Ischemic outcomes after coronary intervention of calcified vessels in acute coronary syndromes. Pooled analysis from the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and

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Journal of the American College of Cardiology Vol. 63, No. 18, 2014� 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2014.01.034

Ischemic Outcomes After CoronaryIntervention of Calcified Vesselsin Acute Coronary Syndromes

Pooled Analysis From the HORIZONS-AMI(Harmonizing Outcomes With Revascularization andStents in Acute Myocardial Infarction) and ACUITY(Acute Catheterization and Urgent Intervention Triage Strategy) Trials

Philippe Généreux, MD,*yz Mahesh V. Madhavan, BA,* Gary S. Mintz, MD,*y Akiko Maehara, MD,*yTullio Palmerini, MD,x Laura LaSalle, BA,y Ke Xu, PHD,y Tom McAndrew, MS,yAjay Kirtane, MD, SM,*y Alexandra J. Lansky, MD,k Sorin J. Brener, MD,y{ Roxana Mehran, MD,y#Gregg W. Stone, MD*yNew York, New York; Montréal, Québec, Canada; Bologna, Italy; and New Haven, Connecticut

From the *N

New York, N

zHôpital du

Canada; xIsof Medicine

New York;

Généreux a

Madhavan

Objectives T

ew York-Presbyterian Ho

ew York; yCardiovasculaSacré-Coeur de Montré

tituto di Cardiologia, Univ

, New Haven, Connecticu

and the #Mount Sinai

nd Palmerini have recei

was supported by a clini

his study sought to determine the frequency and impact of coronary calcification among patients undergoingpercutaneous coronary intervention (PCI) for acute coronary syndromes (ACS).

Background S

mall studies in patients with stable coronary artery disease have suggested a worse prognosis after PCI of calcifiedcompared with noncalcified lesions. Little is known about the impact of coronary calcification on outcomes after PCIfor patients presenting with non–ST-segment elevation and ST-segment elevation ACS.

Methods D

ata from 6,855 patients presenting with ACS in whom PCI was performed were pooled from 2 large-scalerandomized, controlled trials, ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) andHORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction). One-yearoutcomes were analyzed according to the severity of PCI target lesion calcification (none/mild, moderate, or severe)as assessed by an independent angiographic core laboratory.

Results T

arget lesion calcification was severe in 402 patients (5.9%), moderate in 1,788 (26.1%), and none/mild in 4,665(68.1%). Moderate/severe target lesion calcification was more frequent in older patients, men, hypertensivepatients, and those presenting with ST-segment elevation myocardial infarction (STEMI). The unadjusted 1-year ratesof death, cardiac death, definite stent thrombosis, and ischemic target lesion revascularization (TLR) and targetvessel revascularization were significantly increased in patients with moderate/severe target lesion calcification. Bymultivariable analysis, the presence of moderate/severe target lesion calcification was an independent predictor of1-year definite stent thrombosis (hazard ratio [HR]: 1.62; 95% confidence interval [CI]: 1.14 to 2.30; p ¼ 0.007) andischemic TLR (HR: 1.44; 95% CI: 1.17 to 1.78; p ¼ 0.0007).

Conclusions M

oderate/severe lesion calcification was relatively frequent in patients with non–ST-segment elevation ACS andSTEMI and was strongly predictive of stent thrombosis and ischemic TLR at 1 year. (Comparison of Angiomax VersusHeparin in Acute Coronary Syndromes [ACS]; NCT00093158; Harmonizing Outcomes With Revascularization andStents in Acute Myocardial Infarction; NCT00433966) (J Am Coll Cardiol 2014;63:1845–54) ª 2014 by theAmerican College of Cardiology Foundation

spital and Columbia University Medical Center,

r Research Foundation, New York, New York;

al, Université de Montréal, Montréal, Québec,

ersity of Bologna, Bologna, Italy; kYale Schoolt; {New York Methodist Hospital, New York,

Medical Center, New York, New York. Drs.

ved speaker fees from Abbott Vascular. Mr.

cal research fellowship grant from the Doris

Duke Charitable Foundation to Columbia University. Dr. Mintz has served as a

consultant for ACIST Medical Systems; and has served as a consultant and

received grant or fellowship support from Volcano Corporation, Boston Scientific,

and Infraredx. Dr. Mehran has received research grants from Sanofi-Aventis, The

Medicines Company, Abbott Vascular, Boston Scientific, Bristol-Myers Squibb,

and AstraZeneca; has served as a consultant/advisory board member for Abbott

Vascular, Covidien, CSL Behring, Janssen Pharmaceuticals, Maya Medical, Merck

& Co., Inc., Regado Biosciences, Sanofi-Aventis, Eli Lilly and Company, and

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Daiichi Sankyo; and is a sharehold

consultant for Boston Scientific and

have reported that they have no relat

to disclose. The first 2 authors cont

Manuscript received June 19, 2013

accepted January 6, 2014.

