patients, 227 developed the composite end pointf bleeding complications. There was a progressive increasen the frequency of the composite end point of death or MIuring the index hospital stay from 5.8% to 10% withorsening renal function (p � 0.0016), driven primarily bygreater incidence of in-hospital MI among patients with

ower CrCl (p � 0.002). Finally, post-procedure length ofospital stay was greater in patients with worse renalunction at baseline (Table 4).ne-year outcomes. During 1 year of follow-up, 139 pa-

ients (2.9%) died and 395 (8.2%) experienced an MI. The
aplan-Meier curves for survival are displayed in Figure 1.


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ith decreasing CrCl, there was a stepwise increase inortality across all groups (unadjusted p value for trend0.0001) (Table 4). The incidence of MI also increasedith worsening renal function (unadjusted p value for trend.0007). Stent thrombosis (p � 0.99) and repeat revascu-arization (unadjusted p value for trend 0.51) were notifferent among the various groups.Trends in cardiovascular medication usage at 6 and 12onths showed a significant decline in use of guideline-

ecommended pharmacotherapy with decreasing CrCle.g., CrCl �75 ml/min vs. CrCl �30 ml/min) at 1 year,spirin (93% vs. 73%), clopidogrel (72% vs. 63%),ydroxymethylglutaryl-coenzyme A reductase inhibitors86% vs. 65%), and angiotensin-converting enzyme inhibi-ors (52% in vs. 34%) as shown in Table 5. The follow-upates were between 95% and 98% at 6 months and between2% and 94% at 1 year for all CrCl groups.ultivariable analysis. Creatinine clearance was a powerfulredictor of bleeding complications. This observation heldrue even when multiple variables including antithromboticse and baseline hemoglobin were progressively forced intohe model (Table 6). The multivariable-adjusted odds of

Table 1. Baseline Demographic and Clinical Characteristics

>75 ml/min(n � 2,827)

50–75 ml/(n � 1,25

Demographic

Age (yrs), mean � SD 58.86 � 9.57 70.59 � 8.6

Weight (kg) 95.13 � 18.97 79.51 � 13.

BMI (kg/m2) 31.54 � 5.94 27.78 � 4.7

Male 76.7% 63.8%

Creatinine 1.5–2.0 (mg/dl) 0.5% 7.4%

Hgb (g/dl), mean � SD 14.56 � 7.46 13.69 � 6.3

Medical history

Diabetes 33.8% 31.0%

Hypertension 74.5% 79.0%

Hyperlipidemia 72.3% 75.1%

Current smoking 31.1% 16.2%

Congestive heart failure 6.5% 11.8%

MI 37.3% 37.0%

PCI 35.5% 37.2%

CABG 18.2% 26.3%

Indication for PCI

Chronic stable angina 19.8% 22.6%

Positive stress test 36.6% 37.4%

NSTE-ACS 34.7% 31.8%

STEMI 6.5% 3.9%

Other 9.9% 12.4%

p values are based on chi-square test or F test as appropriate.

BMI � body mass index; CABG � coronary artery bypass grafting; Hgb � hemoglobin; MI � myo

coronary intervention; STEMI � ST-segment elevation myocardial infarction.

leeding complications were more than 3� as high in the tinterventions.onlinDownloaded from

30 ml/min CrCl group compared with the referent groupf CrCl �75 ml/min (odds ratio: 3.23, 95% confidencenterval: 1.72 to 6.04) (Table 6).

At 1 year, renal dysfunction emerged as an independentredictor of mortality after adjustment for the risk factors

isted earlier (Table 6). The composite of death and MI alsoncreased across all CrCl groups (p � 0.0001). Individualsith CrCl �30 ml/min had more than 5� the risk of dying

han those with CrCl �75 ml/min (multivariable-adjustedazard ratio: 5.35, 95% confidence interval: 2.86 to 10.02).oticeably, TLR did not increase with renal dysfunction.nalysis of CrCl as a continuous, log-transformed predictoremonstrated similar findings for in-hospital and 1-yearutcomes (data not shown).

iscussion

ur study generated several important results. Renal insuf-ciency was associated with increased in-hospital death andI as well as bleeding complications, even after adjustment

or other clinical factors that could potentially confound

inine Clearance

p Value30–49 ml/min

(n � 571)<30 ml/min(n � 140)

