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Comparison of Effectiveness of Atorvastatin 10 mg Versus 80 mg inReducing Major Cardiovascular Events and Repeat

Revascularization in Patients With Previous PercutaneousCoronary Intervention (Post Hoc Analysis of the Treating

to New Targets [TNT] Study)

Colleen Johnson, MDa, David D. Waters, MDa,*, David A. DeMicco, PharmDb,Andrei Breazna, PhDb, Vera Bittner, MDd, Heiner Greten, MDe, Scott M. Grundy, MD, PhDf, and

John C. LaRosa, MDc, for the Treating to New Targets Steering Committee and Investigators

The Treating to New Targets (TNT) study demonstrated that intensive atorvastatintherapy to achieve low-density lipoprotein cholesterol concentrations well below recom-mended target levels provides an incremental clinical benefit in patients with stablecoronary artery disease. This post hoc analysis of the TNT study was conducted toinvestigate whether this benefit extends to patients with previous percutaneous coronaryintervention (PCI). A total of 10,001 patients with clinically evident coronary arterydisease, including 5,407 patients with previous PCI, were randomized to atorvastatin 10 or80 mg/day and followed for a median of 4.9 years. The primary end point was theoccurrence of a first major cardiovascular event. Revascularization, a component of asecondary end point, was also examined. In patients with previous PCI, mean low-densitylipoprotein cholesterol levels at study end were 79.5 mg/dl in the 80-mg arm and 100.8mg/dl in the 10-mg arm. First major cardiovascular events occurred in 230 patients (8.6%)receiving high-dose atorvastatin and 289 patients (10.6%) receiving low-dose atorvastatin(hazard ratio 0.79, 95% confidence interval 0.67 to 0.94, p � 0.008). Repeat revasculariza-tion during follow-up (PCI or coronary artery bypass grafting) was performed in 466patients (17.3%) in the 80-mg arm and 624 patients (22.9%) in the 10-mg arm (hazard ratio0.73, 95% confidence interval 0.65 to 0.82, p <0.0001). In conclusion, intensive lipidlowering to a mean low-density lipoprotein cholesterol level of 79.5 mg/dl (2.1 mmol/L)with atorvastatin 80 mg/day in patients with previous PCI reduces major cardiovascularevents by 21% and repeat revascularizations by 27% compared with a less intensivelipid-lowering regimen. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102:

1312–1317)

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ercutaneous coronary intervention (PCI) is commonly per-ormed in patients with acute coronary syndromes and inatients with stable coronary disease. The coronary anat-my of patients with previous PCI differs from that of otheroronary patients; severe coronary stenoses have usuallyeen eliminated, but the risk for restenosis and stent throm-osis has been introduced. Although statins have beenhown to stabilize and slow the progression of coronaryesions, they are not generally thought to have an effect

aUniversity of California, San Francisco, San Francisco, California;Pfizer, Inc., New York, New York; cState University of New York Healthcience Center, Brooklyn, New York; dUniversity of Alabama at Birming-am, Birmingham, Alabama; eHanseatisches Herzzentrum, Asklepioslinik St. Georg, Hamburg, Germany; and fUniversity of Texas South-estern Medical Center, Dallas, Texas. Manuscript received May 30,008; revised manuscript received and accepted July 13, 2008.

The Treating to New Targets study was funded by Pfizer, Inc., Nework, New York.

*Corresponding author: Tel: 415-206-8320; fax: 415-206-5100.

EE-mail address: dwaters@medsfgh.ucsf.edu (D.D. Waters).

002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2008.07.023

n restenosis or stent thrombosis. Patients with previousCI (and their physicians) may perceive that they are at

ow risk because of their procedures and thus not adhereigorously to secondary prevention measures, includingtatins. On the basis of the findings of recent studies,ncluding the Treating to New Targets (TNT) study,ggressive lowering of low-density lipoprotein (LDL)holesterol to 70 to 80 mg/dl or lower in coronary pa-ients decreases major cardiovascular events.1–3 How-ver, the role of aggressive lipid lowering in patients withrevious PCI may not be clearly defined. Of the 10,001atients in TNT, 5,407 had previously undergone PCI.his report describes the outcomes of this large group ofatients over 4.9 years of follow-up.

ethods

he design of the TNT study has been described in detailreviously.1,4 All patients gave written informed consent,nd the local research ethics committee or institutional re-iew board at each participating center approved the study.

ligible participants were men and women aged 35 to 75

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1313Coronary Artery Disease/Intensive Lipid Lowering and Previous PC

ears who had clinically evident coronary artery diseaseCAD), defined as �1 of the following: previous myocar-ial infarction (MI), previous or current angina with objec-ive evidence of atherosclerotic CAD, and a history oforonary revascularization. A history of PCI was deter-ined by patient self-report. The exclusion criteria have

lso been described previously.1,4 Randomization occurredrom July 1998 to December 1999.

