Η ΛΙΠΙΔΙΚΗ ΘΕΩΡΙΑ Μία Επανεκτήµηση Ι. Ε. ΚΑΝΟΝΙΔΗΣ ΚΑΘΗΓΗΤΗΣ ΚΑΡΔΙΟΛΟΓΙΑΣ Α.Π.Θ.

NOTHING TO DECLARE

THE LIPID HYPOTHESIS

ΧΟΛΗΣΤΕΡΟΛΗ ΚΑΙ ΘΝΗΤΟΤΗΤΑ ΣΝ 35 Seven Countries Study Θάνατος από ΣΝ /1000 άτοµα 30 25 20 15 10 5 Serbia Northern Europe United States Southern Europe, inland Southern Europe, Mediterranean Japan 0 2.60 (100) 3.25 (125) 3.90 (150) 4.50 (175) 5.15 (200) 5.80 (225) 6.45 (250) 7.10 (275) 7.75 (300) 8.40 (325) 9.05 (350) Ολική χοληστερόλη ορού mmol/l (mg/dl) Verschuren WM et al. JAMA 1995;274(2):131 136.

Θάνατοι από ΣΝ και ολική χοληστερόλη PROCAM 15 11.06 Θάνατοι από ΣΝ/ 1000 ασθενείς/ 6 χρόνια 10 5 3.23 4.18 5.60 7.14 0 4.68 4.71 5.22 5.25 5.69 5.72 6.31 6.34 Επίπεδα (πεµπτηµόρια) ολικής χοληστερόλης (mmol/l) ΣΝ = Στεφανιαία νόσος Adapted from Stamler J et al JAMA 1986;256:2823-2828.

Αυξηµένα επίπεδα χοληστερόλης σχετίζονται µε αυξηµένο κίνδυνο ΣΝ Multiple Risk Factor Intervention Trial (MRFIT) (N=361,662) Framingham Study (N=5209) Age-Adjusted 6-Year CHD Mortality Per 1000 Men 18 16 14 12 10 8 6 4 2 0 140 160 180 200 220 240 260 280 300 320 6-Year CHD Incidence Per 1000 Men 150 125 100 75 50 25 0 204 205-234 235-264 265-294 295 Ολική Χοληστερόλη (mg/dl) Ολική Χοληστερόλη (mg/dl) 1% Μείωση της Ολικής Χοληστερόλης οδηγεί σε 2% Μείωση του Κινδύνου για ΣΝ 1% Αύξηση της Ολικής Χοληστερόλης οδηγεί σε 2% Αύξηση του Κινδύνου για ΣΝ Adapted from Martin MJ et al. Lancet. 1986;2:933-936,. Reproduced from Castelli WP. Am J Med. 1984;76:4-12,.

Relationship Between Cholesterol and CHD Risk: Framingham Study 150 CHD incidence per 1000 125 100 75 50 25 0 <204 (<5.3) 205-234 (5.3-6.1) 235-264 (6.1-6.8) 265-294 (6.8-7.6) >295 (>7.6) Serum total cholesterol, mg/dl (mmol/l) Castelli WP. Am J Med. 1984;76:4-12.

Diet Trials Multifactorial trials Oslo Primary Prevention The New York Trial (1981) Anticoronary Club Study Multiple Risk Factor (1957) Intervention Trial (MRFIT) Los Angeles Veterans (1982,1990) Study (1969) The European Finnish Mental Hospitals Collaborative Trial Study (1979) Minnesota coronary survey (1989)

Los Angeles Veterans Study Effects of cholesterol-lowering fat-modified diet Reduction 13%

Oslo Primary Prevention Trial Trends in serum Cholesterol Reduction 13%

Multiple Risk Factor Intervention Trial (MRFIT)

Trials of Drugs Non Statin Drug Trials l WHO Cooperative Clofibrate Trial (1978,1980) l Lipid Research Clinic Coronary Primary Prevention Trial (LRC CPPT) (1984) l Helsinki Heart Study (1987)

Lipid Research Clinic Coronary Primary Prevention Trial (LRC CPPT) Trends in total and LDLserum Cholesterol Reduction 13,4% Reduction20,8%

