Baisser le LDL Le cas du diabétique DIEVART François Clinique Villette, Dunkerque
Conflits d intérêts Honoraires pour conférences ou conseils pour : Abbott, Astra Zeneca, BMS, Boehringer Ingelheim, IPSEN, Menarini, MSD, Novartis, Pfizer, Roche diagnostics, sanofi aventis france, Servier, Takeda
Des fondamentaux à l actualité
1. le modèle et ses limites 2. le cas du diabétique
Un peu d histoire
Avant 1994
Avant 1994 Prévention secondaire Étude CDP Œstrogènes, hormones thyroïdiennes Baisse du cholestérol Augmentation significative de la mortalité totale
Avant 1994 Prévention primaire Étude OMS (WHO 78 92) clofibrate 10 000 patients suivis > 5 ans Augmentation significative de mortalité totale de 31 %
Avant 1994 : controverse il est possible de diminuer le cholestérol le risque d infarctus diminue mais la mortalité totale augmente
Avant 1994 : controverse La baisse du cholestérol ou le traitement?
Avant 1994 : controverse La baisse du cholestérol ou l effet des traitements utilisés?
1994 Si baisser le cholestérol diminue le risque d IDM mortel Si la réduction du cholestérol n est pas néfaste Diminuer le risque d IDM mortel chez des patients à haut risque doit diminuer la mortalité totale
All Cause Mortality Cause of death Placebo (n=2223) Simvastatin (n=2221) Risk Reduction Coronary 189 111 42% Non-CV 49 46 -Cancer 35 33 -Suicide 4 5 -Trauma 3 1 -Other 7 7 All Deaths 256 182 30% The Lancet, Vol 344, November 19, 1994
All Cause Mortality Cause of death Placebo (n=2223) Simvastatin (n=2221) Risk Reduction Coronary 189 111 42% Non-CV 49 46 -Cancer 35 33 -Suicide 4 5 -Trauma 3 1 -Other 7 7 All Deaths 256 182 30% The Lancet, Vol 344, November 19, 1994
4S Total Mortality: primary endpoint 1.00 Proportion alive 0.95 0.90 0.85 0.80 simvastatin placebo 30% risk reduction Log rank p=0.0003 0.00 0.0 1 2 3 4 5 Years since randomisation 6 4S Group. Lancet 1994;344:1383 1389.
Après 1994
Long and widing road WOSCOPS, AFCaps/TexCaps, PROSPER, HPS, CARDS, ASCOT, MIRACL, TNT. 2005 1994 Framingham HHS WHO CDP 1961 4S
Construction du modèle
2005
Relation réduction d incidence des événements vasculaires majeurs et réduction moyenne du LDL C à 1 an 50% Major CV events 40% Event Reduction 30% 21% 20% 10% 0% 10% 0.5 1.0 1.5 2.0 (0.4 g/l) LDL c reduction mmol/l Lancet 2005; 366: 1267 78
Toute baisse du LDL avec une statine = bénéfice CV
Quelles que soient données démographiques données lipidiques données cliniques
French guidelines LDL > 1,6 g/l or 1 RF => diet (3 months) After 3 months, if LDL not at goal => use drugs AFSSAPS. Mars 2005
Limites du modèle
AURORA Screening Treatment Month: Visit: 14 days 1 0 2 3 3 6 4 12 5 6 monthly 6 Final Patients (n~2750) Inclusion criteria ESRD, on hemodialysis for 3 months 50 80 years Exclusion criteria Statin within 6 months Kidney transplant likely within 1 year Creatine kinase >3xULN ALT >3xULN TSH >1.5xULN Rosuvastatin 10 mg daily (n~1350) Randomization 1:1 Matching placebo (n~1350) Study medication was administered until 620 patients had experienced a major CV event Fellström B et al. Curr Control Trials Cardiovasc Med 2005; 6: 9