76.32 � 8.17 72.07 � 12.61 �0.0001

71.09 � 14.34 72.69 � 18.62 �0.0001

26.09 � 4.84 26.30 � 5.95 �0.0001

44.3% 49.3% �0.0001

25.0% 22.1% �0.0001

12.54 � 2.00 11.90 � 2.25 �0.0001

34.7% 47.1% 0.0013

85.6% 94.3% �0.0001

73.7% 71.0% 0.2675

12.2% 14.4% �0.0001

19.2% 32.4% �0.0001

41.4% 39.9% 0.2505

38.1% 43.9% 0.1417

27.4% 30.9% �0.0001

0.0052

18.7% 17.9%

30.5% 30.7%

38.5% 37.1%

3.7% 0.0%

15.2% 24.3%

infarction; NSTE-ACS � non–ST-segment elevation acute coronary syndrome; PCI � percutaneous

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Latif et al.


41

eath and nonfatal MI also increased in a step-wise fashions CrCl decreased. Despite these important clinical out-omes, renal dysfunction was not associated with an in-reased risk of stent-specific events, including stent throm-osis or clinical restenosis (i.e., TLR). We also found thatuideline-recommended medications were used less fre-

Table 2. Angiographic Characteristics (Lesion-Based)

Creat

>75 ml/min(n � 3,939)

50–75 ml/(n � 1,71

Target vessel

LAD 35.7% 34.5%

Circumflex 23.2% 22.3%

RCA 34.2% 31.9%

LMCA 1.2% 1.5%

SVG 5.8% 9.9%

Lesions treated per patient 1.40 � 0.65 1.37 � 0.6

Lesion classification*

A 12.1% 12.3%

B1 33.9% 31.5%

B2 32.4% 34.2%

C 21.6% 22.0%

Total occlusion 6.8% 5.0%

Bifurcation lesion 12.4% 11.1%

Angiographic thrombus 12.4% 9.3%

p values are based on chi-square test or F-test as appropriate. *Lesion based on American College o

LAD � left anterior descending artery; LMCA � left main coronary artery; RCA � right coronary a

Table 3. Procedural Characteristics

>75 ml/min(n � 2,827)

50–75 m(n � 1

Stents

DES � BMS 3.5% 4.5

DES only 89.5% 87.6

BMS only 6.1% 6.9

Antithrombotic medications

Heparin alone 15.5% 18.2

LMWH alone 0.1% 0.2

DTI alone 27.5% 30.1

Heparin � GP IIb/IIIa 41.4% 38.2

LMWH � GP IIb/IIIa 1.5% 0.4

DTI � GP IIb/IIIa 2.2% 1.6

Other* 11.8% 11.3

Peak ACT (s)†

Heparin alone peak ACT(s) 275 (244–314) 281 (252

Heparin � GP IIb/IIIa (s) 250 (223–285) 260 (229

DTI alone peak ACT(s) 330 (298–372) 342 (303

DTI � GP IIb/IIIa peak ACT (s) 352 (332–389) 375 (361

p values are based on chi-square or F test as appropriate. *Other medication combinations not liste

BMS � bare-metal stent(s); DES � drug-eluting stent(s); DTI � direct thrombin inhibitor; GP � glycoprot


uently as renal function worsened. We found that, consis-ent with other reports, more than 40% of patients under-oing PCI have impaired renal function. We also found thatlmost one-fourth of patients with significant renal insuffi-iency undergoing PCI have only a mild increase in serumreatinine (between 1.5 to 2.0 mg/dl), emphasizing the

learance, All Lesions


(n � 815)<30 ml/min(n � 187)

�0.0001

36.2% 28.3%

24.4% 22.5%

28.3% 32.6%

2.5% 3.7%

8.6% 12.8%

1.43 � 0.67 1.36 � 0.63 0.2818

0.0004

10.0% 6.4%

32.0% 24.6%

32.8% 42.8%

25.2% 26.2%

4.7% 4.3% 0.0098

11.8% 15.5% 0.2776

10.4% 9.1% 0.0038

logy/American Heart Association lesion classification.

VG � saphenous vein graft.

atinine Clearance


(n � 571)<30 ml/min(n � 140)

0.3809

4.2% 5.0%

87.1% 84.3%

7.5% 8.6%

�0.0001

20.3% 29.3%

0% 0

32.9% 33.6%

33.9% 25.7%

0.5% 0

2.1% 1.4%

10.2% 10.0%

285 (253–328) 253 (186–315) 0.0346

260 (233–296) 252 (216–305) 0.0071

348 (311–390) 305 (270–370) 0.0582

334 (323–409) N/A 0.6644

. †Activated clotting time (ACT) values are presented as median values with interquartile ranges.

