Fluvastatin :

Clinical and Safety

Profile
dr. Sutikno Tanuwidjojo
Bagian Kardiologi dan Kedokteran Vaskular
FK. UNDIP / RSUP Dr. Kariadi

Global Disease Mortality

2002
Cardiovascular disease
Malignant neoplasms
Injuries
Respiratory infections
COPD and asthma
HIV/AIDS
Perinatal conditions
Digestive diseases
Diarrhoeal diseases
Tuberculosis
Childhood diseases
Malaria
Diabetes
0

10

Mortality (millions)

15

World Health Organization. The World Health Report 2003: Shaping the Future. 2003.

20

Death from Cardiovascular Causes,

Worldwide, in 1990 and Estimated for 2020

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

Causes of Mortality (%)

* Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.
1
The World Health Report 2001. Geneva. WHO. 2001.

ACS: Tip of the Atherothrombotic Iceberg

Acute Plaque Rupture ACS
(UA/NSTEMI/STEMI)

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.

The relations of lifestyle, established and novel risk factors, and

cardiovascular disease
(Mozaffarian et all, 2008)

Individuals with elevated LDL-C are at increased risk of

CHD

Multiple Risk Factor Intervention Trial

(MRFIT) (n=361,662)

Framingham Study (n=5209)

150

40
30
20
10
0

150

200

250

300

Serum cholesterol (mg/dL)

Each 1% reduction in total cholesterol level
resulted in a 2% decrease in CHD risk

Gotto AM Jr et al. Circulation. 1990;81:1721-1733.

Castelli WP. Am J Med. 1984;76:4-12.

CHD Incidence per 1000

10-year CHD Death Rate

(Deaths per 1000)

50

125
100
75
50
25
0
204

205-234 235-264 265-294 295

Serum cholesterol (mg/dL)

Each 1% increase in total cholesterol level
was associated with a 2% increase in CHD risk

The
commonest
instruments
of suicide are
a knife and
fork
Martin

RELATIONSHIP BETWEEN LDL-C AND

RELATIVE RISK FOR CHD THE LOWER THE
BETTER
3.7
2.9
2.2

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

According to NCEP ATP III Guidelines, Most Adults

Have Elevated Levels of LDL-C
Very high
4.9 mmol/L
(190 mg/dL)

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%

National Cholesterol Education Program Adult Treatment Panel III. JAMA.

2001;285:2486-2497.

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

LDL-C is strongly associated with an

increased risk of atherosclerosis and
CVD events

HDL-C has a protective effect for the

risk of
atherosclerosis and
CHD.
1% decrease
1% change
in LDL-C reduces
CHD risk by
1%1

1.Grundy SM et al. Circulation. 2004; 110: 22739.

2.Gordon DJ, Probstfield JL, Garrison JD et al. Circulation 1989; 79: 8-15.
3.Boden W. American Journal of Cardiology 2000; 86 (suppl): 19L-22L.
4.Manninen V, Elo O, Frick MH et al. JAMA 1988; 260:641-651.
5.Rubins HB, Robins S, Collins D et al. N Engl J Med 1999; 341:410-418

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

Triglyceride Level, mg/dL

Castelli WP. Epidemiology of triglycerides: a view from Framingham American Journal of Cardiology. 1992;70:3H-9H.

Serum Triglycerides as a Risk Factor for Cardiovascular

Diseases in the Asia-Pacific Region
Asia Pacific Cohort Studies Collaboration*

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.

ConclusionsSerum triglycerides are an important and independent

predictor of CHD and stroke risk in the Asia-Pacific region. These
results may have clinical implications for cardiovascular risk
prediction and the use of lipid-lowering therapy.

