Documente Academic
Documente Profesional
Documente Cultură
10
Mortality (millions)
15
World Health Organization. The World Health Report 2003: Shaping the Future. 2003.
20
Atherothrombosis* Is the
Leading Cause of Death
Worldwide1
6.3
Pulmonary Disease
Injuries
AIDS
9.7
Cancer
12.6
19.3
Infectious Disease
22.3
Atherothrombosis*
0
10
15
20
25
30
Clinical
32 million heart
attacks and strokes
per year
Subclinical
Undetected billions are at
high cardiovascular risk.
Due to hypertension,
diabetes, high lipids, tobacco
use, physical inactivity and
unhealthy diet
ACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non-ST-segment elevation myocardial
infarction; STEMI, ST-segment elevation myocardial infarction.
Adapted from Goldstein JA. J Am Coll Cardiol. 2002;39:1464-1467.
40
30
20
10
0
150
200
250
300
50
125
100
75
50
25
0
204
The
commonest
instruments
of suicide are
a knife and
fork
Martin
Relative
Risk for 1.7
CHD
1.3
(Log Scale)
1.0
??
40
70
100
130
160
190
Fig. Log-linear relationship between LDL-C levels and relative risk for
CHD.
This relationship is consistent with a large body of epidemiological
data and
data available from clinical trials of LDL- lowering therapy. These data
suggest
Grundy etthe
al. NCEP
Report. Circulation
2004; CHD
110: 227-239
that for every 30 mg/dl change in LDL-C,
relative
risk for
is
Optimal
<2.6 mmol/L
(<100 mg/dL)
5%
12%
26%
26%
Near or
above optimal
2.6-3.3 mmol/L
(100-129 mg/dL)
31%
High
4.1-4.9 mmol/L
(160-189 mg/dL)
Borderline high
3.3-4.1 mmol/L
(130-159 mg/dL)
Nearly 74% of
US adults have
LDL-C levels
2.6 mmol/L
100 mg/dL
Risk of CHD
-C
L
HD
L)
d
/
g
(m
LDL-C (mg/dL)
Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart
disease. The Framingham Study. American Journal of Medicine. 1977;62:707-14.
Cholesterol and
atherosclerosis
in HDL-C associated
with 1-3% reduction
in CHD risk2-5
3
2.5
Relative Risk
Women
Men
n=5,127
2
1.5
1
0.5
0
50
100
150
200
250
300
350
400
Methods and ResultsWe performed an individual participant data metaanalysis of prospective studies conducted in the Asia-Pacific region. Cox
models were applied to the combined data from 26 studies to estimate the
overall and region-, sex-, and age-specific hazard ratios for major
cardiovascular diseases by fifths of triglyceride values. During 796 671
person-years of follow-up among 96 224 individuals, 670 and 667
deaths as a result of coronary heart disease (CHD) and stroke,
respectively, were recorded. After adjustment for major cardiovascular
risk factors, participants grouped in the highest fifth of triglyceride
levels had a 70% (95% CI, 47 to 96) greater risk of CHD death, an 80%
(95% CI, 49 to 119) higher risk of fatal or nonfatal CHD, and a 50% (95%
CI, 29% to 76%) increased risk of fatal or nonfatal stroke compared
with those belonging to the lowest fifth. The association between
triglycerides and CHD death was similar across subgroups defined by
ethnicity, age, and sex.
(Circulation. 2004;110:2678-2
190 -
Moderately High
Risk
2 risk factors
(10-yr risk 10
20%)
Moderate Risk
Lower Risk
2 risk factors
goal
160
mg/dL
LDL-C level
160 -
goal
goal
mg/dL
mg/dL
130
130 -
goal
100
mg/dL
130
or optional
100
mg/dL*
100 or optional
70
mg/dL*
70 *Therapeutic option
70 mg/dL =1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L;
160 mg/dL = 4.1 mmol/L
25
AHA/ACC
Update
2006
NCEP
2004
Secondary Prevention
4S - Rx
20
LIPID - Placebo
15
10
4S - Placebo
NCEP 2001
Eur Joint 2003
TNT ATV80
PROVE-IT ATV
CARE - Placebo
LIPID - Rx
CARE - Rx
HPS - Rx
TNT ATV10
PROVE-IT - PRA
HPS - Placebo
Primary Prevention
WOSCOPS Placebo
AFCAPS - Placebo
AFCAPS - Rx
WOSCOPS - Rx
ASCOT - Placebo
ASCOT - Rx
0
40
(1.0)
60
(1.6)
80
(2.1)
100
(2.6)
120
(3.1)
140
(3.6)
160
(4.1)
180
(4.7)
200
(5.2)
4S
Statins Have
Revolutionised CVD Risk
Management
simva-
WOSCOPS
prava-
CARE
prava-
LIPID
prava-
AF/TEXCAPS
lova-
HPS
simva-
PROSPER
prava-
ASCOT
atorva-
CARDS
atorva-
TNT
atorva-
2050%
Relative Risk Reduction
In primary and
secondary prevention
In men and women
4085 years of age
In diabetics,
hypertensives, smokers
Lower LDL-C is better
AHA/ACC guidelines
for patients with
CHD*,2
<100 mg/dL
<70 mg/dL
2006
Update
<100 mg/dL:
Goal for all
patients with CHD,2
<70 mg/dL:
A reasonable
goal for all patients
with CHD,2
If it is not possible to attain LDL-C <70 mg/dL
because of a high baseline LDL-C, it generally is
possible to achieve LDL-C reductions of >50%
with more intensive LDL-Clowering therapy,
including drug combinations.