See

Abbreviationsand Acronyms

BMS = bare-metal stent(s)

DES = drug-eluting stent(s)

GPI = glycoprotein IIb/IIIa

inhibitor

NSTEACS = non–ST-segment

elevation acute coronary

syndromes

PCI = percutaneous coronary

intervention

QCA = quantitative coronary

angiography

STEMI = ST-segment

elevation myocardial

infarction

TLR = target lesion

revascularization

Généreux et al. JACC Vol. 63, No. 18, 2014Coronary Calcification and Percutaneous Coronary Intervention May 13, 2014:1845–54

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Compared with bare-metal stents(BMS), drug-eluting stents (DES)improve clinical and angiographicoutcomes in patients with coro-nary artery disease undergoingpercutaneous coronary interven-tion (PCI) (1,2). Although favo-rable results may be achieved withPCI in complex lesions (3–6),patients with moderately andseverely calcified lesions havebeen excluded from enrollment inmost stent trials and still repre-sent a challenge even in the DESera. Coronary calcification mayimpair stent delivery and expan-sion and damage the polymer/drug coating, resulting in im-paired drug delivery and predis-

position to restenosis and stent thrombosis (7). Whereassmall studies in the BMS era demonstrated reduced event-free survival after PCI of calcified compared with non-calcified lesions, surprisingly little is known about the effectof coronary calcification on outcomes after PCI with DES

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(8–12). Moreover, no studies have evaluated the frequencyand impact of coronary calcification in patients presentingwith non–ST-segment elevation acute coronary syndromes(NSTEACS) and ST-segment elevation myocardial infarc-tion (STEMI). We therefore sought to determine the fre-quency and impact of target lesion coronary calcification onclinical events in patients in whom PCI was performed inthe setting of NSTEACS or STEMI in a pooled analysisfrom the large-scale ACUITY (Acute Catheterization andUrgent Intervention Triage Strategy) andHORIZONS-AMI(Harmonizing Outcomes With Revascularization and Stentsin Acute Myocardial Infarction) trials (13,14).

Methods

Study designs and patients. The ACUITY andHORIZONS-AMI trial designs and results have previouslybeen described in detail (13–16). In brief, ACUITY was amulticenter, prospective, randomized trial of 13,819 patientswith moderate- and high-risk NSTEACS who were treatedwith an early invasive strategy. Prior to coronary angiog-raphy, patients were randomly assigned to heparin (unfrac-tionated or low-molecular-weight) plus a glycoprotein IIb/

er in Endothelix. Dr. Stone has served as a

Cardiovascular Systems, Inc. All other authors

ionships relevant to the contents of this paper

ributed equally to this paper.

; revised manuscript received January 5, 2014,

IIIa inhibitor (GPI), bivalirudin plus a GPI, or bivalirudinmonotherapy. Angiography was performed within 72 h ofrandomization, and depending on coronary anatomy, patientswere triaged to PCI, coronary artery bypass graft (CABG)surgery, or medical therapy. In patients undergoing PCI,stent choice (BMS or DES) was per operator discretion. Dualantiplatelet therapy with aspirin and clopidogrel was recom-mended for at least 1 year. In HORIZONS-AMI, 3,602patients with STEMI presenting within 12 h of symptomonset were randomly assigned to unfractionated heparin plusGPI or bivalirudin monotherapy. Immediate coronary angi-ographywas performed after randomization, followed byPCI,CABG, or medical management at physician discretion.Eligible patients were randomized again (3:1) to receivepaclitaxel-eluting stents (Boston Scientific, Natick, Massa-chusetts) or otherwise identical BMS (Boston Scientific).Aspirin and clopidogrel were administered before catheteri-zation; aspirin was continued indefinitely and clopidogrel forat least 1 year (14,16). Patients with severe renal insufficiency(calculated creatinine clearance <30 ml/min) were notincluded in either trial.

Patients in whom qualitative and quantitative coronaryangiography (QCA) was performed comprised the presentstudy population. QCA was performed at the Cardiovas-cular Research Foundation (New York, New York) bytechnicians blinded to randomization and outcomes in allpatients in the HORIZONS-AMI trial and in those en-rolled in the formal ACUITY angiographic substudy, aspreviously described (17). Interobserver and intraobserverQCA core laboratory variability kappa values (50 coronaryangiograms assessed twice [8 weeks apart] by 12 angio-graphic core laboratory technicians) for the degree of targetlesion calcification were 0.83 and 0.89, respectively, repre-senting excellent agreement. Independent clinical eventscommittees, blinded to treatment assignment, adjudicatedall major adverse events in both trials.Objectives and angiographic analysis. The primary studyobjective was to assess the relationship between the presenceand extent of target lesion coronary calcification and the1-year rate of ischemic events, including death, cardiacdeath, reinfarction, definite stent thrombosis, and ischemictarget lesion revascularization (TLR) and target vesselrevascularization. For the present report, we limited ouranalyses to the patients with STEMI in whom PCI wasperformed in the HORIZONS-AMI trial and to thepatients with NSTEACS in whom PCI was performed inthe formal angiographic substudy from ACUITY (17).Endpoint definitions and statistical analysis. The ACUITYand HORIZONS databases were combined, and patientsfrom this pooled population were stratified on the basis ofseverity of coronary artery calcification (none/mild, moder-ate, and severe). The pre-specified angiographic core labo-ratory definition of moderate calcification was radiopaquedensities noted only during the cardiac cycle and typicallyinvolving only one side of the vascular wall. Severe calcifi-cation was defined as radiopaque densities noted without