AURORA: Changes in lipids and hs CRP 120 100 LDL C: 43% reduction 200 160 TG: 16.2% reduction LDL C (mg/dl) 80 60 40 20 p<0.0001 TG (mg/dl) 120 80 40 p<0.0001 Rosuvastatin Placebo HDL C (mg/dl) 0 60 50 40 30 20 10 0 1 2 3 4 5 Year HDL C: 2.9% increase p=0.045 Hs CRP (mg/l) 0 7 6 5 4 3 2 1 0 1 2 3 4 5 Year Hs CRP: 11.5% decrease P<0.0001 0 0 0 1 2 3 4 5 Baseline 3 months 1 year Year Values are means (95% CI) for LDL C, TG and HDL C and medians (95% CI) for Hs CRP; % change from baseline at 3 months is quoted and p values are for change at 3 months versus placebo Rosuvastatin Placebo
AURORA: primary endpoint Kaplan Meier estimate of time to first major CV event 40 35 Placebo Cumulative incidence of primary endpoint (%) 30 25 20 15 10 5 0 Rosuvastatin HR=0.96 (95% CI 0.84 1.11) P=0.59 0 1 2 3 4 5 No. at risk: Years from randomization Rosuvastatin 1390 1152 962 826 551 148 Placebo 1384 1163 952 809 534 153
Limites du modèle Insuffisance rénale dialysée (AURORA, 4D) Insuffisance cardiaque (CORONA, GISSI HF) Hémorragie cérébrale (SPARCL)
Limites du modèle Hypertriglycéridémie isolée: effet clinique non connu quelles valeurs? Intolérance aux statines
JUPITER Trial Design No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dl hscrp >2 mg/l 4-week run-in Rosuvastatin 20 mg (N=8901) Placebo (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA Ridker et al, Circulation 2003;108:2292-2297.
JUPITER Baseline Blood Levels (median, interquartile range) Rosuvastatin Placebo (N = 8901) (n = 8901) hscrp, mg/l 4.2 (2.8 7.1) 4.3 (2.8 7.2) LDL, mg/dl 108 (94 119) 108 (94 119) HDL, mg/dl 49 (40 60) 49 (40 60) Triglycerides, mg/l 118 (85 169) 118 (86 169) Total Cholesterol, mg/dl 186 (168 200) 185 (169 199) [ Mean LDL = 104 mg/dl ] Ridker et al NEJM 2008
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Ridker et al NEJM 2008 Cumulative Incidence 0.00 0.02 0.04 0.06 0.08 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 0 1 2 3 4 Placebo 251 / 8901-44 % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
JUPITER AURORA Predicted Benefit Based on LDL Reduction vs Observed Benefit 55 Proportional reduction in vascular event rate (95% CI) 50 45 40 35 30 25 20 15 10 5 A to Z TNT IDEAL CTT PROVE IT JUPITER OBSERVED hscrp? JUPITER PREDICTED AURORA PREDICTED AURORA CV risk: 9,5 % per year 0 0 0,5 1 Mean LDL cholesterol difference between treatment groups (mmol/l) D après Ridker et al NEJM 2008
Limites du modèle Le plus tôt serait il le mieux?
Jusqu où faut il baisser le cholestérol? Le plus bas est il le mieux?
Relation réduction d incidence des événements vasculaires majeurs et réduction moyenne du LDL C à 1 an 50% Major CV events 40% Event Reduction 30% 21% 20% 10% 0% 10% 0.5 1.0 1.5 2.0 (0.4 g/l) LDL c reduction mmol/l Lancet 2005; 366: 1267 78
Relation entre cholestérol obtenu et réduction du risque d AVC 0.8 Relative Risk Reduction of Stroke 0.6 0.4 0.2 0.0-0.2 MIRACL SCAT CARE VA-HIT PCABGT LIPID PLAC II MAAS REGRESS POSCH 4S KAPS BIP LA WOSCOPS Stockholm CDP Niac CDP Clo -0.4 135 155 174 193 213 232 251 271 290 309 WHO LRC Helsinki Hjermann et al Final Cholesterol (mg/dl) Corvol JC, et al. Arch Intern Med. 2003;163:669-676. With permission.
