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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.


Development of Atherosclerotic Plaques

NormalFatty streak

Foam cells

Lipid-rich plaque

Lipid core

Fibrous cap

Thrombus


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


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


EUROASPIRE IVAσθενείς με LDL-c > 100 mg/dL

100 mg/dl


EUROASPIRE IVAσθενείς με LDL-c > 100 mg/dL

~ ½ ασθενείς εκτός στόχων

100 mg/dl


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.

placeboSacks, 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 significantSacks, F. et al, N Engl J Med 1996; 335:1001-9


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


16


16

Benefit seen by 1 year


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.


18

ProsperThe benefit of treatment in the elderly was the same as the benefit in the

young


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, 2013December 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

≤75 yrs

High intensity

I

>75yrs

Moderate-intensity

IIa

Age Statins


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


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


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: [email protected]


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


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 Guidelines2011


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.


XNN


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


Όσο µειώνεται το GFR τόσο αυξάνονται τα Καρδιαγγειακά Επεισόδια

Go et al N Eng J Med 2004


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


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


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


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)


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)


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

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


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


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



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)



Results From Statin Trials for Patients With Diabetes


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



Computed Tomography (CT)Showing Atherosclerotic Artery


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


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%


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


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


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