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ΠΡΟΣΦΑΤΕΣ ΜΕΛΕΤΕΣ ΣΤΗΝ ΥΠΟΛΙΠΙΔΑΙΜΙΚΗ ΑΓΩΓΗ Ευάγγελος Λυμπερόπουλος Λέκτορας Παθολογίας Ιατρικής Σχολής Παν/μίου Ιωαννίνων.

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Παρουσίαση με θέμα: "ΠΡΟΣΦΑΤΕΣ ΜΕΛΕΤΕΣ ΣΤΗΝ ΥΠΟΛΙΠΙΔΑΙΜΙΚΗ ΑΓΩΓΗ Ευάγγελος Λυμπερόπουλος Λέκτορας Παθολογίας Ιατρικής Σχολής Παν/μίου Ιωαννίνων."— Μεταγράφημα παρουσίασης:

1 ΠΡΟΣΦΑΤΕΣ ΜΕΛΕΤΕΣ ΣΤΗΝ ΥΠΟΛΙΠΙΔΑΙΜΙΚΗ ΑΓΩΓΗ Ευάγγελος Λυμπερόπουλος Λέκτορας Παθολογίας Ιατρικής Σχολής Παν/μίου Ιωαννίνων

2 ΕΠΙΔΡΑΣΗ ΤΟΥ EZETIMIBE ΣΤΗΝ ΑΘΗΡΟΣΚΛΗΡΩΣΗ

3 LRC-CCPT  19% p<0.05 JAMA 1984;251:351-64

4 Cholesterol lowering and cardiovascular events: POSCH trial; New Engl J Med 1990; 323:94 Reduction of LDL cholesterol Myocardial Infarction or death Program on surgical control of the Hyperlipidemias (POSCH)  35% p<0.001

5 Ασθενείς (n=720) Οικογενής ετερόζυγος υπερχοληστερολαιμία LDL-C = 319 mg/dl ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) : Σχεδιασμός της μελέτης EZE 10 mg + SIMVA 80 mg (n=357) SIMVA 80 mg (n=363) CIMT Lipids Safety CIMT Safety Lipids Safety CIMT Lipids Safety Lipids Safety CIMT Safety Επίσκεψη: Εβδομάδα: 1 – Run in / eligibility 2 –4 3 –2 Kastelein JP, et al. Am Heart J 2005;149: CIMT=Πάχυνση Έσω και Μέσου Χιτώνα Καρωτίδας

6 Baseline characteristics Simvastatin Monotherapy Simvastatin plus Ezetimibe All randomized patientsn=363n=357P-value Age (yr) 45.7   Male sex no. (%)179(49%)191 (54%)0.26 Body-mass index 26.7   History of diabetes5(1%)8 (2%)0.38 Hypertension51 (14%)67 (19%)0.09 Current smoking104 (29%)102 (29%)0.98 History of MI26 (7%)14 (4%)0.06 Prior use of statins297 (82%)286 (80%)0.56 Systolic mm Hg 124   Diastolic mm Hg 78  1078 

7 Months LDL-cholesterol ENHANCE Simva Eze-Simva Percentage change from baseline P< % incremental reduction Baseline (mg/dL) 24 months (mg/dL) Simva318 ± ± 60 Eze-Simva319 ± ± 53 Kastelein JP, et al. N Engl J Med 2008;358:

8 Other Lipids and Apolipoproteins Percent Change From Baseline Simvastatin 80EZE/simva 10/80P value Total Cholesterol-31.9± ±0.8<0.01 LDL-cholesterol-39.1± ±0.9<0.01 Triglycerides (median) <0.01 HDL-cholesterol7.8± ± Apo B-33.1± ±0.9 <0.01 Apo A16.9±0.86.3± ENHANCE

9 hsCRP ENHANCE Simva Eze-Simva Median percent change from Baseline p < Months % incremental reduction Baseline 24 months (mg/L) (mg/L) Simva 1.7( ) 1.2( ) Eze-Simva 1.7( ) 0.9( ) Kastelein JP, et al. N Engl J Med 2008;358:

10 Mean cIMT during 24 months of therapy Longitudinal, repeated measures analysis ENHANCE Mean IMT (mm) Simva Eze-Simva Months P=0.88 Kastelein JP, et al. N Engl J Med 2008;358:

11 ΕΡΜΗΝΕΙΑ ΤΩΝ ΑΠΟΤΕΛΕΣΜΑΤΩΝ ΤΗΣ ΜΕΛΕΤΗΣ ENHANCE  Αξιόπιστη μεθοδολογία;  Πλειοτροπικές δράσεις του ezetimibe vs στατίνη σε υψηλές δόσεις;  Πληθυσμός (ασθενείς με FH που ελάμβαναν ήδη θεραπεία με στατίνες);

12 de Groot E, et al. Circulation. (2004) 109[Suppl III]:III-33-III-38. ENHANCE cIMT Methodology Carotid Intima-Media thickness (cIMT) measurements • Measurements were made at a predefined angle of insonation • Only the far-walls of all segments were imaged • Images were stored in DICOM for offline image analyses ENHANCE

13 ΕΡΜΗΝΕΙΑ ΤΩΝ ΑΠΟΤΕΛΕΣΜΑΤΩΝ ΤΗΣ ΜΕΛΕΤΗΣ ENHANCE  Αξιόπιστη μεθοδολογία;  Πλειοτροπικές δράσεις του ezetimibe vs στατίνη;  Πληθυσμός (ασθενείς με FH που ελάμβαναν ήδη θεραπεία με στατίνες);

14 The Compound Ezetimibe no pleiotropic effects? Simvastatin 10 mg group Baseline 4 weeks Flow dependent dilation ( percent change of diameter) Flow dependent dilation ( percent change of diameter) P<0.01 P= n.s Chronic heart failure patients (NYHA III), n=10 per group LDL-c reduction similar in both groups. Simvastatin: 15.6 % Ezetimibe: 15.4% Landmesser et al, Circulation 2005; 111(18): Ezetimibe 10 mg group ENHANCE

15 ΠΛΕΙΟΤΡΟΠΙΚΕΣ ΔΡΑΣΕΙΣ ΤΟΥ EZETIMIBE  Αντιφλεγμονώδης δράση (  hs CRP,  Lp-PLA 2 )  Αντιοξειδωτική δράση: Παράταση λανθάνοντος χρόνου για την οξείδωση της LDL από 144 min σε 195 min (p<0.001)  Αντιαιμοπεταλιακή δράση: Μείωση της συσσώρευσης των αιμοπεταλίων από83±15% σε 60±36% (p=0.04) Br J Clin Pharmacol 2008;65:637-45

16 High dose Statin vs. Low dose Statin + Ezetimibe on endothelial function: Study-design Analysis of: Endothelial function (FMD) Settergren et al.; Eur Heart J. 2008; 29: Randomisation of 39 patients with CAD and dysglycemia to 6 weeks: Simvastatin (80 mg/day) Simvastatin + Ezetimibe ( mg/day)

17 Serum LDL-cholesterol - change after 6 weeks P=n.s. 51.6% 57% Simvastatin +Ezetimibe ( mg/d) n=19 Simvastatin (80 mg/d) n=20 Settergren et al.; Eur Heart J. 2008; 29:

18 Endothelial function - flow-mediated dilation (FMD) P= n.s. SIMVA + EZE ( mg/d) n = 18 SIMVA (80 mg/d) n = 16 Change in FMD (%) Settergren et al.; Eur Heart J. 2008; 29:

19 ΕΡΜΗΝΕΙΑ ΤΩΝ ΑΠΟΤΕΛΕΣΜΑΤΩΝ ΤΗΣ ΜΕΛΕΤΗΣ ENHANCE  Αξιόπιστη μεθοδολογία;  Πλειοτροπικές δράσεις του ezetimibe vs στατίνη σε υψηλές δόσεις;  Πληθυσμός (ασθενείς με FH που ελάμβαναν ήδη θεραπεία με στατίνες);

