Summary
Background
The mechanism underlying statin-induced event reduction in patients with acute coronary syndrome remains unclear.
Aims
To assess the efficacy of rosuvastatin 20 mg versus atorvastatin 80 mg in reducing the apolipoprotein B/apolipoprotein A-1 (apoB/apoA-1) ratio at 3 months. Non-inferiority of rosuvastatin 20 mg versus atorvastatin 80 mg in reducing low-density lipoprotein cholesterol at 1 and 3 months was also assessed.
Methods
Patients with non-ST-elevation acute coronary syndrome were enrolled into this randomized, double blind, parallel-group trial.
Results
In total, 753 patients (369, rosuvastatin 20 mg; 384, atorvastatin 80 mg) were included in the intention-to-treat analysis; 478 patients (226, rosuvastatin 20 mg; 252, atorvastatin 80 mg) were included in the per-protocol analysis. Rosuvastatin 20 mg was more effective than atorvastatin 80 mg in decreasing apoB/apoA-1 ratio at 1 month (−44.4% vs −42.9%, p = 0.02) but not at 3 months (both −44.4%, p = 0.87). Low-density lipoprotein cholesterol decreased by ∼50% after 1 and 3 months in both groups. Non-inferiority of rosuvastatin 20 mg versus atorvastatin 80 mg was demonstrated at 1 month (difference, −0.3% [95% confidence interval, −2.7; +2.1]), but not at 3 months (+1.0% [−1.6; 3.5]) (intention-to-treat analysis). In the per-protocol analysis, non-inferiority of rosuvastatin 20 mg was demonstrated at both 1 (−0.7% [−3.5; 2.0]) and 3 (−0.5% [−3.5; 2.5]) months.
Conclusion
In patients with non-ST-elevation acute coronary syndrome, rosuvastatin 20 mg decreased apoB/apoA-1 ratio at 1 month more than atorvastatin 80 mg. No difference could be shown at 3 months; thus, the primary endpoint was not met.
Résumé
Rationnel
Le mécanisme par lequel les statines réduisent la survenue d’événements dans le syndrome coronaire aigu reste incertain.
Objectifs
L’objectif principal de l’étude CENTAURUS était de comparer l’efficacité de la rosuvastatine 20 mg/j par rapport à l’atorvastatine 80 mg/j sur la réduction du rapport apolipoprotéine B/apolipoprotéine A-1 (apoB/apoA-1) après trois mois de traitement. Un des objectifs secondaires était de démontrer la non-infériorité de la rosuvastatine 20 mg/j par rapport à l’atorvastatine 80 mg/j sur la réduction du LDLc à un et trois mois.
Méthodes
Étude randomisée en double insu chez des patients présentant un syndrome coronaire aigu sans élévation du segment ST.
Résultats
Au total, 753 patients ont été inclus dans l’analyse en intention de traiter (rosuvastatine 20 mg = 369 ; atorvastatine 80 mg = 384) et 478 dans l’analyse en per-protocole (rosuvastatine 20 mg = 226 ; atorvastatine 80 mg = 252). La rosuvastatine 20 mg/j était plus efficace que l’atorvastatine 80 mg/j sur la réduction du rapport apoB/apoA-1 à un mois (−44,4 % vs −42,9 %, p = 0,02) mais pas à trois mois (−44,4 % pour les deux, p = 0,87). Une réduction du LDLc d’environ 50 % à un et à trois mois était obtenue dans les deux groupes. Pour la population en ITT, la non-infériorité de la rosuvastatine 20 mg/j était démontrée à un mois (différence = −0,3 % ; IC95 % = [−2,7 ; +2,1]) mais pas à trois mois (différence = +1,0 % ; IC95 % = [−1,6 ; 3,5]). Dans l’analyse per-protocole, la non-infériorité de la Rosuvastatine 20 mg/j était démontrée à un mois (différence = −0,7 % ; IC95 % = [−3,5 ; 2,0]) et à trois mois (différence = −0,5 % ; IC95 % = [−3,5 ; 2,5]).
