Présentation au sujet: "Investigateur français de l’étude METEOR"— Transcription de la présentation:
1Investigateur français de l’étude METEOR Effect of rosuvastatin on progression of carotid intima media thickness in low risk individuals: Results of the METEOR trialDr Serge KownatorCardiologueThionville, FranceInvestigateur français de l’étude METEORDiapositives extraites de la présentation de JR CRUISE - ACC 2007.
2RationaleCarotid intima media thickness (CIMT) is a reliable marker of atherosclerotic burden, relates to cardiovascular risk factors, and predicts future cardiovascular eventsGreater LDL-C reductions with more intensive statin therapy may result in greater effects on atherosclerosisFurther studies are needed to confirm the effects of efficacious statins in low risk individuals with subclinical disease
3METEOR - objectivesPrimary 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 atherosclerosisSecondary 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 arteryOther secondary end points include the effect of rosuvastatin on:Lipids and lipoproteinsLong-term safetyReferenceCrouse 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):Crouse JR III, et al. JAMA 297(12):
4Sites 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.METEORMETEORMETEOR4
6Study population Major inclusion criteria Men aged years; women aged yearsLDL-C ≥ 120 to < 190 mg/dL (3.1 to < 4.9 mmol/L) with no coronary heart disease (CHD) risk factor other than ageLDL-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
7Study population Major exclusion criteria High risk patientsClinical evidence of atherosclerosisDiabetes mellitus10 year Framingham risk of CHD > 10%Lipid lowering therapy in the previous 12 monthsActive liver disease or hepatic dysfunctionCreatine kinase > 3 x ULN at baseline
8METEOR - patient flow5751 subjects screened for lipids, CV risk and CIMT; 984 randomizedRosuvastatin 40 mgn = 702Placebon = 282ITTn = 624Completed two year follow-upn = 530n = 252Completed two year follow upn = 208No follow up CIMTDiscontinued laterN = 78N = 30N = 94N = 445751 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.ReferenceCrouse 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):Crouse JR III, et al. JAMA 297(12):
9METEOR – baseline characteristics Rosuvastatin (n = 702)Placebo (n = 282)Male gender, n (%)421 (60)167 (59)Mean age (SD), years57 (6.2)57 (6.0)Mean BMI (SD), kg/m227.1 (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), mm1.15 (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.
10METEOR - percentage change† in LDL-C, HDL-C, TG, TC and non-HDL-C 20LDL-CHDL-CTGTCNon-HDL-C*10.1108.02.80.3-0.3-10Mean change from baseline† (%)-15.7-20*-30-33.7The significant slowing of progression of atherosclerosis observed was associated with a substantial 49% reduction in LDL-C and an 8% increase in HDL-C.ReferenceCrouse 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):AbbreviationsLDL-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 = 624-45.1-50-48.8Placebo n = 252**-60*P < vs placebo. †Time-weighted least squares mean change.Crouse JR III, et al. JAMA 297(12):
11METEOR primary end point: Rate of change of maximum IMT at 12 carotid sites Rosuvastatin vs placebo+0.03Placebomm/yr(n = 252)P <(rosuvastatin vs placebo)+0.02ProgressionChange in IMT of 12 carotid sites (mm)+0.01Time(years)120.00This 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.ReferenceCrouse 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):P = NS(rosuvastatin vs zero slope)RegressionRosuvastatin 40 mgmm/yr(n = 624)-0.01Placebo; Change in CIMT (95% CI)Rosuvastatin 40 mg; Change in CIMT (95% CI)Crouse JR III, et al. JAMA 297(12):
12Effect of rosuvastatin on carotid IMT Change in CIMT, mm/y (95% CI)-0.010.00+0.01+0.02End pointPrimaryMax CIMT (for all 12 sites)Secondary; Max CIMT for:CCA sitesCarotid bulb sitesICA sitesMean common carotid* ( to )( to )* ( to )( to )* ( to )( to )** ( to )( to )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 – mm/y 95% CI, to ) 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.ReferenceCrouse 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):* ( to )( to )Rosuvastatin 40mg n = 624Placebo n = 252*P < 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 297(12):
13METEOR – safety % subjects with adverse events Rosuvastatin (n = 700) Placebo(n = 281)Myalgia12.712.1CK > 10 X ULN0.1‡0.7RhabdomyolysisALT > 3 X ULN0.60.4HepatitisProteinuria shift*0.3Renal failureCardiac SAEs0.9Neoplasms1.61.1Deaths1/702†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.
14ConclusionDans 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
15RemarquesMETEOR n’est pas une étude orientée vers la pratique, elle teste un conceptIl n’y a pas d’indication à l’heure actuelle a un traitement par Rosuvastatine 40 mg chez ce type de patientOn ne peut pas monitorer en pratique l’effet du traitement sur la paroi artérielleCertaines études ont montré une régression des lésions infracliniques au niveau carotidienLe niveau de risque des patients et la méthodologie de l’examen n’étaient pas comparables