Any previously prescribed lipid-lowering medicationsere discontinued during screening, and all participants

ompleted a washout period of 1 to 8 weeks. All patientsith LDL cholesterol levels of 130 to 250 mg/dl under-ent an 8-week run-in period of open-label treatmentith atorvastatin 10 mg/day. At the end of the run-inhase, 10,001 participants with LDL levels �130 mg/dl�3.4 mmol/L) were randomized in a double-blind fash-on to atorvastatin 10 or 80 mg/day. Follow-up visitsccurred at week 12; at months 6, 9, and 12 in the firstear; and every 6 months thereafter. Patients were fol-owed for a median of 4.9 years.

The primary end point was the time to the first occur-ence of a major cardiovascular event, defined as death fromAD, nonfatal non-procedure-related MI, resuscitated car-iac arrest, and fatal or nonfatal stroke. Secondary endoints included a major coronary event (defined as deathrom CAD, nonfatal non-procedure-related MI, and resus-itated cardiac arrest), a cerebrovascular event, hospitaliza-ion for heart failure, peripheral artery disease, death fromny cause, any cardiovascular event, and any coronary eventincluding revascularization).

All analyses were performed on an intention-to-treatasis. All randomized patients who were dispensed 1 dose

able 1aseline characteristics of patients with and without previousercutaneous coronary intervention

ariable No Previous PCI Previous PCI(n � 4,594) (n � 5,407)

ge (yrs) 61.9 � 8.6 60.3 � 9.0omen 837 (18.2%) 1,065 (19.7%)hite 4,296 (93.5%) 5,114 (94.6%)

ody mass index (kg/m2) 28.4 � 4.5 28.6 � 4.6urrent smokers 507 (11%) 834 (15.4%)ast smokers 2,959 (64.4%) 3,363 (62.2%)ypertension 2,443 (53.2%) 2,969 (54.9%)iabetes mellitus 729 (15.9%) 772 (14.3%)ngina pectoris 3,581 (77.9%) 4,569 (84.5%)I 2,627 (57.2%) 3,206 (59.3%)ABG surgery 3,198 (69.6%) 1,456 (26.9%)eripheral vascular disease 575 (12.5%) 598 (11.1%)ongestive heart failure 401 (8.7%) 380 (7.0%)erebrovascular accident 250 (5.4%) 267 (4.9%)DL cholesterol (mg/dl)* 97.8 � 17.5 97.3 � 17.7otal cholesterol (mg/dl)* 174.8 � 23.7 174.7 � 24.0igh-density lipoproteincholesterol (mg/dl)*

47.5 � 11.2 47.2 � 10.8

riglycerides (mg/dl)* 133.0 (43–573) 135.0 (37–1,170)

Data are expressed as mean � SD, number (percentage), or medianrange).

* At the end of the run-in period, on atorvastatin 10 mg.

f the study drug were included in the analyses. The primary l

nd secondary composite end points were analyzed from theime of first dose of study drug to the first event accordingo the Kaplan-Meier method. We calculated the frequencyf the primary and secondary efficacy outcomes, andorresponding hazard ratios (HRs) with 95% confidencentervals (CIs), during our analysis of differences be-ween post-PCI patients and non-PCI patients. We re-eated this analysis in the subset of post-PCI patients tossess differences between low-dose and high-dose ator-astatin treatment groups and determine whether high-ose atorvastatin decreased the occurrence of primarynd secondary outcomes.

esults

mong the TNT study population of 10,001 patients, 5,40754%) had previously undergone PCI. The patients with andithout previous PCI are listed in Table 1. Patients withrevious PCI were slightly more likely to be current smok-rs and had a greater prevalence of ongoing angina but wereuch less likely to have had coronary artery bypass graft

CABG) surgery.Of the 5,407 patients with previous PCI, 2,719 patients

ere randomized to atorvastatin 10 mg/day and 2,688 totorvastatin 80 mg/day. The baseline characteristics of these

groups were similar, as listed in Table 2. The meanntervals between previous PCI and study screening were.1 � 2.4 years in the low-dose atorvastatin group and.1 � 2.5 years in the high-dose atorvastatin group.

