«Εδεηηκίκπε- Σηκβαζηαηίλε: Νεώηερα δεδοκέλα ζε αζζελείς σψειού θαρδηαγγεηαθού θηλδύλοσ»

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1 «Εδεηηκίκπε- Σηκβαζηαηίλε: Νεώηερα δεδοκέλα ζε αζζελείς σψειού θαρδηαγγεηαθού θηλδύλοσ» Δημήηπιορ Ρίσηεπ, MD, FESC, FAHA - Διεςθςνηήρ Καπδιολογικήρ Κλινικήρ Εςπωκλινικήρ Αθηνών -- Γενικόρ Γπαμμαηέαρ Ελληνικήρ Εηαιπείαρ Λιπιδιολογίαρ. --Μέλορ ΔΣ ΕΛΙΚΑΡ

2 Μέζη % αλλαγή από ηα απσικά επίπεδα, ζηην LDL-C Μέζη % αλλαγή, από ηα απσικά επίπεδα, ζηην LDL-C* Οι μειώζεις, από ηα αρτικά επίπεδα ηης LDL-C, ποσ επιηεύτθηκαν με ηο INEGY ήηαν ζημανηικά μεγαλύηερες ζε ζτέζη με ηην atorvastatin μόνη ηης ζε κάθε ανηίζηοιτη δοζολογία p< 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/ Προζαρμογή από *Ballantyne CM, Abate N, Zhong Y et al. Am Heart J. 2005;149: Slide 2

3 Mean % change from baseline to week 6 Το INEGY μείωζε ζημανηικά περιζζόηερο ηην LDL-C ζε όλο ηο δοζολογικό εύρος 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) mg (n=1428) % % a 54.8% b 52.3% 56.7% 55.8% a 51.6% 65 61% a a P<0.001; b P=0.001 vs rosuvastatin Adapted from Catapano AL et al Curr Med Res Opin. 2006;22: Slide 3

4 SETTLE Simvastatin / Ezetimibe Therapy to Target Lipids Elevation Μη παπεμβαηική μελέηη για ηην εκηίμηζη ηηρ ςπεπσοληζηεπολαιμίαρ ζε ελληνικό πληθςζμό και ηην σπήζη ηος ζςνδςαζμού ezetimibe/simvastatin 4

5 ΑΠΟΤΕΛΕΣΜΑΤΑ Τηκές ιηπηδίωλ Επίσκεψη 1 Επγαζη.εξεηάζειρ Μέζη ηιμή Ση.απόκλιζη Διάμεζορ Min Max Ν Total Cholesterol (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) TG Επίσκεψη 2 Επγαζη.εξεηάζειρ Μέζη Ση.απόκλιζη Διάμεζορ Min Max Ν ηιμή Total Cholesterol (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) TG Σε όλοςρ ζσεδόν ηοςρ αζθενείρ, 98.5% (n=1491) παπαηηπήθηκε μείυζη ζηην LDL-C καηά ηην επίζκετη 2, και μόνο 1.5% δεν 5 παποςζίαζε μείυζη ηυν επιπέδυν LDL-C

6 ΑΠΟΤΕΛΕΣΜΑΤΑ Πρωηεύολ ηειηθό ζεκείο Ποσοστό ασθενών που πέτυχε το στόχο LDL-C στην επίσκεψη 2 (με βάζη ηιρ επγαζηηπιακέρ ηιμέρ) 26.2% (n=397) (n=1117) 73.8% Σηο ζηότο LDL Εκηός ζηότοσ Οι επεςνηηέρ ζημείυζαν για 106 αζθενείρ όηι πέηςσαν ηον ζηόσο αλλά ηα επγαζηηπιακά εςπήμαηα έδειξαν όηι βπίζκονηαν πάνυ από ηο όπιο πος ηέθηκε καηά ηην επίζκετη 1. Για 7 αζθενείρ ζςνέβη ηο ανηίθεηο, δηλαδή ενώ οι επεςνηηέρ ζημείυζαν πυρ βπίζκονηαν «εκηόρ ζηόσος» η ηιμή LDL-C ήηαν σαμηλόηεπη από αςηή πος είσε οπιζηεί ζηην επίζκετη 1. 6

8 ΣΤΟΦΟΙ LDL ΑΝΑΛΟΓΑ ΜΕ ΤΟΝ ΣΥΝΟΛΙΚΟ ΚΙΝΔΥΝΟ

10 Presented by Terje R. Pedersen Oslo Disclosure: Research grants and/or speaker- / consulting fees from Merck, MSP, Astra-Zeneca, Pfizer

