Archives of Cardiovascular Disease (2008) 101, 399406

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CLINICAL RESEARCH

Effects of rosuvastatin and atorvastatin on the apolipoprotein B/apolipoprotein A-1 ratio in patients with an acute coronary syndrome: The CENTAURUS trial design
Effet de la rosuvastatine et de latorvastatine sur lApoB/ApoA-1 chez les patients avec syndrome coronaire aigu (tude CENTAURUS) Jean-Marc Lablanche a, Nicolas Danchin b, Michel Farnier c, Alain Tedgui d, Eric Vicaut d, Joaquim Alonso e, Peter Crean f, Attilio Leone g, Joa Morais h, Massimo Santini i, Muriel Licour j, Mohamed Farah j, Jean-Claude Tardif k,
a

Hpital cardiologique, CHRU de Lille, Lille, France Hpital europen Georges-Pompidou, Paris, France c NutriConsult, Dijon, France d Hpital Lariboisire, Paris, France e Hospital de Fuenlabrada, Fuenlabrada, Spain f St Jamess Hospital, Dublin, Ireland g CHU de Tivoli, La Louvire, Belgium h Hospital de Santo Andr, Leiria, Portugal i Ospedale S. Filippo Neri, Roma, Italy j AstraZeneca, Rueil-Malmaison, France k Montreal Heart Institute, universit de Montral, 5000, Blanger street, Montreal, Quebec H1T 1C8, Canada
b

Received 24 January 2008; received in revised form 10 March 2008; accepted 14 May 2008 Available online 20 August 2008

KEYWORDS
Acute coronary

Summary Background. The mechanism underlying rapid, statin-induced event reduction in patients with an acute coronary syndrome (ACS) remains to be claried.

Corresponding author. Fax: +1 514 593 2500. E-mail address: Jean-claude.tardif@icm-mhi.org (J.-C. Tardif).

1875-2136/$ see front matter 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.acvd.2008.05.010

400 syndrome; Apolipoprotein; Statin therapy; Trial design

J.-M. Lablanche et al.

Aim. The primary objective is to compare the efcacy of rosuvastatin 20 mg/day and atorvastatin 80 mg/day in reducing the apolipoprotein B/apolipoprotein A-1 (apoB/apoA-1) ratio at three months, in ACS patients. Secondary objectives include a comparison of the effects of early-started rosuvastatin and placebo on inammatory markers. Methods. This is a randomized, double-blind, parallel-group study. Patients with non-STsegment elevation ACS, symptom onset less than 48 h before admission, and for whom a percutaneous coronary intervention is planned, are eligible for inclusion and are randomized into three groups (G1, G2 and G3). The study comprises two double-blind periods. Period 1 starts at hospital admission and lasts until Day 0 (discharge or less or equal to 6 days after admission); patients in G1 receive one tablet of rosuvastatin 20 mg/day and patients in G2 and G3 receive one matching placebo tablet per day. Period 2 starts at Day 0 and lasts for three months; patients in G1 continue to receive rosuvastatin 20 mg/day, patients in G2 receive rosuvastatin 20 mg/day and patients in G3 receive atorvastatin 80 mg/day. Recruitment of 1075 patients will ensure an 80 power to detect a 3% difference in percentage change in the apoB/apoA-1 ratio and a 20% difference in percentage change in high-sensitivity C-reactive protein. Results. Inclusion phase is complete; results will be reported at a later date. Conclusion. This is the rst trial investigating the effect of statins on apolipoproteins in ACS patients. 2008 Elsevier Masson SAS. All rights reserved.

