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ΜΕΙΩΣΗ ΤΩΝ ΕΠΙΠΕΔΩΝ ΤΗΣ LDL ΣΕ ΕΙΔΙΚΕΣ ΟΜΑΔΕΣ ΠΛΗΘΥΣΜΟΥ
Αθηνά ΑραπογιάννηΚαρδιολόγος, Αν. Διευθύντρια Γ΄ Καρδιολογικής
Κλινικής, Ευρωκλινική Αθηνών
Tuesday, March 10, 15
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.
Tuesday, March 10, 15
Development of Atherosclerotic Plaques
NormalFatty streak
Foam cells
Lipid-rich plaque
Lipid core
Fibrous cap
Thrombus
Tuesday, March 10, 15
Source: Yusuf S et al. Lancet. 2004;364:937-952
36
127 10
20
33
0
20
40
60
80
100
Smoking Fruits/Veg
Exercise Alcohol Psycho-social
Lipids All 9 risk factors
PAR
(%)
14 18
90
Diabetes Abdominalobesity
Hyper-tension
Lifestyle factors
50
INTERHEART Study
n=15,152 patients and 14,820 controls in 52 countries
MI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors)
The effect of Modifiable Factors on Riskfor a First Ml
Tuesday, March 10, 15
Source: Yusuf S et al. Lancet. 2004;364:937-952
36
127 10
20
33
0
20
40
60
80
100
Smoking Fruits/Veg
Exercise Alcohol Psycho-social
Lipids All 9 risk factors
PAR
(%)
14 18
90
Diabetes Abdominalobesity
Hyper-tension
Lifestyle factors
50
INTERHEART Study
n=15,152 patients and 14,820 controls in 52 countries
MI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors)
The effect of Modifiable Factors on Riskfor a First Ml
Tuesday, March 10, 15
5
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.
Mean Treatment LDL-C at Follow-up, mg/dL (mmol/L)
Even
t, %
0
30
0 80(2.1)
140(3.6)
200(5.2)
25
20
15
10
5
100(2.6)
40(1.0)
120(3.1)
180(4.7)
4S
4S
CARE
HPS
60(1.6)
LIPID
StatinPlacebo
HPSCARE
LIPID
160(4.1)
PROVE-IT (Atv) PROVE-IT (Pra)
ASCOT
AFCAPS
ASCOT
AFCAPS
WOSCOPS
WOSCOPS
SecondaryPrevention
PrimaryPrevention
IDEAL (Atv)
IDEAL(Sim)
TNT(Atv 80 mg)
TNT (Atv 10 mg)
Η µείωση της LDL-C ελαττώνει τον Κ/Α κίνδυνo
Tuesday, March 10, 15
5
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.
Mean Treatment LDL-C at Follow-up, mg/dL (mmol/L)
Even
t, %
0
30
0 80(2.1)
140(3.6)
200(5.2)
25
20
15
10
5
100(2.6)
40(1.0)
120(3.1)
180(4.7)
4S
4S
CARE
HPS
60(1.6)
LIPID
StatinPlacebo
HPSCARE
LIPID
160(4.1)
PROVE-IT (Atv) PROVE-IT (Pra)
ASCOT
AFCAPS
ASCOT
AFCAPS
WOSCOPS
WOSCOPS
SecondaryPrevention
PrimaryPrevention
IDEAL (Atv)
IDEAL(Sim)
TNT(Atv 80 mg)
TNT (Atv 10 mg)
Η µείωση της LDL-C ελαττώνει τον Κ/Α κίνδυνo
Tuesday, March 10, 15
EUROASPIRE IVAσθενείς με LDL-c > 100 mg/dL
100 mg/dl
Tuesday, March 10, 15
EUROASPIRE IVAσθενείς με LDL-c > 100 mg/dL
~ ½ ασθενείς εκτός στόχων
100 mg/dl
Tuesday, March 10, 15
Tuesday, March 10, 15
Tuesday, March 10, 15
Tuesday, March 10, 15
80% of individuals who die of CAD are >65 y
The absolute risk increases exponentially with age(cumulative risk factor exposure)
Tuesday, March 10, 15
Tuesday, March 10, 15
Tuesday, March 10, 15
Tuesday, March 10, 15
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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.
