Αθηνά Αραπογιάννη Καρδιολόγος, Αν. Διευθύντρια Γ Καρδιολογικής Κλινικής, Ευρωκλινική Αθηνών

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1 ΕΙΩΣΗ ΤΩΝ ΕΠΙΠΕΔΩΝ ΤΗΣ LDL ΣΕ ΕΙΔΙΚΕΣ ΟΜΑΔΕΣ ΠΛΗΘΥΣΜΟΥ Αθηνά Αραπογιάννη Καρδιολόγος, Αν. Διευθύντρια Γ Καρδιολογικής Κλινικής, Ευρωκλινική Αθηνών

2 Conflict of Interest Statement: I have received research supports or honoraria or both from Bristol-Myers Squibb Company, MSD K.K., Βιανεξ ΑΕ, Menarini, AstraZeneca K.K.

3 Development of Atherosclerotic Plaques Normal Fatty streak Lipid-rich plaque Foam cells Fibrous cap Thrombus Lipid core

4 The effect of Modifiable Factors on Risk for a First Ml 100 INTERHEART Study PAR (%) Smoking Fruits/ Veg Exercise Alcohol Hypertension Diabetes Abdominal Psychosocial obesity Lipids All 9 risk factors Lifestyle factors n=15,152 patients and 14,820 controls in 52 countries MI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors) Source: Yusuf S et al. Lancet. 2004;364:

5 The effect of Modifiable Factors on Risk for a First Ml 100 INTERHEART Study PAR (%) Smoking Fruits/ Veg Exercise Alcohol Hypertension Diabetes Abdominal Psychosocial obesity Lipids All 9 risk factors Lifestyle factors n=15,152 patients and 14,820 controls in 52 countries MI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors) Source: Yusuf S et al. Lancet. 2004;364:

6 Η µείωση της LDL-C ελαττώνει τον Κ/Α κίνδυνo Statin Placebo 4S Secondary Prevention Event, % PROVE-IT (Atv) IDEAL (Atv) IDEAL (Sim) HPS TNT (Atv 80 mg) CARE LIPID 4S TNT (Atv 10 mg) PROVE-IT (Pra) ASCOT AFCAPS ASCOT HPS CARE AFCAPS LIPID WOSCOPS WOSCOPS Primary Prevention (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: ; LaRosa JC, et al. N Engl J Med. 2005;352: ; Pedersen TR, et al. JAMA. 2005;294:

7 Η µείωση της LDL-C ελαττώνει τον Κ/Α κίνδυνo Statin Placebo 4S Secondary Prevention Event, % PROVE-IT (Atv) IDEAL (Atv) IDEAL (Sim) HPS TNT (Atv 80 mg) CARE LIPID 4S TNT (Atv 10 mg) PROVE-IT (Pra) ASCOT AFCAPS ASCOT HPS CARE AFCAPS LIPID WOSCOPS WOSCOPS Primary Prevention (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: ; LaRosa JC, et al. N Engl J Med. 2005;352: ; Pedersen TR, et al. JAMA. 2005;294:

8 EUROASPIRE IV Aσθενείς με LDL-c > 100 mg/dl 100 mg/dl

9 EUROASPIRE IV Aσθενείς με LDL-c > 100 mg/dl 100 mg/dl ~ ½ ασθενείς εκτός στόχων

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13 80% of individuals who die of CAD are >65 y The absolute risk increases exponentially with age (cumulative risk factor exposure)

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18 CARE - Study Design Secondary prevention of CHD 80 centers in the US and Canada 4159 men and women aged 21 to 75 enrolled 3 to 20 months post-mi Total-C < 240; LDL-C between 115 and 174; Triglycerides < 350 mg/dl 5 yr Treatment with Pravastatin 40 mg vs. placebo Sacks, F. et al, N Engl J Med 1996; 335:1001-9