MOTS CLS
Syndrome coronaire aigu ; Apolipoprotine ; Statines ; Design de ltude

Rsum Contexte. Le mcanisme par lequel une statine induit une rduction des vnements au cours dun syndrome coronaire aigu (SCA) reste tre lucid. Objectif. Lobjectif principal est de comparer lefcacit de la rosuvastatine 20 mg/j et de latorvastatine 80 mg/j sur la rduction du rapport apolipoproteineB/apolipoproteine A1 (ApoB/ApoA1) trois mois, chez des patients prsentant un SCA. Les objectifs secondaires incluent une comparaison des effets de la rosuvastatine initie prcocement versus placebo sur les marqueurs inammatoires. Mthode. tude randomise en double insu sur trois groupes parallles. Les patients se prsentant avec un SCA sans lvation du segment ST, avec des symptmes dbutant depuis moins de 48 heures avant ladmission, et chez lesquels une angioplastie coronaire a t programme, ont t inclus et randomiss en trois groupes (G1, G2 et G3). Ltude comprend deux priodes en double insu, une priode 1 de ladmission jusqu j0 (sortie de l hpital ou un maximum de six jours aprs ladmission), les patients du groupe G1 rec oivent un comprim de rosuvastatine 20 mg/j et les patients du groupe G2 et G3 rec oivent un comprim de placebo par jour. La priode 2 dbute j0 et dure jusqu trois mois, les patients du groupe G1 continuent recevoir de la rosuvastatine 20 mg/j, les patients du groupe G2 rec oivent de la rosuvastatine 20 mg/j et les patients du groupe G3 rec oivent de latorvastatine 80 mg/j. Le recrutement de 1075 patients assurera une puissance de 80 % pour dtecter 3 % de diffrence sur la variation en pourcentage de lApoB/ApoA1 et 20 % de diffrence pour lhs- C- ractive proteine. La phase dinclusion est actuellement termine, les rsultats seront prsents ultrieurement. Conclusion. Centaurus est la premire tude valuer leffet dune statine sur les apolipoproteines chez les patients avec SCA. 2008 Elsevier Masson SAS. All rights reserved.

Introduction
The updated NCEP ATP III guidelines advocate the consideration of intensive statin therapy for all patients admitted to hospital with an acute coronary syndrome (ACS) a recommendation that arises from the results of studies assessing the benet of early statin treatment in this patient population [15]. The mechanism underlying the early effect of statin therapy is still unclear, but may involve both lipidrelated effects and other purported pleiotropic effects [6], including effects on inammatory markers such as CRP and thrombotic markers.

The elevated plasma levels of CRP detected in the rst days of an ACS may reect not only a high prevalence of myocardial necrosis [7], ischaemia-reperfusion damage or severe coronary atherosclerosis, but also an increased systemic inammatory response, and have been associated with unfavourable short- and long-term prognoses [812]. The Myocardial ischemia reduction with acute cholesterol lowering (MIRACL) study showed that the early use of atorvastatin 80 mg/day potentiated the decline in inammation in patients with ACS compared with placebo [13]. In another double-blind, placebo-controlled study in

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Study population
Nomenclature ACS acute coronary syndrome apoA-1 apolipoprotein A-1 apoB apolipoprotein B CI condence interval CK creatine kinase CK-MB creatine kinase myocardial band isoenzyme CRP C-reactive protein hs-CRP high-sensitivity C-reactive protein LDL-C low-density lipoprotein cholesterol MI myocardial infarction NCEP ATP III National cholesterol education program adult treatment panel III NSTE-ACS non-ST-segment elevation acute coronary syndrome NSTEMI non-ST-segment elevation myocardial infarction PCI percutaneous coronary intervention S.D. standard deviation STEMI ST-segment elevation myocardial infarction TG triglyceride ULN upper limit of normal The inclusion criteria are: age greater than or equal to 18 years; diagnosed with NSTE-ACS; admitted to hospital less than 48 h after the onset of symptoms; evidence of coronary artery disease in addition to ischaemic symptoms; a PCI planned or anticipated within four days for treatment of the index event, in accordance with local or European guidelines for PCI [20]. Patients with NSTE-ACS include those with unstable angina and NSTEMI [21,22]. The exclusion criteria are: STEMI; cholesterol-lowering medication in the preceding month; contraindication for statin treatment; homozygous familial hypercholesterolemia; CK concentration greater than three times ULN and CK-MB concentration less than two times ULN at visit 1 (if CK-MB unavailable, cardiac troponin I or T concentration = 0 at visit 1); planned coronary revascularization other than primary PCI during the current hospitalization; coronary artery bypass graft or PCI in the three months before visit 1; occurrence of ventricular brillation, sustained ventricular tachycardia, complete heart block, new onset atrial brillation with uncontrolled ventricular rate (greater than 100 beats per minute), or paced ventricular rhythm in the four weeks before visit 1; stroke, sepsis, acute pericarditis, or any evidence of systemic or pulmonary embolus in the preceding four weeks; pregnancy; initiation of hormone-replacement or oral contraceptive therapy (in women) in the three months before visit 1.