placeboSacks, F. et al, N Engl J Med 1996; 335:1001-9
Tuesday, March 10, 15
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 significantSacks, F. et al, N Engl J Med 1996; 335:1001-9
Tuesday, March 10, 15
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 significantSacks, F. et al, N Engl J Med 1996; 335:1001-9
Tuesday, March 10, 15
www. Clinical trial results.org
PROSPER5,804 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
Pravastatin40 mg per day
n = 2,891
Placebon = 2,913
Endpoints:! Primary – composite of coronary death,
non-fatal myocardial infarction, and fatal or non-fatal stroke
Lancet 2002; 360: 1623–30
Average follow-up = 3.2 years
Tuesday, March 10, 15
16
Tuesday, March 10, 15
16
Benefit seen by 1 year
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17
Primary EndpointCHD death, Nonfatal MI, Fatal or Nonfatal Stroke
Years
0
5
10
15
20
PlaceboEvents = 473/2913 (16.2%)
PravastatinEvents = 408/2891 (14.1%)
% With Event
15% RRR(P = 0.014)
0 1 2 3
NNT = 48
PROSPER Study Group. Lancet. 2002; 360:1623-30.
Tuesday, March 10, 15
18
ProsperThe benefit of treatment in the elderly was the same as the benefit in the
young
Tuesday, March 10, 15
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
Tuesday, March 10, 15
14,907 very elderly (≥ 80y )
Statin treatment at hospital discharge after AMI was associated with a reduction of all-cause mortality by 42%
Tuesday, March 10, 15
JACC Vol. 62, No. 22, 2013December 3, 2013:2090–9
Tuesday, March 10, 15
>80 y! No RCTs! Frailty! Comorbid conditions! Multiple medication! Life expectancy! Safety concerns ! BIOLOGICALLY HETEROGENOUS
Tuesday, March 10, 15
! > 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
Tuesday, March 10, 15
Tuesday, March 10, 15
2013 ACC/AHA Guideline on the Treatment of
ASCVD
≤75 yrs
High intensity
I
>75yrs
Moderate-intensity
IIa
Age Statins
Tuesday, March 10, 15
STATINSHIGH INTENSITY THERAPY
MODERATE INTENSITY THERAPY
LOW INTENSITY THERAPY
Daily dose lowers LDL-C on average,by approximately ≥50%
Daily dose lowers LDL –C on average,by approximately 30-50%
Daily dose lowers LDL –C <30%
Atorvastatin (40) 80 mg Atorvastatin 10 (20) mg Simvastatin 10 mgRosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg Pravastatin 10-20 mg
Simvastatin 20-40 mg Lovastatin 20 mgPravastatin 40 (80) mg Fluvastatin 20-40 mgLovastatin 40 mg Pitavastatin 1 mgFluvastatin XL 80 mgFluvastatin 40 mg bidPitavastatin 2-4 mg
Tuesday, March 10, 15
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol
consideration of additional factors
a discussion of
- increasing comorbidities- safety considerations- priorities of care
- the potential ASCVD risk reduction benefits- risk of adverse effects- drug-drug interaction
Individuals >75y, Primary Prevention
Tuesday, March 10, 15
ΓΥΝΑΙΚΕΣ ΚΑΙ ΣΝ
Εµφανίζεται 10 χρόνια αργότερα
Συνοδεύεται από πολλά συνυπάρχοντα νοσήµατα
Tuesday, March 10, 15
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
Tuesday, March 10, 15
Meta-analysis of Exclusively Primary Prevention Statin Trials in Women
.1 .5 1 5 10
AFCAPS/TexCAPS 1998
MEGA 2006
JUPITER 2008
0.63 (0.49-0.82) P<0.001P for heterogeneity 0.56ALL
Favors Statin Favors Placebo
(0.34-1.31)
(0.49-1.10)
(0.37-0.80)
21/498
56/2718
70/3375
14/499
40/2638
39/3426
RR 95% CI Placebo Statin
0.67
0.73
0.54
Year
13 154 Women, 240 CVD events
Mora S et al Circulation 2010; 1069Tuesday, March 10, 15
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
Tuesday, March 10, 15
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
Tuesday, March 10, 15
ESC/EAS Guidelines2011
Tuesday, March 10, 15
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.