Lipid Research Clinic Coronary Primary Prevention Trial (LRC CPPT) 2:1 rule

Helsinki Heart Study

Στατίνες l Λοβαστατίνη l Πραβαστατίνη l Συµβαστατίνη l Σεριβαστατίνη l Ατορβαστατίνη l Ροσουβαστατίνη

Aρχικές µελέτες στατινών 1994 4S 1995 WOSCOPS 1996 CARE 1998. AFCAPS/TexCAPS 1998 LIPID Μελέτες πρωτογενούς πρόληψης WOSCOPS AFCAPS/TexCAPS Μελέτες Δευτερογενούς πρόληψης 4S CARE LIPID Απέδειξαν τη Μείωση του Σχετικού Κινδύνου Νοσηρότητας και Θνητότητας στον γενικό πληθυσµό έναντι του Εικονικού Φαρµάκου

WOSCOPS

AFCAPS/TexCAPS primary prevention study

4S Primary End Point: Total Mortality Secondary End Point: Major Coronary Events* 30% RRR P=.0003 34% RRR P=.00001 0 1 2 3 4 5 6 0 1 2 3 4 5 6

*µη θανατ. ΟΕΜ ή θάν. Από ΣΝ; **ισχαιµικά συµβάντα Downs JR et al. JAMA 1998;279:1615-1622. Shepherd J et al. N Engl J Med 1999;333:1301-1307. Scandinavian Simvastatin Study Group. Lancet 1994;344:1383-1389. Sacks FM et al. N Engl J Med 1996;335:1001-1009. LIPID Study Group. N Engl J Med 1998;339:1349-1357. Schwartz GG et al. JAMA 2001;285:1711-1718. Pitt B et al. N Engl J Med 1999;341:70-76. Μελέτες µε Στατίνες Μελέτη Στατίνη Μείωση LDL / κινδ. ΣΝ Πρωτογενής Πρόληψη AFCAPS/TexCAPS Lovastatin - 25% 40%* WOSCOPS Pravastatin - 26% 31%* Δευτερογενής πρόληψη 4S Simvastatin - 35% 34%* CARE Pravastatin - 27% 24%* LIPID Pravastatin - 25% 24%*

Μελέτες πρόληψης Σ.Ν. µε Στατίνες σε Διαβητικούς ασθενείς: Αναλύσεις υποοµάδων Μελέτη Φάρµακο Πρωτοπαθής Πρόληψη AFCAPS/TexCAPS Lovastatin Δευτεροπαθής Πρόληψη Μείωση του κινδύνου για Σ.Ν. Αρ. συνολικά 239 37% Μείωση του κινδύνου για Σ.Ν. διαβητικοίί 43% CARE 4S LIPID 4S-Extended Pravastatin Simvastatin Pravastatin Simvastatin 586 202 782 483 23% 32% 25% 32% 25% (p=0.05) 55% (p=0.002) 19% 42% (p=0.001) Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Pyörälä K et al. Diabetes Care 1997;20:614-620; The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357; Haffner SM et al. Arch Intern Med 1999;159:2661-2667.

HMG-CoA Reductase Inhibitor: Chronological Order of Event Driven Trials Study populations: Primary prevention Acute coronary syndromes (Secondary prevention) Chronic coronary heart disease (Secondary prevention) 1994 4S 2002 PROSPER 1995 WOSCOPS 2002 ALLHAT-LLA 1996 CARE 2002 ASCOT-LLA 1998 AFCAPS/TEXCAPS 2004 PROVE- IT 1998 LIPID 2004 A to Z 2001 MIRACL 2005 TNT 2002 HPS 2005 IDEAL 2008 JUPITER 2010 SEARCH