90 patients admitted within 48 h of ACS onset and with CRP concentration greater or equal to 1.4 mg/dL, a rapid decrease in CRP concentration was seen with the early use of atorvastatin 40 mg/day [14]. In both studies, CRP concentration decreased spontaneously in the placebo group. Our CENTAURUS study is designed to compare the effects of early treatment with rosuvastatin 20 mg/day or atorvastatin 80 mg/day in patients with an ACS. Recent studies have shown that the apoB/apoA-1 ratio may be one of the strongest predictors of acute fatal MI [15,16]. Moreover, apolipoprotein concentration is unaffected by fasting status, unlike LDL-C concentration [17]. A maximal post-MI reduction in LDL-C concentration of 47% occurs at day 7 [18], and TG concentration increases after MI by about 58% [18]. Our study is the rst to evaluate the change in apoB/apoA-1 ratio during the acute phase of ACS. In addition, we will investigate the early effects of rosuvastatin (started before PCI) on inammatory markers.

Randomization
The study is divided into two double-blind periods with randomization at the beginning of the rst period (Fig. 1). Period 1 starts at the hospital admission of the patient for an ACS and lasts until hospital discharge (or for a maximum of six days). Period 2 starts at Day 0 (i.e. at hospital discharge or six days after admission) and lasts for three months. After validation of eligibility, patients are randomized into one of three treatment groups (G1, G2 and G3; Fig. 1) in a ratio of 1:2:2, by means of a telephone call to an interactive voice response system, as soon as possible after informed consent is obtained. Informed consent must be obtained before any study-related examination or drug administration. Participation in a pharmacogenomic substudy is optional, and requires completion of a separate written consent form.

Methods
Trial design
CENTAURUS is an international, multicentre, randomized, double-blind, parallel-group study comparing the efcacy and safety of rosuvastatin 20 mg/day versus atorvastatin 80 mg/day in patients with an ACS. Patients are being recruited from Belgium, Canada, Estonia, France, Greece, Hungary, Ireland, Italy, Portugal, Spain and Tunisia. The study is being conducted in accordance with the Declaration of Helsinki and under the principles of good clinical practice, as laid out in the International conference on harmonisation document Good clinical practice: Consolidated guidance [19].

Intervention
In Period 1, patients receive treatment with either one tablet of rosuvastatin 20 mg/day (G1) or one matching

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Figure 1.

Study design owchart.

placebo tablet per day (G2 and G3). The rst dose should be taken within 48 h of symptom onset, and as soon as possible after randomization (ideally within 2 h of randomization). Two doses of study medication are strongly recommended before the PCI. If the PCI is planned earlier, just after hospital admission, the rst dose of study treatment should be taken after randomization and the second dose as soon as possible after the PCI. A minimum time period of 12 h is recommended between the rst two doses. After Period 1 and throughout Period 2, patients in G1 continue to receive rosuvastatin 20 mg/day, patients in G2

also receive rosuvastatin 20 mg/day and patients in G3 receive atorvastatin 80 mg/day, in accordance with the original randomization. To ensure blinding, patients are instructed to take one tablet and two capsules with water once daily, at any time of the day. Each tablet contains rosuvastatin 20 mg or matching placebo and each capsule contains atorvastatin 40 mg or matching placebo. The rst Period 2 dose takes place on the day after the last Period 1 dose. The nal dose is administered three months later, on the day of visit 4. Investigators provide general diet counselling to patients at the following visits.

