High risk: Moderately high risk:

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1 Μείωση σχετικού και απόλυτου κινδύνου στις υπολιπιδαιµικές µελέτες: αλήθειες, ψέµµατα και στατιστική ηµήτρης Ρίχτερ, MD, FESC, FAHA - ιευθυντής Καρδιολογικής Κλινικής Ευρωκλινικής Αθηνών - Πρόεδρος Ελληνικής Εταιρείας Λιπιδιολογίας - Μέλος Σ ΕΛΙΚΑΡ

2 Τα τελευταία τέσσερα έτη έχω λάβει αµοιβή για συµµετοχή σε µελέτες, ab, ή δορυφορικά συµπόσια από AstraZeneca, Bayer, Sanofi, Pfizer, Vianex, MSD, Unilever, Boehringer, Novartis, Abbott, Galenica, Amgen, Specifar, Menarini, Merck, Pharmaswiss, Winmedica

3 On-treatment LDL-C is closely related to CHD events in statin trials Lower is better 30 4S-plac Event rate (%) S-Rx PROVE-IT-Rx*** LIPID-plac LIPID-Rx CARE-plac PROVE-IT-Rx** HPS-plac HPS-Rx CARE-Rx WOSCOPS-plac TNT-Rx* AFCAPS-plac TNT-Rx** AFCAPS-Rx WOSCOPS-Rx ASCOT-Rx ASCOT-plac On-treatment LDL-C at follow-up (mmol/l, mg/dl) 2 prevention 1 prevention LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart disease; plac=placebo; Rx=treatment *Atorvastatin 10 mg; **Atorvastatin 80 mg; ***Pravastatin 40 mg Adapted from Ballantyne CM. Am J Cardiol 1998; 82: 3Q 12Q. Supplementary data from: HPS. Lancet 2002; 360: Sever PS et al. Lancet 2003; 361: LaRosa JC et al. N Engl J Med 2005; 352: Cannon CP et al. N Engl J Med 2004; 350:

4 2004 PPS ATP III: Updated LDL-C Goals, Treatment Cutpoints Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy High risk: CHD or CHD risk equivalents * (10-year risk >20%) <100 mg/dl (optional: <70 mg/dl) 100 mg/dl 100 mg/dl (<100 mg/dl: consider drug options) Moderately high risk: 2 risk factors (10-year risk 10% 20%) <130 mg/dl (optional: <100 mg/dl) 130 mg/dl 130 mg/dl ( mg/dl: consider drug options) * CHD risk equivalents: clinical manifestations of noncoronary forms of atherosclerotic disease (transient ischemic attacks or stroke of carotid origin >50% obstruction of a carotid artery), diabetes, and 2 risk factors with 10-year risk >20% for hard CHD. The optional LDL-C goal of <70 mg/dl is favored in those at very high risk (eg, people with diabetes, smokers) as well as those with metabolic syndrome, acute coronary syndrome, high TG, and/or non HDL-C <100 mg/dl. Any person at high or moderately high risk with lifestyle-related risk factors is a candidate for TLC to modify these risk factors regardless of LDL-C level. Grundy SM et al. Circulation. 2004;110:

5 Μη βασίζεστε σε συµπεράσµατα που προκύπτουν µόνο από τη λογική, αλλά που αποδεικνύονται έµπρακτα ΙΠΠΟΚΡΑΤΗΣ

6 4S: Scandinavian Simvastatin Survival Study - TRIAL DESIGN - Design Multicenter, randomized, double-blind, placebo-controlled Patients 4444 patients (3617 men, 827 women), aged years, with angina pectoris or previous MI, and high total cholesterol ( mg/dl, mmol/l); patients with MI in previous 6 months or unstable angina excluded Follow up and primary endpoint Primary endpoint: all-cause mortality. Median 5.4 years follow up Treatment Placebo or simvastatin 20 mg each evening, increased or decreased as necessary to 40 or 10 mg each evening to achieve aim of serum total cholesterol mg/dl ( mmol/l )

7 4S: Effect of LDL-C Lowering on Coronary Events in Secondary Prevention Trial in Men and Women % TC -25 LDL-C -35 *P< % CI: -27 to -54. P= HDL-C Nonfatal MI/CHD death -34* CHD death -42 All-cause mortality -30 Subjects: 4,444 (81% men, 19% women) Age range: yr -20 Mean baseline TC: 261 mg/dl Mean baseline LDL-C: 188 mg/dl Duration: 5 yr Intervention: Simvastatin mg/day 4S Group. Lancet. 1994;344:

8 4S: Scandinavian Simvastatin Survival Study - RESULTS continued - Proportion alive All-cause mortality Placebo Simvastatin (RR = 0.7, P=0.0003) Years after randomization Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:

9 4S: Scandinavian Simvastatin Survival Study - RESULTS continued - Coronary events Placebo n=2223 No. (%) Simvastatin n=2221 No. (%) Relative risk (95% CI) P Fatal Definite acute MI Probably MI All (8.5) (5.0) 0.58 ( ) Nonfatal* or fatal 622 (28) 431 (19) 0.66 ( ) < * One or more nonfatal major coronary events Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:

10 LIPID: Effect of Lipid Lowering on Lipid Values and Coronary Events in CHD Patients With Average Cholesterol TC LDL-C 5 HDL-C Nonfatal MI/CHD death CHD death All-cause mortality Subjects: 9,014 (83% men, 17% women) Age range: yr Median baseline TC: 218 mg/dl Median baseline LDL-C: 150 mg/dl Duration: 6 yr Intervention: Pravastatin (40 mg/day) -15 *P< * -24* -22* LIPID Study Group. N Engl J Med. 1998;339:

11 LIPID: Long-term Intervention with Pravastatin in Ischemic Disease Purpose To determine whether pravastatin will reduce coronary mortality and morbidity in patients with AMI or unstable angina pectoris and broad range of initial cholesterol levels Reference LIPID Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:

12 LIPID: Long-term Intervention with Pravastatin in Ischemic Disease - TRIAL DESIGN - Design Randomized, double-blind, placebo-controlled Patients 9014 patients with AMI or hospitalization 3 36 months previously for unstable angina pectoris; baseline cholesterol mg/dl (4 7 mmol/l) Follow up and primary endpoint Follow up mean 6.1 years. Primary endpoint death from CHD Treatment Pravastatin 40 mg daily or placebo. Dietary counseling for both groups

13 LIPID: Long-term Intervention with Pravastatin in Ischemic Disease - RESULTS - Significant reduction in overall mortality, death from CHD and all other pre-specified cardiovascular events Total plasma cholesterol 21% lower than in placebo group at 6 months, falling to 13% at 6.1 years due to discontinuation of treatment in pravastatin group and commencement of open-label therapy in placebo group Pravastatin well tolerated: no significant differences in cancers, accidents, violence, suicide (11 vs. 6 deaths due to trauma or suicide) or myopathy (8 vs. 10 cases) in pravastatin group compared with placebo

14 LIPID: Long-term Intervention with Pravastatin in Ischemic Disease - RESULTS continued - Death from all causes and CHD Placebo Pravastatin Death from all causes Death due to CHD Pravastatin (% of patients) Placebo (% of patients) Death due to CHD Death from all causes Years after randomization Relative reduction in risk (%) 95% CI P < <0.001 LIPID Study Group. N Engl J Med 1998; 339 :

15 LIPID: Long-term Intervention with Pravastatin in Ischemic Disease - RESULTS continued - Relative reduction in risk of cardiovascular outcomes Outcome Placebo n=4502 (%) Pravastatin n=4512 (%) Relative reduction in risk with pravastatin* (%) CHD mortality Overall mortality MI Non-fatal MI or death due to CHD Stroke Coronary revascularization * 95% CI, P<0.001 for all except stroke (P = 0.048) LIPID Study Group. N Engl J Med 1998; 339 :

16 LIPID: Long-term Intervention with Pravastatin in Ischemic Disease - SUMMARY - As seen in other studies, cholesterol-lowering therapy significantly reduced all major cardiovascular events; however, study also specifically demonstrated that pravastatin: reduced both mortality due to CHD and overall mortality had benefit for patients with unstable angina On basis of differences in proportions of patients with an event, for every 1000 patients assigned pravastatin: death from any cause avoided in 30 patients death due to CHD avoided in 19 non-fatal MI/death due to CHD avoided in 35 death due to stroke avoided in 8

17 Heart Protection Study (HPS): Eligibility 20,536 participants (men=15,454, women=5,082) aged years Nonfasting TC 135 mg/dl At increased 5-year risk of CHD death due to prior disease myocardial infarction or other CHD occlusive disease of noncoronary arteries type 1 or type 2 diabetes treated hypertension Statin or antioxidant vitamins not clearly indicated or contraindicated by patient s own doctor HPS Collaborative Group. Lancet. 2002;360:7-22. HPS Collaborative Group. Eur Heart J. 1999;20:

18 Statin Use: Compliance with Study Simvastatin or Use of Nonstudy Statin Years of Follow-up Approx. No. of Patients Simvastatin Allocated Placebo Allocated 1 20,000 89% 4% 2 20,000 85% 9% 3 19,000 84% 17% 4 18,500 83% 24% 5 14,500 82% 32% Study Average 85% 17% Heart Protection Study Collaborative Group. Lancet 2002;360:7 22. Slide Source Lipids Online Slide Library

19 Difference in LDL Cholesterol (Simvastatin Placebo) Years of Follow-up Average: 1.0 ± 0.02 mmol/l 37 ± 0.8 mg/dl Heart Protection Study Collaborative Group. Lancet 2002;360:7 22. Slide Source Lipids Online Slide Library

20 Simvastatin: Cause-Specific Mortality Cause of Death Vascular Simvastatin (10,269) Placebo (10,267) Coronary Other vascular ANY VASCULAR 781 (7.6%) 937 (9.1%) Nonvascular Neoplastic Respiratory Other medical Nonmedical NONVASCULAR 547 (5.3%) 570 (5.6%) ALL CAUSES 1328 (12.9%) 1507 (14.7%) 0.4 Heart Protection Study Collaborative Group. Lancet 2002;360:7 22. Reprinted with permission from Elsevier Science. Risk ratio and 95% CI STATIN Better PLACEBO Better 17% SE 4 reduction (2P<0.0001) 5% SE 6 reduction (NS) 13% SE 4 reduction (2P<0.001) Slide Source Lipids Online Slide Library

21 Simvastatin: Coronary Events and Revascularization Major Coronary Event Major coronary event Simvastatin (10,269) Placebo (10,267) Nonfatal MI Coronary death Risk ratio and 95% CI STATIN Better PLACEBO Better CORONARY EVENTS 898 (8.7%) 1212 (11.8%) 27% SE 4 reduction (2P< ) Revascularization Coronary Noncoronary REVASCULARIZATIONS 939 (9.1%) 1205 (11.7%) 24% SE 4 reduction (2P< ) 0.4 Heart Protection Study Collaborative Group. Lancet 2002;360:7 22. Reprinted with permission from Elsevier Science Slide Source Lipids Online Slide Library

22 Simvastatin: Major Vascular Events by Year People Suffer ring Events (%) Benefit/1000 (SE): Placebo Years of Follow-up Simvastatin 5 (3) 20 (4) 35 (5) 46 (5) 54 (7) 60 (18) Heart Protection Study Collaborative Group. Lancet 2002;360:7 22. Reprinted with permission from Elsevier Science. 6 Slide Source Lipids Online Slide Library

23 Simvastatin: Major Vascular Events by Prior Disease Simvastatin (10,269) Placebo (10,267) Previous MI 999 (23.5%) 1250 (29.4%) Other CHD (not MI) 460 (18.9%) 591 (24.2%) Risk ratio and 95% CI STATIN Better PLACEBO Better No prior CHD CVD 172 (18.7%) 212 (23.6%) PVD 327 (24.7%) 420 (30.5%) Diabetes 276 (13.8%) 367 (18.6%) ALL PATIENTS 2033 (19.8%) 2585 (25.2%) % SE 3 reduction (2P< ) Heart Protection Study Collaborative Group. Lancet 2002;360:7 22. Slide Source Lipids Online Slide Library

24 Simvastatin: Main Conclusions After allowance for noncompliance, 40 mg daily simvastatin safely reduces the risk of heart attack, of stroke, and of revascularization by about one third. 5 years of statin treatment typically prevents these major vascular events in about: 100 of every 1000 people with previous MI 80 " " " other previous CHD 70 " " " cerebrovascular disease 70 " " " other arterial disease 70 " " " diabetes (age 40+) irrespective of cholesterol level (or age, or sex, or other treatments). Heart Protection Study Collaborative Group. Lancet 2002;360:7 22. Slide Source Lipids Online Slide Library

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31 JUPITER study design No history of CAD men 50 yrs women 60 yrs LDL-C <130 mg/dl CRP 2.0 mg/l Placebo run-in Rosuvastatin 20 mg (n=8901) Placebo (n=8901) Visit: Week: monthly Final Lead-in/ eligibility Randomisation Lipids CRP Tolerability Lipids CRP Tolerability Median follow-up 1.9 years Lipids CRP Tolerability HbA 1C CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA 1c =glycated haemoglobin Ridker P et al. N Eng J Med 2008;359:

32 Primary Endpoint JUPITER - Study Endpoints Time to the first occurrence of a major cardiovascular event, composite of: cardiovascular death Stroke MI unstable angina arterial revascularisation Secondary Endpoints: total mortality non-cardiovascular mortality development of diabetes mellitus development of venous thromboembolic events bone fractures discontinuation of study medication due to adverse effects. Ridker PM. Circulation 2003; 108:

33 JUPITER - Patient Flow 89,890 subjects screened 17,802 randomized Rosuvastatin 20mg n=8,901 Placebo n=8,901 Lost to follow up n=44 Lost to follow up n=37 Completed study n=8,857 Completed study n=8,864 Ridker P et al. N Eng J Med 2008;359:

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35 JUPITER - Baseline laboratory parameters * Rosuvastatin Placebo n=8901 n=8901 Total cholesterol (mg/dl) 186 ( ) 185 ( ) LDL cholesterol (mg/dl) 108 (94-119) 108 (94-119) HDL cholesterol (mg/dl) 49 (40-60) 49 (40-60) Triglycerides (mg/dl) 118 (85-169) 118 (86-169) hscrp (mg/l) 4.2 ( ) 4.3 ( ) Glucose (mg/dl) 94 (87-102) 94 (88-102) HbA 1c (%) 5.7 ( ) 5.7 ( ) Glomerular filtration rate, (ml/min/1.73m 2 ) 73.3 ( ) 73.6 ( ) For hscrp, values are the average of the values obtained at two screening and visits *All values are median (interquartile range) or N (%). Ridker P et al. N Eng J Med 2008;359:

36 Cumulati ive Incidence Number at Risk Rosuvastatin Placebo JUPITER - Primary Endpoint Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization Hazard Ratio 0.56 (95% CI ) P< Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1, Placebo Rosuvastatin 20 mg NNT for 2y = 95 5y* = 25 *Extrapolated figure based on Altman and Andersen method Ridker P et al. N Eng J Med 2008;359:

37 JUPITER - Primary Endpoint Components Placebo Rosuvastatin HR 95% CI p-value [n=8901] [n=8901] n (rate ** ) n (rate ** ) Primary Endpoint 251 (1.36) 142 (0.77) <0.001 * (Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation) Non-fatal MI 62 (0.33) 22 (0.12) <0.001 * Fatal or non-fatal MI 68 (0.37) 31 (0.17) Non-fatal stroke 58 (0.31) 30 (0.16) Fatal or non-fatal stroke 64 (0.34) 33 (0.18) Arterial Revascularization 131 (0.71) 71 (0.38) < Unstable angina 27 (0.14) 16 (0.09) CV death, stroke, MI 157 (0.85) 83 (0.45) <0.001 * Revascularization or unstable angina 143 (0.77) 76 (0.41) <0.001 * ** Rates are per 100 person years; Hospitalisation due to unstable angina; *Actual p-value was < HR Hazard Ratio; CI Confidence Limit Ridker P et al. N Eng J Med 2008;359:

38 JUPITER - Total Mortality Death from any cause Cumulativ ve Incidence Number at Risk Rosuvastatin Placebo Hazard Ratio 0.80 (95% CI ) p= Follow-up (years) 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1, ,901 8,852 8,775 6,987 4,319 2,295 1,614 1, Placebo Rosuvastatin 20mg Ridker P et al. N Eng J Med 2008;359:

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47 Σχεδιασµός της µελέτης Πληθυσµός Ασθενών: Στεφανιαία νόσος LDL-C: mg/dL ( mmol/L) Τριγλυκερίδια 600mg/dL ( 6.8mmol/L) Screening και περίοδος έκπλυσης n= 18,469 Ανοιχτή περίοδος n= 15,464 Ατορβαστατίνη 10mg Έναρξη n= 5006 Πληθυσµός ασθενών: Χρόνος ως την εµφάνιση ενός ΜΚΑΣ: στεφανιαία θνητότητα µη θανατηφόρο ΟΕΜ καρδιακή ανακοπή - ανάνηψη θανατηφόρο ή µη θανατηφόρο ΑΕΕ ιπλά-τυφλή περίοδος n= 10,001 LDL-C: <130mg/dL (<3.4mmol/L) Ατορβαστατίνη 10mg ΣτόχοςLD;L-C: 100mg/dL(2.6mmol/L) n= 4995 Ατορβαστατίνη 80mg ΣτόχοςLDL-C: 75mg/dL (1.9mmol/L) 1-8 εβδοµάδες 1-8 εβδοµάδες Μέση διάρκεια παρακολούθησης = 4.9 έτη ΜΚΑΣ: µείζον καρδιαγγειακό σύµβαµα ΑΕΕ: αγγειακό εγκεφαλικό επεισόδιο Από τους LaRosa JC, et al. N Engl J Med. 2005:352