Essais d intervention ayant démontré le bénéfice clinique d un abaissement du LDL en dessous d 1 g/l MIRACL PROVE IT TNT IDEAL SPARCL LDL, baseline 1,24 g/l 1,06 g/l 0,98 g/l 1,22 g/l 1,33 g/l LDL, in control group 1,35 g/l 0,95 g/l 1,01 g/l 1,04 g/l 1,29 g/l LDL, in pts treated with atorvastatin 80 mg/d 0,72 g/l 0,62 g/l 0,77 g/l 0,81 g/l 0,73 g/l LDL difference 0,63 g/l 0,33 g/l 0,24 g/l 0,23 g/l 0,56 g/l Study Follow Up (mean) 4 mois 2 ans 4,9 ans 4,8 ans 4,9 ans Relative risk, coronary events 0,84 0,84 0,80 0,89 0,65 Relativerisk, total mortality 0,94 0,72 1,01 0,98 1,00
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta analysis of data from 170,000 participants in 26 randomised trials Lancet 2010; 376: 1670 81 DOI:10.1016/S0140 6736(10)61350 5 41
Second CTT cycle: more vs less intensive statin therapy Study Treatment comparison N Target population Entry lipid criteria PROVE-IT A 80 vs. P 40 4162 ACS TC 240 mg/dl A to Z S 40 then S 80 vs. placebo then S 20 4497 ACS TC 250 mg/dl TNT A 80 vs. A 10 10,001 Prior CHD LDL-C 130-250 mg/dl TG 600 mg/dl IDEAL A 80 vs. S 20-40 8888 Prior CHD TG 600 mg/dl SEARCH S 80 vs. S 20 12,064 Prior CHD TC 4.5 mmol/l or 3.5 if on statins
MORE VS LESS STATIN Proportional effects on MAJOR VASCULAR EVENTS (unweighted for 1 year LDL C differences) No. of events (% pa) More statin Less statin Relative risk (CI) Nonfatal MI CHD death Any major coronary event 1175 (1.3%) 645 (0.7%) 1725 (1.9%) 1380 (1.5%) 694 (0.7%) 1973 (2.2%) 0.85 (0.76-0.94) 0.93 (0.81-1.07) 0.87 (0.81-0.93) CABG PTCA Unspecified 637 (0.7%) 1166 (1.3%) 447 (0.5%) 731 (0.9%) 1508 (1.8%) 502 (0.6%) 0.86 (0.75-0.99) 0.76 (0.69-0.84) 0.87 (0.74-1.03) Any coronary revascularisation 2250 (2.6%) 2741 (3.2%) 0.81 (0.76-0.85) Ischaemic stroke Haemorrhagic stroke 440 (0.5%) 69 (0.1%) 526 (0.6%) 57 (0.1%) 0.84 (0.71-0.99) 1.21 (0.76-1.91) Unknown stroke Any stroke 63 (0.1%) 572 (0.6%) 80 (0.1%) 663 (0.7%) 0.79 (0.51-1.21) 0.86 (0.77-0.96) Any major vascular event 3837 (4.5%) 4416 (5.3%) 0.85 (0.82-0.89) 99% or 95% CI 0.4 0.6 0.8 1 1.2 1.4 More statin better Less statin better 43
Le plus bas est il le mieux? OUI
Le plus bas est il le mieux? Chez qui?
Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL C reduction, by baseline prognostic factors No. of patients (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction Previous coronary disease: CHD Non-CHD vascular None 8395 (4.5%) 674 (3.1%) 1904 (1.4%) 10123 (5.6%) 802 (3.7%) 2425 (1.8%) 0.79 (0.76-0.82) 0.81 (0.71-0.92) 0.75 (0.69-0.82) Diabetes: Type 1 diabetes Type 2 diabetes No diabetes 145 (4.5%) 2494 (4.2%) 8272 (3.2%) 192 (6.0%) 2920 (5.1%) 10163 (4.0%) 0.77 (0.58-1.01) 0.80 (0.74-0.86) 0.78 (0.75-0.81) Sex: Male Female 8712 (3.5%) 2261 (2.5%) 10725 (4.4%) 2625 (2.9%) 0.77 (0.74-0.80) 0.83 (0.76-0.90) Age (years) 65 >65, 75 >75 6056 (2.9%) 4032 (3.7%) 885 (4.8%) 7455 (3.6%) 4908 (4.6%) 987 (5.4%) 0.78 (0.75-0.82) 0.78 (0.74-0.83) 0.84 (0.73-0.97) Body mass index (kg/m 2 ): <25 25,< 30 30 3030 (3.0%) 5033 (3.3%) 2732 (3.3%) 3688 (3.7%) 6125 (4.1%) 3331 (4.1%) 0.79 (0.74-0.84) 0.78 (0.74-0.82) 0.78 (0.73-0.84) Smoking status: Current smokers Non-smokers 2268 (3.6%) 8703 (3.1%) 2896 (4.7%) 10452 (3.9%) 0.78 (0.73-0.84) 0.78 (0.75-0.82) Total 10973 (13.0%) 13350 (15.8%) 0.78 (0.76-0.80) 99% or 95% CI 0.4 0.6 0.8 1 1.2 1.4 Statin/more better Control/less better 46
Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL C reduction, by baseline prognostic factors No. of patients (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction Treated hypertension: Yes No 6176 (3.7%) 4543 (2.7%) 7350 (4.5%) 5707 (3.5%) 0.80 (0.76-0.84) 0.76 (0.72-0.80) Systolic blood pressure (mm Hg): <140 140,< 160 160 5470 (3.2%) 3145 (3.0%) 2067 (3.6%) 6500 (3.8%) 4049 (3.9%) 2473 (4.5%) 0.80 (0.77-0.85) 0.75 (0.70-0.80) 0.79 (0.73-0.85) Diastolic blood pressure (mm Hg): <80 80,< 90 90 4558 (3.5%) 3670 (3.0%) 2452 (3.0%) 5306 (4.2%) 4587 (3.8%) 3128 (3.9%) 0.81 (0.76-0.85) 0.77 (0.73-0.82) 0.77 (0.72-0.82) Estimated GFR (ml/min/1.73m 2 ): < 60 60, < 90 90 2712 (4.1%) 6161 (3.2%) 1315 (2.5%) 3354 (5.1%) 7540 (4.0%) 1571 (3.0%) 0.77 (0.72-0.83) 0.78 (0.75-0.82) 0.77 (0.69-0.85) HDL-C (mmol/l): 1.0 >1.0, 1.3 >1.3 5032 (4.0%) 3656 (3.1%) 2199 (2.4%) 6165 (5.0%) 4452 (3.9%) 2633 (2.9%) 0.78 (0.75-0.82) 0.77 (0.73-0.82) 0.80 (0.74-0.87) Total 10973 (13.0%) 13350 (15.8%) 0.78 (0.76-0.80) 99% or 95% CI 0.4 0.6 0.8 1 1.2 1.4 Statin/more better Control/less better 47
Avec quels risques?