(Circulation. 2004;110:2678-2

Triglyceride-mediated pathways and coronary

disease:
collaborative analysis of 101 studies

Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Facto

Methods We assessed the 1131T>C (rs662799) promoter polymorphism of the apolipoprotein

A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of
coronary heart disease. We compared disease risk for genetically-raised triglyceride
concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded
for equivalent diff erences in circulating triglyceride concentration in prospective studies (302 430
participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart
disease during 2 79 million person-years at risk). We analysed 1131T>C in 1795 people
without a history of cardiovascular disease who had information about lipoprotein concentration
and diameter obtained by nuclear magnetic resonance spectroscopy.
Findings The minor allele frequency of 1131T>C was 8% (95% CI 79). 1131T>C was not
signifi cantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly
associated with lower HDL cholesterol (mean diff erence per C allele 3 5% [95% CI 2 64
6]; 0 053 mmol/L [0 0390 068]), lower apolipoprotein AI (1 3% [0 32 3]; 0
023 g/L [0 0050 041]), and higher apolipoprotein B (3 2% [1 35 1]; 0 027 g/L
[0 0110 043]). By contrast, for every C allele inherited, mean triglyceride concentration was
16 0% (95% CI 12 918 7), or 0 25 mmol/L (0 200 29), higher (p=4 4102).
The odds ratio for coronary heart disease was 1 18 (95% CI 1 111 26; p=2 610)
per C allele, which was concordant with the hazard ratio of 1 10 (95% CI 1 081 12) per
16% higher triglyceride concentration recorded in prospective studies. 1131T>C was signifi
cantly associated with higher VLDL particle concentration (mean diff erence per C allele 12 2
nmol/L [95% CI 7 716 7]; p=9 310) and smaller HDL particle size (0 14 nm [0
080 20]; p=7 010), factors that could mediate the eff ects of triglyceride.
Interpretation These data are consistent with a causal association between triglyceridemediated pathways and coronary heart disease.

Lancet 2010; 375: 1634

NCEP ATP III: LDL-C Goals

(2004 proposed modifications)
High Risk
CHD or CHD risk
equivalents

190 -

(10-yr risk >20%)

Moderately High
Risk
2 risk factors
(10-yr risk 10
20%)

Moderate Risk

Lower Risk

2 risk factors

< 2 risk factors

(10-yr risk <10%)

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*

Existing LDL-C goals

Proposed LDL-C goals

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

Grundy SM et al. Circulation 2004;110:227239.

INTERHEART: Risk of AMI

Associated with Risk Factors

Odds ratio adj for age, sex, smoke

Yusuf S, et al. Lancet. 2004;364(9438):93752

Effect of Lowering LDL-C on CHD Events

in Statin Trials Lower is Better
30

Event rate (%)

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)

LDL-C achieved mg/dL (mmol/L)

Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
LaRosa JC et al. N Engl J Med 2005;352:1425-1435

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-

All drugs in class

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

Intensive LDL-C Goals for High-Risk Patients

Recommended LDL-C treatment goals
ATP III
Update 20041
<100 mg/dL:
Patients with
CHD or CHD risk
equivalents
(10-year risk >20%)1
<70 mg/dL:
Therapeutic
option for very
high-risk patients1

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.

* And other forms of atherosclerotic disease. 2

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

p13-kinase/protein kinase Akt eNOS

BMP-2/bone formation
Angiogenesis

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

Isoprenoid intermediates of cholesterol modulate many cellular processes

(Liao, 2002)

Effects of Statin on HMG-CoA Reductase Inhibition

Statins

TXA2 t-PA Macrophage

TXA2 Growth

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

Efficacy & Safety of

Cholesterol
Lowering
Treatment:
(Prospective meta analysis of data
from 90056 participants in 14
randomised trials of statin)
Cholesterol Treatment Trialists (CTT) Collaborators, Lancet 2005;366:1267-78

Proportional effects on major vascular events

per mmol/L LDL-cholesterol reduction
Endpoint

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)

Any major cor.

event

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%)

Timing of Benefit in Statin Trials

Meta-analysis of 14 Studies (90,056 Subjects)

Endpoint

Events (%)

RR (CI)

Treatment
(45,054)

Control
(45,002)

Major coronary event

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)

Major vascular event

1747 (3.9%)

1951 (4.3%)

0.90 (0.850.96)

Major coronary event

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)

Major vascular event

1231 (2.9%)

1603 (3.8%)

0.78 (0.730.83)

Major coronary event

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)

Major vascular event

468 (2.8%)

598 (3.8%)

Year 01

Year 12

Year 5+

2
1

Trend test for major vascular events: =13.9; P=0002

0.74 (0.670.82)
0.5
1.0
1.5
Treatment better
Control better

CTTC. Baigent C et al; Lancet 2005

Defining Residual CVD Risk in

Patients With Dyslipidemia
Reduction in rate of first major
coronary events per each 39
mg/dL reduction in LDL-C*

23%

Atherogenic
dyslipidemia
Metabolic
syndrome

Residual
Risk

Diabetes
Hypertension
Smoking

*Cholesterol Treatment Trialists (CTT) Collaborators. Lancet. 2005;366:1267-1278.

