«Επιθετική Υπολιπιδαιμική αγωγή. Ο ρόλος της διπλής αναστολής της χοληστερόλης» ημήτριος Ρίχτερ, MD, FESC, FAHA - ιευθυντής Καρδιολογικής Κλινικής Ευρωκλινικής Αθηνών -- Γενικός Γραμματέας Ελληνικής Εταιρείας Λιπιδιολογίας. --Μέλος Σ ΕΛΙΚΑΡ
Intensive LDL-C C Goals for High Risk Patients Recommended LDL-C treatment goals ATP III Update 2004 1 <100 mg/dl: Patients with CHD or CHD risk equivalents (10 year risk >20%) 1 <70 mg/dl: Therapeutic option for very high risk patients 1 <100 mg/dl <70 mg/dl AHA/ACC guidelines for patients with CHD *,2 <100 mg/dl: Goal for all patients with CHD,2 <70 mg/dl: A reasonable goal for all patients with CHD 2 2006 Update *And other forms of atherosclerotic disease. 2 Factors that place a patient at very high risk: established cardiovascular disease plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (e.g., cigarette smoking); metabolic syndrome (triglycerides 200 mg/dl + non HDL-C 130 mg/dl with HDL-C <40 mg/dl); and acute coronary syndromes. 1 1. Grundy SM et al. Circulation 2004;110:227 239. 2. Smith SC Jr et al. Circulation 2006; 113:2363 2372. If it is not possible to attain LDL-C <70 mg/dl because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of >50% with more intensive LDL-C lowering therapy, including drug combinations. Slide Source Lipids Online Slide Library www.lipidsonline.org
Is Lower Better? Elevated Cholesterol Levels are Associated with an Increased Risk of Mortality 18 Death rate per 1000 men 16 14 12 10 8 6 4 2 0 3.62 (140) 4.14 (160) 4.65 (180) 5.17 (200) 5.69 (220) 6.21 (240) 6.72 (260) 7.24 (280) 7.75 (300) Data from MRFIT study. Martin MJ et al. Lancet 1986;ii:933 936. Serum Total-C, mmol/l (mg/dl)
Αντιμετώπιση των δύο οδών της χοληστερόλης μέσω ιπλής Αναστολής Slide 4
Μέση % αλλαγή, από τα αρχικά επίπεδα, στην LDL-C* Οι μειώσεις, απότααρχικάεπίπεδατηςldl-c, που επιτεύχθηκαν με το INEGY ήταν σημαντικά μεγαλύτερες σε σχέση με την atorvastatin μόνη της σε κάθε αντίστοιχη δοσολογία p<0.001 0 Pooled atorva Pooled Atorva INEGY 10 mg INEGY 10/10 Atorva 20 mg INEGY 10/20 Atorva 40 mg INEGY Atorva 10/40 80 mg INEGY 10/80 Μέση % αλλαγή από τα αρχικά επίπεδα, στην LDL-C -10-20 -30-40 -50-60 -45.3-53.4-36.1-47.1-43.7-50.6-48.3-57.4-52.9-58.6-70 Προσαρμογή από *Ballantyne CM, Abate N, Zhong Y et al. Am Heart J. 2005;149:464-473. Slide 5
Ezetimibe/Simvastatin Significantly Reduced LDL-C Across The Dose Range Ezetimibe/simvastatin Rosuvastatin 0 10/20 mg (n=476) 10 mg (n=475) 10/40 mg (n=477) 20 mg (n=478) 10/80 mg (n=474) 40 mg (n=475) 10/20 10/80 mg (n=1427) 10 40 mg (n=1428) Mean % change from baseline to week 6 45 50 55 60 51.5%* 45.8% 54.8%* 52.3% 61%* 56.7% 55.8%* 51.6% 65 *p 0.001 Adapted from Catapano AL et al Clin Invest Slide 6 Slide 6
SETTLE Simvastatin / Ezetimibe Therapy to Target Lipids Elevation Μηπαρεμβατικήμελέτηγιατην εκτίμηση της υπερχοληστερολαιμίας σε ελληνικό πληθυσμό και την χρήση του συνδυασμού ezetimibe/simvastatin 8
ΑΠΟΤΕΛΕΣΜΑΤΑ Πρωτεύον τελικό σημείο Ποσοστό ασθενών που πέτυχε το στόχο LDL-C στην επίσκεψη 2 (με βάση τις εργαστηριακές τιμές) 26.2% (n=397) (n=1117) 73.8% Στο στόχο LDL Εκτός στόχου Οι ερευνητές σημείωσαν για 106 ασθενείς ότι πέτυχαν τον στόχο αλλά τα εργαστηριακά ευρήματα έδειξαν ότι βρίσκονταν πάνω από το όριο που τέθηκε κατά την επίσκεψη 1. Για 7 ασθενείς συνέβη το αντίθετο, δηλαδή ενώ οι ερευνητές σημείωσαν πως βρίσκονταν «εκτός στόχου» η τιμή LDL-C ήταν χαμηλότερη από αυτή που είχε οριστεί στην επίσκεψη 1. 9