11 Percentage of Patients With First Event Primary Endpoint MCE Intention to Treat Population Hazard ratio: 0.96, p=0.591 Placebo 20 EZ/Simva 10/40 mg 10 No. at Risk Placebo 0 EZ/Simva 10/40 mg Rossebø et al. NEJM. 2008; Years in Study

12 Percentage of Patients With First Event 2nd EP: 30 Ischemic CV Events Intention to Treat Population 20 Hazard ratio: 0.78, p=0.024 Placebo 10 EZ/Simva 10/40 mg No. at risk EZ/Simva 10/40 mg Placebo Rossebø et al. NEJM. 2008; Years in Study

13 Percentage of Patients With First Event Coronary Artery Bypass Grafting (CABG) 30 Intention to Treat Population 20 Hazard ratio: 0.68, p=0.015 Placebo 10 No. at risk Rossebø et al. NEJM. 2008;359 EZ/Simva 10/40 mg Years in Study EZ/Simva 10/40 mg Placebo

14 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.

15 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

16 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

Age-standardized event rate (per 100 person-yr) CKD Subgroup Relationship Between Estimated GFR (egfr) and Clinical Outcomes Death from any cause Cardiovascular events Any hospitalization Total

17 Age-standardized event rate (per 100 person-yr) CKD Subgroup Relationship Between Estimated GFR (egfr) and Clinical Outcomes 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:

18 4D Trial: Neutral effect of statin in hemodialysis patients with diabetes VBWG N = randomized to atorvastatin 20 mg or placebo for 4 years Fatal stroke 103%* P = %* 0 % Change 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:

19 4D study in diabetic hemodialysis patients: no benefit of statin therapy 60 Placebo Cumulative incidence of primary endpoint (%) Atorvastatin p= No. at risk: Time (years) Placebo Atorvastatin D=Die Deutsche Diabetes Dialyse Studie Wanner C et al. N Engl J Med 2005; 353:

20 AURORA: study design Screening Treatment Month: Visit: 14 days 1 Patients (n~2750) Inclusion criteria ESRD, on hemodialysis for 3 months years Exclusion criteria Statin within 6 months Kidney transplant likely within 1 year Creatine kinase >3xULN ALT >3xULN TSH >1.5xULN monthly 6 Rosuvastatin 10 mg daily (n~1350) Randomization 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

21 AURORA: primary endpoint Kaplan-Meier estimate of time to first major CV event Cumulative incidence of primary endpoint (%) Placebo Rosuvastatin HR=0.96 (95% CI ) P= No. at risk: Years from randomization Rosuvastatin Placebo N Engl J Med. 2009;360:

22 SHARP: Assessment of LDL-lowering

23 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%

24 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

25 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)

26 Proportion suffering event (%) SHARP: Major Atherosclerotic Events Risk ratio 0.83 ( ) Logrank 2P= Placebo Eze/simv Years of follow-up

27 Proportional reduction in atherosclerotic event rate (95% CI) CTT: Effects on Major Atherosclerotic Events 30% Statin vs control (21 trials) 25% 20% 15% More vs Less (5 trials) 10% 5% SHARP 32 mg/dl 0% Mean LDL cholesterol difference between treatment groups (mg/dl)

28 Proportional reduction in atherosclerotic event rate (95% CI) CTT: Effects on Major Atherosclerotic Events 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% Mean LDL cholesterol difference between treatment groups (mg/dl)

29 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) Eze/simv better Placebo better

30 SHARP: Effects in subgroups Among 8384 patients originally randomized to eze/simv vs placebo, major vascular events risk ratio = 0.84 (95% CI ; p=0.0010) Similar reductions in major atherosclerotic events in all subgroups studied (including non-dialysis and dialysis patients)

31 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) Eze/simv better Placebo better

32 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 ( ) Tertiary renal outcomes ESRD or death 1477 (47.4%) 1513 (48.3%) 0.97 ( ) ESRD or 2 x creatinine 1190 (38.2%) 1257 (40.2%) 0.94 ( ) Eze/simv better Placebo better

33 Proportion suffering event (%) SHARP: Cancer incidence Risk ratio 0.99 ( ) Logrank 2P=0.89 Eze/simv Placebo Years of follow-up

34 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%)

35 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 events per 1000 treated for 5 years

36 Slide 36

37 Explaining the fall in CHD deaths in USA : RESULTS 342,000 fewer deaths in NEJM 2007; 356: Risk Factors worse +17% Obesity (increase) +7% Diabetes (increase) +10% Risk Factors better -65% Population BP fall -20% Smoking -12% Cholesterol (diet) -24% Physical activity -5% Treatments -47% AMI treatments -10% Secondary prevention -11% Heart failure -9% Angina:CABG & PTCA -5% Hypertension therapies -7% Statins (primary prevention) -5% Unexplained -9% Slide 37

38 Slide 38

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