Investigateur français de l’étude METEOR Effect of rosuvastatin on progression of carotid intima media thickness in low risk individuals: Results of the METEOR trial Dr Serge Kownator Cardiologue Thionville, France Investigateur français de l’étude METEOR Diapositives extraites de la présentation de JR CRUISE - ACC 2007.

Rationale Carotid intima media thickness (CIMT) is a reliable marker of atherosclerotic burden, relates to cardiovascular risk factors, and predicts future cardiovascular events Greater LDL-C reductions with more intensive statin therapy may result in greater effects on atherosclerosis Further studies are needed to confirm the effects of efficacious statins in low risk individuals with subclinical disease

METEOR - objectives Primary objective – to assess whether rosuvastatin therapy over two years could slow progression of CIMT compared to placebo and/or induce regression of CIMT, in all sites of the carotid artery in subjects with a low risk of CHD (Framingham Risk Score < 10%) and evidence of subclinical atherosclerosis Secondary objectives – to assess whether rosuvastatin therapy could slow progression of CIMT compared to placebo and/or induce regression of CIMT, in the common carotid artery, in the carotid bulb, and in the internal carotid artery Other secondary end points include the effect of rosuvastatin on: Lipids and lipoproteins Long-term safety Reference Crouse J, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis. The METEOR Trial. JAMA. 2007;297(12):1344-1345. Crouse JR III, et al. JAMA. 2007. 297(12):1344-1345.

Sites de mesure METEOR METEOR METEOR METEOR METEOR METEOR 4 La méthodologie ultrasonore comporte une mesure de l’EIM au niveau de 6 sites de chaque côté et selon 5 angles. Le résultat pris en compte étant l’épaisseur maximale mesurée. METEOR METEOR METEOR 4

6-week run-in/ eligibility METEOR – study design Double blind, placebo controlled, multicenter trial Rosuvastatin 40 mg 6-week run-in/ eligibility Placebo Randomization 6 12 18 24 Months CIMT Lipids

Study population Major inclusion criteria Men aged 45-70 years; women aged 55-70 years LDL-C ≥ 120 to < 190 mg/dL (3.1 to < 4.9 mmol/L) with no coronary heart disease (CHD) risk factor other than age LDL-C ≥ 120 to < 160 mg/dL (3.1 to < 4.1 mmol/L) with > 1 risk factor and a 10-year CHD risk of < 10% Triglycerides < 500 mg/dL (< 5.7 mmol/L) Maximum CIMT of at least 1.2 mm at any site and less than 3.5 mm in all sites

Study population Major exclusion criteria High risk patients Clinical evidence of atherosclerosis Diabetes mellitus 10 year Framingham risk of CHD > 10% Lipid lowering therapy in the previous 12 months Active liver disease or hepatic dysfunction Creatine kinase > 3 x ULN at baseline

METEOR - patient flow 5751 subjects screened for lipids, CV risk and CIMT; 984 randomized Rosuvastatin 40 mg n = 702 Placebo n = 282 ITT n = 624 Completed two year follow-up n = 530 n = 252 Completed two year follow up n = 208 No follow up CIMT Discontinued later N = 78 N = 30 N = 94 N = 44 5751 individuals were screened and 984 were randomized at 61 centers in the USA and Europe. Participants received rosuvastatin 40 mg or placebo for 24 months. 172 subjects in the rosuvastatin group and 74 in the placebo group withdrew before the end of the study. Participants who had no further CIMTs beyond baseline were excluded from the ITT population. Reference Crouse J, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis. The METEOR Trial. JAMA. 2007;297(12):1344-1345. Crouse JR III, et al. JAMA. 2007. 297(12):1344-1345.

METEOR – baseline characteristics Rosuvastatin (n = 702) Placebo (n = 282) Male gender, n (%) 421 (60) 167 (59) Mean age (SD), years 57 (6.2) 57 (6.0) Mean BMI (SD), kg/m2 27.1 (4.0) 27.5 (4.0) 2+ CHD risk factors, n (%) 223 (32) 111 (39) Smokers, n (%) 22 (3) 16 (6) Hypertension, n (%) 138 (20) 58 (21) HDL-C < 40 mg/dL, n (%) 64 (9) 36 (13) MeanMax CIMT all 12 sites (SD), mm 1.15 (0.19) 1.17 (0.20) LDL-C mg/dL, mean (SD) 155 (24.1) 154 (24.2) SD = standard deviation; BMI = body mass index; CHD = coronary heart disease; MeanMax = mean of the maximum; CIMT = carotid intima-media thickness; LDL-C = low-density lipoprotein cholesterol.

METEOR - percentage change† in LDL-C, HDL-C, TG, TC and non-HDL-C 20 LDL-C HDL-C TG TC Non-HDL-C * 10.1 10 8.0 2.8 0.3 -0.3 -10 Mean change from baseline† (%) -15.7 -20 * -30 -33.7 The significant slowing of progression of atherosclerosis observed was associated with a substantial 49% reduction in LDL-C and an 8% increase in HDL-C. Reference Crouse J, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis. The METEOR Trial. JAMA. 2007;297(12):1344-1345. Abbreviations LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; TG = triglycerides; TC = total cholesterol; nonHDL-C = non-high-density lipoprotein cholesterol. -40 * Rosuvastatin 40 mg n = 624 -45.1 -50 -48.8 Placebo n = 252 * * -60 *P < 0.001 vs placebo. †Time-weighted least squares mean change. Crouse JR III, et al. JAMA. 2007. 297(12):1344-1345.