Proportional effects on SITE SPECIFIC CANCER per mmol/l LDL C reduction No. of first cancers (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction Gastrointestinal 1166 (0.3%) 1194 (0.3%) 0.97 (0.87-1.09) Genitourinary Respiratory 1596 (0.5%) 813 (0.2%) 1645 (0.5%) 814 (0.2%) 0.97 (0.88-1.06) 1.00 (0.88-1.15) Female breast Haematological 267 (0.3%) 305 (0.1%) 241 (0.3%) 291 (0.1%) 1.07 (0.84-1.38) 1.04 (0.84-1.30) Melanoma 159 (0.0%) 142 (0.0%) 1.14 (0.83-1.56) Other/unknown 754 (0.2%) 737 (0.2%) 1.04 (0.89-1.21) Any 5060 (1.4%) 5064 (1.4%) 1.00 (0.96-1.04) 99% or 95% CI 0.4 0.6 0.8 1 1.2 1.4 Statin/more better Control/less better 49
Le bénéfice dépasse largement les risques
CTT Meta analysis Statins decrease mortality Cholesterol Treatment Trialists Collaboration Cause des décés Causes vasculaires: Coronaire AVC Autre vasculaire Vasculaire non coronaire Traitement (n = 45,054) 0.6 0.6 1.2 Evénts (%) Controle (n = 45,002) Statine Control meilleure meilleur 3.4 4.4 0.81 0.6 0.7 1.3 0.91 0.95 0.93 Toute cause vasculaire Cause non vasculaire: Cancer Respiratoire Trauma Autres Toutes non vasculaires Tous décés 4.7 2.4 0.2 0.1 1.1 3.8 5.7 2.4 0.3 0.1 1.2 4.0 8.5 9.7 0.83 1.01 0.82 0.89 0.87 0.95 0.88 0.5 1.0 1.5 Risque relatif CTT Collaborators. Lancet. 2005;366:1267-78.
Even in primary prevention (BMJ 2009)
Sans exclure les précautions d utilisation
French guidelines
Le bénéfice dépasse largement les risques
Et en dehors des statines?
Relation réduction d incidence des événements vasculaires majeurs et réduction moyenne du LDL C à 1 an 50% Major CV events Avec une statine 40% Event Reduction 30% 21% 20% 10% 0% 10% 0.5 1.0 1.5 2.0 (0.4 g/l) LDL c reduction mmol/l Lancet 2005; 366: 1267 78
Inhibiteurs de l absorption du cholestérol Fibrates
Ezetimibe évaluation ENHANCE (2008), eze + S vs S : no effect on carotid IMT (720 pts, 2 years) SEAS (2008), eze + S vs S: no effect on CV events in pts in primary prevention with Aortic Stenosis, slight increase in cancer incidence (1873 pts, 2 years) ARBITER 6 HALTS (2009): S + (Eze vs Niacin): carotid IMT decreased with niacin and didn t change with eze (208 pts, 14 months)
SEAS : Kaplan-Meier Curves for Primary and Secondary Outcomes and Death Rossebø AB et al. N Engl J Med 2008 Sep 2 [Epub ahead of print]
15 10 CARDS RRR = 37% Effects on major CV events PLACEBO 5 ATORVASTATINE 0 0 1 2 3 4 4.75 FIBRATES FIELD RRR = 11% 30 25 20 HPS-Diabète RRR = 24% PLACEBO HPS-Diabète RR = -24% 15 10 SIMVASTATINE 5 0 0 1 2 3 4 5 6 Années de suivi
15 10 CARDS RRR = 37% Effects on major CV events PLACEBO 5 ATORVASTATINE 0 0 1 2 3 4 4.75 FIELD RR = 0,89; ns 30 25 20 HPS-Diabète RRR = 24% PLACEBO HPS-Diabète RR = -24% 15 10 SIMVASTATINE 5 0 0 1 2 3 4 5 6 Années de suivi
French guidelines
Et le HDL?
Lipids: HDL
AFCaps/TexCaps: Objectif Comparer la lovastatine au placebo en prévention du 1er événement coronarien majeur Chez des hommes et des femmes en prévention CV primaire, avec un LDL peu élevé et un HDL bas. JAMA 1998;279:1615-1622
Fatal/Nonfatal MI, Sudden Cardiac Death, Unstable Angina: AFCAPS/TexCAPS 0.07 0.06 Cumulative incidence 0.05 0.04 0.03 0.01 0.00 placebo 0.02 lovastatin 0.0 1 2 3 4 5 >5 37% relative risk reduction p<0.001 Years of follow up Downs JR et al. JAMA 1998;279:1615 1622.