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Assessments
Efcacy assessments comprise measurement of the concentrations of inammatory markers (hs-CRP, soluble CD40, interleukin-10 and interleukin-18) and evaluation of the lipid prole (total cholesterol, LDL-C, high-density lipoprotein cholesterol, TG, apoB and apoA-1). Safety assessments include chemistry tests (creatinine, alanine transaminase, CK and CK-MB), measurement of the concentrations of cardiac troponin (I or T), thyroidstimulating hormone and haemoglobin A1c and adverse events.

Secondary efcacy outcomes

Considering a non-inferiority margin of 3%, an S.D. of 14% and a 2-sided signicance level of 5%, 343 evaluable patients per group will give 80% power to demonstrate non-inferiority in LDL-C concentration reduction from the beginning of Period 2 between rosuvastatin 20 mg/day (G2) and atorvastatin 80 mg/day (G3). The upper limit of the two-sided 95% CI has to be less than 3% to conclude non-inferiority. A 3% non-inferiority margin has been chosen as it corresponds to less than half of the effect of a dose doubling (statins generally produce an extra 6% reduction in LDL-C concentration for every doubling of dose) [25]. To compare the effect of rosuvastatin 20 mg/day and placebo on the concentration of hs-CRP and other inammatory markers at the end of Period 1, 686 placebo-treated patients (G2 plus G3) and 172 rosuvastatin-treated patients (G1) will give approximately 80% power to detect an absolute difference of 20% in hs-CRP percentage change in concentration from baseline, assuming an S.D. of 70% for hsCRP percentage change in concentration from baseline and a 20% adjustment for the use of a non-parametric method in the analysis. Taking all these calculations into consideration, and assuming a 20% drop-out rate, 1075 patients will have to be included.

Pharmacogenomic substudy
Blood samples are taken for the central determination of the concentrations of inammatory markers and cardiac troponin T, and for analysis of potential new markers of cardiovascular disease.

Study outcomes
The primary efcacy outcome is percentage change in the apoB/apoA-1 ratio from Day 0 to three months. The secondary outcomes are as follows: percentage change in lipid concentrations from Day 0 to one month and three months; percentage change in inammatory marker concentrations from randomization to one month and three months; percentage changes in lipid, cardiac troponin and inammatory marker concentrations from randomization to Day 0; percentage of patients reaching their established 2003 European LDL-C concentration target of 2.58 mmol/L (100 mg/dL) [23] at three months; percentage of patients reaching their updated 2004 NCEP ATP III LDL-C concentration target of 70 mg/dL (1.81 mmol/L) [3] at three months; percentage change in hs-CRP concentration from randomization to Day 0 (area under the curve [AUC] of hs-CRP) and to one month and three months; incidence and severity of adverse events and abnormal laboratory values during the study; incidence of major adverse clinical events (death, nonfatal MI, non-fatal stroke, documented unstable angina requiring hospitalization and repeat coronary revascularization) during the study.