METEOR primary end point: Rate of change of maximum IMT at 12 carotid sites Rosuvastatin vs placebo +0.03 Placebo +0.0131 mm/yr (n = 252) P < 0.0001 (rosuvastatin vs placebo) +0.02 Progression Change in IMT of 12 carotid sites (mm) +0.01 Time (years) 1 2 0.00 This graph displays the results of the two-stage primary end point. It’s important when assessing the results from METEOR to remember that the primary end point had 2 stages. These were (i) to examine the difference in CMT between placebo and rosuvastatin, where a significant difference would confirm a slowing of progression with rosuvastatin compared to placebo and (ii) to examine the difference between rosuvastatin and baseline, where a significant difference would confirm regression with rosuvastatin. The two-stage test accounts for the 5:2 randomisation ratio in METEOR. Looking at the first stage, it is apparent that for all carotid sites, the rate of progression was significantly reduced compared with placebo. For the second objective, the rate of change for CRESTOR was negative but the difference compared to baseline was not statistically significant. Reference Crouse J, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis. The METEOR Trial. JAMA. 2007;297(12):1344-1345. P = NS (rosuvastatin vs zero slope) Regression Rosuvastatin 40 mg -0.0014 mm/yr (n = 624) -0.01 Placebo; Change in CIMT (95% CI) Rosuvastatin 40 mg; Change in CIMT (95% CI) Crouse JR III, et al. JAMA. 2007. 297(12):1344-1345.

Effect of rosuvastatin on carotid IMT Change in CIMT, mm/y (95% CI) -0.01 0.00 +0.01 +0.02 End point Primary Max CIMT (for all 12 sites) Secondary; Max CIMT for: CCA sites Carotid bulb sites ICA sites Mean common carotid -0.0014* (-0.0041 to 0.0014) +0.0131 (0.0087 to 0.0174) -0.0038* (-0.0064 to-0.0013) +0.0084 (0.0043 to 0.0124) -0.0040* (-0.0090 to 0.0010) +0.0172 (0.0094 to 0.0251) +0.0039** (-0.0009 to 0.0088) +0.0145 (0.0068 to 0.0221) This slide shows the main results in a graphical format. For each end point, the rate of change over the two year trial is plotted with 95% confidence intervals. This slide demonstrates visually that rosuvastatin slowed the progression on atherosclerosis. Note that for all end points, the rate of progression was significantly reduced compared to placebo. A statistical test to examine whether the CIMT of rosuvastatin treated subjects had regressed significantly from baseline (ie, rate of change of CIMT for CRESTOR compared to no change) showed that whilst the range of change was negative (max CIMT –0.0014 mm/y 95% CI, -0.0041 to 0.0014) and therefore suggestive of regression, the result did not reach statistical significance. Significant regression was observed in the maximum CIMT in the common carotid artery segment. Reference Crouse J, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis. The METEOR Trial. JAMA. 2007;297(12):1344-1345. +0.0004* (-0.0011 to 0.0019) +0.0088 (0.0064 to 0.0112) Rosuvastatin 40mg n = 624 Placebo n = 252 *P < 0.001 RSV vs placebo; **P = 0.02 RSV vs placebo. CIMT = carotid intima media thickness; CCA = common carotid artery; ICA = internal carotid artery. Crouse JR III, et al. JAMA. 2007. 297(12):1344-1345.

METEOR – safety % subjects with adverse events Rosuvastatin (n = 700) Placebo (n = 281) Myalgia 12.7 12.1 CK > 10 X ULN 0.1‡ 0.7 Rhabdomyolysis ALT > 3 X ULN 0.6 0.4 Hepatitis Proteinuria shift* 0.3 Renal failure Cardiac SAEs 0.9 Neoplasms 1.6 1.1 Deaths 1/702† 0/282 *Shift in dipstick urine protein from none/trace at baseline to ≥ 2+ post baseline. †Creutzfeldt-Jakob disease, not related to study treatment. ‡Exercise-associated.

Conclusion Dans une population à bas risque mais ayant des lésions artérielles infra-cliniques on observe une stabilisation de la maladie artérielle sous rosuvastatine par rapport au placebo

Remarques METEOR n’est pas une étude orientée vers la pratique, elle teste un concept Il n’y a pas d’indication à l’heure actuelle a un traitement par Rosuvastatine 40 mg chez ce type de patient On ne peut pas monitorer en pratique l’effet du traitement sur la paroi artérielle Certaines études ont montré une régression des lésions infracliniques au niveau carotidien Le niveau de risque des patients et la méthodologie de l’examen n’étaient pas comparables

Sites de mesure METEOR CAIUS METEOR METEOR ACAPS ACAPS ASAP ACAPS PLAC II METEOR ACAPS PLAC II KAPS ASAP KAPS ACAPS LIPID METEOR ACAPS CAIUS ARBITER METEOR REGRESS MARS

Remarques Des études orientées cette fois vers les évènements cliniques sont nécessaires pour confirmer les résultats observés