Τα Νεώτερα Δεδομένα Στη Μικτή Δυσλιπιδαιμία- Ποια η Θέση Των Πέρα Των Στατινών Φαρμάκων Στη Σύγχρονη Υπολιδαιμική Αγωγή

-
, MD, FESC, FAHA

-
--
, , 62 , 2,
320 mg,
.
:
(1 / x 15 )
= 195 mg/dl ,LDL = 120 mg/dl,
HDL=34 mg/dl, = 390 mg/dl)
(122mg/dl)
(= 28 g/m2, = 110 cm)
(
50 )
= 148/90 mmHg
. = S1, S2, ,
. =
. =
= .
HK= , 60 /
( )
10 ?
1. <1% (X )
2. 1-5% ( )
3. 5-10% ( )
4. > 10% ( )
( )
10
?
1. <5% (X )
2. 5-7,5% ( )
3. 7,5-10% ( )
4. > 10% ( )
US risk score 27,3%
.
- ?
1.
2.
10
-.
/
-
(mmHg)

*

120129
8084
130139
8589
1
140159
9099
2
160179
100109
3
>180
>110
12
>3
,
,

>60
1015%
1520%
2030%
30%
10
<4%
45%
58%
>8%
10
(SCORE)
*, x,
?
1.
2.
3.
E -
LVMI (g/m2) >115 M, >95 W
E -
E -
H :
EDD= 54 mm, ESD= 32 mm, EF= 60%
IVS= 12.5 mm, PW= 12 mm, LVMi= 128 g/m2 (LVH: >115 g/m2)
:
eGFR= 94 ml/min/1.73 m2
24= 18 mg/24
:
Triplex : = 1.5 mm ()
ABI= 1.1
E : PWV= 10 m/s
, 52 , , ,
320 mg, -
( , IMT, o
PWV) .
?
1.
( )
2.
3.
4.
Rationale
= 130/80 mmHg
O .
.
2014
;
, , 62 , 2,
320 mg,
.
:
(1 / x 15 )
= 195 mg/dl ,LDL = 120 mg/dl, HDL=
34 mg/dl, = 390 mg/dl)
(115 mg/dl)
(= 28 g/m2, = 110 cm)
(
50 )
1.
2. . /
3.
4. 40 mg
= 130/80 mmHg
O .
.
= 195 mg/dl ,
LDL = 120mg/dl,
HDL=34 mg/dl,
= 390 mg/dl)
?
1.
2.
3.
4.
5.
1.
Association Between Statins and

Development of Diabetes
Statin
No. Of
patients
Odds Ratio
95% CI
Overall
91,140
1.09
1.02 - 1.17
Atorvastatin
7,773
1.14
0.89 - 1.46
Simvastatin
18,815
1.11
0.97 - 1.26
Rosuvastatin
24,714
1.18
1.04 - 1.33
Pravastatin
33,627
1.03
0.90 - 1.19
Lovastatin
6,211
0.98
0.70 - 1.38
Data sourced from: Sattar N et al. Lancet 2010; DOI:10.1016/S0140-6736(09)61965-6
1.
2.
Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Slide Source:
Slide Source:
Henry C. Ginsberg, MD
College of Physicians & Surgeons , Columbia University, New York
For The ACCORD Study Group
ACCORD Lipid Trial Eligibility

Stable Type 2 Diabetes >3 months
HbA1c 7.5% to 11%
High risk of CVD events = clinical or subclinical disease or

2+ risk factors
Age (limited to <80 years after Vanguard)
40 yrs with history of clinical CVD (secondary prevention)

55 yrs otherwise
Lipids
60 < LDL-C < 180 mg/dl

HDL-C < 55 mg/dl for women/Blacks; < 50 mg/dl otherwise
Triglycerides < 750 mg/dl if on no therapy; < 400 mg/dl otherwise
No contraindication to either fenofibrate or simvastatin
Primary Outcome By Treatment Group and Baseline Subgroups
Trial
(Drug)
HHS
(Gemfibrozil)
BIP
(Bezafibrate)
FIELD
(Fenofibrate)
ACCORD
(Fenofibrate)
Primary Endpoint:
Entire Cohort
(P-value)
-34% (0.02)
Lipid Subgroup
Criterion
TG > 200 mg/dl

LDL-C/HDL-C
> 5.0
Primary
Endpoint:
Subgroup
-71%
TG > 200 mg/dl

-7.3% (0.24)
-11%
-8%
(0.16)
(0.32)
-39.5%
TG > 204 mg/dl
HDL-C < 42
mg/dl
-27%
TG > 204 mg/dl