Meta-Analysis of Intensive Statin Therapy All Endpoints Odds Ratio (95% CI) Odds Reduction High Dose Event Rates No./Total (%) Std Dose Coronary Death or Any Cardiovascular Event OR, 0.84 95% CI, 0.80-0.89 p<0.0001-16% 3972/13798 (28.8) 4445/13750 (32.3) Coronary Death or MI OR, 0.84 95% CI, 0.77-0.91 p=0.00003-16% 1097/13798 (8.0) 1288/13750 (9.4) Cardiovascular Death OR, 0.88 95% CI, 0.78-1.00 p=.054-12% 462/13798 (3.3) 520/13750 (3.8) Non-Cardiovascular Death OR, 1.03 95% CI, 0.88-1.20 p=0.73 +3% 340/13798 (2.5) 331/13750 (2.4) Total Mortality OR, 0.94 95% CI, 0.85-1.04 P=0.20-6% 808/13798 (5.9) 857/13750 (6.2) Stroke OR 0.82 95% CI, 0.71-0.96 p=0.012-18% 316/13798 (2.3) 381/13750 (2.8) 0.5 1 2.5 High-dose statin better High-dose statin worse Cannon CP, et al. Cannon CP, et al. JACC 2006; 48: 438-445.

Εστίαση σε ειδικές οµάδες υψηλού κινδύνου (Οξέα Στεφανιαία Σύνδροµα, Ηλικιωµένοι, ΣΔ, ΑΥ ) µε χαµηλές τιµές χοληστερίνης HPS (Simvastatin 40mg) 20536 pts CARDS (Atorvastatin 10mg) 2838 pts ASCOT (Atorvastatin 10mg) 19342 pts MIRACL (Atorvastatin 80mg) 3086 pts PROSPER (Pravastatin 40 mg) 5084 pts

Heart Protection Study 20536 ασθενείς ηλικίας 40 80 ετών Αυξηµένος Κίνδυνος θανάτου από ΣΝ λόγω: Εµφράγµατος του µυοκαρδίου ή ΣΝ Αρτηριακή αποφρακτική νόσο Σακχαρώδη Διαβήτη ή υπέρταση υπό αγωγή Ολική χοληστερόλη >3.5 mmol/l (>135 mg/dl) Simvastatin 40mg vs placebo Μέσος χρόνος παρακολούθησης : 5 έτη Heart Protection Study Collaborative Group. Lancet 2002;360:7 22.

Heart Protection Study 13% µείωση θνητότητας από οποιαδήποτε αιτία 24% µείωση κύριων αγγειακών συµβάντων 27% µείωση κύριων στεφανιαίων συµβάντων 25% µείωση ΑΕΕ 24% µείωση επαναιµάτωσης Heart Protection Study Collaborative Group. Lancet 2002;360:7 22.

CARDS: 37% Reduction in primary outcome Cumulative hazard (%) 15 10 5 Relative risk reduction 37% 95% CI = 17% 52% P = 0.001 Placebo 127 events Atorvastatin 83 events 0 0 1 2 3 4 4.75 Years Placebo 1410 1351 1306 1022 651 305 Atorvastatin 1428 1392 1361 1074 694 328 Colhoun HM et al. Lancet 2004;364:685-96.

HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA) 10,305 patients with HTN randomized to atorvastatin (10 mg) or placebo for 5 years Cumulative incidence of MI and fatal CHD (%) 4 3 2 1 0 Atorvastatin 90 mg/dl* Placebo 126 mg/dl* P=0.0005 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Follow-up (yr) A statin provides significant benefit in moderate- to high-risk individuals by lowering LDL-C levels below current goals 36% RRR *Post-treatment LDL-C level CHD=Coronary heart disease, HTN=Hypertension, LDL-C=Low density lipoprotein cholesterol, RRR=Relative risk reduction Source: Sever PS et al. Lancet. 2003;361:1149-1158

HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Lipid Lowering Arm (ALLHAT-LLA) 10,355 patients with HTN and >1 CHD risk factor randomized to pravastatin (40 mg) or usual care for 5 years Cumulative rate % 18 15 12 9 6 3 0 32% cross-over among patients with CHD Pravastatin Usual care RR, 0.99; P=0.88 1 2 3 4 5 6 Years The failure to demonstrate benefit with a statin may be the result of a high rate of cross over CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk Source: ALLHAT Collaborative Research Group. JAMA 2002;288:2998-3007

HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial 3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo for 16 weeks Combined CV event rate (%)* 15 15 10 10 5 0 0 17.4% Placebo 14.8% Atorvastatin RR=0.84, P=0.048 4 8 12 16 Weeks Acute intensive statin therapy provides significant CV benefit *Includes death, MI resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. ACS=Acute coronary syndrome, CV=Caradiovascular Source: Schwartz GG et al. JAMA 2001;285:1711-1718

HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) 5,804 patients aged 70-82 years with a history of, or risk factors for, vascular disease randomized to pravastatin (40 mg) or placebo for 3.2 years CHD death, non-fatal MI, stroke (%) 20 10 0 Placebo Pravastatin 15% RRR, P=0.014 0 1 2 3 4 Years A statin provides CV benefit in older men CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: Shepherd J et al. Lancet 2002;360:1623-1630

Εντατικοποίηση της Αγωγής µε χορήγηση Στατινών σε υψηλή δοσολογία σε ασθενείς µε σχετικά χαµηλά επίπεδα LDL PRROVE-IT Pravastatin 40 versus atorvastatin 80mg 4162 pts ΤΝΤ Atorvastatin 10mg versus atorvastatin 80mg 10001pts A to Z Simvastatin 20mg versus Simvastatin 80mg 4162pts IDEAL Simvastatin 20mg versus Atorvastatin 80mg 8888pts

PROVE-IT Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22 Ν = 4,162 hospitalised for ACS 10 days pravastatin 40 mg (n = 2,063) vs atorvastatin 80 mg (n = 2,099) 24 months Primary end points: death, MI, unstable angina, revascularization, stroke

HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) TIMI 22 Study 4,162 pts with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months Recurrent MI, cardiac death, UA, revascularization, or stroke 30 25 20 15 10 5 0 Pravastatin Atorvastatin P=0.005 3 6 9 12 15 18 21 24 27 30 Follow-up (months) 16% RRR Acute intensive statin therapy provides significant CV benefit ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction, UA=Unstable angina Source: Cannon CP et al. NEJM 2004;350:1495-1504

PROVE-IT: Final LDL cholesterol level Pravastatin 40 mg (n = 1,973) Atorvastatin 80 mg (n = 2,003) p Baseline LDL-C Final LDL-C (mg/dl) 104 96 104 62 <0.001 Cannon CP et al N Engl J Med 2004;350:1495-504

HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Treating to New Targets (TNT) Trial 10,001 patients with stable CHD randomized to atorvastatin (80 mg) or atorvastatin (10 mg) for 4.9 years 0.15 Major CV Event* (%) 0.10 Atorvastatin (10 mg) 22% RRR 0.05 Atorvastatin (80 mg) 0.00 P<0.001 0 1 2 3 4 5 6 Years High-dose statin therapy provides benefit in chronic CHD *Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: LaRosa JC et al. NEJM 2005;352:1425-35

HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Cumulative event rate (%)* Aggrastat to Zocor (A to Z) Trial 4,162 patients with an ACS randomized to simvastatin (80 mg) or simvastatin (20 mg) for 24 months 20 15 10 5 Placebo/Simvastatin 20 mg/day Simvastatin 40/80 mg/day HR=0.89, P=0.14 0 0 4 8 12 16 20 24 Time from randomization (months) Acute intensive statin therapy does not provide CV benefit *Includes CV death, MI, readmission for an ACS, and CVA ACS=Acute coronary syndrome, CV=Cardiovascular, CVA=Cerebrovascular accident, MI=Myocardial infarction Source: de Lemos JA et al. JAMA 2004;292:1307-1316

HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Trial 8,888 patients with a history of acute MI randomized to atorvastatin (80 mg) or simvastatin (20 mg) for 5 years Cumulative Hazard (%) 12 Simvastatin (20 mg) 8 Atorvastatin (80 mg) 4 HR=0.89, P=0.07 0 1 2 3 4 5 Years Since Randomization High-dose statin therapy does not provide CV benefit after a MI *Includes coronary death, hospitalization for nonfatal acute MI, or cardiac arrest with resuscitation CV=Cardiovascular, HR=Hazard ratio, MI=Myocardial infarction Source: Pedersen TR et al. JAMA 2005;294:2437-2445

IDEAL: Baseline and follow-up levels of LDL cholesterol Study arm Baseline (mg/dl) 1 year (mg/ dl) 5 years (mg/ dl) Simvastatin 20 mg 121.4 102.0 99.8 Atorvastatin 80 mg 121.6 79.1 80.0 Pedersen TR et al. JAMA 2005; 294:2437-2445.

HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) 17,802 men (>50 years) and women (>60 years) with LDL-C <130 mg/dl and hs-crp >2 mg/l randomized to rosuvastatin (20 mg) or placebo for up to 5 years* Cumulative incidence of CV death, MI, stroke, hospitalization for unstable angina, and arterial revascularization 0.00 0.04 0.08 Rosuvastatin Placebo 0 1 2 3 4 Follow-up (years) 44% RRR P<0.00001, NNT=25 A statin provides benefit in those with elevated hs-crp levels *The study was stopped prematurely after 1.9 years CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction Ridker PM et al. NEJM 2008;359:2195-2207

ΣΤΑΤΙΝΕΣ ΚΑΙ ΕΠΙΒΡΑΔΥΝΣΗ ΤΗΣ ΕΞΕΛΙΞΗΣ ΤΗΣ ΑΘΗΡΩΜΑΤΙΚΗΣ ΝΟΣΟΥ Εκτίµηση µε στερφανιογραφία CLAS 1987 FATS 1990 POSCH 1990 Lifestyle Heart Trial 1990

ΣΤΑΤΙΝΕΣ ΚΑΙ ΕΠΙΒΡΑΔΥΝΣΗ ΤΗΣ ΕΞΕΛΙΞΗΣ ΤΗΣ ΑΘΗΡΩΜΑΤΙΚΗΣ ΝΟΣΟΥ Εκτίµηση µε IVUS Επιθετική µείωση λιπιδίων Μελέτη REVERSAL: JAMA 2004;291: 1071-1080 Μελέτη ASTEROID: JAMA 2006;295: 1556-1565

Statins reduce all-cause death: Meta-analysis of 14 trials Ν = 90,056 Cause of death Vascular causes: CHD Stroke Other vascular Any non-chd vascular Any vascular death Non-vascular causes: Cancer Respiratory Trauma Other/unknown Any non-vascular Any death Treatment (45,054) 3.4 4.4 0.81 0.6 0.6 1.2 4.7 2.4 0.2 0.1 1.1 3.8 Events (%) Control (45,002) 0.6 0.7 1.3 5.7 2.4 0.3 0.1 1.2 4.0 8.5 9.7 RR 0.91 0.95 0.93 0.83 1.01 0.82 0.89 0.87 0.95 0.88-17% -12% 0.5 Treatment better 1.0 Control better 1.5 CTT Collaborators. Lancet. 2005;366:1267-78.

Statin benefit independent of baseline lipids: Metaanalysis of 14 trials Groups Total cholesterol (mg/dl) 201 >201-251 >251 LDL cholesterol (mg/dl) 135 >135-174 >174 HDL cholesterol (mg/dl) 35 >35-43 >43 Triglycerides (mg/dl) 124 >124-177 >177 Treatment (45,054) 13.5 16.6 0.76 13.9 17.4 0.79 15.2 19.7 0.80 13.4 14.2 15.8 18.2 14.3 11.4 13.4 13.8 15.3 Events (%) Control (45,002) 16.7 17.6 20.4 22.7 18.2 14.2 16.8 18.0 18.8 Treatment better Control better RR 0.76 0.79 0.81 0.78 0.79 0.79 0.79 0.78 0.80 Overall 17.8 14.1 Major vascular events: CHD death, MI, stroke, coronary revascularization 0.79 0.5 1.0 1.5 CTT Collaborators. Lancet. 2005;366:1267-78.