Conclusion
Chez les patients présentant un syndrome coronaire aigu sans élévation du segment ST, la rosuvastatine 20 mg/j diminue significativement le rapport apoB/apoA-1 par rapport à l’atorvastatine 80 mg/j après un mois de traitement. Cette différence n’est pas confirmée à trois mois, l’objectif principal n’a pas été atteint.
Abbreviations
ACS
acute coronary syndrome
apoA-1
apolipoprotein A-1
apoB
apolipoprotein B
HDL-C
high-density lipoprotein cholesterol
LDL-C
low-density lipoprotein cholesterol
Background
The updated National Cholesterol Education Program Adult Treatment Panel III guidelines recommend that intensive therapy should be considered for all patients admitted to hospital for an acute coronary syndrome (ACS) . Two meta-analyses have shown that early intensive statin therapy in patients with ACS is associated with a reduced rate of death and cardiovascular events . In the PROVE IT study, comparing atorvastatin 80 mg with pravastatin 40 mg, a significant reduction in major adverse clinical events was observed in favour of more intensive statin treatment . In that study, the median concentration of low-density lipoprotein cholesterol (LDL-C) was lowered from 106 mg/dL to 62 mg/dL in the atorvastatin 80 mg group.
The relative value of the decrease in the apolipoprotein (apo)B/apoA-1 ratio and LDL-C concentration in the evaluation of statin efficacy remains unclear . Although elevated LDL-C is recognised as a major risk factor, data are accumulating which suggest that the apoB/apoA-1 ratio may be an important predictor of acute myocardial infarction . While the European guidelines for the prevention of cardiovascular disease state that it is not yet established whether the apoB/apoA-1 ratio should be used as a treatment goal, they also refer to it as one of the strongest risk markers . Moreover, apolipoprotein concentrations are unaffected by fasting status, unlike LDL-C concentration . Several early studies have reported that variations in lipoprotein concentrations after ACS occur within 24 to 48 hours after the onset of chest pain . However, many such studies did not measure LDL-C directly and used non-fasting or retrospective data . The more recent LUNAR study demonstrated no significant variations in lipid values during the acute phase of ACS . Although small changes in LDL-C, total cholesterol and high-density lipoprotein cholesterol (HDL-C) concentrations were observed, the changes did not appear to be clinically meaningful. It is now widely accepted that measurement of lipid concentrations at admission for ACS is an appropriate strategy for determining the correct use of lipid-lowering medication during the acute phase.
CENTAURUS (Comparison of the Effects Noted in The ApoB/apoA-1 ratio Using Rosuvastatin or atorvastatin in patients with acUte coronary Syndrome) was designed to evaluate the respective effects of rosuvastatin 20 mg and atorvastatin 80 mg in decreasing the apoB/apoA-1 ratio and LDL-C concentration in patients with ACS and planned or anticipated percutaneous coronary intervention. Treatment had to be initiated within 6 days after hospital admission. The main hypothesis tested was that rosuvastatin 20 mg would be superior to atorvastatin 80 mg in reducing the apoB/apoA-1 ratio at 3 months when initiated at hospital discharge or at a maximum of 6 days after admission. A secondary objective was to show that rosuvastatin 20 mg was non-inferior to atorvastatin 80 mg in reducing LDL-C concentration at 1 and 3 months.
Methods
The CENTAURUS protocol has been described previously . Briefly, CENTAURUS was an international, multicentre, randomized, double blind, parallel-group study, conducted in 101 centres in Belgium, Canada, Estonia, France, Greece, Hungary, Ireland, Italy, Portugal, Spain and Tunisia. Patients above or equal to 18 years of age diagnosed with non-ST elevation-ACS, admitted to hospital less than 48 hours after the onset of symptoms and for whom a percutaneous coronary intervention was planned or anticipated within 4 days for treatment of the index event, were eligible for inclusion in the study. Evidence of coronary artery disease, by history, electrocardiography, angiography, echocardiography or scintigraphy was mandatory. Elevated plasma biomarkers (myocardial enzyme) also represented acceptable evidence of coronary artery disease.