Factors that place a patient at very high risk: established cardiovascular disesase (CVD) plus:
multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (eg, cigarette smoking); metabolic
syndrome (triglycerides [TG] 200 mg/dL + nonHDL-C 130 mg/dL with HDL-C <40 mg/dL); and acute coronary
syndromes.1
1. Grundy SM et al. Circulation.
Circulation. 2004;110:227239; 2. Smith SC Jr et al. Circulation, 2006; 113:23632372.
Acetyl-CoA + Acetoacetyl-CoA
HMG-CoA
HMG-CoA
Statins
X
reductase
Mevalonate
Farnesyl-PP
Dolichol
Haem
Ubiquinone
Ras
Cellular growth
Proliferation
Squalene
Geranylgeranyl-PP
Cholesterol
Lipoprotein
Vitamin D
Cdc42
Rac1
RhoA
eNOSs, t-PA
Bile acids
Steroid hormones
PAI-1, ET-1
Actin
NAD(P)H oxidase
Proliferation
cytoskeleton
and migration
Oxidative stress
Rac1
MMPs
hs-CRP
ROS
TF Adhesion Molecule
Platelet
Activation
Vascular
Thrombotic Plaque
Inflammation
Stability
Effect
SMC
Hypertrophy
RhoA
ET-1
AT1 Receptor
NO
Endothelial
Dysfunction
SMC
Proliferation
Vasoconstriction
Hypertension
Atherosclerosis
Cardiovascular
Diseases
RR (CI)
Events (%)
Treatment
(45054)
Control
(45002)
Non-fatal MI
2001 (4.4%)
2769 (6.2%)
0.74(0.70-0.79)
CHD death
1548 (3.4%)
1960 (4.4%)
0.81(0.75-0.87)
3337 (7.4%)
4420 (9.8%)
0.77(0.74-0.80)
CABG
PTCA
Unspecified
713 (1.6%)
510 (1.1%)
1397 (3.1%)
1006 (2.2%)
658 (1.5%)
1770 (3.9%)
0.75(0.69-0.82)
0.79(0.69-0.90)
0.76(0.69-0.84)
Any coronary
revasc.
2620 (5.8%)
3435 (7.6%)
0.76(0.73-0.80)
Haemorrhagic
stroke
Presumed isch.
Stroke
105 (0.2%)
1235 (2.8%)
99 (0.2%)
1518 (3.4%)
1.05(0.78-1.41)
0.81(0.74-0.89)
1340(CTT)
(3.0%)
Any
stroke
Cholesterol
Treatment Trialists
Collaborators. Lancet, 2005;366
:1267-78
6354(14.1%)
0.5
1.0
1.5
0.83
(0.78-0.88)
Control
better
Effect p<0.0001
1617
(3.7%)
Treatment
better
7994(17.8%)
Events (%)
RR (CI)
Treatment
(45,054)
Control
(45,002)
805 (1.8%)
980 (2.2%)
0.86 (0.770.95)
Coronary revascularisation
795 (1.8%)
841 (1.9%)
0.95 (0.841.08)
Stroke
297 (0.7%)
311 (0.7%)
0.96 (0.791.17)
1747 (3.9%)
1951 (4.3%)
0.90 (0.850.96)
653 (1.5%)
856 (2.0%)
0.78 (0.700.87)
Coronary revascularisation
488 (1.1%)
653 (1.5%)
0.76 (0.660.87)
Stroke
264 (0.6%)
363 (0.8%)
0.75 (0.620.90)
1231 (2.9%)
1603 (3.8%)
0.78 (0.730.83)
274 (1.5%)
380 (2.2%)
0.71 (0.590.84)
Coronary revascularisation
203 (1.2%)
272 (1.6%)
0.73 (0.590.90)
Stroke
99 (0.5%)
119 (0.7%)
0.79 (0.571.10)
468 (2.8%)
598 (3.8%)
Year 01
Year 12
Year 5+
2
1
0.74 (0.670.82)
0.5
1.0
1.5
Treatment better
Control better
23%
Atherogenic
dyslipidemia
Metabolic
syndrome
Residual
Risk
Diabetes
Hypertension
Smoking
Cholesterol Treatment
Trialist (CTT)
Collaboration -2010
CTT-2010 Messages
2-3 mmol/L reduction of LDL-C would reduce risk of occlusive vascular event by
40-50%
CTT-2010 Messages
Efficacy
Safety
Flexibility/Convenience
Effect on atherosclerosis
LDL-C lowering
HDL-C raising
Triglyceride lowering
Cost-effectiveness
Fewer events
(Ballantyne, et all; 20
Ballantyne et al, 2
Fluvastatin:
Clinical
and
Safety
Profile
Randomised, placebo-controlled trials of fluvastatin with primary or
secondary clinical endpoints
LCAS
LISA
FLARE
LIPS
Ballantyne et al, 2
Ballantyne et al, 20
Ballantyne et al, 2
Ma et all, 20
Cox univariate analysis of incidence of hazards ratios (HRs) with 95% CIs
adjusted for age, sex, concomitant medication usage, and mean dose for
patients with new-onset diabetes (NOD) according to prescriptions for
statins.
