Archives of Cardiovascular Disease (2008) 101, 399—406

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CLINICAL RESEARCH

Effects of rosuvastatin and atorvastatin on theapolipoprotein B/apolipoprotein A-1 ratio in patientswith an acute coronary syndrome: The CENTAURUStrial design

Effet de la rosuvastatine et de l’atorvastatine sur l’ApoB/ApoA-1 chez lespatients avec syndrome coronaire aigu (étude CENTAURUS)

Jean-Marc Lablanchea, Nicolas Danchinb,Michel Farnierc, Alain Tedguid, Eric Vicautd,Joaquim Alonsoe, Peter Creanf, Attilio Leoneg,Joa Moraish, Massimo Santini i, Muriel Licour j,Mohamed Farahj, Jean-Claude Tardif k,∗

a Hôpital cardiologique, CHRU de Lille, Lille, Franceb Hôpital européen Georges-Pompidou, Paris, Francec NutriConsult, Dijon, Franced Hôpital Lariboisière, Paris, Francee Hospital de Fuenlabrada, Fuenlabrada, Spainf St James’s Hospital, Dublin, Irelandg CHU de Tivoli, La Louvière, Belgiumh Hospital de Santo André, Leiria, Portugali Ospedale S. Filippo Neri, Roma, Italyj AstraZeneca, Rueil-Malmaison, Francek Montreal Heart Institute, université de Montréal, 5000, Bélanger street,Montreal, Quebec H1T 1C8, Canada

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

KEYWORDSAcute coronary

SummaryBackground. — The mechanism underlying rapid, statin-induced event reduction in patients withan acute coronary syndrome (ACS) remains to be clarified.

∗ 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 J.-M. Lablanche et al.

syndrome;Apolipoprotein;Statin therapy;Trial design

Aim. — The primary objective is to compare the efficacy of rosuvastatin 20 mg/day and ator-vastatin 80 mg/day in reducing the apolipoprotein B/apolipoprotein A-1 (apoB/apoA-1) ratio atthree months, in ACS patients. Secondary objectives include a comparison of the effects ofearly-started rosuvastatin and placebo on inflammatory markers.Methods. — This is a randomized, double-blind, parallel-group study. Patients with non-ST-segment elevation ACS, symptom onset less than 48 h before admission, and for whom apercutaneous coronary intervention is planned, are eligible for inclusion and are randomizedinto three groups (G1, G2 and G3). The study comprises two double-blind periods. Period 1 startsat 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 receiveone matching placebo tablet per day. Period 2 starts at Day 0 and lasts for three months; patientsin G1 continue to receive rosuvastatin 20 mg/day, patients in G2 receive rosuvastatin 20 mg/dayand patients in G3 receive atorvastatin 80 mg/day. Recruitment of 1075 patients will ensure an80 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 first trial investigating the effect of statins on apolipoproteins in ACSpatients.© 2008 Elsevier Masson SAS. All rights reserved.

MOTS CLÉSSyndrome coronaireaigu ;Apolipoprotéine ;Statines ;Design de l’étude

RésuméContexte. — Le mécanisme par lequel une statine induit une réduction des évènements au coursd’un syndrome coronaire aigu (SCA) reste à être élucidé.Objectif. — L’objectif principal est de comparer l’efficacité de la rosuvastatine 20 mg/j etde l’atorvastatine 80 mg/j sur la réduction du rapport apolipoproteineB/apolipoproteine A1(ApoB/ApoA1) à trois mois, chez des patients présentant un SCA. Les objectifs secondairesincluent une comparaison des effets de la rosuvastatine initiée précocement versus placebo surles marqueurs inflammatoires.Méthode. — Étude randomisée en double insu sur trois groupes parallèles. Les patients seprésentant avec un SCA sans élévation du segment ST, avec des symptômes débutant depuismoins de 48 heures avant l’admission, et chez lesquels une angioplastie coronaire a été pro-grammée, ont été inclus et randomisés en trois groupes (G1, G2 et G3). L’étude comprend deuxpériodes en double insu, une période 1 de l’admission jusqu’à j0 (sortie de l’ hôpital ou unmaximum de six jours après l’admission), les patients du groupe G1 recoivent un comprimé derosuvastatine 20 mg/j et les patients du groupe G2 et G3 recoivent un comprimé de placebo parjour. La période 2 débute à j0 et dure jusqu’à trois mois, les patients du groupe G1 continuentà recevoir de la rosuvastatine 20 mg/j, les patients du groupe G2 recoivent de la rosuvastatine20 mg/j et les patients du groupe G3 recoivent de l’atorvastatine 80 mg/j. Le recrutement de1075 patients assurera une puissance de 80 % pour détecter 3 % de différence sur la variationen pourcentage de l’ApoB/ApoA1 et 20 % de différence pour l’hs- C- réactive proteine.