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

This meta-analysis further confirms the

lower is better hypothesis for LDL-C
There was no indication that intensive
lowering of LDL-C resulted in increased
risk of haemorrhagic stroke, cancer
or non-vascular mortality
Greater reductions in LDL-C can be
achieved safely with regimens that
involve newer, more potent statins

Putting Statin Risks and Benefits

into Context
DRUGS

Comparing with other risks

How Do We Choose Statin ?

Efficacy

Safety

Low drug interaction potential

Good tolerability

Flexibility/Convenience

Effect on atherosclerosis
LDL-C lowering
HDL-C raising
Triglyceride lowering

lack of need for dose adjustment in different patient groups

taken at any time of day with or without food

Cost-effectiveness

More patients reaching guideline goals at same or lower

price

Fewer events

Least-squares means (SE) for

percent change in lipid
parameters from baseline to week
24

(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

Corsini et all, 2002

Fluvastatin Reduces Cardiac

Mortality in Patients with
Coronary Heart Disease

Ballantyne et al, 2

Ballantyne et al, 20

Ballantyne et al, 2

Statins and risk of incident diabetes: a

collaborative
meta-analysis of randomised statin
Methods We searched Medline, Embase,
and the Cochrane Central Register of Controlled
trials
Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included
only trials with more than 1000 patients, with identical follow-up in both groups and duration of
more than 1 year. We excluded trials of patients with organ transplants or who needed
haemodialysis. We used the I statistic to measure heterogeneity between trials and
calculated risk estimates for incident diabetes with random-effect meta-analysis.
Findings We identified 13 statin trials with 91140 participants, of whom 4278 (2226
assigned statins and 2052 assigned control treatment) developed diabetes during a
mean of 4 years. Statin therapy was associated with a 9% increased risk for incident
diabetes (odds ratio [OR] 109; 95% CI 102117), with little heterogeneity (I=11%)
between trials. Meta-regression showed that risk of development of diabetes with statins was
highest in trials with older participants, but neither baseline body-mass index nor change in
LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255
(95% CI 150852) patients with statins for 4 years resulted in one extra case of
diabetes.
Interpretation Statin therapy is associated with a slightly increased risk of development
of diabetes, but the risk is low both in absolute terms and when compared with the
reduction in coronary events. Clinical practice in patients with moderate or high
cardiovascular risk or existing cardiovascular disease should not change.

Sattar, et all; Lancet 2010; 375: 7

Statins and New-Onset Diabetes: A

Retrospective Longitudinal Cohort Study
Background: Statins have been linked to new-onset diabetes (NOD);
however, the effect of statins on the development of NOD in patients
with hypertension and dyslipidemia has not been well studied.
Objective: The goal of this study was to investigate the association
between statins and NOD.
Methods: This was a retrospective cohort study performed by using
data from claim forms provided to the central regional branch of the
Bureau of National Health Insurance in Taiwan from July 2006 to
December 2009. Prescriptions for statins before the index date were
retrieved from a prescription database. We estimated the hazards
ratios (HRs) of NOD associated with statin use. Nondiabetic subjects
served as the reference group.
Results: A total of 1360 (8.5%) NOD cases were identified among
16,027 patients with hypertension and dyslipidemia during the study
period.