19 CARE - Observations Fatal CHD + nonfatal MI + CABG + PTCA Women vs. Men: 46% vs. 20% Current smokers vs. other: 33% vs. 22% < 60 yr vs. > 60 yr: 20% vs. 27% EF < 40% vs. > 40%: 28% vs. 23% Hypertension, yes vs. no: 23% vs. 24% Diabetes, yes vs. no: 25% vs. 23% Prior PTCA/CABG, yes vs. no: 22% vs. 25% p values for all subgroups were statistically significant Sacks, F. et al, N Engl J Med 1996; 335:1001-9

20 CARE - Observations Fatal CHD + nonfatal MI + CABG + PTCA Women vs. Men: 46% vs. 20% Current smokers vs. other: 33% vs. 22% < 60 yr vs. > 60 yr: 20% vs. 27% EF < 40% vs. > 40%: 28% vs. 23% Hypertension, yes vs. no: 23% vs. 24% Diabetes, yes vs. no: 25% vs. 23% Prior PTCA/CABG, yes vs. no: 22% vs. 25% p values for all subgroups were statistically significant Sacks, F. et al, N Engl J Med 1996; 335:1001-9

21 PROSPER 5,804 high-risk elderly patients! Age years! Pre-existing vascular disease (coronary, cerebral, or peripheral)! High-risk for vascular disease (smoking, hypertension, or diabetes)! Total cholesterol mg/dl Pravastatin 40 mg per day n = 2,891 Placebo n = 2,913 www. Clinical trial results.org Average follow-up = 3.2 years Endpoints:! Primary composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke Lancet 2002; 360:

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23 Benefit seen by 1 year 16

24 Primary Endpoint CHD death, Nonfatal MI, Fatal or Nonfatal Stroke Placebo Events = 473/2913 (16.2%) 15% RRR (P = 0.014) % With Event 10 5 Pravastatin Events = 408/2891 (14.1%) NNT = Years PROSPER Study Group. Lancet. 2002; 360:

25 Prosper The benefit of treatment in the elderly was the same as the benefit in the young 18

26 LOWER USE OF STATINS IN ELDERLY POST-MI PATIENTS GRACE (Global Registry of Acute Coronary Events) Euro Heart Survey on ACS <40% of MI patients >75 y are prescribed statins at discharge

27 14,907 very elderly ( 80y ) Statin treatment at hospital discharge after AMI was associated with a reduction of all-cause mortality by 42%

28 JACC Vol. 62, No. 22, 2013 December 3, 2013:2090 9

29 >80 y! No RCTs! Frailty! Comorbid conditions! Multiple medication! Life expectancy! Safety concerns! BIOLOGICALLY HETEROGENOUS

30 ! > 70 y! Primary prevention! Atorvastatin 40 mg vs Placebo! Primary end points : All cause mortality or need for permanent residential care, Death from any cause or documented assessment of need for permanent residential care! 5 y RCT, n=12 000,

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32 2013 ACC/AHA Guideline on the Treatment of ASCVD Age Statins 75 yrs >75yrs High intensity Moderateintensity I IIa

33 STATINS HIGH INTENSITY THERAPY Daily dose lowers LDL-C on average,by approximately 50% MODERATE INTENSITY THERAPY Daily dose lowers LDL C on average,by approximately 30-50% LOW INTENSITY THERAPY Daily dose lowers LDL C <30% Atorvastatin (40) 80 mg Atorvastatin 10 (20) mg Simvastatin 10 mg Rosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg Pravastatin mg Simvastatin mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2-4 mg Lovastatin 20 mg Fluvastatin mg Pitavastatin 1 mg

34 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol Individuals >75y, Primary Prevention consideration of additional factors - increasing comorbidities - safety considerations - priorities of care a discussion of - the potential ASCVD risk reduction benefits - risk of adverse effects - drug-drug interaction

35 ΓΥΝΑΙΚΕΣ ΚΑΙ ΣΝ Εµφανίζεται 10 χρόνια αργότερα Συνοδεύεται από πολλά συνυπάρχοντα νοσήµατα

36 Participants in clinical trials by gender. Stramba-Badiale M Eur Heart J 2010;31: Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oxfordjournals.org