Tuesday, March 10, 15
XNN
Tuesday, March 10, 15
Η ΧΝΝ είναι ΠΚ για Καρδιαγγειακή Νόσο Η Καρδιαγγειακή Νόσος είναι ΠΚ για την εξέλιξη της ΧΝΝ
Menon V et al. Am J Kidney Dis. 2005;45(1):223–232.
K.N
XNN
Παραδοσιακοί Καρδιαγγειακοί Παράγοντες
Κινδύνου
Μη Παραδοσιακοί Καρδιαγγειακοί Παράγοντες
Κινδύνου
Tuesday, March 10, 15
Όσο µειώνεται το GFR τόσο αυξάνονται τα Καρδιαγγειακά Επεισόδια
Go et al N Eng J Med 2004
Tuesday, March 10, 15
5 Στάδια εξέλιξης Χρόνιας Νεφρικής Νόσου
STAGE 1
Kidneydamagewith normalor increasedkidneyfunction
STAGE 2
Kidneydamagewith mildlyimpairedkidneyfunction
STAGE 3
Moderately impairedkidneyfunction
STAGE 4
Severelyimpairedkidneyfunction
STAGE 5
Kidneyfailure
GFR (mL/min/1.73 m2 )130 90 60 30 15
At risk Treatment Transplant
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/
Dialysis or
Transplant
GFR ≥90 <90 <60 <30 <15
Tuesday, March 10, 15
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
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).
>90 60-89 30-59GFR
Tuesday, March 10, 15
Tuesday, March 10, 15
Tuesday, March 10, 15
Tuesday, March 10, 15
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
Tuesday, March 10, 15
SHARP: Σχεδιασμός Μελέτης
Tuesday, March 10, 15
0 1 2 3 4 5 Years of follow-up
0
5
10
15
20
25
Prop
ortio
n su
fferin
g ev
ent (
%)
Risk ratio 0.83 (0.74 – 0.94) Logrank 2P=0.0022
SHARP: Κύρια Αθηροσκληρωτικά Επεισόδια
↓17%
(Στεφανιαίος θάνατος, Ε.Μ, Μη- αιμορραγικό εγκεφαλικό, ή όποια επαναγγείωση)
Tuesday, March 10, 15
0 1 2 3 4 5 Years of follow-up
0
5
10
15
20
25
Prop
ortio
n su
fferin
g ev
ent (
%)
Risk ratio 0.83 (0.74 – 0.94) Logrank 2P=0.0022
Placebo
Eze/simv 10/20 mg
SHARP: Κύρια Αθηροσκληρωτικά Επεισόδια
↓17%
(Στεφανιαίος θάνατος, Ε.Μ, Μη- αιμορραγικό εγκεφαλικό, ή όποια επαναγγείωση)
Tuesday, March 10, 15
Conclusion: Statin therapy reduces the risk of major CV events in pts with CKD including those receiving dialysis.
Tuesday, March 10, 15
Tuesday, March 10, 15
Tuesday, March 10, 15
Καρδιαγγειακή Νόσος: Κύρια αιτία θανάτου στους Διαβητικούς ασθενείς
Adapted from Morrish NJ, et al. Diabetologia. 2001;44(suppl 2):S14–S21.
Men Women
54%Cardiovascular
49%Cardiovascular
14%Cancer
3%Diabetes
8%Renal
22%All others
20%All others
14%Renal
3%Diabetes
14%Cancer
Tuesday, March 10, 15
Ο Σ.Δ. έχει καθιερωθεί ως «ισοδύναµο» Σ.Ν.
Fatal and nonfatal MI in subjects with and without type 2 diabetes mellitus
CHD = coronary heart disease; MI = myocardial infarction*7-year incidence of fatal and nonfatal MI in 1373 nondiabetic and 1059 diabetic subjectsAdapted from Haffner SM, et al. N Engl J Med. 1998;339:229–234.