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42

dvantage of using CrCl over serum creatinine, as theosage of certain antithrombotic medications need to bedjusted on the basis of CrCl.

Table 4. Clinical Outcomes

>75 ml/min(n � 2,827)

50–7(n �

In-hospital

Death 0.1%

MI 5.7%

Death or MI 5.8%

Composite bleeding* 3.3%

TIMI major 0.2%

TIMI minor 0.8%

Access site complications† 1.9%

Transfusion 1.6%

Post-procedure length ofstay (days), mean � SD (n)

1.56 � 2.37 (2,826) 1.63 �

1-yr

Death 1.5%

MI 7.2%

Death or MI 8.5% 1

Stent thrombosis 1.3%

Any repeat revascularization 11.9% 1

Target lesionrevascularization

4.2%

Nontarget lesionrevascularization

7.4%

Death or MI or repeatrevascularization

18.0% 2

p values are based on linear, logistic, or exact logistic regression with 1 variable for 4 creatinine clearan

of access site complication, TIMI major, TIMI minor bleeding and transfusion. †Access site complica

hematoma necessitating surgical repairs.

MI � myocardial infarction; TIMI � Thrombolysis In Myocardial Infarction.

Figure 1. Kaplan-Meier Survival Curve for 1-Year Death


leeding complications in CKD. Renal dysfunction has beenhown to be a risk factor for bleeding complications inatients undergoing PCI in the setting of STEMI as well as

eatinine Clearance

p Valuein)

30–49 ml/min(n � 571)

<30 ml/min(n � 140)

0.9% 0.0% 0.0206

8.2% 10.0% 0.0023

8.4% 10.0% 0.0016

8.8% 14.3% �0.0001

1.2% 0.0% 0.5587

1.2% 0.0% 0.0567

3.0% 0.7% 0.3121

6.3% 13.6% �0.0001

,253) 2.19 � 2.73 (571) 2.49 � 2.84 (140)

5.8% 13.6% �0.0001

10.7% 11.4% 0.0007

15.1% 22.1% �0.0001

1.1% 1.4% 0.9906

9.5% 11.4% 0.5111

3.3% 4.3% 0.7045

6.3% 6.4% 0.7491

21.5% 27.9% 0.0003

ps. Post-procedure length of stay is based on simple regression. *Composite bleeding � composite

retroperitoneal bleeding, thrombosis of access vessel, femoral arterial aneurysm or

Cr

5 ml/m1,253

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7.3%

7.4%

5.0%

0.3%

1.3%

2.9%

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2.3%

1.5%

3.1%

4.5%

8.6%

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CS (13,14). Few previous studies have demonstrated ainear increase in bleeding after PCI with a concomitantecrease in CrCl (15,16). However, these analyses wereither performed in the setting of randomized controlledrials or were in the era of bare-metal stents and non-ontemporary antithrombotic therapy, in contrast to ourtudy, which was performed in the real-world setting.

In our study, patients with CrCl 30 to 49 ml/min hadigher peak activated clotting times and were particularlyore susceptible to hemorrhagic complications. Whereas

here has been increasing emphasis on proper medicationosing in patients with renal insufficiency, one possiblexplanation for our finding is that moderate degrees of renalnsufficiency might have been overlooked in some patients.n particular, estimation of renal function on the basis oferum creatinine alone might have led to inadvertent over-osing of antithrombotic medications that are renally me-abolized, including GP IIb/IIIa inhibitors such as eptifi-atide. Recently, Alexander et al. (17,18) reported that renalysfunction was an independent predictor of excessiveosing of heparins and GP IIb/IIIa inhibitors and of TIMI

Table 5. Follow-Up Medication Usage

CrCl >75 ml/min CrCl 50–75 ml/min

At 6 months (n � 2,682) (n � 1,215)

Aspirin 92.6% 89.7%

Statins 84.6% 81.3%

ACE inhibitor 50.7% 47.5%

Clopidogrel 84.3% 80.7%

At 12 months (n � 2,598) (n � 1,183)

Aspirin 92.7% 90.4%

Statins 85.8% 83.8%

ACE Inhibitor 51.8% 47.8%

Clopidogrel 71.9% 68.6%

Denominator � patients who were followed up at 6 months and 12 months, respectively. p values

ACE � angiotensin-converting enzyme; CrCl � creatinine clearance; Statins � hydroxymethylgluta

Table 6. Multivariate Analysis

Outcome CrCl 50–75 ml/min CrCl 30–49 ml/min

In-hospital events

MI 1.089 [0.800–1.483] 1.169 [0.771–1.772]