37 Meta-analysis of Exclusively Primary Prevention Statin Trials in Women Women, 240 CVD events Year RR 95% CI Placebo Statin AFCAPS/TexCAPS ( ) 21/498 14/499 MEGA ( ) 56/ /2638 JUPITER ( ) 70/ /3426 ALL P for heterogeneity ( ) P< Mora S et al Circulation 2010; 1069 Favors Statin Favors Placebo

38 The present study, however, does not indicate any sex differences in the beneficial effects of statins in either primary or secondary prevention. JACC 2012;59:572-82

39 Conclusion : Statin therapy is associated with significant decreases in CV events and in all-cause mortality in women and men. Statin therapy should be used in appropriate patients without regard to sex

40 ESC/EAS Guidelines 2011

41 2013 ACC/AHA Guideline on the Treatment of Because the RCT evidence shows that the benefit of statin treatment is proportional to baseline ASCVD risk, treatment decisions for women should be based on the level of ASCD risk.

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43 Η ΧΝΝ είναι ΠΚ για Καρδιαγγειακή Νόσο Η Καρδιαγγειακή Νόσος είναι ΠΚ για την εξέλιξη της ΧΝΝ XNN Παραδοσιακοί Καρδιαγγειακοί Παράγοντες Κινδύνου Μη Παραδοσιακοί Καρδιαγγειακοί Παράγοντες Κινδύνου K.N Menon V et al. Am J Kidney Dis. 2005;45(1):

44 Όσο µειώνεται το GFR τόσο αυξάνονται τα Καρδιαγγειακά Επεισόδια Go et al N Eng J Med 2004

45 5 Στάδια εξέλιξης Χρόνιας Νεφρικής Νόσου At risk Treatment Transplant STAGE 1 STAGE 2 STAGE 3 STAGE 4 STAGE 5 Kidney damage with normal or increased kidney function Kidney damage with mildly impaired kidney function Moderately impaired kidney function Severely impaired kidney function Kidney failure Dialysis or Transplant GFR 90 <90 <60 <30 < GFR (ml/min/1.73 m 2 ) KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes in Chronic Kidney Disease July 2006 National Kidney Foundation.

46 Effect of Pravastatin on Cardiovascular Events in People With Chronic Kidney Disease (Pravastatin Pooling Project-WOSCOPS,LIPID,CARE ) A, Primary outcome (fatal coronary disease, nonfatal MI, or coronary revascularization). GFR > Figure 1. Unadjusted incidence of clinical outcomes by level of kidney function and treatment group in subjects with known coronary disease at baseline. Marcello Tonelli et al. Circulation. 2004;110:

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50 SHARP: Προφίλ ασθενών Ιστορικό Χρόνιας Νεφρικής Νόσου Χ.Ν.Ν Όχι σε διάλυση: Kάθαρση κρεατινίνης! Άνδρες: 1.7 mg/dl (150 µmol/l)! Γυναίκες: 1.5 mg/dl (130 µmol/l) Σε διάλυση: αιμοκάθαρση ή περιτονική διάλυση Ηλικία 40 έτη Χωρίς ιστορικό εμφράγματος ή στεφανιαίας επαναγγείωσης Χωρίς ένδειξη αλλά ούτε και αντένδειξη για υπολιπιδαιμική θεραπεία

51 SHARP: Σχεδιασμός Μελέτης

52 SHARP: Κύρια Αθηροσκληρωτικά Επεισόδια (Στεφανιαίος θάνατος, Ε.Μ, Μη- αιμορραγικό εγκεφαλικό, ή όποια επαναγγείωση) 25 Proportion suffering event (%) Risk ratio 0.83 ( ) Logrank 2P= % Years of follow-up

53 SHARP: Κύρια Αθηροσκληρωτικά Επεισόδια (Στεφανιαίος θάνατος, Ε.Μ, Μη- αιμορραγικό εγκεφαλικό, ή όποια επαναγγείωση) 25 Proportion suffering event (%) Risk ratio 0.83 ( ) Logrank 2P= % Placebo Eze/simv 10/20 mg Years of follow-up