05
101520253035404550
No Prior MI Prior MI
Inci
denc
e*, %
(n=890)(n=1304) (n=69) (n=169)
No DiabetesDiabetes
3.5
20.2 18.8
45
NSDM MI
Tuesday, March 10, 15
Slide Source:Lipids Online Slide Librarywww.lipidsonline.org
27%(n=2426)
The risk reduction in major coronary events observed in pts with DM was similar to that of the total study group
Tuesday, March 10, 15
Slide Source:Lipids Online Slide Librarywww.lipidsonline.org
CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke
Cum
ulat
ive
Haz
ard,
(%
)
Years0 1 2 3 4
14101428
13511392
PlaceboAtorvastatin
4.75
13061361
10221074
651694
305328
Placebo127 events
Atorvastatin 10mg83 events
Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.
37%RRRp=0.001
(n=2,838)
Tuesday, March 10, 15
Slide Source:Lipids Online Slide Librarywww.lipidsonline.org
Results From Statin Trials for Patients With Diabetes
Tuesday, March 10, 15
Tuesday, March 10, 15
LDLcholesterol
40-75
Moderate intensity
I A
High intensity
IIa B
<40 yrs,>75yrs
Balance between
IIa C
DiabAge Statins
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol
Tuesday, March 10, 15
Slide Source:Lipids Online Slide Librarywww.lipidsonline.org
Computed Tomography (CT)Showing Atherosclerotic Artery
Tuesday, March 10, 15
Distribution of male and female patients in 4S by age
Tatu A. Miettinen et al. Circulation. 1997;96:4211-4218
(post hoc analysis)
CAD, DM simvastatin vs placebo
Tuesday, March 10, 15
Kaplan-Meier survival curves for all-cause mortality for patients ≥65 and <65 years of age.
Tatu A. Miettinen et al. Circulation. 1997;96:4211-4218
(post hoc analysis)
4S
34%30%
Tuesday, March 10, 15
Tuesday, March 10, 15
Lancet 2010; 376: 1670–81 DOI:10.1016/S0140-6736(10)61350-5
60
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis
of data from 170,000 participants in 26 randomised trials
Tuesday, March 10, 15
Previous coronary disease: CHD Non-CHD vascular None
Diabetes: Type 1 diabetes Type 2 diabetes No diabetesSex: Male FemaleAge (years)≤65
>65, ≤75>75
Body mass index (kg/m2): <25≥25,< 30≥30
Smoking status: Current smokers Non-smokers
8395 (4.5%)674 (3.1%)
1904 (1.4%)
145 (4.5%)2494 (4.2%)8272 (3.2%)
8712 (3.5%)2261 (2.5%)
6056 (2.9%)4032 (3.7%)885 (4.8%)
3030 (3.0%)5033 (3.3%)2732 (3.3%)
2268 (3.6%)8703 (3.1%)
10123 (5.6%)802 (3.7%)
2425 (1.8%)
192 (6.0%)2920 (5.1%)
10163 (4.0%)
10725 (4.4%)2625 (2.9%)
7455 (3.6%)4908 (4.6%)
987 (5.4%)
3688 (3.7%)6125 (4.1%)3331 (4.1%)
2896 (4.7%)10452 (3.9%)
0.79 (0.76 - 0.82)0.81 (0.71 - 0.92)0.75 (0.69 - 0.82)
0.77 (0.58 - 1.01)0.80 (0.74 - 0.86)0.78 (0.75 - 0.81)
0.77 (0.74 - 0.80)0.83 (0.76 - 0.90)
0.78 (0.75 - 0.82)0.78 (0.74 - 0.83)0.84 (0.73 - 0.97)
0.79 (0.74 - 0.84)0.78 (0.74 - 0.82)0.78 (0.73 - 0.84)
0.78 (0.73 - 0.84)0.78 (0.75 - 0.82)
0.4 0.6 0.8 1 1.2 1.499% or 95% CI61
No. of patients (% pa)
Statin/more Control/lessRelative risk (CI) per
mmol/l LDL-C reduction
Statin/more better
Control/lessbetter
Total 10973 (13.0%) 13350 (15.8%) 0.78 (0.76 - 0.80)
Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction, by baseline prognostic
Tuesday, March 10, 15
Recommended