48 Κύρια Έκβαση Αποτελεσµατικότητας: Σύνοψη Καταληκτικό σηµείο Αριθµός ασθενών (%) Ατορβαστατίνη 10mg (n= 5006) Ατορβαστατίνη 80mg (n= 4995) HR P Μείζον ΚΑ σύµβαµα 548 (10.9) 434 (8.7) 0.78 <0.001 Στεφανιαίοι θάνατοι 127 (2.5) 101 (2.0) Μη θανατηφόρο ΟΕΜ 308 (6.2) 243 (4.9) Ανανήπτουσα καρδιακή ανακοπή 26 (0.5) 25 (0.5) Θανατηφόρο/Μη θανατηφόρο ΑΕΕ 155 (3.1) 117 (2.3) LaRosa JC, et al. N Engl J Med. 2005:352

49 Absolute Rates of Major CV Events & Any CV Events by Smoking Status Current smokers vs. Either other group P< Event rat te (%) Difference in major CV events between current and former smokers = 4.5% Frey P et al. Am J Cardiol. 2011;107:145

50 Absolute Major CV Event Rates by Smoking Status and Statin Therapy Major CV event rate (%) Smoking status Frey P et al. Am J Cardiol. 2011;107:145

51 Efficacy Outcomes Outcome Apixaban (N=9120) Event Rate (%/yr) Warfarin (N=9081) Event Rate (%/yr) HR (95% CI) P Value Stroke or systemic embolism* (0.66, 0.95) Stroke (0.65, 0.95) Ischemic or uncertain (0.74, 1.13) 0.42 Hemorrhagic (0.35, 0.75) <0.001 Systemic embolism (SE) (0.44, 1.75) 0.70 All-cause death* (0.80, 0.998) Stroke, SE, or all-cause death (0.81, 0.98) Myocardial infarction (0.66, 1.17) 0.37 * Part of sequential testing sequence preserving the overall type I error

52 Balance of Efficacy and Safety Endpo oint (%) CV Death / MI / Stroke Clopidogrel Prasugrel events HR 0.81 ( ) P= NNT = TIMI Major NonCABG Bleeds Prasugrel Clopidogrel Days events HR 1.32 ( ) P=0.03 NNH = 167

53 ΑΣΘΕΝΕΙΣ ΤΗΣ ΜΕΛΕΤΗΣ Ανδρες και γυναίκες άνω των 55 ετών σε κίνδυνο για την εκδήλωση µείζονος καρδιαγγειακού επεισοδίου µε: Στεφανιαία νόσο: Έµφραγµα µυοκαρδίου (πριν από >1 µήνα) Σταθερή στηθάγχη (πριν από >1 µήνα) µε θετική δοκ. κοπώσεως ή βλάβη άνω των 2 αγγείων στη στεφανιογραφία. Αγγειοπλαστική για πολυαγγειακή νόσο (πριν από >1 µήνα) Στεφανιαία παράκαµψη (πριν από >4 χρόνια)

54 ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ ΠΛΗΘΥΣΜΟΥ ΜΕΛΕΤΗΣ Στους ασθενείς αυτούς η µέση ετήσια συχνότης επεισοδίων είναι περίπου 5% ή περίπου 40 φορές µεγαλύτερη του γενικού πληθυσµού. Eχουν διάχυτη αθηροσκλήρωση µε µεγάλη πιθανότητα εκδήλωσης νέου επεισοδίου. Αντιπροσωπεύει µεγάλο τµήµα του γενικού πληθυσµού. Συµπεριέλαβε µεγάλο αριθµό γυναικών και διαβητικούς.

55 Κύρια τελικά σηµεία - Ραµιπρίλη / Placebo Ραµιπρίλη (%) Placebo Αριθ. ασθενών (%) Σχετικός κίνδυνος 95% CI p Καρδιαγγ.θάνατος+εµφ.µυοκαρδίου+εγκεφ.επεισόδιο <0.001 Καρδιαγγ. θάνατος <0.001 Εµφραγµα µυοκαρδίου <0.001 Εγκεφαλικό επεισόδιο <0.001 Μη καρδιαγγ. θάνατος Θάνατος από όλες τις αιτίες

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59 Are preventive drugs preventive enough? A study of patients expectation of benefit from preventive drugs. Only 27% of subjects would take a drug offering 5% or less absolute risk reduction over five years Trewby PN et al Clin med 2002,2,527

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