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Table 1Baseline Clinical Characteristics of Patients Stratified by the Severity ofTarget Lesion Calcification

No/MildCalcification(N ¼ 4,665)

ModerateCalcification(N ¼ 1,788)

SevereCalcification(N ¼ 402) p Value

Age, yrs 59.2 (51.7–69.0) 63.1 (55.0–72.0) 65.3 (55.8–74.0) <0.0001

Male 3,385/4,665 (72.6) 1,342/1,788 (75.1) 292/402 (72.6) 0.12

Diabetes 1,143/4,651 (24.6) 418/1,784 (23.4) 103/402 (25.6) 0.52

Insulin treated 324/4,651 (7.0) 114/1,784 (6.4) 35/402 (8.7) 0.25

Hypertension 2,849/4,652 (61.2) 1,112/1,784 (62.3) 249/402 (61.9) 0.71

Hyperlipidemia 2,452/4,630 (53.0) 934/1,780 (52.5) 201/399 (50.4) 0.60

Current smoker 1,842/4,658 (39.5) 667/1,779 (37.5) 141/401 (35.2) 0.10

Previous myocardial infarction 1,076/4,598 (23.4) 406/1,765 (23.0) 72/398 (18.1) 0.05

Previous PCI 1,440/4,652 (31.0) 493/1,782 (27.7) 93/401 (23.2) 0.0005

Previous CABG 579/4,658 (12.4) 243/1,786 (13.6) 58/402 (14.4) 0.28

Previous stroke 165/2,609 (6.3) 54/804 (6.7) 11/144 (7.6) 0.78

Renal insufficiency 642/4,362 (14.7) 326/1,657 (19.7) 107/374 (28.6) <0.0001

Left ventricular ejection fraction 62.6 (53.8–70.8) 61.3 (52.1–69.0) 59.6 (51.7–67.8) <0.0001

Baseline laboratory values

WBC count, � 103/l 9.1 (7.1–11.6) 9.4 (7.4–11.8) 10.0 (7.8–12.2) <0.0001

Hemoglobin, g/dl 14.3 (13.2–15.3) 14.2 (13.2–15.3) 14.1 (13.1–15.3) 0.33

Platelet count, �103/mm3 236.0 (197.0–282.0) 237.0 (199.0–279.0) 238.0 (195.0–286.0) 0.84

Clinical presentation

STEMI 2,036/4,665 (43.6) 976/1,788 (54.6) 256/402 (63.7) <0.0001

NSTEMI 1,396/4,665 (29.9) 444/1,788 (24.8) 86/402 (21.4) <0.0001

Unstable angina 1,233/4,665 (26.4) 368/1,788 (20.8) 60/402 (14.9) <0.0001

Values are median (interquartile range) or n/N (%). Hypertension is defined as previous diagnosis of hypertension and on antihypertensive medication onadmission. Hyperlipidemia is defined as previous diagnosis of hyperlipidemia and on lipid-lowering medication on admission. Renal insufficiency is definedas a calculated creatinine clearance rate <60 ml/min by the Cockcroft-Gault equation.CABG ¼ coronary artery bypass graft; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST-

segment elevation myocardial infarction; WBC = white blood cells.

Table 2Independent Predictors of the Presence ofModerate/Severe Target Lesion Calcification

Hazard Ratio (95% CI) p Value

Age (per 10-yr increase) 1.29 (1.23–1.35) <0.0001

Male 1.29 (1.12–1.50) <0.0001

STEMI 1.55 (1.37–1.76) <0.0001

Hypertension 1.12 (1.02–1.31) 0.02

Other covariates included in the model were current smoker, diabetes (any), previous myocardialinfarction, previous CABG surgery, renal insufficiency, hyperlipidemia, baseline WBC count, and leftventricular ejection fraction.CI ¼ confidence interval; other abbreviations as in Table 1.

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cardiac motion prior to contrast injection and generallyinvolving both sides of the arterial wall (18). Major adversecardiovascular events (MACE) were defined as the com-posite of death, reinfarction, and unplanned revasculariza-tion for ischemia. The specific definitions of the componentsof MACE have been previously described (13,14).

Categorical data were compared by the chi-square test orFisher exact test if the expected number of observations inany cell was <5. Continuous data are presented as mean� SD or median � interquartile range and were comparedusing the analysis of variance or Kruskal-Wallis test asappropriate. The 30-day event rates were estimated usingKaplan-Meier time-to-event methodology and were com-pared using the log-rank test. Multivariable regressionanalysis using Cox proportional hazards models to assess forindependent predictors for the presence of target lesioncoronary artery calcification and for the association betweenthe presence of coronary calcification and 1-year ischemicoutcomes were performed with variable entry/stay criteria of0.1/0.1. Variables included into the model were carefullyselected to avoid overfitting of the model. Because of therelatively small number of patients with severe coronarycalcification, the moderate and severe target lesion calcifica-tion groups were pooled for these analyses. Values ofp< 0.05 were considered to be statistically significant, and allp values are 2-sided. Statistical analyses were performed us-ing SAS version 9.2 (SAS Institute, Cary, North Carolina).