La phase d’inclusion est actuellement terminée, les résultats seront présentés ultérieure-ment.Conclusion. — Centaurus est la première étude à évaluer l’effet d’une statine sur les apolipopro-

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ntroduction

he updated NCEP ATP III guidelines advocate the consider-tion of intensive statin therapy for all patients admitted toospital with an acute coronary syndrome (ACS) — a recom-endation that arises from the results of studies assessing

he benefit of early statin treatment in this patient popu-ation [1—5]. The mechanism underlying the early effect of

tatin therapy is still unclear, but may involve both lipid-elated effects and other purported pleiotropic effects [6],ncluding effects on inflammatory markers such as CRP andhrombotic markers.

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The elevated plasma levels of CRP detected in the firstays of an ACS may reflect not only a high prevalencef myocardial necrosis [7], ischaemia-reperfusion damager severe coronary atherosclerosis, but also an increasedystemic inflammatory response, and have been associ-ted with unfavourable short- and long-term prognoses8—12].

The Myocardial ischemia reduction with acute choles-

erol lowering (MIRACL) study showed that the earlyse of atorvastatin 80 mg/day potentiated the decline innflammation in patients with ACS compared with placebo13]. In another double-blind, placebo-controlled study in

CENTAURUS trial design

Nomenclature

ACS acute coronary syndromeapoA-1 apolipoprotein A-1apoB apolipoprotein BCI confidence intervalCK creatine kinaseCK-MB creatine kinase myocardial band isoenzymeCRP C-reactive proteinhs-CRP high-sensitivity C-reactive proteinLDL-C low-density lipoprotein cholesterolMI myocardial infarctionNCEP ATP III National cholesterol education program

adult treatment panel IIINSTE-ACS non-ST-segment elevation acute coronary

syndromeNSTEMI non-ST-segment elevation myocardial

infarctionPCI percutaneous coronary interventionS.D. standard deviationSTEMI ST-segment elevation myocardial infarction

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TG triglycerideULN upper limit of normal

90 patients admitted within 48 h of ACS onset and withCRP concentration greater or equal to 1.4 mg/dL, a rapiddecrease in CRP concentration was seen with the earlyuse of atorvastatin 40 mg/day [14]. In both studies, CRPconcentration decreased spontaneously in the placebogroup.

Our CENTAURUS study is designed to compare the effectsof early treatment with rosuvastatin 20 mg/day or atorvas-tatin 80 mg/day in patients with an ACS. Recent studieshave shown that the apoB/apoA-1 ratio may be one of thestrongest predictors of acute fatal MI [15,16]. Moreover,apolipoprotein concentration is unaffected by fasting status,unlike LDL-C concentration [17]. A maximal post-MI reduc-tion in LDL-C concentration of 47% occurs at day 7 [18], andTG concentration increases after MI by about 58% [18]. Ourstudy is the first to evaluate the change in apoB/apoA-1 ratioduring the acute phase of ACS. In addition, we will investi-gate the early effects of rosuvastatin (started before PCI)on inflammatory markers.

Methods

Trial design

CENTAURUS is an international, multicentre, randomized,double-blind, parallel-group study comparing the efficacyand safety of rosuvastatin 20 mg/day versus atorvastatin80 mg/day in patients with an ACS. Patients are beingrecruited from Belgium, Canada, Estonia, France, Greece,Hungary, Ireland, Italy, Portugal, Spain and Tunisia.