ΑΠΟΤΕΛΕΣΜΑΤΑ Τιμές λιπιδίων Επίσκεψη 1 Εργαστ.εξετάσεις Μέση τιμή Στ.απόκλιση ιάμεσος Min Max Ν Total Cholesterol (mg/dl) 247.8 37.4 245.0 119.0 450.0 1513 LDL-C (mg/dl) 163.7 31.2 162.0 74.0 350.0 1509 HDL-C (mg/dl) 45.1 11.6 42.0 16.0 152.0 1509 TG 173.8 80.4 160 42.0 890.0 1511 Επίσκεψη 2 Εργαστ.εξετάσεις Μέση Στ.απόκλιση ιάμεσος Min Max Ν τιμή Total Cholesterol (mg/dl) 182.1 28.9 182.0 95.0 385.0 1494 LDL-C (mg/dl) 106.9 23.8 103.6 34.0 322.0 1493 HDL-C (mg/dl) 48.1 10.5 46.0 22.0 135.0 1493 TG 136.7 46.3 135.0 15.0 613.0 1493 Σε όλους σχεδόν τους ασθενείς, 98.5% (n=1491) παρατηρήθηκε μείωση στην LDL-C κατά την επίσκεψη 2, και μόνο 1.5% δεν 10 παρουσίασε μείωση των επιπέδων LDL-C
Presented by Terje R. Pedersen Oslo Disclosure: Research grants and/or speaker- / consulting fees from Merck, MSP, Astra-Zeneca, Pfizer
Primary Endpoint MCE 50 Intention to Treat Population Percentage of Patients With First Event 40 30 20 10 Hazard ratio: 0.96, p=0.591 Placebo EZ/Simva 10/40 mg No. at Risk Placebo 0 EZ/Simva 10/40 mg Rossebø et al. NEJM. 2008;359 0 1 2 3 4 5 Years in Study 906 817 713 618 53 884 791 696 586 56
2nd EP: Ischemic CV Events 30 Intention to Treat Population Percentage of Patients With First Event 20 10 Hazard ratio: 0.78, p=0.024 Placebo EZ/Simva 10/40 mg No. at risk EZ/Simva 10/40 mg Placebo Rossebø et al. NEJM. 2008;359 0 0 1 2 3 4 5 Years in Study 917 898 867 838 823 788 769 729 76 76
Coronary Artery Bypass Grafting (CABG) 30 Intention to Treat Population Percentage of Patients With First Event 20 10 Hazard ratio: 0.68, p=0.015 Placebo EZ/Simva 10/40 mg 0 0 1 2 3 4 5 No. at risk Years in Study EZ/Simva 10/40 mg Placebo 925 909 887 862 848 819 797 761 80 80 Rossebø et al. NEJM. 2008;359
The results of the Study of Heart and Renal Protection (SHARP) Colin Baigent, Martin Landray on behalf of the SHARP Investigators Disclosure: SHARP was sponsored, designed, run, and analysed by the University of Oxford. Funding was received from Merck, the UK MRC, British Heart Foundation, and Australian NHMRC.
SHARP: Rationale Risk of vascular events is high among patients with chronic kidney disease Lack of clear association between cholesterol level and vascular disease risk Pattern of vascular disease is atypical, with a large proportion being non atherosclerotic Previous trials of LDL lowering therapy in chronic kidney disease are inconclusive
SHARP: Eligibility History of chronic kidney disease not on dialysis: elevated creatinine on 2 occasions Men: 1.7 mg/dl (150 µmol/l) Women: 1.5 mg/dl (130 µmol/l) on dialysis: haemodialysis or peritoneal dialysis Age 40 years No history of myocardial infarction or coronary revascularization Uncertainty: LDL lowering treatment not definitely indicated or contraindicated
CKD Subgroup Relationship Between Estimated GFR (egfr) and Clinical Outcomes Age-standardized event rate (per 100 person-yr) Death from any cause Cardiovascular events Any hospitalization Total events = 51,424 Total events = 139,011 Total events = 554,651 egfr (ml/min/1.73 m 2 ) Kaiser Permanente Renal Registry, n=1,120,295 adults aged 20 years Median follow-up = 2.84 years Go AS et al. N Engl J Med. 2004;351:1296-1305.