Results

From the angiographic substudy of ACUITY (NSTEACS)and HORIZONS-AMI (STEMI), 3,587 and 3,268 pa-tients, respectively, undergoing PCI were pooled, for a total of6,855 patients comprising the study population. A total of8,381 target lesions were present, of which 451 (5.4%), 2,138(25.5%), and 5,792 (69.1%) were assessed by the angiographiccore laboratory as heavily calcified, moderately calcified, andnone/mildly calcified, respectively. Target lesion calcificationwas severe in 402 patients (5.9%) in whom PCI was per-formed in 550 total lesions; moderate in 1,788 patients(26.1%) in whom PCI was performed in 2,430 total lesions;and none/mild in 4,665 patients (68.1%) in whom PCI was

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performed in 5,829 total lesions. A total of 54 patients hadboth moderately and severely calcified lesions.Patient characteristics, angiographic findings, and treatmentrandomization. As shown in Table 1 and Online Table 1,compared with patients without calcified lesions, patients with

Table 3Angiographic Characteristics and Proceduof Target Lesion Calcification

No/MildCalcification(N ¼ 4,665)

Antithrombotic medication

Bivalirudin monotherapy 1,914/4,665 (41.0)

Bivalirudin þ GPI 901/4,665 (19.3)

Heparin þ GPI 1,850/4,665 (39.7)

Number of lesions treated 1.31 � 0.67

Number of stents implanted 1.31 � 0.74

Drug-eluting stent 3,660/4,609 (79.4)

Lesion level

Baseline QCA

Lesion length, mm 13.0 (10.0–19.0)

RVD, mm 2.79 (2.41–3.15)

MLD, mm 0.53 (0.07–0.89)

Diameter stenosis, % 80.2 (66.3–97.9)

Total occlusion 1,444/5,824 (24.8)

Tortuosity (moderate/severe) 107/5,811 (1.8)

Thrombus 2,144/5,813 (36.9)

Bifurcation present 2,218/5,829 (38.1)

Target vessel

Right coronary artery 2,143/5,818 (36.8)

Left circumflex 1,499/5,818 (25.8)

Left anterior descending 2,155/5,818 (37.0)

2-vessel disease 1,562/4,658 (33.2)

3-vessel disease 1,541/4,658 (33.1)

Extent of disease, mm 33.5 (19.8–53.0)

Final QCA

MLD, mm

In-stent 2.70 (2.37–3.03)

In-segment 2.32 (1.97–2.70)

Residual degree stenosis, %

In-stent 6.7 (3.6–10.5)

In-segment 16.5 (10.7–23.2)

Acute gain, mm

In-stent 2.13 (1.67–2.57)

Vessel level

TIMI flow grade

Baseline TIMI 0/1 1,713/5,810 (29.5)

Baseline TIMI 2 641/5,810 (11.0)

Baseline TIMI 3 3,456/5,810 (59.5)

Final TIMI 0/1 93/5,780 (1.6)

Final TIMI 2 303/5,780 (5.2)

Final TIMI 3 5,384/5,780 (93.1)

Post-PCI complications

Final no reflow 8/5,782 (0.1)

Final perforation 3/5,782 (0.1)

Final dissection 13/3,308 (0.4)

Final abrupt closure 7/5,783 (0.1)

Values are n/N (%), mean � SD, or median (interquartile range).GPI ¼ glycoprotein IIb/IIIa inhibitor; MI ¼ myocardial infarction; MLD ¼ mini

reference vessel diameter; TIMI ¼ Thrombolysis In Myocardial Infarction; TLR ¼

more extensive target lesion calcification were more likely to beolder, have renal insufficiency, lower left ventricular ejectionfraction, and higher white blood cell count at baseline andmore frequently had undergone prior PCI. Target lesioncalcification was more frequent among the STEMI population

ral Outcomes Stratified by the Severity

ModerateCalcification(N ¼ 1,788)