The lipid levels in PCI patients at baseline, after the-week run-in period with atorvastatin 10 mg/day, are listedn Table 1. Baseline lipid levels of the PCI patients wereimilar between the 80- and 10-mg atorvastatin groups, as

able 2aseline characteristics of randomized patients with previousercutaneous coronary intervention according to treatment group

ariable Atorvastatin 10 mg Atorvastatin 80 mg(n � 2,719) (n � 2,688)

ge (yrs) 60.1 � 9.1 60.4 � 8.9omen 551 (20.3%) 514 (19.1%)hite 2,575 (94.7%) 2,539 (94.5%)

ody mass index (kg/m2) 28.7 � 4.8 28.5 � 4.5urrent smokers 400 (14.7%) 434 (16.1%)ast smokers 1,716 (63.1%) 1,647 (61.3%)ypertension 1,495 (55.0%) 1,474 (54.8%)iabetes mellitus 370 (13.6%) 402 (15.0%)ngina pectoris 2,294 (84.4%) 2,275 (84.6%)I 1,609 (59.2%) 1,597 (59.4%)ABG surgery 739 (27.2%) 717 (26.7%)eripheral vascular disease 292 (10.7%) 306 (11.4%)ongestive heart failure 197 (7.2%) 183 (6.8%)erebrovascular accident 137 (5.0%) 130 (4.8%)DL cholesterol (mg/dl)* 97.5 � 17.7 97.0 � 17.6otal cholesterol (mg/dl)* 174.8 � 24.2 174.7 � 23.8igh-density lipoproteincholesterol (mg/dl)*

47.1 � 10.7 47.2 � 10.9

riglycerides (mg/dl)* 134.0 (37–1,170) 136.5 (37–636)

Data are expressed as mean � SD, number (percentage), or medianrange).

* At the end of the run-in period, on atorvastatin 10 mg.

isted in Table 2.

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1314 The American Journal of Cardiology (www.AJConline.org)

In the atorvastatin 80 mg group, LDL cholesterol waseduced from 162.7 mg/dl before the 8-week run-in periodo 79.5 mg/dl at study end, a 51% reduction. Over the sameeriod, LDL cholesterol in the atorvastatin 10 mg groupecreased from 163.1 to 100.8 mg/dl, a 38% reduction.igh-density lipoprotein cholesterol levels were similar in

he high- and low-dose atorvastatin groups during treat-ent.First major cardiovascular events (cardiac death, MI,

esuscitated cardiac arrest, or stroke) occurred in 519 pa-ients (9.6%) who had undergone PCI before study entrynd in 463 patients (10.1%) without previous PCI (HR 0.94,5% CI 0.83 to 1.07, p � 0.36).

Among PCI patients, primary end point events occurredn 230 patients (8.6%) in the atorvastatin 80 mg groupompared with 289 patients (10.6%) in the 10-mg group,orresponding to a 21% relative risk reduction and a 2.1%bsolute risk reduction (HR 0.79, 95% CI 0.67 to 0.94, p �.008). The Kaplan-Meier curves for the primary outcomen the 2 treatment groups of PCI patients are shown inigure 1.

During follow-up, 466 patients (17.3%) in the high-dose

HR = 0.79 (95% CI 0.67, 0.94)P=0.008

Atorvastatin 10 mg (n=2719)Atorvastatin 80 mg (n=2688)

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igure 1. Cumulative incidence of major cardiovascular (CV) events inatients with previous PCI.

HR = 0.73 (95% CI 0.65, 0.82)P<0.0001

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igure 2. Cumulative incidence of repeat revascularization in patients withrevious PCI.

torvastatin group and 624 patients (22.9%) in the low-dose p

torvastatin group underwent repeat coronary revasculariza-ion, either CABG surgery or PCI, representing a 27%elative risk reduction and a 5.6% absolute risk reductionHR 0.73, 95% CI 0.65 to 0.82, p �0.0001). The Kaplan-

eier curves for this outcome are shown in Figure 2. Therst revascularization during follow-up was CABG sur-ery in 98 of the 466 patients in the 80-mg group and in26 of the 624 patients in the 10-mg group (21.0% vs0.2%, p � NS).