Non-Statin Cholesterol Reductions Also Reduce CHD 35 30 CHD Event Reduction 25 20 15 10 CDP - Niacin Upjohn - colestipol POSCH Stockholm - clofibrate + Niacin Primary prevention trials Secondary prevention trials 5 LRC- CPPT - Cholestyramine 0 0 5 10 15 20 25 30 35 40 TC Reduction Adapted from Lavine GN et al. N Engl J Med. 1995;332:512-521

Statin Cholesterol Reductions Reduce CHD 25 4S-PL Primary prevention trials treatment arm Percent with CHD Event 20 15 10 5 0 CARE-Rx HPS-Rx 4S-Rx AFCAPS-Rx LIPID-PL CARE-PL HPS-PL LIPID-Rx WOSCOPS-Rx AFCAPS-PL WOSCOPS-PL 50 70 90 110 130 150 170 190 210 Primary prevention trials placebo arm Secondary prevention trials placebo arm Secondary prevention trials treatment arm Secondary and primary prevention trials treatment arm Secondary and primary prevention trials treat Placebo arm LDL cholesterol (mg/dl)

Συσχέτιση της αυξηµένης LDL-C και του καρδιαγγειακού κινδύνου, σε κλινικές µελέτες 30 25 Statin Placebo 4S Secondary Prevention Event, % 20 15 10 5 PROVE-IT (Atv) IDEAL (Atv) TNT (Atv 80 mg) IDEAL (Sim) HPS CARE LIPID TNT (Atv 10 mg) PROVE-IT (Pra) AFCAPS 4S HPS CARE AFCAPS LIPID WOSCOPS WOSCOPS Primary Prevention 0 ASCOT ASCOT 0 40 60 80 (1.0) (1.6) (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) 200 (5.2) Mean Treatment LDL-C at Follow-up, mg/dl (mmol/l) Atv = atorvastatin; Pra = pravastatin; Sim = simvastatin; PROVE-IT = Pravastatin or AtorVastatin Evaluation and Infection Therapy; IDEAL = Incremental Decrease in Endpoints through Aggressive Lipid Lowering; ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial; AFCAPS = Air Force Coronary Atherosclerosis Prevention Study; WOSCOPS = West of Scotland Coronary Prevention Study Adapted from Rosenson RS. Expert Opin Emerg Drugs. 2004;9:269 279; LaRosa JC, et al. N Engl J Med. 2005;352:1425 1435; Pedersen TR, et al. JAMA. 2005;294:2437 2445.

Reductions in LDL-C with Statins Reduce the Progression of Arterial Lumen Stenosis 0.06 Placebo Progression (MLD decrease, mm/yr) 0.05 0.04 0.03 0.02 0.01 MARS Drug therapy PLAC I CCAIT REGRESS LCAS MAAS LCAS PLAC I REGRESS CCAIT MARS MAAS 0 70 (1.8) 90 (2.3) 110 (2.8) 130 (3.4) 150 (3.9) 170 (4.4) 190 (5.0) LDL-C achieved mg/dl (mmol/l) MLD minimum lumen diameter Ballantyne CM et al. Am J Cardiol 1998;82:3Q 12Q.

REVERSAL 20 N=502 Μεταβολή του όγκου του αθηρώµατος (mm 3 ) 15 10 5 0 5 10 15 80 70 60 50 40 30 20 10 0 10 20 % µεταβολή της LDL-C Η συνεχής µπλε γραµµή δείχνει τη σχέση µεταξύ της µέσης µεταβολής της LDL-C και της µεταβολής του όγκου του αθηρώµατος από ανάλυση γραµµικής παλινδρόµησης. Η διακεκοµµένες πράσινες γραµµές δείχνουν το άνω και κάτω 95% όριο εµπιστοσύνης για τις µέσες τιµές. Τροποποιηµένο από Nissen S et al JAMA 2004;291:1071 1080.