SevereCalcification(N ¼ 402) p Value

735/1,788 (41.1) 173/402 (43.0) 0.73

284/1,788 (15.9) 51/402 (12.7) <0.0001

769/1,788 (43.0) 178/402 (44.3) 0.02

1.40 � 0.75 1.38 � 0.86 <0.0001

1.50 � 0.89 1.53 � 0.96 <0.0001

1,376/1,764 (78.0) 303/380 (79.7) 0.44

14.4 (10.1–21.0) 14.9 (10.0–20.0) <0.0001

2.80 (2.45–3.19) 2.84 (2.43–3.19) 0.08

0.52 (0.00–0.89) 0.44 (0.00–0.84) 0.0003

81.0 (66.6–100.0) 84.3 (67.2–100.0) 0.0004

720/2,428 (29.7) 211/550 (38.4) <0.0001

52/2,422 (2.1) 18/549 (3.3) 0.06

1,073/2,422 (44.3) 299/549 (54.5) <0.0001

1,121/2,430 (46.1) 264/550 (48.0) <0.0001

980/2424 (40.4) 259/549 (47.2) <0.0001

527/2424 (21.7) 92/549 (16.8) <0.0001

907/2424 (37.4) 189/549 (34.4) 0.42

660/1787 (36.9) 136/401 (33.9) 0.04

677/1787 (37.9) 164/401 (40.9) <0.0001

43.0 (25.9–63.3) 46.7 (30.1–70.5) <0.0001

2.71 (2.39–3.05) 2.69 (2.38–3.01) 0.31

2.32 (1.96–2.68) 2.26 (1.87–2.65) 0.02

7.0 (3.3–11.4) 7.14 (2.7–12.3) 0.26

17.7 (11.3–24.6) 18.5 (12.7–30.0) <0.0001

2.17 (1.72–2.65) 2.18 (1.72–2.68) 0.04

869/2,421 (35.9) 255/548 (46.5) <0.0001

325/2,421 (13.4) 69/548 (12.6) 0.008

1,227/2,421 (50.7) 224/548 (40.9) <0.0001

52/2,407 (2.2) 26/548 (4.7) <0.0001

149/2,407 (6.2) 51/548 (9.3) 0.0003

2,206/2,407 (91.6) 471/548 (85.9) <0.0001

7/2,411 (0.3) 5/547 (0.9) 0.001

3/2,408 (0.1) 0/547 (0.0) 0.43

8/1,203 (0.7) 4/213 (1.9) 0.01

9/2,411 (0.4) 6/547 (1.1) <0.0001

mum lumen diameter; PCI ¼ percutaneous coronary intervention; RVD ¼target lesion revascularization.

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Table 4 1-Year Rates of Major Events Stratified by the Severity of Target Lesion Calcification

No/MildCalcification(N ¼ 4,665)

ModerateCalcification(N ¼ 1,788)

SevereCalcification(N ¼ 402) p Value

Moderate/SevereCalcification(N ¼ 2,190) p Value*

Death 128 (2.8) 73 (4.2) 25 (6.3) 0.0001 98 (4.6) 0.0002

Cardiac 83 (1.8) 50 (2.8) 16 (4.0) 0.002 66 (3.1) 0.001

Noncardiac 39 (0.9) 21 (1.3) 8 (2.1) 0.06 29 (1.4) 0.06

MI 326 (7.3) 133 (7.6) 37 (9.4) 0.22 170 (8.0) 0.23

Q-wave 72 (1.6) 49 (2.8) 6 (1.5) 0.005 55 (2.6) 0.005

Non–Q-wave 257 (5.7) 87 (5.0) 31 (7.9) 0.08 118 (5.5) 0.87

Death or MI 430 (9.5) 189 (10.7) 56 (14.1) 0.005 245 (11.3) 0.01

Ischemic TLR 261 (6.0) 140 (8.2) 22 (8.7) 0.002 162 (8.2) 0.002

Ischemic TVR 331 (7.5) 157 (9.2) 31 (11.0) 0.05 188 (9.4) 0.02

MACE 582 (12.9) 269 (15.3) 67 (19.9) 0.003 336 (16.1) 0.001

Stent thrombosis

Definite 78 (1.7) 50 (2.9) 7 (1.9) 0.01 57 (2.7) 0.008

Probable 29 (0.7) 8 (0.5) 2 (0.5) 0.72 10 (0.5) 0.43

Definite/probable 107 (2.5) 58 (3.4) 9 (2.4) 0.08 67 (3.2) 0.047

Values are Kaplan-Meier estimates presented as n (%). *No/mild versus moderate/severe.MACE ¼ major adverse cardiac events; TVR ¼ target vessel revascularization; other abbreviations as in Table 3.

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than in the NSTEACS population. By multivariable analysis,advanced age, male sex, history of hypertension, and STEMIpresentation were independent predictors of moderate/severetarget lesion calcification (Table 2).

Compared with those without calcification, moderatelyand severely calcified lesions were longer, were more oftentotal occlusions and bifurcations, and were more likely tocontain thrombi (Table 3, Online Table 2). Patients withmoderate and severe target lesion calcification also had moreextensive coronary disease, requiring a greater number ofstents implanted. A similar proportion of DES were usedin all groups. Patients with greater target lesion calcificationwere more likely to have suboptimal angiographic resultsafter PCI, with higher residual stenosis, more slow flow, noreflow, dissection, and abrupt closure.Clinical outcomes. As shown in Table 4 and Figures 1 and2, PCI in patients with moderately and severely calcified

Figure 1Adverse Outcomes Through 1 Year Accordingto Severity of Target Lesion Calcification

Comparison of the cumulative event rates through 1 year in patients stratified by

no to mildly, moderately, and severely calcified target lesions. Rates of death,

cardiac death, definite stent thrombosis (ST), ischemia-driven target revasculari-

zation, and major adverse cardiovascular events (MACE) all demonstrated signif-

icant overall trends between the calcification groups. MI ¼ myocardial infarction;

TLR ¼ target lesion revascularization.