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

Comparative benefits of statins in the primary and secondary prevention

of major coronary events and all-cause mortality: a network metaanalysis of placebo-controlled and active-comparator trials
Methods: We systematically studied 199,721 participants in 92 placebo-controlled and activecomparator trials comparing atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and
simvastatin in participants with, or at risk of developing, cardiovascular disease. We performed pairwise
and network meta-analyses for major coronary events and all-cause mortality outcomes, taking into
account the dose differences across trials.
Results: There were only a few trials that evaluated fluvastatin. Most frequent comparisons occurred
between pravastatin and placebo, atorvastatin and placebo, and rosuvastatin and atorvastatin. Across
all populations, statins were significantly more effective than control in reducing all-cause mortality (OR
0.87, 95% credible interval 0.820.92) and major coronary events (OR 0.69, 95% CI 0.640.75). In
terms of reducing major coronary events, atorvastatin (OR 0.66, 95% CI 0.480.94) and fluvastatin (OR
0.59, 95% CI 0.360.95) were significantly more effective than rosuvastatin at comparable doses. In
participants with cardiovascular disease, statins significantly reduced deaths (OR 0.82, 95% CI 0.75
0.90) and major coronary events (OR 0.69, 95% CI 0.620.77). Atorvastatin was significantly more
effective than pravastatin (OR 0.65, 95% CI 0.430.99) and simvastatin (OR 0.68, 95% CI 0.380.98) for
secondary prevention of major coronary events. In primary prevention, statins significantly reduced
deaths (OR 0.91, 95% CI 0.830.99) and major coronary events (OR 0.69, 95% CI 0.610.79) with no
differences among individual statins. Across all populations, atorvastatin (80%), fluvastatin (79%), and
simvastatin (62%) had the highest overall probability of being the best treatment in terms of both
outcomes. Higher doses of atorvastatin and fluvastatin had the highest number of significant
differences in preventing major coronary events compared with other statins. No significant
heterogeneity or inconsistency was detected.
Conclusions: Statins significantly reduce the incidence of all-cause mortality and major coronary events
as compared to control in both secondary and primary prevention. This analysis provides evidence for
potential differences between individual statins, which are not fully explained by their low-density
lipoprotein cholesterol-reducing effects. The observed differences between statins should be
investigated in future prospective studies.
Naci et al, European Journal of Preventive

Network of eligible pairwise comparisons for (A) all-cause

mortality and (B) major coronary events in placebo-controlled
and active-comparator trials of participants with and without prior
coronary heart disease at baseline (overall population).
Connecting lines indicate the direct pairwise comparison
between two treatments (knumber of pairwise comparisons;
Noverall number of participants; odds ratios and 95%
confidence intervals are given). Arrows depict the direction of
comparison (e.g. atorvastatin vs.control). Supplementary
Figures S1 (all-cause mortality) and S2 (major coronary events)
provide separate network diagrams for secondary and primary
prevention populations. A total of 93 out of 101 comparisons are
shown in these network diagrams as eight trials compared the
same statin (high vs. low dose comparisons), which are not
depicted in this figure.

Naci et al, 2013

Efficacy & Safety of

Cholesterol Lowering Treatment

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

Statin Tolerability and

Safety Liver Effects
Elevations in liver transaminase
levels are infrequent but recognised
complication of treatment with statins*
Before statin therapy:
Liver function tests recommended
Caution in patients who consume excessive
quantities of alcohol and/or have a history
of liver disease
Contraindicated in patients with active liver
disease
ALT >3 x ULN on 2 successive occasions

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

Rosuvastatin Worldwide Reports

(AZ global database)

(AERS database)

Reporting rate per

1,000,000 US prescriptions**

120

cerivastatin

fluvastatin

100

atorvastatin

120
100

lovastatin

80

pravastatin

80

simvastatin

60

ezetimibe

60

rosuvastatin

40

40

rosuvastatin AZ global database

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

*All spontaneous reports including expedited, periodic and direct reports.

**US reporting rates based on FDA Adverse Events Reporting System made
available through Freedom of Information Act divided by US prescribing data
supplied by IMS to the end of August 2005.
Cerivastatin reports received after September 1, 2001, are excluded.
Due to a change in the way AERS reports are recorded, AERS data
corresponding to the period March to August 2005 differs from previous data as
it may include non-US reports and those of clinical trial origin. For this reason,
the data corresponding to this period is plotted as a dotted line.

Reporting rate per 1,000,000

rosuvastatin prescriptions worldwide

US Reports*

Global reporting rate for rosuvastatin based on spontaneous report counts of

rhabdomyolysis within AstraZeneca global drug safety database divided by estimated
worldwide prescriptions to end February 2006. Total prescriptions based on IMS data
from US, Canada, UK, France, Italy and The Netherlands; rest of world prescriptions
based on actual sales calculations.

Update: 1 June 2006

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.