Κατευθυντήριες Οδηγίες

Ανώτατα «Φυσιολογικά» Επίπεδα Χοληστερόλης 1950 300 mg/dl 1970 250 mg/dl 1987 200 mg/dl 2003 190 mg/dl Μελλοντικά... 150 mg/dl?

l Evolution of Guidelines Driven By Clinical Evidence NCEP ATP I 1988 Early Data Angiographic Trials Framingham 1981 Atherosclerosis Study Group 1984 LRC-CPPT 1984 MRFIT 1986 Coronary Drug Project 1986 Helsinki Heart Study 1987 CLAS 1987 FATS 1990 POSCH 1990 Lifestyle Heart Trial 1990 STARS 1992 Meta-Analyses Outcomes Trials 4S 1994 WOSCOPS 1995 CARE 1996 LIPID 1998 AFCAPS/ TexCAPS 1998 VA-HIT 1999 Recent Data HPS 2002 ALLHAT 2002 PROSPER 2002 ASCOT-LLA 2003 PROVE IT 2004 CARDS 2004 TNT 2005 IDEAL 2005 Holme 1990 Rossouw 1991

NCEP ATP III: Στόχοι LDL-C 190 - (2004 προτεινόµενες τροποποιήσεις) Υψηλού κινδύνου ΣΝ ή Ισοδύναµο (10-ετή κίνδ. >20%) Μετρίως υψηλού κινδύνου 2 παρ. κινδ. (10-ετή κίνδ. Μετρίου κινδύνου 2 παρ. κινδ. (10-ετή κίνδ. Μικρού κινδύνου < 2 παρ. κινδ. <10%) 10 20%) στόχος 160 mg/dl LDL-C επίπεδα 160-130 - 100-70 - στόχος 100 mg/dl 70 mg/ dl* στόχος 130 mg/dl 100 mg/dl* στόχος 130 mg/dl Υπάρχοντες στόχοι LDL Νέοι στόχοι LDL *θεραπευτικές επιλογές 70 mg/dl =1.8 mmol/l; 100 mg/dl = 2.6 mmol/l; 130 mg/dl = 3.4 mmol/ L; 160 mg/dl = 4.1 mmol/l Grundy SM et al. Circulation 2004;110:227 239.

Is Lower Better? Relationship between LDL- C and CV Event Rate 30 4S - Pl Event rate (%) 25 20 15 10 5 0 40 (1.0) Rx - Statin therapy Pl Placebo Pra pravastatin Atv - atorvastatin LIPID - Rx AFCAPS - Rx ASCOT - Rx 4S - Rx CARE - Rx HPS - Rx TNT Atv10 TNT Atv80 PROVE-IT - Pra PROVE-IT Atv 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) HPS - Pl AFCAPS - Pl ASCOT - Pl LDL-C achieved mg/dl (mmol/l) Secondary Prevention CARE - Pl 140 (3.6) LIPID - Pl WOSCOPS Pl WOSCOPS - Rx 160 (4.1) 180 (4.7) Rosenson RS. Exp Opin Emerg Drugs 2004;9(2):269-279, LaRosa JC et al. N Engl J Med 2005;352:1425-1435. 6 Primary Prevention 200 (5.2)

Ασθενείς που περιελήφθησαν στην IMPROVE-IT Patients with ACS up to 10d (median 5) LDL 50-100 under treatment 50-125 without treatment

Ασθενείς που περιελήφθησαν στην IMPROVE-IT l l l l l l 18.144pts 1.147 sites 39 countries 5 years 15,8pts/site 3,1pts/site/year

IMPROVE-IT

FOURIER

FOURIER VALUES UNDER PCSK9.. 70mg 87% 40mg 67% 25MG 4,2%

Comorbidities in IMPROVE-IT l Diabetes 27% l Hypertension 61,3% l Smokers 33,3% Comorbidities in FOURRIER l Diabetes 36,7% l Hypertension 80,1% l Smokers 28%

CHD Risk According to HDL-C Level Framingham Study 4.0 4.0 CHD risk ratio 3.0 2.0 1.0 2.0 1.0 0 25 45 65 HDL-C (mg/dl) CHD=Coronary heart disease, HDL-C=Highdensity lipoprotein cholesterol Source: Kannel WB. Am J Cardiol 1983;52:9B 12B

Συµπεράσµατα H Λιπιδική θεωρία ισχύει σε ευρυ φάσµα τιµών LDL Θα πρέεπει όµως να καθοριστουν κατώτερα όρια τιµών που δεν θα πρέπει να είναι κατώτερα του 50 mg

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