Cardiovascular Endpoints: AFCAPS/TexCAPS Subjects with No History of CHD and Average Cholesterol Number of events Outcomes placebo (n=3301) lovastatin (n=3304) RRR (%) p value Fatal or nonfatal MI + unstable angina + sudden cardiac death* 183 116 37 <0.001 Revascularisation 157 106 33 <0.001 Fatal and nonfatal MI 95 57 40 0.002 Unstable angina 87 60 32 0.02 * primary endpoint, RRR relative risk reduction Downs JR et al. JAMA 1998;279:1615 1622.
1. le modèle et ses limites 2. le cas du diabétique
De quoi décèdent les diabétiques? 50 40 Décès (%) 30 20 10 0 Maladie cardiaque ischémique Autre maladie cardiaque Diabète Cancer AVC Infection Autre Dans 75 % des cas le décès est de cause CV Adapté de GEISS LS. et al. In Diabetes in America. 2nd ed. 1995 : 233-257
Diabète de type 2 : un risque coronarien élevé Comparaison de l incidence des IM pendant 7 ans en fonction des antécédents ou non d IM 45 40 35 30 25 20 15 10 5 0 Patients sans antécédent d IM Patients ayant un antécédent d IM 3,5 % 18,8 % Patients non diabétiques 20,2 % 45 % Patients diabétiques de type 2 HAFFNER SM. et al. NEJM 1998 ; 339 : 229 234.
Une maladie associée à un risque CV élevé Incidence à 7ans des événements CV (%) Non diabétiques : 50 45 40 35 30 25 20 15 10 5 0 Diabétiques : -MI +MI Non coronariens ( - IM) -MI +MI -MI +MI -MI +MI -MI +MI -MI +MI Coronariens ( + IM) IDM AVC Décès CV Haffner SM et al. N Engl J Med 1998;339:229-234.
Le diabète est il un équivalent coronarien? Qu est ce que cela veut dire?
PLAN Le diabète est il un équivalent coronarien? MAIS
PLAN Le diabète est il un équivalent coronarien? MAIS Physiopathologie différente
Diabetic Atheromas Have a Different Pathobiology Than Nondiabetic Atheromas 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 P=.001 Inflammation Diabetes (n=36) No diabetes (n=32) 250 200 150 100 50 0 P=.0001 Neovascularization 0.6 0.5 0.4 0.3 0.2 0.1 0 P=.005 Collagen III Diabetes Diabetes Diabetes No diabetes No diabetes No diabetes Purushothaman K R et al. J Am Coll Cardiol. 2006;47(suppl A):295A.
PLAN Le diabète est il un équivalent coronarien? MAIS Études non concordantes (dépend des caractéristiques des patients)
Major Cardiovascular Events at 6-12 Month Follow-Up 14 12 10 8 6 4 2 0 % of Patients No diabetes with Vascular Disease (n=988) p<0.001 Diabetes without Vascular Disease (n=694) 11.2 Diabetes with Vascular Disease (n=587) p=0.41 p=0.0064 p<0.0001 p<0.0001 p=0.070 7.6 5 5 3.7 3.5 3.5 2.9 2.8 2.6 1.8 2 2.1 1.2 0.6 0.7 0.9 1.5 Death MI Unstable Angina PCI or CABG TIA or Stroke Composite On file at Canadian Heart Research Centre.