lesions was associated with higher unadjusted 1-year rates ofdeath, death/MI, ischemia-driven TLR and target vesselrevascularization, stent thrombosis, and MACE. Among pa-tients with calcified target lesions, event rates tended to begreater in patients with heavy compared with moderatecalcification. Among patients who received >1 stent anddeveloped definite/probable stent thrombosis within 1 year,there were 4 of 9 (44.4%) in the severe calcification group, 33of 58 (56.9%) in the moderate calcification group (37 of 67[55.2%] in the combined moderate/severe calcification group),and 46 of 107 (43%) in the none/mild calcification group (p¼0.11). By multivariable analysis, PCI of moderate/severe targetlesion calcification was independently associated with 1-yearrates of definite stent thrombosis (hazard ratio [HR]: 1.62;95% confidence interval: 1.14 to 2.30; p ¼ 0.007) andischemic TLR (HR: 1.44; 95% confidence interval: 1.17 to1.78; p ¼ 0.0007) but not with death or MI (Table 5).

Discussion

The current report, drawn from a cohort of 6,855 patientsundergoing PCI for ACS (NSTEACS and STEMI) is by farthe largest study to date to specifically evaluate the incidence,predictors, and impact of target lesion calcification on prog-nosis after stent implantation in this high-risk patient pop-ulation. The main results of the present study were as follows:1) target lesions in NSTEACS and STEMI were frequentlycalcified, as assessed by an angiographic core laboratory;2) PCI in patients with moderately and severely calcifiedtarget lesions compared with those with no or mild calcifi-cation was associated with suboptimal angiographic resultsand procedural complications; and 3) PCI of calcified lesionswas independently predictive of adverse ischemic outcomes,including definite stent thrombosis and unplanned ischemia-driven repeat revascularization within 1 year post-PCI, ascompared with patients in whom all target lesions had no oronly mild calcification.

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Figure 2 Time-to-Event Curves Through 1 Year According to the Severity of Target Lesion Calcification

Comparison of the cumulative event rates through 1 year in patients stratified by no to mildly (none/mild) compared with moderately to severely (moderate/severe) calcified

target lesions. (A) All-cause death. (B) Cardiac death. (C) Definite stent thrombosis. (D) Ischemia-driven target lesion revascularization. HR ¼ hazard ratio; other abbreviation

as in Figure 1.

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Lesions responsible for ACS are typically considered tobe soft, lipid rich, friable, and not calcified (19). Contrary tothese expectations, by commonly accepted core laboratoryangiographic criteria, moderately or severely calcified coro-nary lesions were surprisingly frequent in the present study.Indeed, approximately 27% of patients with NSTEACS and38% of patients with STEMI had one or more moderately/severely calcified target lesions requiring PCI. Mostprior randomized DES trials (1–5,20–26) excluded patientswith operator-assessed moderate or severe target lesioncalcification. Nonetheless, 29.4% of the treated lesions inthe ACUITY and HORIZONS-AMI trials were moder-ately or severely calcified as assessed by an independentangiographic core laboratory, evidence that interventionalcardiologists underestimate the severity of calcification.Other contemporary DES studies in which a “real-world”population was enrolled have also reported high rates oftarget lesion calcification. In the COMPARE (Comparisonof the Everolimus-Eluting XIENCE-V Stent With the

Paclitaxel-Eluting TAXUS LIBERTÉ Stent in All-Comers)trial, in which 59.7% of 1,800 enrolled patients had ACS,33.3% of lesions were reported to be calcified (27).

Previous small to moderately sized studies, mostly fromthe BMS era, reported higher rates of peri-proceduralcomplications and/or restenosis after PCI of calcifiedlesions (10–12,28). Surprisingly few reports, however, havecommented on the safety and efficacy of DES treatment ofcalcified lesions. In the largest prior study of 1,537 patientsundergoing PCI of moderately/severely calcified lesions(653 of whom received DES by operator preference), DESuse was associated with lower rates of adverse ischemicoutcomes than BMS (12). No prior study has examined theimpact of target lesion calcification specifically in a high-riskACS population, in whom 1-year rates of cardiac death andstent thrombosis are increased. The present large-scale studyof 6,855 patients with ACS undergoing PCI, approximately80% of whom were treated with DES, demonstratedthat treatment of calcified target lesions remains a strong

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Table 5 Independent Predictors of 1-Year Clinical Outcomes