20 LIPID (pediatric) ENHANCE ASAP Frequency Mean CIMT (mm) 2.4 Baseline cIMT in LIPID (pediatric), ASAP and ENHANCE ENHANCE Baseline mean cIMT (mm) LIPID (pediatric) 0.495±0.050 ASAP 0.920±0.200 ENHANCE 0.695±0.130 Normal value (40-49 years)= mm

21 21 Επέκταση ASAP: Η Ατορβαστατίνη Σταμάτησε Μακροπρόθεσμα την Εξέλιξη της Καρωτιδικής Αθηροσκλήρυνσης Μεταβολή στο μέσο ΙΜΤ καρωτίδας van Wissen S et al. Am J Cardiol. 2005;95: Έτη IMT (mm) ASAPΕπέκταση ASAP Ατορβαστατίνη 80 mgΣιμβαστατίνη 40 mg

22 SANDS JACC 2008;52:

23 SANDS Reducing LDL-C to aggressive targets resulted in similar regression of carotid IMT in patients who attained equivalent LDL-C reductions from a statin alone or statin plus ezetimibe. Common carotid artery IMT increased in those achieving standard targets. LDL-C fall: ezetimibe +statin = 31 mg/dl (n=69) statin only = 32 mg/dl (n=154) standard treatment = 1 mg/dl (n=204)

24 SANDS Changes in HDL and TG were also similar between the ezetimibe + statin and statin alone groups. BUT, what was the baseline carotid IMT? and in the ezetimibe + statin and statin alone groups, respectively. Change in carotid IMT at 36 months: – (95% CI: – 0.05 to 0.003) and – (0.03 to 0.008) in the ezetimibe + statin and statin alone groups, respectively. JACC 2008;52:

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27 Rossebø et al. NEJM. 2008;359 Patient Definition  Men and Women  Age years  Asymptomatic  Valvular AS: ▬ Aortic valve thickening on echocardiographic evaluation ▬ Doppler jet velocity ≥2.5 - ≤4.0 m/sec  Normal LV systolic function

28 Rossebø et al. NEJM. 2008;359 Study Design  Randomized  Double blind  Placebo controlled  Multicenter  4 Weeks placebo/diet run-in  Simvastatin 40 mg + ezetimibe 10 mg or placebo  Median duration: 4.5 year (minimum follow-up 4 years)

29 Rossebø et al. NEJM. 2008;359 Baseline Characteristics Placebo Simva + Ezetimibe n= 929n= 944 Age (years) Women (%) SBP (mm Hg) DBP (mm Hg)82 Smoker (%)1820 Ex-smoker (%)3735 Never smoker (%)45 BMI (kg/m 2)

30 Rossebø et al. NEJM. 2008;359 LDL-Cholesterol Intention to Treat Population Year Mean (mg/dL) ±SE EZ/Simva 10/40 mg Placebo  61%

31 Rossebø et al. NEJM. 2008;359 Primary Endpoint MCE Intention to Treat Population Years in Study Percentage of Patients With First Event EZ/Simva 10/40 mg Placebo EZ/Simva 10/40 mg No. at Risk Hazard ratio: 0.96, p=

32 Rossebø et al. NEJM. 2008;359 2nd EP: Aortic Valve Events Years in Study Placebo EZ/Simva 10/40 mg No. at Risk Intention to Treat Population EZ/Simva 10/40 mg Placebo Hazard ratio: 0.97, p=0.732 Percentage of Patients With First Event

33 Rossebø et al. NEJM. 2008;359 Aortic Valve Replacement Placebo Intention to Treat Population Years in Study EZ/Simva 10/40 mg No. at risk Hazard ratio: 1.00, p= Percentage of Patients With First Event EZ/Simva 10/40 mg Placebo

34 Rossebø et al. NEJM. 2008;359 Peak Aortic - Jet Velocity Intention to Treat Population EZ/Simv a 10/40 mg Placebo Year 1Year 2Last Follow-up Time Change from Baseline (m/sec) Mean (±SE)

35 Rossebø et al. NEJM. 2008;359 2nd EP: Ischemic CV Events Placebo EZ/Simva 10/40 mg No. at risk Percentage of Patients With First Event Intention to Treat Population Years in Study Hazard ratio: 0.78, p=0.024 EZ/Simva 10/40 mg Placebo  22%