PLAN Le diabète est il un équivalent coronarien? MAIS Antiagrégants plaquettaires
Antithrombotic Trialists Collaboration: VASCULAR EVENTS Category APT CTRL Reduction Prior MI 13.5% 17.0% 25%±4 Acute MI 10.4% 14.2% 30%±4 Prior stroke/tia 17.8% 21.4% 22%±4 Acute stroke 8.2% 9.1% 11%±3 Other high risk* CAD 6.2% 8.9% 37%±5 Embolic risk 13.5% 16.8% 26%±7 PAD 5.8% 7.1% 23%±8 Other 11.3% 12.6% 13%±7 All trials 10.7% 13.2% 22%±2 0.0 0.5 1.0 1.5 2.0
Antithrombotic Trialists Collaboration Effects on VASCULAR EVENTS in patients with OTHER HIGH-RISK CONDITIONS Category APT CTRL Reduction Haemodialysis 2.9% 4.9% 41%±16 Diabetes 15.7% 16.7% 7%±8 Carotid disease 10.6% 12.8% 19%±22 All high-risk patients 22%±2 (P<0.0001) 0.0 0.5 1.0 1.5 2.0
PLAN Le diabète est il un équivalent coronarien? MAIS Lipides
Results: primary outcome CHD events (CHD death + nonfatal MI) Placebo Fenofibrate HR = 0.89 95% CI = 0.75 1.05 P=0.16
Relation entre réduction d incidence des événements vasculaires majeurs et réduction moyenne du LDL C à 1 an 50% Major CV events 40% Event Reduction 30% 21% 20% 10% 0% 10% 0.5 1.0 1.5 2.0 (0.4 g/l) LDL c reduction mmol/l Lancet 2005; 366: 1267 78
Collaborative Atorvastatin Diabetes Study (CARDS) Patient Population Type 2 diabetes mellitus Men and women 40 75 years of age Primary CHD and stroke prevention LDL C 160 mg/dl ( 4.14 mmol/l) TG 600 mg/dl ( 6.78 mmol/l) 1 additional RF HTN (or on HTN treatment) Retinopathy Albuminuria Current smoking 2838 patients Atorvastatin 10 mg (n=1428) 4-year follow-up Double-blind placebo (n=1410) Primary endpoint: time to first major CV event (CHD death, nonfatal MI, unstable angina, resuscitated cardiac arrest, coronary revascularization, stroke Secondary endpoints: total mortality, any CV endpoint, lipids, and lipoproteins Colhoun HM et al. Lancet 2004;364:685-696.
CARDS: Patient Baseline Lipids Total cholesterol (mg/dl) (mmol/l) LDL cholesterol (mg/dl) (mmol/l) HDL cholesterol (mg/dl) (mmol/l) Triglycerides* (mg/dl) (mmol/l) Placebo (n = 1410) Mean (SD) 207 (32) 5.35 (0.82) 117 (27) 3.02 (0.70) 55 (13) 1.42 (0.34) 148 (104 212) 1.67 (1.17 2.40) Atorvastatin (n = 1428) Mean (SD) 207 (32) 5.36 (0.83) 118 (28) 3.04 (0.72) 54 (12) 1.39 (0.32) 150 (106 212) 1.70 (1.20 2.40) *Median (interquartile range) Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.
CARDS: Lipid Levels by Treatment Total Cholesterol (mg/dl) Average difference 26%, 54 mg/dl; P<0.0001 LDL Cholesterol (mg/dl) Average difference 40%, 46 mg/dl; P<0.0001 Median TC (mg/dl)* 240 Placebo 160 Atorvastatin 80 0 0 1 2 3 4 4.5 Years of Study Median LDL-C (mg/dl)* 160 Placebo 120 80 40 Atorvastatin 0 0 1 2 3 4 4.5 Years of Study Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.
CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke Cumulative Hazard, (%) Placebo Atorvastatin 15 10 5 Relative Risk Reduction 37% (95% CI, 17 52) P = 0.001 0 0 1 2 3 4 Years 1410 1428 1351 1392 Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier. 1306 1361 1022 1074 Placebo 127 events Atorvastatin 83 events 651 694 4.75 305 328
Messages Le diabète est associé à une augmentation du risque CV Le diabétique partage certains caractères physiopathologiques avec le coronarien L effet du traitement des coronariens n est pas identique chez le diabétique: antiagrégant Si le risque est supérieur, corriger le surrisque avec les moyens validés (statines pour tous, PA en dessous de 140/90 mm Hg)
Merci de votre attention B
Back up B
CHARISMA Trial Design Patients age 45 years at high risk of Low dose ASA 75 162 mg/day atherothrombotic events (n=15603) R Double-blind treatment up to 1040 primary efficacy events* Clopidogrel 75 mg/day (n=7802) 1-month visit Low dose ASA 75 162 mg/day 3-month visit Visits every 6 months Final visit (Fixed study end date) Placebo 1 tablet/day (n=7801) * MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death; event-driven trial Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263 268.