Hazard Ratio (95% CI) p Value

All-cause death

Moderate/severe target lesioncalcification

1.10 (0.81–1.48) 0.55

Age (per 10-yr increase) 1.73 (1.47– 2.02) <0.0001

Diabetes 2.10 (1.56–2.83) <0.0001

Baseline renal insufficiency 1.85 (1.30–2.64) 0.0007

Thrombus 1.44 (1.07–1.93) 0.02

Cardiac death

Moderate/severe target lesioncalcification

1.03 (0.70–1.50) 0.89

Age (per 10-yr increase) 1.86 (1.59–2.17) <0.0001

Diabetes 2.06 (1.42–3.00) 0.0002

Baseline minimal luminal diameter 0.47 (0.29–0.77) 0.002

Randomized to bivalirudin 0.68 (0.47–0.98) 0.04

Extent of disease (per 1-mm increase) 1.01 (1.00–1.01) 0.05

MI

Moderate/severe target lesioncalcification

1.06 (0.86–1.30) 0.58

Baseline renal insufficiency 1.75 (1.41–2.17) <0.0001

Prior CABG surgery 1.61 (1.27–2.05) <0.0001

Lesion length 1.01 (1.01–1.02) 0.0002

Number of attempted vessels 1.39 (1.13–1.72) 0.002

Thrombus 0.75 (0.59–0.92) 0.006

Prior percutaneous coronaryintervention

1.33 (1.06–1.67) 0.01

Previous MI 1.30 (1.03–1.63) 0.03

Definite stent thrombosis

Moderate/severe target lesioncalcification

1.62 (1.14–2.30) 0.007

Age (per 10-yr increase) 0.85 (0.74–0.98) 0.003

Baseline minimal luminal diameter 0.62 (0.41–0.95) 0.03

Ischemia-driven TLR

Moderate/severe target lesioncalcification

1.44 (1.17–1.78) 0.0007

Prior PCI 1.80 (1.46–2.21) <0.0001

Diabetes (insulin treated) 1.80 (1.31–2.45) 0.0002

Age (per 10-yr increase) 0.87 (0.78–0.96) 0.002

Drug-eluting stent 0.78 (0.62–0.99) 0.04

Other covariates included in the models all-cause death: drug-eluting stent, male sex, hypertension,previous MI, previous PCI, previous CABG, number of attempted vessels, any left anterior descendingartery (LAD) attempted, randomized to bivalirudin, extent of disease, lesion length, baseline RVD,baseline MLD, and modified American College of Cardiology (MACC)/American Heart Association>B2; cardiac death: drug-eluting stent, male sex, hypertension, previous MI, and number ofattempted vessels;myocardial infarction: drug-eluting stent, age, male sex, diabetes, hypertension,any LAD attempted, randomized to bivalirudin, extent of disease, baseline RVD, baseline MLD, MACC>B2, and left ventricular ejection fraction (LVEF) (core laboratory assessed); ischemia-driven TLR:male sex, diabetes, current cigarette smoker, hypertension, previous MI, previous CABG, number ofattempted vessels, any LAD attempted, baseline creatinine clearance <60 ml/min, baseline WBCcount, randomized to bivalirudin, randomized to heparin, LVEF (core laboratory assessed), extent ofdisease, ostial lesion, lesion length, presence of thrombus, TIMI 0/1, baseline RVD, baseline degreestenosis, baselineMLD,MACC>B2, biomarker positive, and final no reflow; definite stent thrombosis:drug-eluting stent, male sex, diabetes, hypertension, previous MI, number of attempted vessels,randomized to bivalirudin, and extent of disease.Abbreviations as in Tables 2 and 3.

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predictor for adverse safety and efficacy outcomes in thecontemporary PCI era. After adjustment for imbalances inmeasured confounders, treatment of calcified target lesionscompared with no calcification was independently associatedwith a 62% increase in stent thrombosis and a 44% increasein ischemic TLR within 1 year of the procedure.

Several mechanisms may explain the poor outcomes afterPCI of calcified lesions. First, it is well known that stentunderexpansion is frequent in heavily calcified lesions andmay increase the risk for restenosis and stent thrombosis(29–31). As shown in the current report, the presence ofcalcifications was associated with an increase in the rate ofischemic events at 1 year, especially inside the first 30 days(Fig. 1, Online Fig. 1), reflecting the detrimental impactof calcifications during stent implantation and resulting inan increase in acute and subacute stent failure. Second,difficulty in delivering stents may lead to structural devicedamage and, in the case of DES, may result in tearing orstripping the polymer, creating a prothrombotic/inflam-matory nidus and/or promoting neointimal proliferation(7). Third, a relationship between the severity of cal-cification and blood thrombogenicity has been reported.Borissoff et al. (32) demonstrated a positive independentassociation between greater in vivo thrombin generation andthe presence and severity of coronary calcification. Similarly,Chirumamilla et al. (33) showed that patients treated withaspirin and clopidogrel in whom severe coronary calcifica-tion was versus was not visualized by intravascular ultra-sound (IVUS) had higher platelet reactivity after PCI.Finally, several genetic loci have recently been associatedwith the development of vascular calcification and clinicalevents such as myocardial infarction (34,35). In the presentstudy, PCI of calcified lesions was associated with subop-timal post-PCI results, including the more frequent oc-currence of serious angiographic complications such as noreflow, dissection, and abrupt closure and lower final ratesof Thrombolysis in Myocardial Infarction flow grade 3. PCIof calcified lesions in the setting of high platelet reactivity(as is typically present in ACS [36]) may represent theperfect storm for both procedural complications as well asearly and late stent thrombosis. Inclusive of the above, thepresence of coronary calcification may represent a marker ofpoorer outcome and may not be the entire cause of worseoutcome at follow-up. Although target lesion calcificationwas identified as an independent predictor of stentthrombosis and TLR, it is possible that even if technicaladvances were to obviate the negative consequences ofcalcification itself, the outcomes of these patients may stillbe worse.