The study is being conducted in accordance with the Dec-laration of Helsinki and under the principles of good clinicalpractice, as laid out in the International conference on har-monisation document ‘‘Good clinical practice: Consolidatedguidance’’ [19].

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tudy population

he 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 ofsymptoms;evidence of coronary artery disease in addition toischaemic symptoms;a PCI planned or anticipated within four days for treat-ment of the index event, in accordance with local orEuropean guidelines for PCI [20].

Patients with NSTE-ACS include those with unstablengina 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-MBconcentration less than two times ULN at visit 1 (if CK-MBunavailable, cardiac troponin I or T concentration = 0 atvisit 1);planned coronary revascularization other than primaryPCI during the current hospitalization;coronary artery bypass graft or PCI in the three monthsbefore visit 1;occurrence of ventricular fibrillation, sustained ventricu-lar tachycardia, complete heart block, new onset atrialfibrillation with uncontrolled ventricular rate (greaterthan 100 beats per minute), or paced ventricular rhythmin the four weeks before visit 1;stroke, sepsis, acute pericarditis, or any evidence of sys-temic or pulmonary embolus in the preceding four weeks;pregnancy;initiation of hormone-replacement or oral contraceptivetherapy (in women) in the three months before visit 1.

andomization

he study is divided into two double-blind periods with ran-omization at the beginning of the first period (Fig. 1).eriod 1 starts at the hospital admission of the patient forn ACS and lasts until hospital discharge (or for a maxi-um of six days). Period 2 starts at Day 0 (i.e. at hospitalischarge or six days after admission) and lasts for threeonths.After validation of eligibility, patients are randomized

nto one of three treatment groups (G1, G2 and G3; Fig. 1)n a ratio of 1:2:2, by means of a telephone call to annteractive voice response system, as soon as possible afternformed consent is obtained. Informed consent must bebtained before any study-related examination or drugdministration. Participation in a pharmacogenomic sub-tudy is optional, and requires completion of a separateritten consent form.

ntervention

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

402 J.-M. Lablanche et al.

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lacebo tablet per day (G2 and G3). The first dose should beaken within 48 h of symptom onset, and as soon as possiblefter randomization (ideally within 2 h of randomization).wo doses of study medication are strongly recommendedefore the PCI. If the PCI is planned earlier, just after hos-ital admission, the first dose of study treatment should be

aken after randomization and the second dose as soon asossible after the PCI. A minimum time period of 12 h isecommended between the first two doses.

After Period 1 and throughout Period 2, patients in G1ontinue to receive rosuvastatin 20 mg/day, patients in G2

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lso receive rosuvastatin 20 mg/day and patients in G3eceive atorvastatin 80 mg/day, in accordance with theriginal randomization. To ensure blinding, patients arenstructed to take one tablet and two capsules with waternce daily, at any time of the day. Each tablet containsosuvastatin 20 mg or matching placebo and each capsule

ontains atorvastatin 40 mg or matching placebo. The firsteriod 2 dose takes place on the day after the last Period 1ose. The final dose is administered three months later, onhe day of visit 4. Investigators provide general diet coun-elling to patients at the following visits.

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CENTAURUS trial design

Assessments

Efficacy assessments comprise measurement of the con-centrations of inflammatory markers (hs-CRP, soluble CD40,interleukin-10 and interleukin-18) and evaluation of the lipidprofile (total cholesterol, LDL-C, high-density lipoproteincholesterol, TG, apoB and apoA-1).

Safety assessments include chemistry tests (creatinine,alanine transaminase, CK and CK-MB), measurement ofthe concentrations of cardiac troponin (I or T), thyroid-stimulating hormone and haemoglobin A1c and adverseevents.

Pharmacogenomic substudy

Blood samples are taken for the central determination ofthe concentrations of inflammatory markers and cardiactroponin T, and for analysis of potential new markers of car-diovascular disease.