Overall Population: Prior Medical History Clopidogrel + ASA (%) Placebo + ASA (%) Characteristic (n=7802) (n=7801) Hypertension 73.3 73.9 Hypercholesterolemia 73.7 74.2 Congestive heart failure 6.0 5.9 Prior MI 34.2 34.9 Atrial fibrillation 3.8 3.7 Prior stroke 24.9 24.3 TIA 12.0 11.9 Diabetes 42.3 41.7 PAD 22.6 22.7 PCI 22.4 23.1 CABG 19.5 19.9 Carotid endarterectomy 5.4 5.2 Peripheral angioplasty or bypass 11.3 11.0 Diabetic nephropathy 12.9 12.9 Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death) Cumulative event rate (%) 8 6 4 2 Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] P=0.22 0 0 6 12 18 24 30 Months since randomization First Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death *All patients received ASA 75-162 mg/day The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo) Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Results for Primary Endpoint by Prior Medical History p value Characteristic N HR (95% CI) interaction Diabetes Yes 6566 0.99 (0.84, 1.17) 0.28 No 9047 0.87 (0.74, 1.03) Hypertension Yes 11483 0.95 (0.83, 1.08) 0.57 No 4120 0.87 (0.68, 1.12) Hypercholesterolemia Yes 11535 0.95 (0.83, 1.10) 0.46 No 4068 0.87 (0.70, 1.07) History of CABG Yes 3079 1.05 (0.82, 1.34) 0.28 No 12524 0.90 (0.79, 1.03) History of PCI Yes 3554 0.90 (0.69, 1.17) 0.77 No 12049 0.94 (0.82, 1.07) History of MI Yes 5397 0.83 (0.69, 1.00) 0.13 No 10205 1.00 (0.86, 1.17) History of Stroke Yes 3837 0.85 (0.69, 1.04) 0.29 No 11766 0.97 (0.84, 1.12) Multiple Risk Factors 3284 1.20 (0.91, 1.59) 0.045 Manifest CV Disease 12153 0.88 (0.77, 0.998) Clopidogrel Better 0.5 1 1.5 Placebo Better Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Statin Therapy Reduces CVD Events in DM Approximately to Un Rx d Risk in Non Diabetics CTT Meta Analysis of 14 Statin Trials a Major Vascular Event Rate b, % 40 Control CVD Risk Higher Than Patients 34,9 With No Diabetes on Placebo Treatment c 30 20 10 29,6 Residual Risk 24,8 19,4 Residual Risk 0 Diabetes a 4.3 year mean follow up of 18 686 patients with diabetes; n = 71 370 patients with no diabetes b Nonfatal MI, CHD death, stroke, or coronary revascularization c Event rate per 1 mmol/l (39 mg/dl) reduction in LDL C No Diabetes CTT Collaborators. Lancet. 2008;371:117 125.
Flow of patients 9795 randomised 6051 Australia, 2351 New Zealand, 1393 Finland 4900 Placebo 4895 Fenofibrate 200 mg 5 withdrew consent 10 lost to follow-up 4 withdrew consent 12 lost to follow-up 4856 (99%) primary outcome confirmed 4852 (99%) primary outcome confirmed
Proportional effects on cause-specific mortality per mmol/l reduction in LDL cholesterol in participants presenting with or without diabetes Cholesterol Treatment Trialists' (CTT) Collaborators Lancet 2008;371:117-25