Death or MI 1.096 [0.807–1.490] 1.166 [0.771–1.762]

Composite bleeding 1.179 [0.807–1.723] 1.607 [1.014–2.545]

Cumulative 12-month events

Death 1.714 [1.069–2.747] 2.360 [1.346–4.140]

Death or MI 1.315 [1.043–1.659] 1.488 [1.083–1.989]

TLR 1.321 [0.916–1.905] 0.998 [0.570–1.749]

CI � confidence interval; CrCl � creatinine clearance; OR � odds ratio; MI � myocardial infarction; TLR � t


ajor bleeding among patients presenting with ACS andhat this practice was more common in women than in men.he appropriate dosing of heparin in patients with CKDas not been studied very well (19). Although excess dosingf antithrombotic agents could also have played a role inncreased bleeding complications of patients with CKD, weere unable to prove this association in the EVENT

egistry, because doses of GP IIb/IIIa antagonists were notystematically collected in our study cohort. It is also likelyhat patients with CKD are at increased risk of bleeding,ven in the absence of dosing errors. For example, renalnsufficiency has been associated with several abnormalitiesf primary hemostasis, particularly platelet dysfunctionharacterized by decreased release of adenosine triphosphatend decreased serotonin content in dense granules (20).

Blood transfusions, even after adjusting for baselineemoglobin, were more often administered in patients withecreased renal function, a finding that could be related tolower threshold for transfusion in patients with severeKD. Previous studies have shown an increase in blood

ransfusions in patients with CKD after PCI (3,21).

CrCl 30–49 ml/min CrCl <30 ml/min

(n � 558) (n � 133) p Value

85.3% 76.7% �0.0001

79.2% 69.9% �0.0001

43.9% 39.8% 0.0001

78.0% 67.7% �0.0001

(n � 531) (n � 132) p Value

86.3% 72.7% �0.0001

81.4% 65.2% �0.0001

39.9% 34.1% �0.0001

65.0% 62.9% �0.0001

d on logistic regression with 1 variable for 4 creatinine groups.

zyme A reductase inhibitors.

Adjusted OR (95% CI)

CrCl <30 ml/minMultivariate

p ValueMinus Continuous

log CrCl p Value

1.615 [0.872–2.991] 0.1727 1.150 [0.879–1.504] 0.3073

1.584 [0.855–2.933] 0.1839 1.151 [0.882–1.503] 0.3004

3.140 [1.735–5.682] 0.0004 1.517 [1.166–1.973] 0.0019

5.357 [2.863–10.021] �0.0001 1.692 [1.338–2.093] �0.0001

2.192 [1.464–3.281] 0.0001 1.374 [1.167–1.617] 0.0001

1.213 [0.516–2.847] 0.5753 1.070 [0.769–1.489] 0.6866

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schemic outcomes in CKD. Our study showed a markedncrease in in-hospital and 1-year cardiovascular events afterCI as renal function worsened. Other smaller and retro-pective studies have shown increased mortality and MIithin 1 year after PCI with DES (22), even when theegree of renal insufficiency is mild (23). However, the largeopulation of patients with varying degrees of renal dys-unction in our study provides greater power to examine aroader spectrum of outcomes, including death as well asncreased long-term risk of MI, in this patient population.

One of the strengths of our study was that systematicollection of pre- and post-procedure cardiac markers al-owed for reliable detection of periprocedural ischemicvents without ascertainment bias. Indeed, we observed atepwise increased incidence of periprocedural MI withorsening renal function. Of note, the use of GP IIb/IIIa

ntagonists decreased with worsening renal function, whichould have played a role in the increased incidence ofost-procedural MI in patients with CKD, given theirroven role in reducing these complications (24).Studies have shown that the need for repeat revascular-

zation in patients with CKD has decreased with the adventf DES (21,25). However, a recent study showed that theeed for repeat revascularization increases with renal dys-unction, even in patients receiving DES (26). Renal failureas also been implicated as an independent predictor oftent thrombosis with DES, being second only to prematureiscontinuation of clopidogrel (27). However, repeat revas-ularization or stent thrombosis was not found to bencreased in patients with CKD at 1-year follow-up in ournalysis, questioning earlier findings.