Exclusion criteria included:
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ST-segment elevation myocardial infarction;
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cholesterol-lowering medication in the preceding month;
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contraindication for statin treatment;
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homozygous familial hypercholesterolaemia;
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creatine kinase concentration that was more than three times the upper limit of the normal range and creatine kinase myocardial band isoenzyme concentration that was less than two times the upper limit of normal at visit 1 (if creatine kinase myocardial band isoenzyme was unavailable, cardiac troponin I or T concentration = 0 at visit 1 was to be considered as an exclusion criterion);
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planned coronary revascularization other than primary percutaneous coronary intervention during hospitalization;
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coronary artery bypass graft or percutaneous coronary intervention in the 3 months before visit 1;
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occurrence of ventricular fibrillation, sustained ventricular tachycardia, complete heart block, new onset atrial fibrillation with uncontrolled ventricular rate (greater than 100 beats per minute), or paced ventricular rhythm in the 4 weeks before visit 1;
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stroke, sepsis, acute pericarditis or any evidence of systemic or pulmonary embolus in the preceding 4 weeks;
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pregnancy;
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and initiation of hormone-replacement or oral contraceptive therapy (in women) in the 3 months before visit 1.
Written informed consent was obtained from all patients included in the trial. The study was approved by Institutional Review Boards according to local regulation and was conducted in accordance with Good Clinical Practice guidelines.
The study consisted of two double-blind periods with randomization at the beginning of the first period. The first period ran from admission of the patient for ACS to hospital discharge (or a maximum of 6 days); the second period ran from hospital discharge (day 0 [baseline]) to 3 months. Patients were randomized to one of three treatment arms in a 1:2:2 ratio:
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rosuvastatin 20 mg from admission until end of the study (‘early rosuvastatin 20 mg’ group);
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placebo from admission until day 0, followed by rosuvastatin 20 mg until end of the study (rosuvastatin 20 mg group);
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and placebo from admission until day 0, followed by atorvastatin 80 mg until end of the study (atorvastatin 80 mg group).
Randomization was performed with the use of an interactive voice-response system. To ensure blinding during the first period, patients received rosuvastatin 20 mg or matching placebo tablets. During the second period, patients received one tablet (rosuvastatin 20 mg or matching placebo) and two capsules (atorvastatin 40 mg or matching placebo) once daily.
The first period of the study between admission and hospital discharge aimed at evaluating the effect of early treatment with rosuvastatin (‘early rosuvastatin 20 mg’) compared with placebo on inflammatory markers during the first 6 days of ACS. Results from this treatment period will be reported separately.
The primary efficacy variable was the percentage change at 3 months from baseline in the apoB/apoA-1 ratio. Secondary variables were:
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percentage changes at 1 month from baseline in the apoB/apoA-1 ratio;
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percentage changes in fasting LDL-C after 1 and 3 months;
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percentage of patients reaching the 2003 European or updated American Heart Association/American College of Cardiology LDL-C target of 2.58 mmol/L (100 mg/dL) at 3 months;
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percentage of patients reaching the updated National Cholesterol Education Program Adult Treatment Panel III LDL-C target of 1.81 mmol/L (70 mg/dL) at 3 months;
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total cholesterol, HDL-C, triglycerides, apoA-1 and apoB concentrations at 1 month and at 3 months.
Concentrations of LDL-C were determined at all visits by the Friedewald equation, except when the triglyceride concentration was greater than 400 mg/dL (4.52 mmol/L), in which case β-quantification measurement of LDL-C was used.
Safety and tolerability were assessed throughout the trial by reviewing patients’ reports, investigators’ observations and results of specific tests and measurements. An independent critical event committee assessed and classified major adverse clinical events according to predefined criteria.