HDL-C < 34
mg/dl
-31%
2
-
= 155 mg/dl ,
LDL = 90 mg/dl,
HDL=35 mg/dl,
= 165 mg/dl

NSTEMI
1. HDL- TG
2. LDL < 70
3. LDL 50 mg/dl
IMPROVE-IT
LDL-C (<70 mg/dL)

(<55 mg/dL)
;
LDL
2,3

, /,

;1
= , = , = .
1. Cannon CP et al. Am Heart J. 2008;156:826832. 2. Califf RM et al. Am Heart J. 2010;159:705709. 3. Blazing MA et al. Am Heart J. 2014; doi: 10.1016/j.ahj.2014.05.004.
2013 ACC/AHA Cholesterol Treatment

Guideline Perspective
Stone N.J., et al Circulation 2013 Nov 12 {Epub ahead of print}
Mean cIMT during 24 months of therapy

Longitudinal, repeated measures analysis
0.80
Mean IMT (mm)
0.75
P=0.88
0.70
0.65
0.60
ENHANCE
12
Months
18
24
Simva
Eze-Simva
51
2nd EP:
Aortic Valve Events
Percentage of Patients With

First Event
50
Intention to Treat Population
40
Placebo
30
Hazard ratio: 0.97, p=0.732

EZ/Simva 10/40 mg
20
10
No. at Risk
EZ/Simva 10/40 mg
Placebo
Rosseb et al. NEJM. 2008;359
914
895
2
3
Years in Study
836
814
732
725
4
635
611
5
55
58
Ischemic CV Events
30
Intention to Treat Population
Percentage of Patients With

First Event
2nd EP:
20
Hazard ratio: 0.78, p=0.024
Placebo
EZ/Simva 10/40 mg
10
0
0
No. at risk
EZ/Simva 10/40 mg
Placebo
Rosseb et al. NEJM. 2008;359
3
Years in Study
917
898
867
838
823
788
769
729
76
76
SHARP: Major Atherosclerotic Events
Proportion suffering event (%)
25
Risk ratio 0.83 (0.74 0.94)

Logrank 2P=0.0022
20
Placebo
15
Eze/simv
10
0
0
Years of follow-up
CTT: Effects on Major Atherosclerotic Events
Proportional reduction in
atherosclerotic event rate (95% CI)
30%
Statin vs control
(21 trials)
25%
20%
More vs Less
(5 trials)
15%
SHARP
32 mg/dL
10%
5%
0%
0
10
20
30
Mean LDL cholesterol difference

between treatment groups (mg/dL)
40
CTT: Effects on Major Atherosclerotic Events
Proportional reduction in
atherosclerotic event rate (95% CI)
30%
Statin vs control
(21 trials)
25%
20%
SHARP
17% risk
reduction
More vs Less
(5 trials)
15%
SHARP
32 mg/dL
10%
5%
0%
0
10
20
30
Mean LDL cholesterol difference

between treatment groups (mg/dL)
40
Pravastatin or Atorvastatin in Infection

Therapy (PROVE IT): Study Design
Patient population
Men and women aged
18 years
Hospitalized within 10
days of acute MI or highrisk unstable angina (UA)
TC 240 mg/dL
Atorvastatin 80 mg
(n=2099)
4162 patients
Stable condition, enrolled

after percutaneous
coronary intervention
(PCI), if planned
Pravastatin 40 mg
(n=2063)
18 to 36 months
Primary efficacy end point
Composite of death from any cause, MI, documented UA requiring

rehospitalization, revascularization, and stroke
Cannon CP et al. N Engl J Med. 2004;350:1495-1504.
PROVE IT: Early and Sustained Benefit With

Atorvastatin Compared With Pravastatin
Death or major cardiovascular event
(%)
Occurrence of primary composite end point

(death, MI, UA requiring rehospitalization, revascularization, stroke)
30
16% RRR in
composite
end point
P=.005
25
Pravastatin
(40 mg)
20
Atorvastatin
(80 mg)
15
10
5
0
0
12 15 18 21
Follow-up (months)
Adapted from Cannon CP et al. N Engl J Med. 2004;350:1495-1504.
24
27
30
IMPROVE-IT: 1-3