Recently, more emphasis is being laid on bleeding com-lications as a determinant of mortality in patients afterCI. However, our results indicate that even after correcting

or bleeding complications, outcomes remain worse inatients with lower CrCl. Therefore, in patients with CKD,dditional factors attributable to CKD as well as underuse ofecommended cardioprotective medications could accountor worse outcomes. It has been reported that cardioprotec-ive medications are less often used in the management ofatients with CKD (28). To our knowledge, our study is therst to show the paradoxical underuse of cardioprotectiverugs after PCI in a CKD population. Use of medicationsuch as aspirin, clopidogrel, statins, and angiotensin-onverting enzyme inhibitors decreased in a step-wise fash-on with the drop in CrCl at 1 year. Although furthertudies are needed to evaluate the safety and efficacy ofuideline-recommended therapies in patients with CKD, iteems paradoxical that cardiovascular pharmacotherapy iseing underused in patients who might benefit the most.imitations. Although our data were collected prospectively,he current analysis was not specified prospectively. Conse-uently, the data collected did not include whether the
nticoagulants were dosed on the basis of CrCl or serum

reatinine or whether renal function was considered at all inose selection. Similarly, transfusion was a major compo-ent of the composite bleeding end point, and we did notollect data regarding indication for transfusion. We hadimited power to evaluate some end points such as stenthrombosis and to evaluate dialysis patients separately.imilarly, we did not collect information on post-procedureenal failure or dialysis as complications of PCI.

The Cockcroft-Gault equation was used for estimation ofrCl. This formula might overestimate CrCl in obeseatients. Although the number of patients who receivedare-metal stents was small, we did not compare theutcomes of patients receiving DES with those of patientseceiving bare-metal stents.

onclusions

enal dysfunction, as determined by CrCl, is a powerfulndependent predictor of in-hospital bleeding complicationsnd 1-year ischemic events including death and nonfatal MIn the current era of DES and antithrombotic therapy.aradoxically, suboptimal long-term use of guideline-

ecommended cardiovascular pharmacotherapy is observedn patients with CKD after PCI. With the aging of theopulation and the increase in the number of patients withKD, the need for their inclusion in ongoing and future

ardiovascular trials to determine whether current therapeu-ic approaches are effective is as great as ever.

eprint requests and correspondence: Dr. Jorge F. Saucedo, 920tanton L. Young Boulevard, WP 3010, Oklahoma City, Okla-oma 73104. E-mail: [email protected].

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1. Halkin A, Mehran R, Casey CW, et al. Impact of moderate renalinsufficiency on restenosis and adverse clinical events after paclitaxel-eluting and bare metal stent implantation: results from the TAXUS-IVtrial. Am Heart J 2005;150:1163–70.

2. Das P, Moliterno DJ, Charnigo R, et al. Impact of drug-eluting stentson outcomes of patients with end-stage renal disease undergoingpercutaneous coronary revascularization. J Inv Cardiol 2006;18:405–8.

3. Zhang RY, Ni JW, Hu J, et al. Long term clinical outcomes in patientswith moderate renal insufficiency undergoing stent based percutaneouscoronary intervention. Chin Med J 2006;119:1176–81.

4. Karvouni E, Kastritis DG, Ioannidis JP. Intravenous glycoproteinIIb/IIIa receptor antagonists reduce mortality after percutaneous cor-onary interventions. J Am Coll Cardiol 2003;41:26–32.

5. Lemos PA, Arampatzis CA, Hoye A, et al. Impact of baseline renalfunction on mortality after percutaneous coronary intervention withsirolimus-eluting stents or bare metal stents. Am J Cardiol 2005;95:167–72.

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7. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, andoutcome of thrombosis after successful implantation of drug-elutingstents. JAMA 2005;293:2126–30.

8. Tonelli M, Bohm C, Pandeya S, Gill J, Levin A, Kiberd BA. Cardiacrisk factors and the use of cardioprotective medications in patients withchronic renal insufficiency. Am J Kidney Dis 2001;37:484–9.

ey Words: angioplasty � chronic kidney disease �
oronary disease � drug-eluting stents.


doi:10.1016/j.jcin.2008.06.012 2009;2;37-45 J. Am. Coll. Cardiol. Intv.

Saucedo, on behalf of the EVENT Investigators Donald E. Cutlip, David J. Moliterno, Deborah Nassif, John J. Lopez, Jorge F.

Faisal Latif, Neal S. Kleiman, David J. Cohen, Michael J. Pencina, Chen-Hsing Yen, Events) Registry

Report From the EVENT (Evaluation of Drug Eluting Stents and IschemicPatients With Chronic Kidney Disease in the Era of Drug-Eluting Stents: A

In-Hospital and 1-Year Outcomes Among Percutaneous Coronary Intervention

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