The combined end point of a major cardiovascular eventr coronary revascularization occurred in 594 patients22.1%) in the high-dose atorvastatin group compared with71 patients (28.4%) in the low-dose atorvastatin group, a5% relative risk reduction and a 6.3% absolute risk reduc-ion (HR 0.75, 95% CI 0.67 to 0.83, p �0.0001), as shownn Figure 3. The number of PCI patients needed to treat with0 mg/day instead of 10 mg/day of atorvastatin over the 4.9ears of follow-up to prevent major cardiovascular events ororonary revascularization was 16.

There was no difference in the rates of documentedngina between the 10-mg (14.0%) and 80-mg (13.9%)torvastatin groups.

Patients in the 2 treatment groups were divided intouintiles according to their LDL cholesterol levels at 3onths, as listed in Table 3. The mean LDL cholesterol

evel in the highest quintile was 121 mg/dl, and that in theowest quintile was 54 mg/dl. A stepwise reduction inajor cardiovascular events was seen from the highest to

he lowest quintile of LDL cholesterol, from 11.7% to.6% (p �0.001). A similar pattern of event reductionas seen for repeat revascularization, from 25.2% to5.1% (p �0.001).

Among the 5,407 patients with previous PCI, 1,456 hadlso had previous CABG surgery. As depicted in Figure 4,he rates of major cardiovascular events and of revascular-zation during follow-up were much higher in the groupith previous PCI and previous CABG surgery than in theroup with previous PCI alone. Nevertheless, the relativeeductions in major cardiovascular events and repeat revas-ularization with atorvastatin 80 mg compared with 10 mgere quite similar in previous PCI patients with and without

HR = 0.75 (95% CI: 0.67, 0.83)p <0.0001

Atorvastatin 10 mg (n = 2719)Atorvastatin 80 mg (n = 2688)

Relative risk reduction = 25%

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igure 3. Cumulative incidence of major cardiovascular (CV) events andevascularization in patients with previous PCI.

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1315Coronary Artery Disease/Intensive Lipid Lowering and Previous PC

In the cohort with PCI at baseline, discontinuations fromherapy because of treatment-related adverse events duringhe 4.9 years of follow-up occurred in 130 patients (4.8%)n the atorvastatin 80 mg group and in 65 patients (2.4%) in thetorvastatin 10 mg group. Treatment-related myalgia waseported in 1.6% of patients in the high-dose atorvastatinroup and in 1.4% of patients in the low-dose atorvastatinroup. No post-PCI patient experienced a persistent eleva-ion of creatine phosphokinase, defined as 2 consecutive mea-urements obtained within 4 to 10 days that were �10 timeshe upper limit of the normal range. Persistent elevations inlanine aminotransferase or aspartate aminotransferase levelshat were �3 times the upper limit of normal occurred in 1.1%f patients in the high-dose atorvastatin group and 0.2% ofatients in the low-dose atorvastatin group.

iscussion

hese results demonstrate that patients with previous PCI

igure 4. Relative risk and 95% CIs for major cardiovascular (CV) events, rrevious PCI and with and without previous CABG surgery. The reductionimilar across the 4 subgroups.

able 3vent rates according to on-treatment low-density lipoprotein cholesterol

ariable

�64

ean LDL cholesterol level (mg/dl) 54o. of patients in 10-mg/80-mg groups 60/957ajor cardiovascular event* 67 (6.6%)evascularization (CABG surgery or PCI)* 154 (15.1%)ajor cardiovascular event or revascularization* 193 (19.0%)

* p �0.0001.

ho have their LDL cholesterol levels lowered to about 80 s

g/dl with atorvastatin 80 mg/day have significantly betterutcomes than those who have their LDL cholesterol levelsowered to about 100 mg/dl with atorvastatin 10 mg/day.ompared with the less aggressively treated patients, those

n the atorvastatin 80 mg group experienced a 21% reduc-ion in the relative risk for a major cardiovascular event and

27% reduction in the relative risk for repeat coronaryevascularization (either CABG surgery or PCI) during aedian follow-up period of 4.9 years. The number needed

o treat with atorvastatin 80 mg/day instead of 10 mg/day torevent 1 of these events was 16.

