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

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

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.

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

The effect of Modifiable Factors on Risk for a First Ml 100 INTERHEART Study 90 80 PAR (%) 60 40 36 33 50 20 14 12 7 18 10 20 0 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;364:937-952

Η µείωση της LDL-C ελαττώνει τον Κ/Α κίνδυνo 30 25 Statin Placebo 4S Secondary Prevention Event, % 20 15 10 5 0 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 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. 5

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

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

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

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

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

PROSPER 5,804 high-risk elderly patients! Age 70 82 years! Pre-existing vascular disease (coronary, cerebral, or peripheral)! High-risk for vascular disease (smoking, hypertension, or diabetes)! Total cholesterol 155-348 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: 1623 30

Benefit seen by 1 year 16

Primary Endpoint CHD death, Nonfatal MI, Fatal or Nonfatal Stroke 20 15 Placebo Events = 473/2913 (16.2%) 15% RRR (P = 0.014) % With Event 10 5 Pravastatin Events = 408/2891 (14.1%) NNT = 48 0 0 1 2 3 Years PROSPER Study Group. Lancet. 2002; 360:1623-30. 17

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

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

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

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

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

! > 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, 2014-2019

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

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 10-20 mg Simvastatin 20-40 mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2-4 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg

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

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

Participants in clinical trials by gender. Stramba-Badiale M Eur Heart J 2010;31:1677-1681 Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women 13 154 Women, 240 CVD events Year RR 95% CI Placebo Statin AFCAPS/TexCAPS 1998 0.67 (0.34-1.31) 21/498 14/499 MEGA 2006 0.73 (0.49-1.10) 56/2718 40/2638 JUPITER 2008 0.54 (0.37-0.80) 70/3375 39/3426 ALL P for heterogeneity 0.56 0.63 (0.49-0.82) P<0.001.1.5 1 5 10 Mora S et al Circulation 2010; 1069 Favors Statin Favors Placebo

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

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

ESC/EAS Guidelines 2011

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.

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):223 232.

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

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 <15 130 90 60 30 15 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. http://www.kidney.org/professionals/kdoqi/

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 >90 60-89 30-59 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;110:1557-1563

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

SHARP: Σχεδιασμός Μελέτης

SHARP: Κύρια Αθηροσκληρωτικά Επεισόδια (Στεφανιαίος θάνατος, Ε.Μ, Μη- αιμορραγικό εγκεφαλικό, ή όποια επαναγγείωση) 25 Proportion suffering event (%) 20 15 10 5 Risk ratio 0.83 (0.74 0.94) Logrank 2P=0.0022 17% 0 0 1 2 3 4 5 Years of follow-up

SHARP: Κύρια Αθηροσκληρωτικά Επεισόδια (Στεφανιαίος θάνατος, Ε.Μ, Μη- αιμορραγικό εγκεφαλικό, ή όποια επαναγγείωση) 25 Proportion suffering event (%) 20 15 10 5 Risk ratio 0.83 (0.74 0.94) Logrank 2P=0.0022 17% Placebo Eze/simv 10/20 mg 0 0 1 2 3 4 5 Years of follow-up

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

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.

Ο Σ.Δ. έχει καθιερωθεί ως «ισοδύναµο» Σ.Ν. Fatal and nonfatal MI in subjects with and without type 2 diabetes mellitus Incidence*, % 50 45 40 35 30 25 20 15 10 5 0 No Diabetes Diabetes 3.5 20.2 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;339:229 234.

(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 www.lipidsonline.org

CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke Placebo Cumulative Hazard, (%) Atorvastatin 0 1 2 3 4 Years 1410 1428 1351 1392 Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier. (n=2,838) 1306 1361 1022 1074 Placebo 127 events Atorvastatin 10mg 83 events 651 694 4.75 305 328 37% RRR p=0.001 Slide Source: Lipids Online Slide Library www.lipidsonline.org

Results From Statin Trials for Patients With Diabetes Slide Source: Lipids Online Slide Library www.lipidsonline.org

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

Computed Tomography (CT) Showing Atherosclerotic Artery Slide Source: Lipids Online Slide Library www.lipidsonline.org

Distribution of male and female patients in 4S by age (post hoc analysis) Tatu A. Miettinen et al. Circulation. 1997;96:4211-4218 CAD, DM simvastatin vs placebo

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;96:4211-4218

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: 1670 81 DOI:10.1016/S0140-6736(10)61350-5 60

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%) 10123 (5.6%) 802 (3.7%) 2425 (1.8%) 0.79 (0.76-0.82) 0.81 (0.71-0.92) 0.75 (0.69-0.82) Diabetes: Type 1 diabetes Type 2 diabetes No diabetes 145 (4.5%) 2494 (4.2%) 8272 (3.2%) 192 (6.0%) 2920 (5.1%) 10163 (4.0%) 0.77 (0.58-1.01) 0.80 (0.74-0.86) 0.78 (0.75-0.81) Sex: Male Female 8712 (3.5%) 2261 (2.5%) 10725 (4.4%) 2625 (2.9%) 0.77 (0.74-0.80) 0.83 (0.76-0.90) Age (years) 65 >65, 75 >75 6056 (2.9%) 4032 (3.7%) 885 (4.8%) 7455 (3.6%) 4908 (4.6%) 987 (5.4%) 0.78 (0.75-0.82) 0.78 (0.74-0.83) 0.84 (0.73-0.97) Body mass index (kg/m 2 ): <25 25,< 30 30 3030 (3.0%) 5033 (3.3%) 2732 (3.3%) 3688 (3.7%) 6125 (4.1%) 3331 (4.1%) 0.79 (0.74-0.84) 0.78 (0.74-0.82) 0.78 (0.73-0.84) Smoking status: Current smokers Non-smokers 2268 (3.6%) 8703 (3.1%) 2896 (4.7%) 10452 (3.9%) 0.78 (0.73-0.84) 0.78 (0.75-0.82) Total 10973 (13.0%) 13350 (15.8%) 0.78 (0.76-0.80) 99% or 95% CI 0.4 0.6 0.8 1 1.2 1.4 Statin/more better Control/less better 61