36 Rossebø et al. NEJM. 2008;359 Coronary Artery Bypass Grafting (CABG) 30 Years in Study Placebo EZ/Simva 10/40 mg No. at risk Percentage of Patients With First Event Intention to Treat Population Hazard ratio: 0.68, p=0.015 EZ/Simva 10/40 mg Placebo

37 Rossebø et al. NEJM. 2008;359 Major CV Events - Components ITT Population Major CV Events CV Death AVR CHF Nonfatal MI CABG PCI Hospitalized UAP Non hem. Stroke Endpoints Favors PlaceboFavors EZ/Simva 10/40 mg Hazard Ratio (95% CI) # of Events Placebo EZ/Simva * *p=0.02 vs Placebo

38 Rossebø et al. NEJM. 2008;359 Clinical Adverse Events (AE) PlaceboEZ/ Simva N=929N=943* nnp= Any serious AE (SAE) Drug discon. due to SAE7977 Musculoskeletal AE Myopathy / Rhabdo00 New cancer Recurrent, same site53 Cancer, total All Patients as Treated Population

39 Rossebø et al. NEJM. 2008;359 Fatal Cancer Placebo EZ/Simva 10/40 mg No. at risk P=0.05 Unadjusted P=0.06 With Log-rank continuity correction Years in Study Hazard ratio: 1.67 Cumulative Percentage EZ/Simva 10/40 mg Placebo Intention to Treat Population n=23 (2.5%) n=39 (4.1%)

40 Rossebø et al. NEJM. 2008;359 Incident Cancer Site Placebo (N=929) EZ/simva (N=943) nn Lip, oral pharynx, Oesophagus1 1 Stomach15 Large bowel / intestine89 Pancreas14 Liver gallbladder, bile ducts32 Lung107 Other respiratory01 Skin (any)818 Breast58 Prostate1321 Kidney2 2 Bladder7 7 Genital4 4 Hemathological5 7 Other/unspecified7 12 All differences are non-significant All Patients as Treated Population

41 Rossebø et al. NEJM. 2008;359 All Cause Mortality Intention to Treat Population Placebo EZ/Simva 10/40 mg No. risk Years in Study Hazard ratio: 1.04, p= EZ/Simva 10/40 mg Placebo Cumulative Percentage

42 Rossebø et al. NEJM. 2008; Peto R et al, N Engl J Med 2008;359

43

44 Comments: 1.Carcinogens would be expected to increase cancers as time progress. The opposite was found in SEAS. 2.The increase in cancer is across the whole range. Some cancers were less in the combination therapy. 3. The much larger SHARP and IMPROVE-IT do not show any increase in cancer.

45 ‘These findings in the SEAS trial plus the interim data from ongoing trials should not prompt patients to stop taking Vytorin or any other cholesterol lowering drug’ FDA 21 AUG 2008

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47 CRP predicts risk of MI and stroke in apparently healthy men CRP=C-reactive protein; MI=myocardial infarction *p=0.02 versus quartile 1; ***p<0.001 versus quartile 1 Quartile of CRP Relative risk of ischaemic stroke * Quartile of CRP Relative risk of MI *** Ridker PM et al. N Engl J Med 1997; 336: 973–979

48 AFCAPS/TexCAPS However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses. Ridker et al, New Engl J Med 2001;344: Low LDL, Low hsCRP Low LDL, High hsCRP Statin EffectiveStatin Not Effective [A] [B] Low LDL, Low hsCRP Low LDL, High hsCRP Statin EffectiveStatin Not Effective AFCAPS/TexCAPS Low LDL Subgroups RR

49 Rosuvastatin 20 mg (N=8901) MIStrokeUnstable Angina Angina CVD Death CABG/PTCA JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP 4-week run-in Ridker et al, Circulation 2003;108: No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L JUPITER Trial Design Placebo (N=8901) Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela

50 JUPITER Inclusion and Exclusion Criteria, Study Flow 89,863 Screened 17,802 Randomized 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo Reason for Exclusion (%) LDL-C > 130 mg/dL 53 hsCRP < 2.0 mg/L 37 Withdrew Consent 4 Diabetes 1 Hypothyroid <1 Liver Disease <1 TG > 500 mg/dL <1 Age out of range <1 Current Use of HRT <1 Cancer <1 Poor Compliance/Other 3 8,600 Completed Study 120 Lost to follow-up 8,600 Completed Study 120 Lost to follow-up 8,901 Included in Efficacy and Safety Analyses 8,901 Included in Efficacy and Safety Analyses 89,890 Screened Men > 50 years Women > 60 years No CVD, No DM LDL < 130 mg/dL hsCRP > 2 mg/L 17,802 Randomized Reason for Exclusion (%) LDL > 130 mg/dL 52 hsCRP < 2.0 mg/L 36 Withdrew Consent 5 Diabetes 1 Hypothyroid <1 Liver Disease <1 TG > 500 mg/dL <1 Age out of range <1 Current Use of HRT <1 Cancer <1 Poor Compliance/Other 3 4 week Placebo Run-In 8,857 Completed Study 44 Lost to follow-up 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo 8,864 Completed Study 37 Lost to follow-up 8,901 Included in Efficacy and Safety Analyses 8,901 Included in Efficacy and Safety Analyses Ridker et al NEJM 2008

51 JUPITER Baseline Clinical Characteristics Rosuvastatin Placebo (N = 8901)(n = 8901) Age, years (IQR)66.0( )66.0 ( ) Female, N (%)3,426 (38.5)3,375(37.9) Ethnicity, N (%) Caucasian 6,358(71.4)6,325(71.1) Black1,100(12.4)1,124(12.6) Hispanic1,121(12.6)1,140(12.8) Blood pressure, mm (IQR) Systolic134( )134( ) Diastolic80(75-87)80(75-87) Smoker, N (%)1,400(15.7)1,420(16.0) Family History, N (%)997(11.2)1,048(11.8) Metabolic Syndrome, N (%)3,652(41.0)3,723(41.8) Aspirin Use, N (%)1,481(16.6)1,477(16.6) All values are median (interquartile range) or N (%) Ridker et al NEJM 2008

52 JUPITER Baseline Blood Levels (median, interquartile range) RosuvastatinPlacebo (N = 8901)(n = 8901) hsCRP, mg/L4.2( )4.3 ( ) LDL, mg/dL 108 ( )108( ) HDL, mg/dL49(40 – 60)49(40 – 60) Triglycerides, mg/L118( )118 ( ) Total Cholesterol, mg/dL186 ( )185( ) Glucose, mg/dL94(87 – 102)94(88 – 102) HbA1c, %5.7(5.4 – 5.9)5.7 (5.5 – 5.9) All values are median (interquartile range). [ Mean LDL = 104 mg/dL ] Ridker et al NEJM 2008

53 hsCRP (mg/L) LDL (mg/dL) Months TG (mg/dL) HDL (mg/dL) Months JUPITER Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP LDL decrease 50 percent at 12 months hsCRP decrease 37 percent at 12 months HDL increase 4 percent at 12 months TG decrease 17 percent at 12 months Ridker et al NEJM 2008

54 JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Placebo 251 / 8901 Rosuvastatin 142 / 8901 HR 0.56, 95% CI P < Number Needed to Treat (NNT 5 ) = % Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6318,4126,5403,8931,9581, ,9018,6218,3536,5083,8721,9631, Ridker et al NEJM 2008

55 JUPITER Individual Components of the Primary Endpoint *Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death Endpoint RosuvastatinPlaceboHR 95%CI P Primary Endpoint* < Non-fatal MI < Any MI < Non-fatal Stroke Any Stroke Revascularization or Unstable Angina < MI, Stroke, CV Death < Ridker et al NEJM 2008

56 JUPITER Implications for Primary Prevention Among men and women age 50 or over: If LDL-C >Target (130 mg/dL), treat If diabetic, treat If hsCRP >2 mg/L, treat?? A simple evidence-based approach to statin therapy for primary prevention.

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