4D Trial: Neutral effect of statin in hemodialysis patients with diabetes VBWG N = 1.255 randomized to atorvastatin 20 mg or placebo for 4 years 20 10 Fatal stroke 103%* P = 0.04 12%* 0 % Change -10-20 -30-40 Baseline LDL-C 121 mg/dl 8%* NS 18%* P = 0.03 NS -50 LDL-C Nonfatal MI CHD death Stroke Coronary events Cerebrovasc events *Relative risk reduction Wanner C et al. N Engl J Med. 2005;353:238-48.
4D study in diabetic hemodialysis patients: no benefit of statin therapy 60 50 Placebo p=0.37 Cumulative incidence of primary endpoint (%) 40 30 20 10 Atorvastatin 0 0 1 2 3 4 5 6 No. at risk: Time (years) Placebo 636 532 383 252 136 51 19 Atorvastatin 619 515 378 252 136 58 29 4D=Die Deutsche Diabetes Dialyse Studie Wanner C et al. N Engl J Med 2005; 353: 238 248
AURORA: study design Screening Treatment Month: Visit: 14 days 1 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 0 2 3 3 6 4 12 5 6- monthly 6 Rosuvastatin 10 mg daily (n~1350) Randomization 1:1 Matching placebo (n~1350) Final 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: primary endpoint Kaplan-Meier estimate of time to first major CV event Cumulative incidence of primary endpoint (%) 40 35 30 25 20 15 10 5 0 Placebo 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 N Engl J Med. 2009;360:1395-407
SHARP: Assessment of LDL lowering
SHARP: Baseline characteristics Characteristic Mean (SD) or % Age 62 (12) Men 63% Systolic BP (mm Hg) 139 (22) Diastolic BP (mm Hg) 79 (13) Body mass index 27 (6) Current smoker 13% Vascular disease 15% Diabetes mellitus 23% Non dialysis patients only (n=6247) egfr (ml/min/1.73m 2 ) 27 (13) Albuminuria 80%
SHARP: Compliance and LDL C reduction at study midpoint Eze /simv Placebo Compliant 66% 64% Non study statin 5% 8% Any lipid lowering 71% 8% ~2/3 compliance LDL C reduction of 32 mg/dl with 2/3 compliance, equivalent to 50 mg/dl with full compliance
SHARP: Main outcomes Key outcome Major atherosclerotic events (coronary death, MI, non haemorrhagic stroke, or any revascularization) Subsidiary outcomes Major vascular events (cardiac death, MI, any stroke, or any revascularization) Components of major atherosclerotic events Main renal outcome End stage renal disease (dialysis or transplant)
SHARP: Major Atherosclerotic Events 25 Proportion suffering event (%) 20 15 10 5 Risk ratio 0.83 (0.74 0.94) Logrank 2P=0.0022 Placebo Eze/simv 0 0 1 2 3 4 5 Years of follow up
CTT: Effects on Major Atherosclerotic Events Proportional reduction in atherosclerotic event rate (95% CI) 30% Statin vs control (21 trials) 25% 20% 15% 10% 5% More vs Less (5 trials) SHARP 32 mg/dl 0% 0 10 20 30 40 Mean LDL cholesterol difference between treatment groups (mg/dl)
CTT: Effects on Major Atherosclerotic Events Proportional reduction in atherosclerotic event rate (95% CI) 30% Statin vs control (21 trials) 25% 20% 15% 10% 5% More vs Less (5 trials) SHARP 32 mg/dl SHARP 17% risk reduction 0% 0 10 20 30 40 Mean LDL cholesterol difference between treatment groups (mg/dl)