Statistical analysis
The statistical analysis of Period 2 data will include all patients who have taken greater than or equal to one dose of study medication, have a baseline lipid measurement at Day 0 and have greater than or equal to one post-baseline measurement of one lipid variable. The analyses will be done using the last observation carried forward method. The statistical analysis of Period 1 data will comprise secondary endpoints only and will include all patients who have taken greater than or equal to one dose of study medication, have greater than or equal to one lipid variable or inammatory marker measurement at admission and greater than or equal to one lipid variable or inammatory marker measurement post-admission. Analyses will use observed data. The safety population will consist of all randomized patients who have taken greater than or equal to one dose of study medication. A per-protocol population will also be dened, to provide for the occurrence of an unforeseen event that requires a sensitivity analysis. Percentage change in the apoB/apoA-1 ratio from Day 0 to three months will be compared between G2 and G3 using an analysis of variance, with treatment and country included in the model. The hypothesis of superiority of rosuvastatin compared with atorvastatin will be tested by an upper limit of 95% CI for the difference between treatments being less than zero. Data from G1 will be summarized only. Percentage change in LDL-C concentration from Day 0 to one month and three months will be compared between G2 and G3 using the same method as for the primary efcacy outcome. Percentage change in other lipid concentrations from Day 0 to one month and three months will be summarized. Percentage change in hs-CRP concentration from randomization to Day 0 will be compared between G1 and G2

Sample size
Primary efcacy outcome
The aim of the study is to demonstrate the superiority of rosuvastatin 20 mg/day over atorvastatin 80 mg/day in terms of ability to reduce the apoB/apoA-1 ratio at three months. A 3% difference in apoB/apoA-1 reduction is considered to be clinically meaningful [24]. To detect such a difference between G2 and G3, assuming an S.D. of 14%, with a two-sided test, an alpha risk of 5% and a power of 80%, 343 evaluable patients per group are required.

404 Table 1 Sources Thompson et al. (PACT) [38] The effect of early, intensive statin therapy on acute coronary syndrome.

J.-M. Lablanche et al.

Forest plot of any cardiovascular event by duration of treatment

Den Hartog et al. (PAIS) [30 Kinlay et al. (MIRACL) [13] Liem et al. (FLORIDA) [35] De Lemos et al. (A-Z) [29] Arntz et al. (LCAD) [27] Cannon et al. (PROVE-IT) [1] Dupuis et al. (RECIFE) [31] Serruys et al. (LIPS) [37] Colivicchi et al. [28] Kayikcioglu et al. (PTT) [33] Okazaki et al. (ESTABLISH) [36] Kesteloot et al. (LAMIL) [34]
A meta-analysis of randomised controlled trials [26] investigating the effect of early, intensive statin therapy on patients with an acute coronary syndrome [32].

plus G3 using a non-parametric Wilcoxon rank sum test. Data from the assessments will also be described by the median and 10th, 25th, 75th and 90th percentiles. The percentage change in hs-CRP concentration from Day 0 to one month and three months, and all the percentage changes in the concentrations of other inammatory markers and cardiac troponin will be summarized descriptively. The data relating to hs-CRP from randomization to Day 0 will also be explored using plots and AUC (assuming that more than three measurements are available between randomization and Day 0). The percentage of patients reaching the 2003 European LDL-C concentration target [23] and updated 2004 NCEP ATP III LDL-C concentration target [3] will be presented, with 95% CI in each group.

Interim analysis and timelines

No interim analysis is planned. The nal version of the protocol was approved by the local ethics committees in December 2005. The rst patient was enrolled in January 2006 and by June 2007, 1120 patients had been enrolled.

Discussion
Some new data have been published since the design and start of the CENTARUS trial. In the A to Z trial, the hsCRP concentrations achieved 30 days and four months after ACS were found to be associated independently with longterm survival [26]. In another study, atorvastatin 40 mg/day was shown to reduce CRP concentration rapidly in patients admitted within 48 h of onset of ACS and with CRP concentration greater than or equal to 1.4 mg/dL [14]. In CENTAURUS, the hs-CRP concentration will be estimated at 30 days and three months. More recently, a meta-analysis was published on 13 randomized controlled trials in patients with an ACS