54 Conclusion: Statin therapy reduces the risk of major CV events in pts with CKD including those receiving dialysis.

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57 Καρδιαγγειακή Νόσος: Κύρια αιτία θανάτου στους Διαβητικούς ασθενείς Men Women 22% All others 20% All others 8% Renal 54% Cardiovascular 14% Renal 49% Cardiovascular 3% Diabetes 14% Cancer 3% Diabetes 14% Cancer Adapted from Morrish NJ, et al. Diabetologia. 2001;44(suppl 2):S14 S21.

58 Ο Σ.Δ. έχει καθιερωθεί ως «ισοδύναµο» Σ.Ν. Fatal and nonfatal MI in subjects with and without type 2 diabetes mellitus Incidence*, % No Diabetes Diabetes DM (n=1304) (n=890) (n=69) (n=169) No Prior MI NS MI 18.8 Prior MI 45 CHD = coronary heart disease; MI = myocardial infarction *7-year incidence of fatal and nonfatal MI in 1373 nondiabetic and 1059 diabetic subjects Adapted from Haffner SM, et al. N Engl J Med. 1998;339:

59 (n=2426) 27% The risk reduction in major coronary events observed in pts with DM was similar to that of the total study group Slide Source: Lipids Online Slide Library

60 CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke Placebo Cumulative Hazard, (%) Atorvastatin Years Colhoun HM et al. Lancet 2004;364: Reprinted with permission from Elsevier. (n=2,838) Placebo 127 events Atorvastatin 10mg 83 events % RRR p=0.001 Slide Source: Lipids Online Slide Library

61 Results From Statin Trials for Patients With Diabetes Slide Source: Lipids Online Slide Library

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63 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol LDLcholester ol Diab Age Statins <40 yrs, >75yrs Moderate intensity High intensity Balance between I A IIa B IIa C

64 Computed Tomography (CT) Showing Atherosclerotic Artery Slide Source: Lipids Online Slide Library

65 Distribution of male and female patients in 4S by age (post hoc analysis) Tatu A. Miettinen et al. Circulation. 1997;96: CAD, DM simvastatin vs placebo

66 4S Kaplan-Meier survival curves for all-cause mortality for patients 65 and <65 years of age. (post hoc analysis) 30% 34% Tatu A. Miettinen et al. Circulation. 1997;96:

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68 Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials Lancet 2010; 376: DOI: /S (10)

69 Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction, by baseline prognostic No. of patients (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction Previous coronary disease: CHD Non-CHD vascular None 8395 (4.5%) 674 (3.1%) 1904 (1.4%) (5.6%) 802 (3.7%) 2425 (1.8%) 0.79 ( ) 0.81 ( ) 0.75 ( ) Diabetes: Type 1 diabetes Type 2 diabetes No diabetes 145 (4.5%) 2494 (4.2%) 8272 (3.2%) 192 (6.0%) 2920 (5.1%) (4.0%) 0.77 ( ) 0.80 ( ) 0.78 ( ) Sex: Male Female 8712 (3.5%) 2261 (2.5%) (4.4%) 2625 (2.9%) 0.77 ( ) 0.83 ( ) Age (years) 65 >65, 75 > (2.9%) 4032 (3.7%) 885 (4.8%) 7455 (3.6%) 4908 (4.6%) 987 (5.4%) 0.78 ( ) 0.78 ( ) 0.84 ( ) Body mass index (kg/m 2 ): <25 25,< (3.0%) 5033 (3.3%) 2732 (3.3%) 3688 (3.7%) 6125 (4.1%) 3331 (4.1%) 0.79 ( ) 0.78 ( ) 0.78 ( ) Smoking status: Current smokers Non-smokers 2268 (3.6%) 8703 (3.1%) 2896 (4.7%) (3.9%) 0.78 ( ) 0.78 ( ) Total (13.0%) (15.8%) 0.78 ( ) 99% or 95% CI Statin/more better Control/less better 61