Study outcomes

The primary efficacy outcome is percentage change in theapoB/apoA-1 ratio from Day 0 to three months. The sec-ondary outcomes are as follows:• percentage change in lipid concentrations from Day 0 to

one month and three months;• percentage change in inflammatory marker concentra-

tions from randomization to one month and three months;• percentage changes in lipid, cardiac troponin and inflam-

matory marker concentrations from randomization toDay 0;

• percentage of patients reaching their established 2003European LDL-C concentration target of 2.58 mmol/L(100 mg/dL) [23] at three months;

• percentage of patients reaching their updated 2004NCEP 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 random-ization 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 abnormallaboratory values during the study;

• incidence of major adverse clinical events (death, non-fatal MI, non-fatal stroke, documented unstable anginarequiring hospitalization and repeat coronary revascular-ization) during the study.

Sample size

Primary efficacy outcomeThe aim of the study is to demonstrate the superior-ity of rosuvastatin 20 mg/day over atorvastatin 80 mg/day

in terms of ability to reduce the apoB/apoA-1 ratio atthree months. A 3% difference in apoB/apoA-1 reductionis considered to be clinically meaningful [24]. To detectsuch a difference between G2 and G3, assuming an S.D.of 14%, with a two-sided test, an alpha risk of 5% anda power of 80%, 343 evaluable patients per group arerequired.

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econdary efficacy outcomesonsidering a non-inferiority margin of 3%, an S.D. of 14%nd a 2-sided significance level of 5%, 343 evaluable patientser group will give 80% power to demonstrate non-inferiorityn LDL-C concentration reduction from the beginning oferiod 2 between rosuvastatin 20 mg/day (G2) and atorvas-atin 80 mg/day (G3). The upper limit of the two-sided 95%I has to be less than 3% to conclude non-inferiority. A 3%on-inferiority margin has been chosen as it corresponds toess than half of the effect of a dose doubling (statins gen-rally produce an extra 6% reduction in LDL-C concentrationor every doubling of dose) [25].

To compare the effect of rosuvastatin 20 mg/day andlacebo on the concentration of hs-CRP and other inflam-atory markers at the end of Period 1, 686 placebo-treatedatients (G2 plus G3) and 172 rosuvastatin-treated patientsG1) will give approximately 80% power to detect an abso-ute difference of 20% in hs-CRP percentage change inoncentration from baseline, assuming an S.D. of 70% for hs-RP percentage change in concentration from baseline and20% adjustment for the use of a non-parametric method

n the analysis.Taking all these calculations into consideration, and

ssuming a 20% drop-out rate, 1075 patients will have to bencluded.

tatistical analysis

he statistical analysis of Period 2 data will include allatients who have taken greater than or equal to one dose oftudy medication, have a baseline lipid measurement at Dayand have greater than or equal to one post-baseline mea-

urement of one lipid variable. The analyses will be donesing the last observation carried forward method.

The statistical analysis of Period 1 data will comprise sec-ndary endpoints only and will include all patients who haveaken greater than or equal to one dose of study medication,ave greater than or equal to one lipid variable or inflam-atory marker measurement at admission and greater than

r equal to one lipid variable or inflammatory marker mea-urement post-admission. Analyses will use observed data.

The safety population will consist of all randomizedatients who have taken greater than or equal to one dosef study medication. A per-protocol population will also beefined, to provide for the occurrence of an unforeseenvent that requires a sensitivity analysis.

Percentage change in the apoB/apoA-1 ratio from Day 0o three months will be compared between G2 and G3 usingn analysis of variance, with treatment and country includedn the model. The hypothesis of superiority of rosuvastatinompared with atorvastatin will be tested by an upper limitf 95% CI for the difference between treatments being lesshan zero. Data from G1 will be summarized only.

Percentage change in LDL-C concentration from Day 0 tone month and three months will be compared between G2nd G3 using the same method as for the primary efficacy

utcome. Percentage change in other lipid concentrationsrom Day 0 to one month and three months will be summa-ized.

Percentage change in hs-CRP concentration from ran-omization to Day 0 will be compared between G1 and G2

404 J.-M. Lablanche et al.

Table 1 The effect of early, intensive statin therapy on acute coronary syndrome.