SHARP: SHARP: Major Major Atherosclerotic Vascular Events Events Event Eze/simv (n=4650) Placebo (n=4620) Risk ratio & 95% CI Major coronary event 213 (4.6%) 230 (5.0%) Non haemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularization 284 (6.1%) 352 (7.6%) Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022) Other cardiac death 162 (3.5%) 182 (3.9%) Haemorrhagic stroke 45 (1.0%) 37 (0.8%) Other major vascular events 207 (4.5%) 218 (4.7%) 5.4% SE 9.4 reduction (p=0.57) Major vascular event 701 (15.1%) 814 (17.6%) 15.3% SE 4.7 reduction (p=0.0012) 0.6 0.8 1.0 1.2 1.4 Eze/simv Placebo better better
SHARP: Effects in subgroups Among 8384 patients originally randomized to eze/simv vs placebo, major vascular events risk ratio = 0.84 (95% CI 0.75 0.93; p=0.0010) Similar reductions in major atherosclerotic events in all subgroups studied (including non dialysis and dialysis patients)
SHARP: Major Atherosclerotic Events by renal status at randomization Eze/simv (n=4650) Placebo (n=4620) Risk ratio & 95% CI Non dialysis (n=6247) 296 (9.5%) 373 (11.9%) Dialysis (n=3023) 230 (15.0%) 246 (16.5%) Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022) No significant heterogeneity between non dialysis and dialysis patients (p=0.25) 0.6 0.8 1.0 1.2 1.4 Eze/simv better Placebo better
SHARP: Renal outcomes Event Eze/simv (n=3117) Placebo (n=3130) Risk ratio & 95% CI Main renal outcome End stage renal disease (ESRD) 1057 (33.9%) 1084 (34.6%) 0.97 (0.89 1.05) Tertiary renal outcomes ESRD or death 1477 (47.4%) 1513 (48.3%) 0.97 (0.90 1.04) ESRD or 2 x creatinine 1190 (38.2%) 1257 (40.2%) 0.94 (0.86 1.01) 0.6 0.8 1.0 1.2 1.4 Eze/simv better Placebo better
SHARP: Cancer incidence 25 Proportion suffering event (%) 20 15 10 5 Risk ratio 0.99 (0.87 1.13) Logrank 2P=0.89 Eze/simv Placebo 0 0 1 2 3 4 5 Years of follow up
SHARP: Safety Myopathy Eze/simv (n=4650) Placebo (n=4620) CK >10 x but 40 x ULN 17 (0.4%) 16 (0.3%) CK >40 x ULN 4 (0.1%) 5 (0.1%) Hepatitis 21 (0.5%) 18 (0.4%) Persistently elevated ALT/AST >3x ULN 30 (0.6%) 26 (0.6%) Complications of gallstones 85 (1.8%) 76 (1.6%) Other hospitalization for gallstones 21 (0.5%) 30 (0.6%) Pancreatitis without gallstones 12 (0.3%) 17 (0.4%)
SHARP: Conclusions No increase in risk of myopathy, liver and biliary disorders, cancer, or nonvascular mortality No substantial effect on kidney disease progression Two thirds compliance with eze/simv reduced the risk of major atherosclerotic events by 17% (consistent with meta analysis of previous statin trials) Similar proportional reductions in all subgroups (including among dialysis and non dialysis patients) Full compliance would reduce the risk of major atherosclerotic events by one quarter, avoiding 30 40 events per 1000 treated for 5 years
IMPROVE-IT Πολυκεντρική, τυχαιοποιημένη, διπλή-τυφλή μελέτη με ενεργό συγκριτικό μέσο 18,000 ασθενείς με ACS, συμπεριλαμβανομένου οξέος ΕΜ ή ασταθούς στηθάγχης Οι ασθενείς θα τυχαιοποιηθούν είτε σε εζετιμίμπη/σιμβαστατίνη 10/40 mg είτε σε σιμβαστατίνη 40 mg ανά ημέρα Κύριοτελικόσημείοείναιησύνθεσηθανάτουαπό καρδιαγγειακή αίτια, μείζονα συμβάματα των στεφανιαίων,* ή μη θανατηφόρο αγγειακό εγκεφαλικό επεισόδιο Οι ασθενείς θα παρακολουθούνται για τουλάχιστον δυόμισι έτη ACS=οξύ στεφανιαίο σύνδρομο * Περιλαμβάνουν μη θανατηφόρο ΕΜ, ασταθή στηθάγχη που απαιτεί νοσηλεία στο νοσοκομείο, επαναγγείωση των στεφανιαίων μετά από τουλάχιστον 30 ημέρες τυχαιοποιημένης θεραπείας Slide 37
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