[1,4,2738] . Time to initiation of treatment ranged from one day to 14 days, with a median duration of four days. In CENTAURUS, statin treatment will start less than or equal to six days after hospitalization. The meta-analysis provides evidence that early, intensive statin therapy is associated with a reduction in adverse cardiovascular outcomes, particularly cardiovascular death, unstable angina and revascularization, when prescribed within 14 days of hospitalization for ACS. These benets took more than four months to begin to accrue and were sustained for two years (Table 1). There was no signicant evidence that reduction in LDL-C concentration inuenced these results [32]. The atorvastatin for reduction of myocardial damage during angioplasty acute coronary syndromes (ARMYDA-ACS) study in patients with NSTE-ACS [39] undergoing early coronary angiography (<48 h) and PCI was published after the meta-analysis. Patients were randomized to pretreatment with atorvastatin (80 mg, 12 h before PCI, with a further 40 mg preprocedure [N = 86]) or placebo (N = 85). Patients already receiving statin therapy were excluded. Short-term pretreatment with atorvastatin reduced the incidence of cardiac events compared with placebo, with the difference being driven essentially by a signicant reduction in periprocedural MI. To date, no data have been published on the effect of statins on apoB or apoA-1 in patients with ACS.

Conclusion
CENTAURUS will provide important information on the anti-inammatory effects of early treatment with rosuvastatin 20 mg/day, and will be the rst trial to compare the effects of rosuvastatin 20 mg/day and atorvastatin 80 mg/day on lipid proles and to explore the change in the apoB/apoA-1 ratio, in patients with an ACS.

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11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1998;31:14605. Mueller C, Buettner HJ, Hodgson JM, et al. Inammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a very early invasive strategy in 1042 consecutive patients. Circulation 2002;105:14125. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003;107:3639. Toss H, Lindahl B, Siegbahn A, et al. Prognostic inuence of increased brinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. Circulation 1997;96:420410. Kinlay S, Schwartz GG, Olsson AG, et al. High-dose atorvastatin enhances the decline in inammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation 2003;108:15606. Macin SM, Perna ER, Farias EF, et al. Atorvastatin has an important acute anti-inammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study. Am Heart J 2005;149:4517. Rosenson RS. Myocardial injury: the acute phase response and lipoprotein metabolism. J Am Coll Cardiol 1993;22:93340. Walldius G, Jungner I, Holme I, et al. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001;358:202633. Pfohl M, Schreiber I, Liebich HM, et al. Upregulation of cholesterol synthesis after acute myocardial infarction is cholesterol a positive acute phase reactant? Atherosclerosis 1999;142:38993. Faulkner MA, Hilleman DE, Destache CJ, et al. Potential inuence of timing of low-density lipoprotein cholesterol evaluation in patients with acute coronary syndrome. Pharmacotherapy 2001;21:105560. ICH. Harmonised Tripartite Guideline. Guideline for good clinical practice. 10 June 1996 ed. 53 p. http://www.ich.org/ LOB/media/MEDIA482.pdf. Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005;26:80447. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction 2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2002;106:1893900. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tiroban. N Engl J Med 2001;344:187987. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil 2003;10:S110. Jones PH, Hunninghake DB, Ferdinand KC, et al. Effects of rosuvastatin versus atorvastatin, simvastatin, and pravastatin on non-high-density lipoprotein cholesterol, apolipoproteins, and lipid ratios in patients with hypercholesterolemia: additional results from the STELLAR trial. Clin Ther 2004;26: 138899. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341:498511.

Funding
Funding and sponsorship for the CENTAURUS trial are provided by AstraZeneca SAS, Rueil-Malmaison, France. The funding source helps to rene the study design and assists with data collection, management and analysis. The scientic conduct of the study is independent of the funding source.
[10]

[11]

[12]

Conict of interest
None declared.
[13]

Acknowledgements
The CENTAURUS Steering Committee initiated the trial, and will review the data independently, conrm all statistical analyses independently, and support the preparation of all manuscripts for publication. The Steering Committee comprises: J.-M. Lablanche, France; J.-C. Tardif, Canada; J. Alonso, Spain; P. Crean, Ireland; A. Leone, Belgium; J. Morais, Portugal; and M. Santini, Italy. The Endpoint Adjudication Committee comprises: P. Gueret, France; I. Mahet, France; and M. White, Canada.
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