(NSTEMI, STEMI
(STEMI 30% )
10
EZ/Simva
10/40 mg
Simva
40 mg
N = 18.1412

2,5
FDA 80 mg.
( ) LDL 97 mg/dL 10.000 .
IMPROVE IT = IMProved Reduction of Outcomes: Vytorin Efficacy International Trial.
1. Cannon CP et al. Am Heart J. 2008;156:826-832. 2. Califf RM, et al. Am Heart J. 2010;159:705-709.
3. http://clinicaltrials.gov/ct2/show/NCT00202878?term=improve-it&rank=1

/
(N=9077)
(N=9067)
80mg, %
27
, %
42
42
6.0
5.9

, %/
0.6
0.6
, %/
0.10
0.09
91
91
1
, %
,
%
97 = 5314 97
= 97,822
= 104,135
1

30

()
= , = , = , = , PCI =
, CABG = .
1. Cannon CP et al. Am Heart J. 2008;156:826832.
1
( ,
NSTEMI, STEMI) 10
24
LDL-c:
24
50 125 mg/dL
50 100 mg/dL (>4 )

350 mg/dL
STEMI 1/3 .1,2

= , = , = , NSTEMI =
ST, STEMI = ST, = , CK-MB =
, = , CABG = .
1. Cannon CP et al. Am Heart J. 2008;156:826832. 2. Blazing MA et al. Am Heart J. 2014; doi: 10.1016/j.ahj.2014.05.004.
(N=9077)
%
/
(N=9067)
%
()
64
64
24
25
27
27
21
21
29 / 47 / 24
29 / 47 / 24
(IQR)
5 (3, 8)
5 (3, 8)
. / PCI
88 / 70
88 / 70
35
36
95 (79, 110)
95 (79,110)
STEMI / NSTEMI /

LDL-C (mg/dL, IQR)
http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469669.pdf
LDL-c 1
LDL-C
95 mg/dL (2,5 mmol/L)
.
80 mg LDL-C >79 mg/dL,
2011.
1. Blazing MA et al. Am Heart J. 2014; doi: 10.1016/j.ahj.2014.05.004.

LDL-C CTT

LDL-C

.

LDL-C
Laufs U et al. Eur Heart J. 2014;doi:10.1093/eurheartj/ehu228.
LDL-C
1 Yr Mean
LDL-C
TC
TG
HDL
hsCRP
Simva
69.9
145.1
137.1
48.1
3.8
EZ/Simva
53.2
125.8
120.4
48.7
3.3
in mg/dL
-16.7
-19.3
-16.7
+0.6
-0.5
Median Time avg

69. vs. 53.7 mg/dL
ITT
Cardiovascular death, MI, documented unstable angina requiring rehospitalization,
coronary revascularization (30 days), or stroke
HR 0.936 CI (0.887, 0.988)
p=0.016
Simva 34.7%
2742 events
NNT= 50
EZ/Simva 32.7%
2572 events
6,4 % RRR
7-year event rates
3
ITT
0.936
Primary
CVD/MI/UA/Cor Revasc/CVA
0.948
Secondary #1
All D/MI/UA/Cor Revasc/CVA
0.912
Secondary #2
CHD/MI/Urgent Cor Revasc
0.945
Secondary #3
CVD/MI/UA/All Revasc/CVA
0.8
1.0
Ezetimibe/Simva
Better
Simva*
EZ/Simva*
p-value
34.7
32.7
0.016
40.3
38.7
0.034
18.9
17.5
0.016
36.2
34.5
0.035
1.1
Simva
Better
UA, documented unstable angina requiring rehospitalization; Cor Revasc, coronary revascularization
(30 days after randomization); All D, all-cause death; CHD, coronary heart disease death;
All Revasc, coronary and non-coronary revascularization (30 days)
*7-year
event rates (%)
KA
/ /
All-cause death
HR
0.99
Simva*
15.3
EZ/Simva*
15.4
p-value
0.782
CVD
1.00
6.8
6.9
0.997
CHD
0.96
5.8
5.7
0.499
0.87
14.8
13.1
0.002
0.86
4.8
4.2
0.052
0.79
4.1
3.4
0.008
Cor revasc 30d
0.95
23.4
21.8
0.107
UA
1.06
1.9
2.1
0.618
CVD/MI/stroke
0.90
22.2
20.4
0.003
-13%
MI
Stroke
Ischemic stroke
-21%
0.6
1.0
Ezetimibe/Simva
Better
1.4
Simva
Better
*7-year
event rates (%)
,
,
HR 0.90 CI (0.84, 0.97)
p=0.003
NNT= 56
Simva 22.2%
1704 events
EZ/Simva 20.4%
1544 events
10 % RRR
7-year event rates