Advanced age, male sex, hypertension, and STEMI pre-sentation were independently associated with the presence ofcalcified target lesions in the current study. In prior studiesof patients with stable coronary artery disease, in addition toolder age, the extent of atherosclerosis and prior CABGwere identified as independent predictors of calcification(37,38). This discrepancy may in part be explained by thedifferent nature of the study populations (ACS vs. stablecoronary disease). In addition, patients with chronic kidneydisease (whether or not requiring dialysis) frequently haveextensive coronary calcification, in part due to secondaryhyperparathyroidism (39). This population was underrep-resented in our study population.

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Whether lesion decalcification prior to stent implantationcan improve event-free survival of patients with calcifiedlesions is an area of ongoing investigation. Despite initialenthusiasm (40–44), the use of rotational atherectomy priorto paclitaxel-eluting stent implantation in severely calcifiedlesions did not improve 9-month clinical or angiographicoutcomes in the ROTAXUS (Rotational Atherectomy Priorto Taxus Stent Treatment for Complex Native CoronaryArtery Disease) randomized trial (45). Although rotationalatherectomy facilitated stent delivery and allowed a higherrate of immediate procedural success in this study, in-stent late loss at 9 months was greater after rotationalatherectomy compared with lesion preparation with con-ventional balloon angioplasty alone prior to stenting (0.44 �0.58 mm vs. 0.31 � 0.52 mm; p ¼ 0.04). These data areconsistent with the results from studies in the balloon an-gioplasty and BMS eras, which reported higher rates ofrestenosis with rotational atherectomy (40,43,46–53).Greater neointimal hyperplasia with rotational atherectomymay be due to thermal injury, platelet activation, and medialinjury (54,55). Moreover, use of rotational atherectomy inthe setting of NSTEACS and STEMI in which thrombus isalmost always present (even if angiographically unapparent)is considered an absolute contraindication. It is not thereforesurprising that only 48 patients (0.7%) underwent rotationalatherectomy in the present study. Ongoing and plannedstudies will determine whether the prognosis after PCI ofcalcified lesions can be improved by use of novel, less trau-matic devices for plaque debulking (56), perhaps coupledwith current-generation metallic DES or bioresorbablevascular scaffolds, both of which are more potent thanpaclitaxel-eluting stents at reducing restenosis.Study limitations. The fact that an experienced indepen-dent angiographic core laboratory analyzed all 6,855 an-giograms in the present report is a major strength, removingthe element of operator variability and bias inherent in allprior studies. The large sample size of the present analysisalso affords robust identification of predictors of target lesioncalcification and adverse events. Independent adjudicationof clinical events blinded to the angiographic findings isalso notable. However, as an observational post-hoc analysis,the present analysis can only identify correlations, notprove causality. Despite adjustment for measured covari-ates, residual confounding may be present. The results ofthe present study should therefore be considered hypothe-sis generating. Even though the degree of calcificationwas assessed by experienced angiographic core laboratorytechnicians, the severity of calcification is underestimatedby angiography compared with IVUS (57,58). The presentstudy was underpowered to determine whether PCI ofseverely calcified as compared with moderately calcifiedtarget lesions was an independent predictor of adverse out-comes, as suggested in unadjusted analyses. Moreover, byarbitrary convention, only heavy calcification contributesto the SYNTAX score (59), a definition equivalent to thatof severe calcification by QCA (18). The present report

suggests that in addition to heavy or severe calcification,moderate calcification, as assessed by an experienced an-giographic core laboratory, also has significant impact onischemic outcomes and therefore might be included in futurerisk models. Prospective validation of this concept isrequired. The studies pooled in the current report includedimplantation of approximately 20% of BMS and 80% first-generation DES. Given recent reports showing superioroutcomes with second-generation DES (60), our findingsmay have been different had more contemporary stents beenused. However, whether second-generation DES performbetter in severely calcified lesions has yet to be demonstrated.IVUS was not required in the present study, and whether itsuse would improve risk stratification or treatment outcomesin calcified ACS lesions is unknown. Finally, the currentreport was limited to a 1-year follow-up after stent im-plantation. Longer-term patient assessment is required todetermine if the adverse outcomes after PCI of calcifiedtarget lesions continue to accrue over time.

Conclusions

Target lesions in patients with NSTEACS and STEMI arefrequently moderately or severely calcified, and PCI of suchlesions was independently predictive of stent thrombosis andunplanned ischemia-driven TLR at 1 year, as compared withtreatment of lesions with absent or only mild calcification.Novel approaches are urgently needed to improve outcomesof high-risk patients with ACS with calcified lesionsundergoing PCI.

Reprint requests and correspondence: Dr. Gregg W. Stone,Columbia University Medical Center, Cardiovascular ResearchFoundation, 111 East. 59th Street, 11th Floor, New York, NewYork 10022. E-mail: [email protected].

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Key Words: coronary calcification - NSTEMI - PCI - STEMI.

APPENDIX

For supplemental tables and a figure, please see the online version of thisarticle.