Statistical analysis
A total of 343 evaluable patients per treatment group (rosuvastatin 20 mg and atorvastatin 80 mg) were required to detect a 3% difference in the primary efficacy variable with a two-sided 5% significance level and 80% power, assuming a standard deviation of 14% for the apoB/apoA-1 ratio. This number of evaluable patients (343 per group) also provided 80% power to demonstrate non-inferiority between rosuvastatin 20 mg and atorvastatin 80 mg in change in LDL-C concentrations, considering a non-inferiority margin of 3%, a standard deviation of 14% and a two-sided significance level of 5%. The upper limit of the two-sided 95% confidence interval had to be less than 3% to conclude non-inferiority.
Analysis of all efficacy variables was performed in the intention-to-treat population, which included all patients who had taken at least one dose of study medication after hospital discharge, had a baseline lipid measurement at day 0 and at least one post-day 0 measurement for at least one lipid variable. For robustness, non-inferiority analysis for change in LDL-C concentrations was also conducted in the per-protocol population, which comprised all patients in the intention-to-treat population who did not have major deviations from protocol.
Percentage change in the apoB/apoA-1 ratio from day 0 to 3 months was compared using the Wilcoxon rank sum test and the Hodges-Lehman median estimate, with 95% confidence interval, of the difference between rosuvastatin 20 mg and atorvastatin 80 mg groups, due to the rejection of assumption of normality. Difference between groups in the percentage change in LDL-C concentrations was estimated in the same way as in the main analysis. The non-inferiority analysis for change in LDL-C concentrations was performed with the upper limit of the 95% confidence interval for the difference between rosuvastatin 20 mg and atorvastatin 80 mg being less than 3% for both the intention-to-treat and per-protocol populations. Percentage changes from day 0 to 1 and 3 months in other lipid variables were presented descriptively.
Data for all randomized patients who received at least one study drug dose were included in the safety and/or tolerability assessments. A treatment-emergent adverse event was defined as any adverse event that began in the treatment period, provided the event was not present during the previous period. Statistical analysis was conducted using SAS software, version 8.2 (SAS Institute, Inc., Cary, NC, USA).
Results
Patient disposition
Between January 2006 and June 2007, a total of 1120 patients were screened for enrolment. Of these, 1115 were randomized and 1108 patients received at least one dose of treatment. Of the 1108 treated patients, 887 received placebo during the first period of the study and went on to receive either rosuvastatin 20 mg or atorvastatin 80 mg during the second period; 58 of 887 patients discontinued before receiving rosuvastatin 20 mg or atorvastatin 80 mg ( Fig. 1 ) and 753 (369, rosuvastatin 20 mg; 384, atorvastatin 80 mg) had at least one initial and one subsequent measurement of lipid variables and were included in the intention-to-treat analysis. Of these 753 patients, 226 rosuvastatin 20 mg and 252 atorvastatin 80 mg patients had no major protocol deviation and were included in the per-protocol population. The main reasons for exclusion from the per-protocol population included non-fasting blood samples collected for laboratory assessments under treatment ( n = 107 [53, rosuvastatin 20 mg; 54, atorvastatin 80 mg]), non-compliance with study medication (compliance < 80%: n = 104 [51, rosuvastatin 20 mg; 53, atorvastatin 80 mg]) and taking forbidden medication during the study ( n = 34 [19, rosuvastatin 20 mg; 15, atorvastatin 80 mg]). A total of 359 rosuvastatin 20 mg and 369 atorvastatin 80 mg patients completed the study ( Fig. 1 ).
Demographic and baseline characteristics
Baseline characteristics were similar between the treatment groups ( Table 1 ). Lipid variables at baseline are displayed in Table 2 for the intention-to-treat population. Treatment was initiated on average 4.5 days and 4.6 days after the onset of the ACS for the patients in the rosuvastatin 20 mg and atorvastatin 80 mg groups, respectively.