Sources Forest plot of any cardiovascular event by duration of treatment

Thompson et al. (PACT) [38]

Den Hartog et al. (PAIS) [30Kinlay 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

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lus G3 using a non-parametric Wilcoxon rank sum test. Datarom the assessments will also be described by the mediannd 10th, 25th, 75th and 90th percentiles.

The percentage change in hs-CRP concentration from Dayto one month and three months, and all the percentage

hanges in the concentrations of other inflammatory mark-rs and cardiac troponin will be summarized descriptively.he data relating to hs-CRP from randomization to Day 0 willlso be explored using plots and AUC (assuming that morehan three measurements are available between randomiza-ion and Day 0).

The percentage of patients reaching the 2003 Euro-ean LDL-C concentration target [23] and updated 2004CEP ATP III LDL-C concentration target [3] will be pre-ented, with 95% CI in each group.

nterim analysis and timelines

o interim analysis is planned. The final version of therotocol was approved by the local ethics committees inecember 2005. The first patient was enrolled in January006 and by June 2007, 1120 patients had been enrolled.

iscussion

ome new data have been published since the design andtart of the CENTARUS trial. In the A to Z trial, the hs-RP concentrations achieved 30 days and four months afterCS were found to be associated independently with long-erm survival [26]. In another study, atorvastatin 40 mg/dayas shown to reduce CRP concentration rapidly in patientsdmitted within 48 h of onset of ACS and with CRP concentra-

ion greater than or equal to 1.4 mg/dL [14]. In CENTAURUS,he hs-CRP concentration will be estimated at 30 days andhree months.

More recently, a meta-analysis was published on 13andomized controlled trials in patients with an ACS

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1,4,27—38] . Time to initiation of treatment ranged fromne day to 14 days, with a median duration of four days.n CENTAURUS, statin treatment will start less than orqual to six days after hospitalization. The meta-analysisrovides evidence that early, intensive statin therapy isssociated with a reduction in adverse cardiovascular out-omes, particularly cardiovascular death, unstable anginand revascularization, when prescribed within 14 days ofospitalization for ACS. These benefits took more than fouronths to begin to accrue and were sustained for two

ears (Table 1). There was no significant evidence thateduction in LDL-C concentration influenced these results32].

The atorvastatin for reduction of myocardial damage dur-ng angioplasty acute coronary syndromes (ARMYDA-ACS)tudy in patients with NSTE-ACS [39] undergoing early coro-ary angiography (<48 h) and PCI was published after theeta-analysis. Patients were randomized to pretreatmentith atorvastatin (80 mg, 12 h before PCI, with a further0 mg preprocedure [N = 86]) or placebo (N = 85). Patientslready receiving statin therapy were excluded. Short-termretreatment with atorvastatin reduced the incidence ofardiac events compared with placebo, with the differenceeing driven essentially by a significant reduction in peripro-edural MI.

To date, no data have been published on the effect oftatins on apoB or apoA-1 in patients with ACS.

onclusion

ENTAURUS will provide important information on thenti-inflammatory effects of early treatment with rosu-

astatin 20 mg/day, and will be the first trial toompare the effects of rosuvastatin 20 mg/day and ator-astatin 80 mg/day on lipid profiles and to explore thehange in the apoB/apoA-1 ratio, in patients with anCS.

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CENTAURUS trial design

Funding

Funding and sponsorship for the CENTAURUS trial are pro-vided by AstraZeneca SAS, Rueil-Malmaison, France. Thefunding source helps to refine the study design and assistswith data collection, management and analysis. The sci-entific conduct of the study is independent of the fundingsource.

Conflict of interest

None declared.

Acknowledgements

The CENTAURUS Steering Committee initiated the trial, andwill review the data independently, confirm all statisti-cal analyses independently, and support the preparation ofall manuscripts for publication. The Steering Committeecomprises: 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 Adju-dication Committee comprises: P. Gueret, France; I. Mahet,France; and M. White, Canada.

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