Ma et all, 20
Statin therapy can safely reduce the 5 yr incidence of major coronary events,
coronary revascularization & stroke by about one fifth per mmol/L reduction in
LDL Chol (irrespective of initial lipid profile & the absolute reduction in LDL Chol
achieved) (1)
This findings reinforce the need to consider prolonged statin treatment with
substantial LDL Chol reduction in all patients at high risk of any type of major
vascular events
There was no evidence of any threshold within the cholesterol range
studied, suggesting that reduction of LDL cholesterol by 23 mmol/L
would reduce risk by about 4050%. (2)
The potential hazards of lowering LDL cholesterol with these statin regimens
seemed to be extremely small in relation to the clear benefits in many
circumstances.
No significant effects were observed on deaths due to cancer or other nonvascular causes (RR 097, 95% CI 092103; p=03) or on cancer incidence
(RR 100, 95% CI 096104; p=09), even at low LDL cholesterol
concentrations. (2)
1. Cholesterol Treatment Trialists (CTT) Collaborators, Lancet 2005;366:12672. Cholesterol Treatment Trialists (CTT) Collaborators, Lancet 2010; 376: 16
Some Definitions
Myalgia:
Muscle symptoms reported by the patient
Myopathy:
Muscle symptoms with CK elevation >10x ULN
Rhabdomyolysis:
Widespread muscle injury with CK >10x ULN
and accompanying organ (renal) damage.
Myoglobinuria/emia feature
Market USA
Rhabdomyolisis pada Fluvastatin
paling rendah
Ceriva
Date approved
Fatal cases of
rhabdomyolysis*
No. of prescriptions
(millions)
Reporting rate
(per 1 million Rx)
Lova
Prava
Simva
Fluva
Atorva
8/87
10/91
12/91
12/93
12/96
6/97
19
14
31
99.2
81.4
116
37.4
140
9.8
0.19
0.04
0.12
0.04
3.16
* Cases reported to the FDA Adverse Event Reporting System through June 2001.
Data are through May 2001 and are from the National Prescription Audit Plus, excluding the Long
Term Care Channel.
Number of cases divided by the number of prescriptions. Note the reporting rate is not the incidence
rate.
Staffa JA et al. N Engl J Med. 2002;346:539-540.
Reporting Rates of
Rhabdomyolysis
with Lipid-modifying
Therapy
Semiannual Reporting Rates for All Reports of Rhabdomyolysis
(AERS database)
120
cerivastatin
fluvastatin
100
atorvastatin
120
100
lovastatin
80
pravastatin
80
simvastatin
60
ezetimibe
60
rosuvastatin
40
40
20
20
03/99- 09/99- 03/00- 09/00- 03/01- 09/01- 03/02- 09/02- 03/03- 09/03- 03/04- 09/04- 03/05- 03/03- 09/03- 03/04- 09/04- 03/05- 09/0508/99 02/00 08/00 02/01 08/01 02/02 08/02 02/03 08/03 02/04 08/04 02/05 08/05 08/03 02/04 08/04 02/05 08/05 02/06
US Reports*
Summary
Statins significantly reduce the incidence of all-cause
mortality and major coronary events as compared to control
in both secondary and primary prevention.
Fluvastatin represents a choice for:
patients needing moderate LDL-cholesterol reductions to
achieve LDL-cholesterol goals;
patients requiring combination therapy with other lipidlowering agents;
patients taking multiple medications that place them at
high risk for drug interactions during statin therapy; and
high-risk patient populations, including patients who have
undergone coronary intervention procedures and patients
with renal disease.