Patients who have undergone successful PCI are widelyssumed to be at relatively low risk, at least compared withther patients with CAD. As shown in Figure 4, this wasrue in TNT for patients with previous PCI without previousABG surgery, in whom the event rates were lower than thevent rates in patients without any previous revasculariza-ion or the event rates in patients with previous CABG

arization (revasc), and the combination of both in patients with and withoutts with 80 mg compared with 10 mg of atorvastatin (ATV) was relatively

patients with percutaneous coronary intervention

Quintiles of LDL Cholesterol Level (mg/dl)

64–76 77–89 90–104 �105

70 83 96 12102/760 573/514 775/251 957/138

8 (8.3%) 101 (9.3%) 116 (11.3%) 128 (11.7%)7 (16.7%) 227 (20.9%) 233 (22.7%) 276 (25.2%)8 (21.5%) 270 (24.8%) 302 (29.4%) 336 (30.7%)

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urgery. We have previously reported that TNT patients

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1316 The American Journal of Cardiology (www.AJConline.org)

ith previous CABG surgery have a high event rate anderive great benefit from being treated with 80 mg rather 10g of atorvastatin.5 Patients with histories of previousABGs surgery and PCI have the highest event rate of thegroups, probably because they have more extensive cor-

nary disease of longer duration.Although the event rate is relatively low in post-PCI

atients without previous CABG surgery, it is still substan-ial if repeat revascularization is included. The effect ofggressive treatment is also substantial: primary cardiovas-ular events or revascularization occurred during follow-upn 26% of patients in the 10-mg group and 20.4% of patientsn the 80-mg group.

Large clinical trials have shown that statins do notrevent restenosis after balloon angioplasty.6 – 8 How-ver, statins have been demonstrated to reduce majordverse cardiac events after PCI.9,10 The Lescol Interven-ion Prevention Study (LIPS) randomized 1,677 patientsfter PCI to either fluvastatin 80 mg/day or placebo andollowed them for a median of 3.9 years.9 The compositerimary end point, defined as cardiac death, nonfatal MI, oreintervention procedure, occurred in 21.4% of the fluva-tatin patients and 26.7% of the placebo patients (HR 0.78,5% CI 0.64 to 0.95, p � 0.01). No large studies haveompared different statins, or 2 doses of the same statin, inatients with previous PCI.

As listed in Table 3, the major cardiovascular eventate and the revascularization rate were closely related toDL cholesterol levels during follow-up. Stepwise re-uctions in events were apparent down to the lowest LDLholesterol quintile, in which the mean LDL cholesterolevel was 54 mg/dl. A similar relation between on-treat-ent LDL cholesterol and events was reported in the

ntire TNT cohort.11

The progression of lesions that were originally notevere enough to require PCI is common during theong-term follow-up of PCI patients12,13 and is likely toe the main cause of coronary events now that restenosiss no longer a major problem. More aggressive LDLholesterol lowering with high doses of a potent statinlows the progression of these early lesions comparedith less aggressive statin treatment, as shown by intra-

oronary ultrasound.14 The better outcome in the atorva-tatin 80 mg group in TNT is probably related to thisechanism, in PCI patients and in the entire population.

mproved plaque stability may also contribute to theeduction in events.15,16

The main limitation of this study is that data related toCI were not collected at the time of study enrollment.hus, we have no information as to the number of treated

esions per patient or even as to whether or not stents weresed. Patients were enrolled in 1998 and 1999, and the meannterval between PCI and enrollment was 2.4 years; thus, aubstantial proportion of patients probably received balloonngioplasty only. The frequency and type of complicationsfter PCI have changed since the TNT patients underwentCI. However, many patients from that era are still avail-ble for follow-up.

This study does not provide information on the effect ofreatment during the early period after PCI, because patients

ere only enrolled after a mean interval of 2.4 years. The

ndication for PCI is often an acute coronary syndrome, andigh-dose atorvastatin has been shown to reduce eventsfter acute coronary syndromes in 2 trials.3,17 The TNTohort consisted primarily of Caucasian men. Whether sim-lar results would have been found in other racial groups isnknown.

cknowledgment: A full list of TNT investigators has beenublished previously.9

1. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC,Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treatingto New Targets (TNT) Investigators. Intensive lipid lowering withatorvastatin in patients with stable coronary disease. N Engl J Med2005;352:1425–1435.

2. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ,Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J, forthe Incremental Decrease in End Points Through Aggressive LipidLowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dosesimvastatin for secondary prevention after myocardial infarction: theIDEAL study: a randomized controlled trial. JAMA 2005;294:2437–2445.

3. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, BelderR, Joyal SV, Hill KA, Pfeffer MA, Skene A, for the Pravastatin orAtorvastatin Evaluation and Infection Therapy–Thrombolysis In Myo-cardial Infarction 22 Investigators. Intensive versus moderate lipidlowering with statins after acute coronary syndromes. N Engl J Med2004;350:1495–1504.

4. Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK,Shear C; Treating to New Targets (TNT) Investigators. Treating toNew Targets (TNT) study: does lowering low-density lipoproteincholesterol levels below currently recommended guidelines yield in-cremental clinical benefit? Am J Cardiol 2004;93:154–158.

5. Shah SJ, Waters DD, Barter P, Kastelein JJP, Shepherd J, Wenger NK,DeMicco DA, Breazna A, LaRosa JC. Intensive lipid-lowering withatorvastatin for secondary prevention in patients following coronaryartery bypass surgery. J Am Coll Cardiol 2008;51:1938–1943.

6. Weintraub WS, Boccuzzi SJ, Klein JL, Kosinski AS, King SB III,Ivanhoe R, Cedarholm JC, Stillabower ME, Talley JD, DeMaio SJ, etal, for the Lovastatin Restenosis Trial Study Group. Lack of effect oflovastatin on restenosis after coronary angioplasty. N Engl J Med1994;331:1331–1337.

7. Bertrand ME, McFadden EP, Fruchart JC, Van Belle E, Commeau P,Grollier G, Bassand JP, Machecourt J, Cassagnes J, Mossard JM, et al;PREDICT Trial Investigators. Effect of pravastatin on angiographicrestenosis after coronary balloon angioplasty. J Am Coll Cardiol 1997;30:863–869.

8. Serruys PW, Foley DP, Jackson G, Bonnier H, Macaya C, Vrolix M,Branzi A, Shepherd J, Suryapranata H, de Feyter PJ, et al. A random-ized placebo-controlled trial of fluvastatin for prevention of restenosisafter successful coronary balloon angioplasty; final results of the Flu-vastatin Angiographic Restenosis (FLARE) trial. Eur Heart J 1999;20:58–69.

9. Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M,Branzi A, Bertolami MC, Jackson G, Strauss B, Meier B. Fluvastatinfor prevention of cardiac events following successful first percutane-ous coronary intervention: a randomized controlled trial. JAMA 2002;287:3215–3222.

0. Mood GR, Bavry AA, Roukoz H, Bhatt DL. Meta-analysis of therole of statin therapy in reducing myocardial infarction followingelective percutaneous coronary intervention. Am J Cardiol 2007;100:919 –923.

1. LaRosa JC, Grundy SM, Kastelein JJ, Kostis JB, Greten H; Treating toNew Targets (TNT) Steering Committee and Investigators. Safety andefficacy of atorvastatin-induced very low-density lipoprotein choles-terol levels in patients with coronary heart disease (a post hoc analysisof the Treating to New Targets [TNT] study). Am J Cardiol 2007;100:747–752.

2. Glaser R, Selzer F, Faxon DP, Laskey WK, Cohen HA, Slater J, Detre

KM, Wilensky RL. Clinical progression of incidental, asymptomatic

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1317Coronary Artery Disease/Intensive Lipid Lowering and Previous PC

lesions discovered during culprit vessel coronary intervention.Circulation 2005;111:143–149.

3. Lehmann KG, Maas AC, van Domburg R, de Feyter PJ, van den BrandM, Serruys PW. Repeat interventions as a long-term treatment strategyin the management of progressive coronary artery disease. J Am CollCardiol 1996;27:1398–1405.

4. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, VogelRA, Crowe T, Howard G, Cooper CJ, Brodie B, et al: REVERSALInvestigators. Effect of intensive compared with moderate lipid-low-ering therapy on progression of coronary atherosclerosis: a randomizedcontrolled trial. JAMA 2004;291:1071–1080.

5. Takano M, Mizuno K, Yokoyama S, Seimiya K, Ishibashi F, Oka-

matsu K, Uemura R. Changes in coronary plaque color and morphol-

ogy by lipid-lowering therapy with atorvastatin: serial evaluation bycoronary angioscopy. J Am Coll Cardiol 2003;42:680–686.

6. Yokoyama M, Komiyama N, Courtney BK, Nakayama T, NamikawaS, Kuriyama N, Koizumi T, Nameki M, Fitzgerald PJ, Komuro I.Plasma low-density lipoprotein reduction and structural effects oncoronary atherosclerotic plaques by atorvastatin as clinically assessedwith intravascular ultrasound radio-frequency signal analysis: a ran-domized prospective study. Am Heart J 2005;150:287e1–287e7.

7. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, WatersD, Zeiher A, Chaitman BR, Leslie S, Stern T. Effects of atorvastatin onearly recurrent ischemic events in acute coronary syndromes. TheMIRACL study: a randomized controlled trial. JAMA 2001;265:1711–

1718.