-
Simva
EZ/Simva
Male
Female
34.9
34.0
33.3
31.0
Age < 65 years

Age 65 years
30.8
39.9
29.9
36.4
30.8
45.5
30.2
40.0
Prior LLT
No prior LLT
43.4
30.0
40.7
28.6
LDL-C > 95 mg/dl

LDL-C 95 mg/dl
31.2
38.4
29.6
36.0
No diabetes
Diabetes
0.7
Ezetimibe/Simva
Better
1.0
Simva
Better
1.3
7-year
event rates
*p-interaction = 0.023, otherwise > 0.05
IMPROVE-IT vs. CTT -:

IMPROVE-IT
CTT Collaboration.
Lancet 2005; 366:1267-78;
Lancet 2010;376:1670-81.
ITT
No statistically significant differences in cancer or muscle- or
gallbladder-related events
Simva
n=9077
%
EZ/Simva
n=9067
%
ALT and/or AST3x ULN
2.3
2.5
0.43
Cholecystectomy
1.5
1.5
0.96
Gallbladder-related AEs
3.5
3.1
0.10
Rhabdomyolysis*
0.2
0.1
0.37
Myopathy*
0.1
0.2
0.32
Rhabdo, myopathy, myalgia with CK elevation*
0.6
0.6
0.64
Cancer* (7-yr KM %)
10.2
10.2
0.57
* Adjudicated by Clinical Events Committee
% = n/N for the trial duration

IMPROVE-IT:
:
:
:
)
:
LDL-C

( LDL-C 53 vs. 70 mg/dL 1

LDL-C,

LDL-c
1
on-treatment
1 & 2
on-treatment & intention-to-treat

Τα Νεώτερα Δεδομένα Στη Μικτή Δυσλιπιδαιμία- Ποια η Θέση Των Πέρα Των Στατινών Φαρμάκων Στη Σύγχρονη Υπολιδαιμική Αγωγή

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Τα Νεώτερα Δεδομένα Στη Μικτή Δυσλιπιδαιμία- Ποια η Θέση Των Πέρα Των Στατινών Φαρμάκων Στη Σύγχρονη Υπολιδαιμική Αγωγή

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-

, MD, FESC, FAHA

US risk score 27,3%

LVMI (g/m2) >115 M, >95 W

Association Between Statins and

Data sourced from: Sattar N et al. Lancet 2010; DOI:10.1016/S0140-6736(09)61965-6

ACCORD Lipid Trial Eligibility

High risk of CVD events = clinical or subclinical disease or

40 yrs with history of clinical CVD (secondary prevention)

60 < LDL-C < 180 mg/dl

No contraindication to either fenofibrate or simvastatin

Primary Outcome By Treatment Group and Baseline Subgroups

TG > 200 mg/dl

TG > 200 mg/dl

TG > 204 mg/dl

LDL-C (<70 mg/dL)

2013 ACC/AHA Cholesterol Treatment

Stone N.J., et al Circulation 2013 Nov 12 {Epub ahead of print}

Mean cIMT during 24 months of therapy

Mean IMT (mm)

Aortic Valve Events

Percentage of Patients With

Intention to Treat Population

Hazard ratio: 0.97, p=0.732

Intention to Treat Population

Percentage of Patients With

Hazard ratio: 0.78, p=0.024

SHARP: Major Atherosclerotic Events

Proportion suffering event (%)

Risk ratio 0.83 (0.74 0.94)

CTT: Effects on Major Atherosclerotic Events

Mean LDL cholesterol difference

CTT: Effects on Major Atherosclerotic Events

Mean LDL cholesterol difference

Pravastatin or Atorvastatin in Infection

Stable condition, enrolled

Primary efficacy end point

Composite of death from any cause, MI, documented UA requiring

Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

PROVE IT: Early and Sustained Benefit With

Occurrence of primary composite end point

Adapted from Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

STEMI 1/3 .1,2

Laufs U et al. Eur Heart J. 2014;doi:10.1093/eurheartj/ehu228.

Median Time avg

7-year event rates

Cor revasc 30d

7-year event rates

Age < 65 years

LDL-C > 95 mg/dl

*p-interaction = 0.023, otherwise > 0.05

IMPROVE-IT vs. CTT -:

ALT and/or AST3x ULN

Rhabdo, myopathy, myalgia with CK elevation*

* Adjudicated by Clinical Events Committee

% = n/N for the trial duration

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